Τετάρτη, 17 Ιουλίου 2019

Allergy and Immunology


Sat Jun 24, 2017 21:43
  MD-2 regulates LPS-induced NLRP3 inflammasome activation and IL-1beta secretion by a MyD88/NF-κB-dependent pathway in alveolar macrophages cell line
updated on Sun Jun 25, 2017 02:14 by Alexandros G. Sfakianakis via Allergy Rhinology Immunology Asthma
S01615890.gif

Publication date: October 2017
Source:Molecular Immunology, Volume 90
Author(s): Man Luo, Lijuan Hu, Dandan Li, Yanying Wang, Yuting He, Lei Zhu, Weiying Ren
Myeloid differentiation protein 2 (MD-2) is required in the recognition of lipopolysaccharide (LPS) by toll-like receptor 4 (TLR4), and participates in LPS-induced alveolar macrophage (AM) inflammation during acute lung injury (ALI). Activation of the NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome aggravates inflammation in LPS-induced ALI. However, there is currently little known about the relationship between MD-2 signaling and the NLRP3 inflammasome. This study showed that NLRP3 expression, IL-1beta (IL-1β) secretion, and pyroptosis were up-regulated after LPS stimulation in the NR8383 AM cell-line. MD-2 gene knock-down reduced LPS-induced mRNA and protein expression of NLRP3 and IL-1β secretion in NR8383 cells, and inhibited the MyD88/NF-κB signaling pathway. Conversely, over-expression of MD-2 not only heightened NLRP3, MyD88, and NF-κB p65 protein expression, it also aggravated the LPS-induced inflammatory response. Furthermore, the NF-κB inhibitor SN50 had a beneficial role in decreasing NLRP3 and caspase-1 mRNA and protein expression. The observations suggest that MD-2 helps to regulate LPS-induced NLRP3 inflammasome activation and the inflammatory response in NR8383 cells, and likely does so by affecting MyD88/NF-κB signaling.



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Sat Jun 24, 2017 11:28
  A New Marker for Regulatory Macrophages.
updated on Sat Jun 24, 2017 15:59 by Alexandros G. Sfakianakis via Allergy Rhinology Immunology Asthma
No abstract available

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Fri Jun 23, 2017 21:38
  RNAi knock-down of the Bemisia tabaci Toll gene (BtToll) increases mortality after challenge with destruxin A
updated on Sat Jun 24, 2017 02:08 by Alexandros G. Sfakianakis via Allergy Rhinology Immunology Asthma
Publication date: August 2017
Source:Molecular Immunology, Volume 88
Author(s): Can Zhang, Shao-Qiao Yan, Bin-Bin Shen, Shaukat Ali, Xing-Min Wang, Feng-Liang Jin, Andrew G.S. Cuthbertson, Bao-Li Qiu
Bemisia tabaci (Gennadius) Middle East-Asia Minor 1 (MEAM1) is a well known invasive insect species. Little information is available on immune system of B. tabaci to date. In this study, one of the Toll-like receptors (TLR; namely BtToll) was cloned in MEAM1 B. tabaci which contains an open reading frame of 3153bp, encoding putative 1050 amino acids. Phylogenetic analysis indicated that BtToll is highly identitical with other members of the TLR family. Transcripts of BtToll detected through qRT-PCR were expressed in all developmental stages of B. tabaci and the highest expression level was observed in the 3rd nymphal instar. BtToll was highly expressed in response to immune challenge. RNA interference was used to knockdown the BtToll expression in adults through the oral route which resulted in significant reduction of BtToll transcript. When the adults were challenged with a mycotoxin from entomogenous fungi − destruxin A (DA) and RNAi, the median lethal concentration (LC50) decreased by 70.67% compared to DA treatment only. Our results suggest that BtToll is an important component of the B. tabaci immune system. RNAi technology using dsToll combined with general control methods (using toxin only) can be used as a potential strategy in integrated B. tabaci management programs.



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Fri Jun 23, 2017 14:55
  Reproduction of the atopic march in an adult after allogeneic bone marrow transplantation from an atopic sibling
updated on Fri Jun 23, 2017 16:55 by Alexandros G. Sfakianakis via Allergy Rhinology Immunology Asthma
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Publication date: Available online 22 June 2017
Source:Annals of Allergy, Asthma & Immunology
Author(s): Milagros Lázaro, Lourdes Vázquez, Francisco Javier Munoz-Bellido, Maria Teresa Gracia, Sonia Arriba-Mendez, Ignacio Dávila




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Fri Jun 23, 2017 11:50
  Taking Kidneys for Granted? Time to Reflect on the Choices We Make.
updated on Fri Jun 23, 2017 16:55 by Alexandros G. Sfakianakis via Allergy Rhinology Immunology Asthma
No abstract available

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Fri Jun 23, 2017 11:50
  Authors' Reply: Does low Hepatic Artery Flow Increase Rate of Biliary Strictures in Deceased Donor Liver Transplantation?.
updated on Fri Jun 23, 2017 16:55 by Alexandros G. Sfakianakis via Allergy Rhinology Immunology Asthma
No abstract available

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Fri Jun 23, 2017 11:50
  Exosomes: From Cell Debris to Potential Biomarkers in Transplantation.
updated on Fri Jun 23, 2017 16:55 by Alexandros G. Sfakianakis via Allergy Rhinology Immunology Asthma
No abstract available

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Fri Jun 23, 2017 11:50
  Early Outcomes of the New UK Deceased Donor Kidney Fast-track Offering Scheme.
updated on Fri Jun 23, 2017 16:55 by Alexandros G. Sfakianakis via Allergy Rhinology Immunology Asthma
Background: The UK Kidney Fast-Track Scheme (KFTS) was introduced in 2012 to identify kidneys at high risk of discard and to rapidly facilitate transplantation. A retrospective analysis of kidneys transplanted through the KFTS was undertaken. Methods: UK Transplant Registry data were collected on deceased donor kidneys implanted between 1 November 2012 and 30 April 2015 (DBD donors) and 1 March 2013 and 30 April 2015 (DCD donors). Posttransplant outcomes included 1-year eGFR and death-censored graft survival (DCGS). Results: Over the study period, 523 deceased donor kidneys were transplanted through the KFTS and 4,174 via the standard National Kidney Allocation Scheme (NKAS). Kidneys in the KFTS were more likely to be from older, diabetic donors, had a higher frequency of poor ex vivo perfusion, longer cold ischaemic times and were transplanted into older recipients. One-year DCGS of KFTS and NKAS DBD donor kidneys was similar (94% versus 95%; p=0.70), but for DCD donor kidneys DCGS was lower in those allocated via the KFTS (91% versus 95%; p=0.04). Median 1-year eGFR for DBD donor kidneys was lower in those allocated via the KFTS (49 versus 52 mL/min/1.73m2; p=0.01), but for DCD kidneys there was no difference (45 versus 48 mL/min/1.73m2; p=0.10). Conclusions: Although KFTS kidneys have less favourable donor, graft, and recipient risk factors than NKAS kidneys, short-term graft and patient outcomes are acceptable. National schemes that identify and rapidly offer kidneys at high risk of discard may contribute to minimising the unnecessary discard of organs. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Fri Jun 23, 2017 11:50
  Alan Ting, PhD, 1943-2017, The Transplantation Society Eastern Secretary 1986-88.
updated on Fri Jun 23, 2017 16:55 by Alexandros G. Sfakianakis via Allergy Rhinology Immunology Asthma
No abstract available

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Fri Jun 23, 2017 11:50
  The Evolution of Oxygen Carrier Solutions for Machine Perfusion.
updated on Fri Jun 23, 2017 16:55 by Alexandros G. Sfakianakis via Allergy Rhinology Immunology Asthma
No abstract available

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Fri Jun 23, 2017 11:50
  Trends in Characteristics of Patients Listed for Liver Transplantation Will Lead to Higher Rates of Waitlist Removal Due to Clinical Deterioration.
updated on Fri Jun 23, 2017 16:55 by Alexandros G. Sfakianakis via Allergy Rhinology Immunology Asthma
Background: Changes in the epidemiology of end stage liver disease may lead to increased risk of dropout from the liver transplant waitlist. Anticipating the future of liver transplant waitlist characteristics is vital when considering organ allocation policy. Methods: We performed a discrete event simulation to forecast patient characteristics and rate of waitlist dropout. Estimates were simulated from 2015-2025. The model was informed by data from the Organ Procurement and Transplant Network, 2003-2014. National data are estimated along with forecasts for 2 regions. Results: NASH will increase from 18% of waitlist additions to 22% by 2025. Hepatitis C will fall from 30% to 21%. Listings over age 60 will increase from 36% to 48%. The hazard of dropout will increase from 41% to 46% nationally. Wait times for transplant for patients listed with a MELD between 22 and 27 will double. Region 5, which transplants at relatively higher MELD scores, will experience an increase from 53% to 64% waitlist dropout. Region 11, which transplants at lower MELD scores, will have an increase in waitlist dropout from 30% to 44%. Conclusions: The liver transplant waitlist size will remain static over the next decade due to patient dropout. Liver transplant candidates will be older, more likely to have NASH and will wait for transplantation longer even when listed at a competitive MELD score. There will continue to be significant heterogeneity among transplant regions where some patients will be more likely to drop out of the waitlist than receive a transplant. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Fri Jun 23, 2017 11:50
  Does Low Hepatic Artery Flow Increase Rate of Biliary Strictures in Deceased Donor Liver Transplantation?.
updated on Fri Jun 23, 2017 16:55 by Alexandros G. Sfakianakis via Allergy Rhinology Immunology Asthma
No abstract available

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Fri Jun 23, 2017 11:50
  Utility of IL-2 Complexes in Promoting the Survival of Murine Orthotopic Forelimb Vascularized Composite Allografts.
updated on Fri Jun 23, 2017 16:55 by Alexandros G. Sfakianakis via Allergy Rhinology Immunology Asthma
Background: Vascularized composite allografts (VCA) are novel, life-enhancing forms of transplantation (Tx). However, host immune responses to the various VCA components, especially those involving skin, are complex and make selection of appropriate therapy challenging. While the interplay between Foxp3+ T regulatory (Treg) cells and CD4 and CD8 effector T cells is of central importance in determining the acceptance or rejection of solid organ allografts, there is little information available concerning the contribution of Tregs to VCA survival. In addition, the effects of therapeutic expansion in vivo of host Treg populations on VCA survival are unknown. Methods: We established a fully MHC-disparate (BALB/c->C57BL/6) murine orthotopic forelimb Tx model to explore the benefits of pre and post-Tx IL-2/anti-IL-2 monoclonal antibody complex (IL-2C) administration to expand the host Treg population and thereby attempt to promote Treg-dependent VCA survival. Results: Both strategies expanded the Treg population in vivo and prolonged VCA survival (p

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Fri Jun 23, 2017 11:50
  Severe Allograft Rejection and Autoimmune Hemolytic Anemia After Anti-PD1 Therapy in a Kidney Transplanted Patient.
updated on Fri Jun 23, 2017 16:55 by Alexandros G. Sfakianakis via Allergy Rhinology Immunology Asthma
No abstract available

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Fri Jun 23, 2017 09:05
  Imatinib may be considered as first-line treatment for both locally advanced and distant primary multifocal oral melanoma, for which surgery or radiotherapy of the primary tumor is impossible.
updated on Fri Jun 23, 2017 16:55 by Alexandros G. Sfakianakis via Allergy Rhinology Immunology Asthma
Πέμπτη, 22 Ιουνίου 2017
Treatment of Primary and Metastatic Multifocal Mucosal Melanoma of the Oral Cavity with Imatinib
Treatment of Primary and Metastatic Multifocal Mucosal Melanoma of the Oral Cavity with Imatinib: Background: Mucosal melanoma of the oral cavity is a rare entity and accounts for less than 1–3% of all melanomas. Contrary to cutaneous melanoma, primary oral melanoma more commonly harbors mutations in c-KIT. Methods: A 64-year-old man presented with asymptomatic, multiple, brown-to-black macules in the oral cavity. A biopsy was taken and histopathology exhibited mucosal melanoma. In molecular analysis, a c-KIT mutation was proven and a CT scan revealed pulmonary metastases. Due to the multifocality of the lesions, the metastases, and the mutation status, a therapy with imatinib was initiated. Results: After 1 year of therapy, progressive disease in the lung was noticed. Therefore, the therapy was switched to a PD-1 antagonist and a CTL-4 antibody. Conclusions: Our case suggests that imatinib may be considered as first-line treatment for both locally advanced and distant primary multifocal oral melanoma, for which surgery or radiotherapy of the primary tumor is impossible.

Case Rep Oncol 2017;10:558–563






Ιματινίμπη

Μοιραστείτε

 Ευρετήριο Αναφορές

Δραστική ουσία

Ονομασίες

ELΕλληνικάΙματινίμπη

ENΑγγλικάImatinib

Σύντομη περιγραφή

Η ιματινίμπη (imatinib) είναι ένας αναστολέας της πρωτεϊνικής τυροσινικής κινάσης, που ανστέλλει την Bcr-Abl τυροσινική κινάση, που παράγεται παθολογικά από το χρωμόσωμα Φιλαδέλφειας στην χρόνια μυελογενή λευκαιμία. Η ιματινίμπη αναστέλλει επίσης τον υποδοχέα της τυροσινικής κινάσης για τον αυξητικό παράγοντα των αιμοπεταλίων [platelet derived growth factor (PDGF)] και τον παράγοντα των βλαστικών κυττάρων (SCF), που ονομάζεται c-kit.



Ανατομική/θεραπευτική/χημική (ATC) ταξινόμηση

ΚωδικόςΤίτλοςΚατηγοριοποίηση

 L01XE01 ImatinibL Αντινεοπλασματικοί και ανοσοτροποποιητικοί παράγοντες → L01 Aντινεοπλασματικά φάρμακα → L01X Άλλοι αντινεοπλασματικοί παράγοντες → L01XE Αναστολείς των πρωτεϊνικών κινασών

Κεφάλαια συνταγολογίου ΕΟΦ

ΑριθμόςΤίτλοςΚατηγοριοποίηση

 08.06.05.03 Ιματινίμπη (Imatinib)08 Αντινεοπλασματικά και ανασοκατασταλτικά φάρμακα → 08.06 Άλλα αντινεοπλασματικά φάρμακα → 08.06.05 Αναστολείς της πρωτεϊνικής κινάσης

Αναγνωριστικό UNII



BKJ8M8G5HI - IMATINIB



Αριθμοί CAS



152459-95-5 - ιματινίμπη



Έννοια SNOMED-CT



414460008 - Imatinib (substance)





Φάρμακα που περιέχουν σε αποκλειστικότητα τη δραστική

Ομαδοποίηση κατά:  Οδό χορήγησηςΦαρμακοτεχνική μορφήΣυγκέντρωσηΔιανομέας

Κ Όνομα σκευάσματος Οδός χ/σης Φ/κή μορφή Συγκέντρωση Λ.Τ. Κόστος

 Aenorasis Α.Ε.

  IMATINIB/AENORASIS F.C.TAB 100MG/TAB BTx60 (PVC/PE/PVDC/Alu Blisters)  ORAL TAB_FILM_COATED  100MG/TAB  734,35 €  97,0217 € / g

  IMATINIB/AENORASIS F.C.TAB 400MG/TAB BTx30 (PVC/PE/PVDC/Alu Blisters)  ORAL TAB_FILM_COATED  400MG/TAB  1.385,56 €  93,9433 € / g

 Demo Α.Β.Ε.Ε.

  IMATINIB/DEMO CAPS 100MG/CAP BTx60 (PA-Aluminium/PVC/Aluminium Blisters) ORAL  CAP  100MG/CAP  734,35 €  97,0217 € / g

  IMATINIB/DEMO CAPS 400MG/CAP BTx30 (PA-Aluminium/PVC/Aluminium Blisters) ORAL  CAP  400MG/CAP  1.385,56 €  93,9433 € / g

 Novartis Europharm Ltd

    GLIVEC 100MG/CAP ΒΤΧ120  ORAL  CAP  100MG/CAP  1.803,79 €  135,9233 € / g

    GLIVEC F.C.TAB 100MG/TAB BTX60  ORAL  TAB_FILM_COATED  100MG/TAB  1.113,94 €  149,2683 € / g

    GLIVEC F.C.TAB 400MG/TAB BTX30  ORAL  TAB_FILM_COATED  400MG/TAB  2.111,17 €  144,5308 € / g

 Proton Pharma Α.Ε.

    IMATEK CAPS 100MG/CAP BTx60 CAPS (PA/ALU/PVC/ALU BLISTERS) (Τα blister είναι των 15 ή 10 καψακίων)  ORAL  CAP  100MG/CAP  734,35 €  97,0217 € / g

    IMATEK CAPS 400MG/CAP BTx30 CAPS (PA/ALU/PVC/ALU BLISTERS) (Τα blister είναι των 15 ή 10 καψακίων)  ORAL  CAP  400MG/CAP  1.385,56 €  93,9433 € / g

 Sandoz Pharmaceuticals d.d.

  IMATINIB/SANDOZ F.C.TAB 100MG/TAB BTx6 x10 (PVC-ALU BLISTERS)  ORAL TAB_FILM_COATED  100MG/TAB  734,35 €  97,0217 € / g

  IMATINIB/SANDOZ F.C.TAB 400MG/TAB BTx3 x10 (PVC/PE/PVDC-ALU BLISTERS)  ORAL TAB_FILM_COATED  400MG/TAB  1.385,56 €  93,9433 € / g

 Teva Pharmaceuticals B.V.

  IMATINIB TEVA F.C.TAB 100MG/TAB BTx60 σε OPA/AL/PVC/AL BLISTER OPA/AL/PVC/AL BLISTER  ORAL  TAB_FILM_COATED  100MG/TAB  697,78 €  92,1900 € / g

    IMATINIB TEVA F.C.TAB 100MG/TAB BTx60 σε PVC/PE/PVDC/PE/PVC/AL BLISTER PVC/PE/PVDC/PE/PVC/AL BLISTER  ORAL  TAB_FILM_COATED  100MG/TAB  697,78 € 92,1900 € / g

  IMATINIB TEVA F.C.TAB 100MG/TAB BTx60x1 σε OPA/AL/PVC/AL BLISTER OPA/AL/PVC/AL BLISTER  ORAL  TAB_FILM_COATED  100MG/TAB  697,78 €  92,1900 € / g

  IMATINIB TEVA F.C.TAB 100MG/TAB BTx60x1 σε PVC/PE/PVDC/PE/PVC/AL BLISTER PVC/PE/PVDC/PE/PVC/AL BLISTER  ORAL  TAB_FILM_COATED  100MG/TAB  697,78 € 92,1900 € / g

  IMATINIB TEVA F.C.TAB 400MG/TAB BTx30 σε OPA/AL/PVC/AL BLISTER OPA/AL/PVC/AL BLISTER  ORAL  TAB_FILM_COATED  400MG/TAB  1.385,56 €  93,9433 € / g

    IMATINIB TEVA F.C.TAB 400MG/TAB BTx30 σε PVC/PE/PVDC/PE/PVC/AL BLISTER PVC/PE/PVDC/PE/PVC/AL BLISTER  ORAL  TAB_FILM_COATED  400MG/TAB  1.385,56 € 93,9433 € / g

  IMATINIB TEVA F.C.TAB 400MG/TAB BTx30x1 σε OPA/AL/PVC/AL BLISTER OPA/AL/PVC/AL BLISTER  ORAL  TAB_FILM_COATED  400MG/TAB  1.385,56 €  93,9433 € / g

  IMATINIB TEVA F.C.TAB 400MG/TAB BTx30x1 σε PVC/PE/PVDC/PE/PVC/AL BLISTER PVC/PE/PVDC/PE/PVC/AL BLISTER  ORAL  TAB_FILM_COATED  400MG/TAB  1.385,56 € 93,9433 € / g

 Vianex A.E.

  VIANIB CAPS 100MG/CAP BTx60 (PA-Alu/PVC/Alu Blisters)  ORAL  CAP  100MG/CAP 734,35 €  97,0217 € / g

  VIANIB CAPS 400MG/CAP BTx30 (PA-Alu/PVC/Alu Blisters)  ORAL  CAP  400MG/CAP 1.385,56 €  93,9433 € / g

 Vocate Α.Ε.

    IMATINIB/VOCATE CAPS 100MG/CAP BTx60 caps σε blisters (PVC/PE/PVDC/ALU)  ORAL CAP  100MG/CAP  697,79 €  92,1900 € / g

    IMATINIB/VOCATE CAPS 400MG/CAP BTx30 caps σε blisters (PVC/PE/PVDC/ALU)  ORAL CAP  400MG/CAP  1.385,56 €  93,9433 € / g



Πηγή: Γαληνός Οδηγός Φαρμάκων







Imatinib
From Wikipedia, the free encyclopedia
Imatinib
Imatinib2DACS.svg
Ball-and-stick model of the imatinib molecule
Clinical data
Trade names Gleevec, Glivec, others
AHFS/Drugs.com Monograph
MedlinePlus a606018
License data
EU EMA: by Imatinib
US FDA: IMATINIB
Pregnancy
category
AU: D
US: D (Evidence of risk)
Routes of
administration by mouth
ATC code
L01XE01 (WHO)
Legal status
Legal status
AU: S4 (Prescription only)
CA: ℞-only
UK: POM (Prescription only)
US: ℞-only
Pharmacokinetic data
Bioavailability 98%
Protein binding 95%
Metabolism liver (mainly CYP3A4-mediated)
Biological half-life 18 h (imatinib)
40 h (active metabolite)
Excretion Fecal (68%) and kidney (13%)
Identifiers
IUPAC name[show]
Synonyms STI-571
CAS Number
152459-95-5 Yes
220127-57-1 (mesilate)
PubChem CID
5291
IUPHAR/BPS
5687
DrugBank
DB00619 Yes
ChemSpider
5101 Yes
UNII
BKJ8M8G5HI
KEGG
D08066 Yes
ChEBI
CHEBI:45783 Yes
ChEMBL
CHEMBL941 Yes
PDB ligand
STI (PDBe, RCSB PDB)
ECHA InfoCard 100.122.739
Chemical and physical data
Formula C29H31N7O
Molar mass 493.603 g/mol
589.7 g/mol (mesilate)
3D model (Jmol)
Interactive image
SMILES[show]
InChI[show]
  (verify)
Imatinib, sold under the brand names Gleevec among others, is a chemotherapy medicationused to treat cancer. Specifically, it is used for chronic myelogenous leukemia (CML) and acute lymphocytic leukemia (ALL) that is Philadelphia chromosome-positive (Ph+) and certain types ofgastrointestinal stromal tumors (GIST), systemic mastocytosis, and myelodysplastic syndrome. It is taken by mouth.[1]
Common side effects include vomiting, diarrhea, muscle pain, headache, and rash. Severe side effects may include fluid retention, gastrointestinal bleeding, bone marrow suppression, liver problems, and heart failure. Use during pregnancy may result in harm to the baby. Imatinib works by stopping the Bcr-Abl tyrosine-kinase. This either slows growth or results in programmed cell death of certain type of cancer cells.[1]
Imatinib was approved for medical use in the United States in 2001.[1] It is on the World Health Organization's List of Essential Medicines, the most effective and safe medicines needed in ahealth system.[2] The wholesale cost in the developing world is about 1,386.49 to 19,162.50 USD a year.[3] In the United States a typical dose for a year has a wholesale cost of $84,408.78,[4] while in the United Kingdom the NHS was paying about 20,980 pounds ($28327) in 2016.[5] A generic version became available in the UK as of 2017.[6]
Contents
  [hide]
1Medical uses
1.1Chronic myelogenous leukemia
1.2Gastrointestinal stromal tumors
1.3Other
2Contraindications and cautions
3Side effects
4Interactions
5Overdose
6Mechanism of action
6.1Other pathways affected
7Pharmacokinetics
8Interactions
9History
10Costs
10.1Patent litigation in India
11Research
12See also
13References
14External links
Medical uses[edit]
Imatinib is used to treat chronic myelogenous leukemia (CML), gastrointestinal stromal tumors(GISTs) and a number of other malignancies.
Chronic myelogenous leukemia[edit]
The U.S. Food and Drug Administration (FDA) has approved imatinib as first-line treatment forPhiladelphia chromosome-positive CML, both in adults and children. The drug is approved in multiple contexts of Philadelphia chromosome-positive CML, including after stem cell transplant, in blast crisis, and newly diagnosed.[7]
Due in part to the development of imatinib and related drugs, the five year survival rate for people with chronic myeloid leukemia increased from 31% in 1993 to 59% in 2003 to 2009.[8]
Gastrointestinal stromal tumors[edit]
The FDA first granted approval for advanced GIST patients in 2002. On 1 February 2012, imatinib was approved for use after the surgical removal of KIT-positive tumors to help prevent recurrence.[9] The drug is also approved in unresectable KIT-positive GISTs.[7]
Other[edit]
The FDA has approved imatinib for use in adults with relapsed or refractory Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL), myelodysplastic/ myeloproliferative diseases associated with platelet-derived growth factor receptor gene rearrangements, aggressive systemic mastocytosis without or an unknown D816V c-KIT mutation, hypereosinophilic syndrome and/or chronic eosinophilic leukemia who have the FIP1L1-PDGFRα fusion kinase (CHIC2 allele deletion) or FIP1L1-PDGFRα fusion kinase negative or unknown, unresectable, recurrent and/or metastatic dermatofibrosarcoma protuberans.[7] On 25 January 2013, Gleevec was approved for use in children with Ph+ ALL.[10]
For treatment of progressive plexiform neurofibromas associated with neurofibromatosis type I, early research has shown potential for using the c-KIT tyrosine kinase blocking properties of imatinib.[11][12][13][14]
Contraindications and cautions[edit]
The only known contraindication to imatinib is hypersensitivity to imatinib.[15] Cautions include:[16]
Hepatic impairment
Risk of severe CHF or left ventricular dysfunction, especially in patients with comorbidities
Pregnancy, risk of embryo-fetal toxicity
Risk of fluid retention
Risk of growth stunting in children or adolescents
Side effects[edit]
See also: List of adverse effects of imatinib

bcr-abl kinase (green), which causes CML, inhibited by imatinib (red; small molecule).
The most common side effects include feeling sick (nausea), diarrhea, headaches, leg aches/cramps, fluid retention, visual disturbances, itchy rash, lowered resistance to infection, bruising or bleeding, loss of appetite;[17] weight gain, reduced number of blood cells (neutropenia, thrombocytopenia, anemia), andedema.[18] Although rare, restoration of hair color has been reported as well.[19][20] Severe congestive cardiac failure is an uncommon but recognized side effect of imatinib and mice treated with large doses of imatinib show toxic damage to their myocardium.[21]
If imatinib is used in prepubescent children, it can delay normal growth, although a proportion will experience catch-up growth during puberty.[22]
Interactions[edit]
Its use is advised against in patients on strong CYP3A4 inhibitors such as clarithromycin, chloramphenicol,ketoconazole, ritonavir and nefazodone due to its reliance on CYP3A4 for metabolism.[16] Likewise it is a CYP3A4, CYP2D6 and CYP2C9 inhibitor and hence concurrent treatment with substrates of any of these enzymes may increase plasma concentrations of said drugs.[16]
Overdose[edit]
Medical experience with imatinib overdose is limited.[23] Treatment is supportive.[23] Imatinib is highly plasma protein-bound:[23] dialysis is unlikely to be helpful removing imatinib.
Mechanism of action[edit]
Mechanism of action of imatinib
Imatinib
Drug mechanism
1IEP.png
Crystallographic structure of tyrosine-protein kinase ABL (rainbow colored, N-terminus = blue, C-terminus = red) complexed with imatinib (spheres, carbon = white, oxygen = red, nitrogen = blue).[24]
Therapeutic use chronic myelogenous leukemia
Biological target ABL, c-kit, PDGF-R
Mechanism of action Tyrosine-kinase inhibitor
External links
ATC code L01XE01
PDB ligand id STI: PDBe, RCSB PDB
LIGPLOT 1iep
Imatinib is a 2-phenyl aminopyrimidine derivative that functions as a specific inhibitor of a number of tyrosine kinase enzymes. It occupies the TKactive site, leading to a decrease in activity.
There are a large number ofTK enzymes in the body, including the insulin receptor. Imatinib is specific for the TKdomain in abl (the Abelson proto-oncogene), c-kit andPDGF-R (platelet-derived growth factor receptor).
In chronic myelogenous leukemia, the Philadelphia chromosome leads to a fusion protein of abl withbcr (breakpoint cluster region), termed bcr-abl. As this is now a constitutively active tyrosine kinase, imatinib is used to decrease bcr-abl activity.
The active sites of tyrosine kinases each have a binding site for ATP. The enzymatic activitycatalyzed by a tyrosine kinase is the transfer of the terminal phosphate from ATP to tyrosine residues on its substrates, a process known as protein tyrosine phosphorylation. Imatinib works by binding close to the ATP binding site of bcr-abl, locking it in a closed or self-inhibited conformation, and therefore inhibiting the enzyme activity of the protein semi-competitively.[25] This fact explains why many BCR-ABL mutations can cause resistance to imatinib by shifting its equilibrium toward the open or active conformation.[26]
Imatinib is quite selective for bcr-abl, though it does also inhibit other targets mentioned above (c-kit and PDGF-R), but acts on no other knowntyrosine kinases. Imatinib also inhibits the abl protein of non-cancer cells, but these cells normally have additional redundant tyrosine kinases, which allows them to continue to function even if abl tyrosine kinase is inhibited. Some tumor cells, however, have a dependence on bcr-abl.[27]Inhibition of the bcr-abl tyrosine kinase also stimulates its entry in to the nucleus, where it is unable to perform any of its normal anti-apoptopicfunctions, leading to tumor cell death.[28]
Other pathways affected[edit]
The Bcr-Abl pathway has many downstream pathways including[29]
the Ras/MapK pathway, which leads to increased proliferation due to increased growth factor-independent cell growth.
It also affects the Src/Pax/Fak/Rac pathway. This affects the cytoskeleton, which leads to increased cell motility and decreased adhesion.
The PI/PI3K/AKT/BCL-2 pathway is also affected. BCL-2 is responsible for keeping the mitochondria stable; this suppresses cell death by apoptosis and increases survival.
The last pathway that Bcr-Abl affects is the JAK/STAT pathway, which is responsible for proliferation.[29]
Pharmacokinetics[edit]
Imatinib is rapidly absorbed when given by mouth, and is highly bioavailable: 98% of an oral dose reaches the bloodstream. Metabolism of imatinib occurs in the liver and is mediated by several isozymes of the cytochrome P450 system, including CYP3A4 and, to a lesser extent, CYP1A2,CYP2D6, CYP2C9, and CYP2C19. The main metabolite, N-demethylated piperazine derivative, is also active. The major route of elimination is in the bile and feces; only a small portion of the drug is excreted in the urine. Most of imatinib is eliminated as metabolites; only 25% is eliminated unchanged. The half-lives of imatinib and its main metabolite are 18 h and 40 h, respectively. It blocks the activity of Abelson cytoplasmic tyrosine kinase (ABL), c-Kit and the platelet-derived growth factor receptor (PDGFR). As an inhibitor of PDGFR, imatinib mesylate appears to have utility in the treatment of a variety of dermatological diseases. Imatinib has been reported to be an effective treatment for FIP1L1-PDGFRalpha+ mast cell disease, hypereosinophilic syndrome, and dermatofibrosarcoma protuberans.[30]
Interactions[edit]
Since imatinib is mainly metabolised via the liver enzyme CYP3A4, substances influencing the activity of this enzyme change the plasma concentration of the drug. An example of a drug that increases imatinib activity and therefore side effects by blocking CYP3A4 is ketoconazole. The same could be true of itraconazole, clarithromycin, grapefruit juice, among others. Conversely, CYP3A4 inductors like rifampicin and St. John's Wort reduce the drug's activity, risking therapy failure. Imatinib also acts as an inhibitor of CYP3A4, 2C9 and 2D6, increasing the plasma concentrations of a number of other drugs like simvastatin, ciclosporin, pimozide, warfarin, metoprolol, and possibly paracetamol. The drug also reduces plasma levels of levothyroxin via an unknown mechanism.[18]
As with other immunosuppressants, application of live vaccines is contraindicated because the microorganisms in the vaccine could multiply and infect the patient. Inactivated and toxoid vaccines do not hold this risk, but may not be effective under imatinib therapy.[31]
History[edit]
Imatinib was invented in the late 1990s by scientists at Ciba-Geigy (which merged with Sandoz in 1996 to become Novartis), in a team led by biochemist Nicholas Lydon and that included Elisabeth Buchdunger and Jürg Zimmermann[32] and its use to treat CML was driven by oncologistBrian Druker of Oregon Health & Science University (OHSU).[33] Other major contributions to imatinib development were made by Carlo Gambacorti-Passerini, a physician, scientist, and hematologist at University of Milano Bicocca, Italy, John Goldman at Hammersmith Hospital in London, UK, and later on by Charles Sawyers of Memorial Sloan-Kettering Cancer Center.[34] Druker led the clinical trials confirming its efficacy inCML.[35]
Imatinib was developed by rational drug design. After the Philadelphia chromosome mutation and hyperactive bcr-abl protein were discovered, the investigators screened chemical libraries to find a drug that would inhibit that protein. With high-throughput screening, they identified 2-phenylaminopyrimidine. This lead compound was then tested and modified by the introduction of methyl and benzamide groups to give it enhanced binding properties, resulting in imatinib.[36]
When Novartis tested imatinib in rats, mice, rabbits, dogs, and monkeys in 1996, it was found to have several toxic effects; in particular, results indicating liver damage in dogs nearly stopped drug development completely. However, favorable results in studies with monkeys and in vitrohuman cells allowed testing to continue in humans.[37][38][39]
The first clinical trial of Gleevec took place in 1998 and the drug received FDA approval in May 2001, only two and a half years after the new drug application was submitted.[32][40] On the same month it made the cover of TIME magazine as a "bullet" to be used against cancer. Druker, Lydon and Sawyers received the Lasker-DeBakey Clinical Medical Research Award in 2009 for "converting a fatal cancer into a manageable chronic condition".[34]
During the FDA review, the tradename of the drug for the US market was changed from "Glivec" to "Gleevec" at the request of the FDA, to avoid confusion with Glyset, a diabetes drug.[41][42][43]
A Swiss patent application was filed on imanitib and various salts on in April 1992, which was then filed in the EU, the US, and other countries in March and April 1993.[44][45] and in 1996 United States and European patent offices issued patents listing Jürg Zimmermann as the inventor.[44][46]
In July 1997, Novartis filed a new patent application in Switzerland on the beta crystalline form of imatinib mesylate (the mesylate salt of imatinib). The "beta crystalline form" of the molecule is a specific polymorph of imatinib mesylate; a specific way that the individual molecules pack together to form a solid. This is the actual form of the drug sold as Gleevec/Glivec; a salt (imatinib mesylate) as opposed to a free base, and the beta crystalline form as opposed to the alpha or other form.[47]:3 and 4 In 1998, Novartis filed international patent applications claiming priority to the 1997 filing.[48][49] A United States patent was granted in 2005.[50]
Costs[edit]

A box of 400-milligram Glivec tablets (Novartis), as sold in Germany.
In 2013, more than 100 cancer specialists published a letter in Blood saying that the prices of many new cancer drugs, including imatinib, are so high that people in the United States couldn't afford them, and that the level of prices, and profits, was so high as to be immoral. Signatories of the letter included Brian Druker, Carlo Gambacorti-Passerini, and John Goldman, developers of imatinib.[51][52] They wrote that in 2001, imatinib was priced at $30,000 a year, which was based on the price of interferon, then the standard treatment, and that at this price Novartis would have recouped its initial development costs in two years. They wrote that after unexpectedly becoming a blockbuster, Novartis increased the price to $92,000 per year in 2012, with annual revenues of $4.7 billion. Other physicians have complained about the cost.[53][54][55] By 2016, the average wholesale price had increased to $120,000 a year, according to an analysis prepared for the Washington Post by Stacie Dusetzina of the University of North Carolina at Chapel Hill. When competitive drugs came on the market, they were sold at a higher price to reflect the smaller population, and Novartis raised the price of Gleevec to match them.[56]
A 2012 economic analysis funded by Bristol-Myers Squibb estimated that the discovery and development of imatinib and related drugs had created $143 billion in societal value at a cost to consumers of approximately $14 billion. The $143 billion figure was based on an estimated 7.5 to 17.5 year survival advantage conferred by imatinib treatment, and included the value (discounted at 3% per annum) of ongoing benefits to society after the imatinib patent expiration.[57]
Prices for a 100 mg pill of Gleevec internationally range from $20 to $30,[58] although generic imatinib is cheaper, as low as $2 per pill.[59]
Patent litigation in India[edit]
Main article: Novartis v. Union of India & Others
Novartis fought a seven-year, controversial battle to patent Gleevec in India, and took the case all the way to the Indian Supreme Court. The patent application at the center of the case was filed by Novartis in India in 1998, after India had agreed to enter the World Trade Organization and to abide by worldwide intellectual property standards under the TRIPS agreement. As part of this agreement, India made changes to its patent law, the biggest of which was that prior to these changes, patents on products were not allowed, while afterwards they were, albeit with restrictions. These changes came into effect in 2005, so Novartis' patent application waited in a "mailbox" with others until then, under procedures that India instituted to manage the transition. India also passed certain amendments to its patent law in 2005, just before the laws came into effect.[60]
The patent application[49][61] claimed the final form of Gleevec (the beta crystalline form of imatinib mesylate).[62]:3 In 1993, during the time India did not allow patents on products, Novartis had patented imatinib, with salts vaguely specified, in many countries but could not patent it in India.[44][46]The key differences between the two patent applications, were that 1998 patent application specified the counterion (Gleevec is a specific salt – imatinib mesylate) while the 1993 patent application did not claim any specific salts nor did it mention mesylate, and the 1998 patent application specified the solid form of Gleevec – the way the individual molecules are packed together into a solid when the drug itself is manufactured (this is separate from processes by which the drug itself is formulated into pills or capsules) – while the 1993 patent application did not. The solid form of imatinib mesylate in Gleevec is beta crystalline.[63]
As provided under the TRIPS agreement, Novartis applied for Exclusive Marketing Rights (EMR) for Gleevec from the Indian Patent Office and the EMR was granted in November 2003.[64] Novartis made use of the EMR to obtain orders against some generic manufacturers who had already launched Gleevec in India.[65][66]
When examination of Novartis' patent application began in 2005, it came under immediate attack from oppositions initiated by generic companies that were already selling Gleevec in India and by advocacy groups. The application was rejected by the patent office and by an appeal board. The key basis for the rejection was the part of Indian patent law that was created by amendment in 2005, describing the patentability of new uses for known drugs and modifications of known drugs. That section, 3d, specified that such inventions are patentable only if "they differ significantly in properties with regard to efficacy."[65][67] At one point, Novartis went to court to try to invalidate Section 3d; it argued that the provision was unconstitutionally vague and that it violated TRIPS. Novartis lost that case and did not appeal.[68] Novartis did appeal the rejection by the patent office to India's Supreme Court, which took the case.
The Supreme Court case hinged on the interpretation of Section 3d. The Supreme Court issued its decision in 2013, ruling that the substance that Novartis sought to patent was indeed a modification of a known drug (the raw form of imatinib, which was publicly disclosed in the 1993 patent application and in scientific articles), that Novartis did not present evidence of a difference in therapeutic efficacy between the final form of Gleevec and the raw form of imatinib, and that therefore the patent application was properly rejected by the patent office and lower courts.[69]
Research[edit]
One study demonstrated that imatinib mesylate was effective in patients with systemic mastocytosis, including those who had the D816V mutation in c-KIT.[70] However, since imatinib binds to tyrosine kinases when they are in the inactive configuration and the D816V mutant of c-KIT is constitutively active, imatinib does not inhibit the kinase activity of the D816V mutant of c-KIT. Experience has shown, however, that imatinib is much less effective in patients with this mutation, and patients with the mutation comprise nearly 90% of cases of mastocytosis.
Imatinib was initially thought to have a potential role in the treatment of pulmonary hypertension. It was shown to reduce both the smooth muscle hypertrophy and hyperplasia of the pulmonary vasculature in a variety of disease processes, including portopulmonary hypertension.[71] However, a long-term trial of Imatinib in people with pulmonary arterial hypertension was unnsuccessful, and serious and unexpected adverse events were frequent. These included 6 subdural hematomas and 17 deaths during or within 30 days of study end.[72]
In systemic sclerosis, the drug has been tested for potential use in slowing down pulmonary fibrosis. In laboratory settings, imatinib is being used as an experimental agent to suppress platelet-derived growth factor (PDGF) by inhibiting its receptor (PDGF-Rβ). One of its effects is delayingatherosclerosis in mice without[73] or with diabetes.[74]
Mouse animal studies have suggested that imatinib and related drugs may be useful in treating smallpox, should an outbreak ever occur.[75]
In vitro studies identified that a modified version of imatinib can bind to gamma-secretase activating protein (GSAP). GSAP selectively increases the production and accumulation of neurotoxic beta-amyloid plaques,which suggests that molecules which target GSAP and are able to crossblood–brain barrier are potential therapeutic agents for treating Alzheimer's disease.[76] Another study suggests that imatinib may not need to cross the blood–brain barrier to be effective at treating Alzheimer's, as the research indicates the production of beta-amyloid may begin in the liver. Tests on mice indicate that imatinib is effective at reducing beta-amyloid in the brain.[77] It is not known whether reduction of beta-amyloid is a feasible way of treating Alzheimer's, as an anti-beta-amyloid vaccine has been shown to clear the brain of plaques without having any effect on Alzheimer symptoms.[78]
A formulation of imatinib with a cyclodextrin (Captisol) as a carrier to overcome the blood–brain barrier is also currently considered as an experimental drug for lowering and reversing opioid tolerance. Imatinib has shown reversal of tolerance in rats.[79] Imatinib is an experimental drug in the treatment of desmoid tumor or aggressive fibromatosis.
See also[edit]
Bcr-Abl tyrosine-kinase inhibitor
History of cancer chemotherapy
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Jump up^ Holmes C, Boche D, Wilkinson D, Yadegarfar G, Hopkins V, Bayer A, Jones RW, Bullock R, Love S, Neal JW, Zotova E, Nicoll JA (July 2008). "Long-term effects of Abeta42 immunisation in Alzheimer's disease: follow-up of a randomised, placebo-controlled phase I trial".Lancet. 372 (9634): 216–23. PMID 18640458. doi:10.1016/S0140-6736(08)61075-2.
Jump up^ Eliminating Morphine Tolerance – Reformulated Imatinib 23 Feb 2012, 5:00 PST
External links[edit]
NCI Drug Information Summary for Patients
Imatinib bound to proteins in the PDB


Alexandros Sfakianakis
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Fri Jun 23, 2017 08:57
  Children who swallowed multiple magnetic foreign bodies.Gastrointestinal perforation and intestinal obstruction. The magnetic foreign bodies caused local bowel wall tissue ischemia necrosis and perforation as well as other complications associated with fistula formation. The magnets were finally removed by laparotomy surgery.
updated on Fri Jun 23, 2017 16:55 by Alexandros G. Sfakianakis via Allergy Rhinology Immunology Asthma
Πέμπτη, 22 Ιουνίου 2017
Children who swallowed multiple magnetic foreign bodies.Gastrointestinal perforation and intestinal obstruction. The magnetic foreign bodies caused local bowel wall tissue ischemia necrosis and perforation as well as other complications associated with fistula formation. The magnets were finally removed by laparotomy surgery.
Clinical experience in the treatment of children who swallowed multiple magnetic foreign bodies: A report of five cases:

Abstract


Background
Several clinical reports have been published on complications resulting from swallowing multiple magnetic foreign bodies. This study aimed to summarize the clinical experience of managing children who swallowed multiple magnetic foreign bodies.




Methods
We reviewed the clinical records of five children who swallowed multiple magnetic foreign bodies and were admitted to our hospital during June 2012 to June 2014. Details of the patients' presentation, imaging studies, complications and treatment were recorded.




Results
All five children suffered from gastrointestinal perforation and intestinal obstruction. The magnetic foreign bodies caused local bowel wall tissue ischemia necrosis and perforation as well as other complications associated with fistula formation. The magnets were finally removed by laparotomy surgery.




Conclusion
If magnetic foreign bodies cannot be removed by endoscopy, an operation is suggested as soon as possible to avoid serious complications.

Αναρτήθηκε από
Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182
6948891480
alsfakia@gmail.com
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Fri Jun 23, 2017 08:18
  Barrier lipid replacement strategy for the prevention of atopic dermatitis and allergic sensitisation
updated on Fri Jun 23, 2017 16:55 by Alexandros G. Sfakianakis via Allergy Rhinology Immunology Asthma
Πέμπτη, 22 Ιουνίου 2017
Barrier lipid replacement strategy for the prevention of atopic dermatitis and allergic sensitisation
A randomised trial of a barrier lipid replacement strategy for the prevention of atopic dermatitis and allergic sensitisation: The PEBBLES Pilot Study:

Abstract
It is hypothesised that the impaired skin barrier in atopic dermatitis (AD) allows the immune system to be exposed to environmental allergens, resulting in sensitisation and allergic disease[1]. Two small trials recently found that routine use of emollients reduced the incidence of AD during the active treatment period by approximately half [2, 3]. It remains unknown if prophylactic use of emollients can prevent the development of AD beyond the treatment period (as opposed to simply delay its onset) or if this reduction in AD leads to a reduced risk of allergic sensitisation.
This article is protected by copyright. All rights reserved.
Αναρτήθηκε από
Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182
6948891480
alsfakia@gmail.com
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Fri Jun 23, 2017 05:55
  Cytomegalovirus DNA is highly prevalent in the blood of patients with asthma and is associated with age and asthma traits
updated on Fri Jun 23, 2017 16:55 by Alexandros G. Sfakianakis via Allergy Rhinology Immunology Asthma
Abstract
CMV IgG antibodies have been associated with inflammageing and immunosenescence. We aimed to assess the presence of CMV DNA in the blood of adult and elderly patients with bronchial asthma to establish potential association of CMV DNAemia with asthma and asthma characteristics. Eighty-five elderly asthmatics, 74 younger asthma patients and 114 age-matched controls were recruited. The CMV DNA was detected using commercial artus assay in 10.7% of asthma patients, but was negative in all control individuals. The secondary assay identified CMV DNA in 41.5% of asthmatics and 13.3% of control subjects (p<0.001). Presence of CMV DNA was associated with increased risk of asthma and CMV DNA copy numbers correlated with some asthma traits, including respiratory parameters, and exhaled breath Nitric Oxide. We conclude, that CMV infection is associated with asthma and may contribute to the pathogenesis of asthmatic inflammation.

This article is protected by copyright. All rights reserved.



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  Evaluation of G2 Citric Acid-Based Dendrimer as an Adjuvant in Veterinary Rabies Vaccine
updated on Fri Jun 23, 2017 03:26 by Alexandros G. Sfakianakis via Allergy Rhinology Immunology Asthma
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Thu Jun 22, 2017 08:47
  The dietary intake of flavonoids reduces the risk of developing certain types of cancers.Anticancer and preventive effects against prostate,colorectal,breast,thyroid,lung,and ovarian cancers,Flavonoids include the following subfamilies: flavones, flavanols, isoflavones, flavonols, flavanones, and flavanonols, which differ in their ring substituents and extent of saturation.............................................................................................................................Silymarin, genistein, quercetin, daidzein, luteolin, kaempferol, apigenin, and epigallocatechin 3-gallate.Their chemopreventive efficacy is mediated by inhibiting the development of new cancer cells;preventing carcinogens from reaching their activation sites; and decreasing the toxicity of certain compounds by inhibiting their metabolism.The molecular mechanisms by which flavonoids produce their anticancer and preventive effects include (1) induction of apoptosis ; (2) cell cycle arrest at G1
updated on Thu Jun 22, 2017 13:11 by Alexandros G. Sfakianakis via Allergy Rhinology Immunology Asthma
http://orl-agios.blogspot.com/2017/06/the-preclinical-anticancer-effect-of.html

Flavonoids present in foods were considered non-absorbable because they are bound to sugars as beta-glycosides. However, we found that human absorption of the quercetin glycosides from onions (52%) is far better than that of the pure aglycone (24%). Flavonol glycosides might contribute to the antioxidant defences of blood. Dietary flavonols and flavones probably do not explain the cancer-protective effect of vegetables and fruits; a protective effect against cardiovascular disease is not conclusive.Flavonoids and their polymers constitute a large class of food constituents, many of which alter metabolic processes and have a positive impact on health. Flavonoids are a subclass of polyphenols. They generally consist of two aromatic rings, each containing at least one hydroxyl, which are connected through a three-carbon "bridge" and become part of a six-member heterocyclic ring. The flavonoids are further divided into subclasses based on the connection of an aromatic ring to the heterocyclic ring, as well as the oxidation state and functional groups of the heterocyclic ring. Within each subclass, individual compounds are characterized by specific hydroxylation and conjugation patterns. Many flavonoids in foods also occur as large molecules (tannins). These include condensed tannins (proanthocyanidins), derived tannins and hydrolysable tannins. For proanthocyanidins, three subclasses (15 characterized) have been identified in foods. Monomers are connected through specific carbon-carbon and ether linkages to form polymers. Derived tannins are formed during food handling and processing, and found primarily in black and oolong teas. Flavonoids are widely distributed in nature, albeit not uniformly. As a result, specific groups of foods are often rich sources of one or more subclasses of these polyphenols. The polyphenolic structure of flavonoids and tannins renders them quite sensitive to oxidative enzymes and cooking conditions. Scientists in several countries have estimated intakes of a few subclasses of flavonoids from limited food composition databases. These observations suggest large differences in consumption, due in part to cultural and food preferences among populations of each country.

Flavonoids (specifically flavanoids such as the catechins) are "the most common group of polyphenoliccompounds in the human diet and are found ubiquitously in plants".[6] Flavonols, the original bioflavonoids such as quercetin, are also found ubiquitously, but in lesser quantities. The widespread distribution of flavonoids, their variety and their relatively low toxicity compared to other active plant compounds (for instance alkaloids) mean that many animals, including humans, ingest significant quantities in their diet. Foods with a high flavonoid content include parsley,[7] onions,[7] blueberries and other berries,[7] black tea,[7] green tea and oolong tea,[7] bananas, all citrus fruits, Ginkgo biloba, red wine, sea-buckthorns, anddark chocolate (with a cocoa content of 70% or greater). Further information on dietary sources of flavonoids can be obtained from the US Department of Agriculture flavonoid database.[7]


40880_2017_217_Fig1_HTML.gif



Flavonoid
From Wikipedia, the free encyclopedia

Molecular structure of theflavone backbone (2-phenyl-1,4-benzopyrone)

Isoflavan structure

Neoflavonoids structure
Flavonoids (or bioflavonoids) (from the Latin word flavus meaning yellow, their color in nature) are a class ofplant and fungus secondary metabolites.

Chemically, flavonoids have the general structure of a 15-carbon skeleton, which consists of two phenyl rings (A and B) and heterocyclic ring (C). This carbon structure can be abbreviated C6-C3-C6. According to the IUPACnomenclature,[1][2] they can be classified into:

flavonoids or bioflavonoids
isoflavonoids, derived from 3-phenylchromen-4-one (3-phenyl-1,4-benzopyrone) structure
neoflavonoids, derived from 4-phenylcoumarine (4-phenyl-1,2-benzopyrone) structure
The three flavonoid classes above are all ketone-containing compounds, and as such, are anthoxanthins (flavonesand flavonols). This class was the first to be termed bioflavonoids. The terms flavonoid and bioflavonoid have also been more loosely used to describe non-ketone polyhydroxy polyphenol compounds which are more specifically termed flavanoids. The three cycle or heterocycles in the flavonoid backbone are generally called ring A, B and C. Ring A usually shows a phloroglucinol substitution pattern.

Contents
  [hide]
1Biosynthesis
2Functions of flavonoids in plants
3Subgroups
3.1Anthoxanthins
3.2Flavanones
3.3Flavanonols
3.4Flavans
3.5Anthocyanidins
4Isoflavonoids
5Dietary sources
5.1Parsley
5.2Blueberries
5.3Black tea
5.4Citrus
5.5Wine
5.6Cocoa
5.7Peanut
6Dietary intake
7Research
7.1In vitro
7.2Antioxidant
7.3Inflammation
7.4Cancer
7.5Cardiovascular diseases
7.6Antibacterial
8Synthesis, detection, quantification, and semi-synthetic alterations
8.1Color spectrum
8.2Availability through microorganisms
8.3Tests for detection
8.4Quantification
8.5Semi-synthetic alterations
9See also
10References
11Further reading
12External links
12.1Databases
Biosynthesis[edit]
Main article: Flavonoid biosynthesis
Functions of flavonoids in plants[edit]
Flavonoids are widely distributed in plants, fulfilling many functions. Flavonoids are the most important plant pigments for flower coloration, producing yellow or red/blue pigmentation in petals designed to attract pollinator animals. In higher plants, flavonoids are involved in UV filtration, symbiotic nitrogen fixation and floral pigmentation. They may also act as chemical messengers, physiological regulators, and cell cycle inhibitors. Flavonoids secreted by the root of their host plant help Rhizobia in the infection stage of their symbiotic relationship with legumes like peas, beans, clover, and soy. Rhizobia living in soil are able to sense the flavonoids and this triggers the secretion of Nod factors, which in turn are recognized by the host plant and can lead to root hair deformation and several cellular responses such as ion fluxes and the formation of a root nodule. In addition, some flavonoids have inhibitory activity against organisms that cause plant diseases, e.g. Fusarium oxysporum.[3]

Subgroups[edit]
Over 5000 naturally occurring flavonoids have been characterized from various plants. They have been classified according to their chemical structure, and are usually subdivided into the following subgroups (for further reading see[4]):

Anthoxanthins[edit]
Anthoxanthins are divided into two groups:[5]

Group Skeleton Examples
Description Functional groups Structural formula
3-hydroxyl 2,3-dihydro
Flavone 2-phenylchromen-4-one
Flavone skeleton colored.svg
Luteolin, Apigenin, Tangeritin
Flavonol
or
3-hydroxyflavone 3-hydroxy-2-phenylchromen-4-one
Flavonol skeleton colored.svg
Quercetin, Kaempferol, Myricetin, Fisetin, Galangin,Isorhamnetin, Pachypodol, Rhamnazin,Pyranoflavonols, Furanoflavonols,
Flavanones[edit]
Flavanones

Group Skeleton Examples
Description Functional groups Structural formula
3-hydroxyl 2,3-dihydro
Flavanone 2,3-dihydro-2-phenylchromen-4-one
Flavanone skeleton colored.svg
Hesperetin, Naringenin, Eriodictyol,Homoeriodictyol
Flavanonols[edit]
Flavanonols

Group Skeleton Examples
Description Functional groups Structural formula
3-hydroxyl 2,3-dihydro
Flavanonol
or
3-Hydroxyflavanone
or
2,3-dihydroflavonol 3-hydroxy-2,3-dihydro-2-phenylchromen-4-one
Flavanonol skeleton colored.svg
Taxifolin (orDihydroquercetin),Dihydrokaempferol
Flavans[edit]

Flavan structure
Include flavan-3-ols (flavanols), flavan-4-ols and flavan-3,4-diols.

Skeleton Name
Flavan-3ol Flavan-3-ol (flavanol)
Flavan-4ol Flavan-4-ol
Flavan-3,4-diol Flavan-3,4-diol (leucoanthocyanidin)
Flavan-3-ols (flavanols)
Flavan-3-ols use the 2-phenyl-3,4-dihydro-2H-chromen-3-ol skeleton
Examples: Catechin (C), Gallocatechin (GC), Catechin 3-gallate (Cg), Gallocatechin 3-gallate (GCg), Epicatechins (Epicatechin (EC)),Epigallocatechin (EGC), Epicatechin 3-gallate (ECg), Epigallocatechin 3-gallate (EGCg)
Theaflavin
Examples: Theaflavin-3-gallate, Theaflavin-3'-gallate, Theaflavin-3,3'-digallate
Thearubigin
Proanthocyanidins are dimers, trimers, oligomers, or polymers of the flavanols
Anthocyanidins[edit]

Flavylium skeleton of anthocyanidins
AnthocyanidinsAnthocyanidins are the aglycones of anthocyanins; they use the flavylium (2-phenylchromenylium) ion skeletonExamples: Cyanidin, Delphinidin, Malvidin, Pelargonidin, Peonidin, Petunidin
Isoflavonoids[edit]
Isoflavonoids
Isoflavones use the 3-phenylchromen-4-one skeleton (with no hydroxyl group substitution on carbon at position 2)
Examples: Genistein, Daidzein, Glycitein
Isoflavanes
Isoflavandiols
Isoflavenes
Coumestans
Pterocarpans
Dietary sources[edit]

Parsley is a source of flavones.

Blueberries are a source of dietary anthocyanidins.

A variety of flavonoids are found incitrus fruits, including grapefruit.
Flavonoids (specifically flavanoids such as the catechins) are "the most common group of polyphenoliccompounds in the human diet and are found ubiquitously in plants".[6] Flavonols, the original bioflavonoids such as quercetin, are also found ubiquitously, but in lesser quantities. The widespread distribution of flavonoids, their variety and their relatively low toxicity compared to other active plant compounds (for instance alkaloids) mean that many animals, including humans, ingest significant quantities in their diet. Foods with a high flavonoid content include parsley,[7] onions,[7] blueberries and other berries,[7] black tea,[7] green tea and oolong tea,[7] bananas, all citrus fruits, Ginkgo biloba, red wine, sea-buckthorns, anddark chocolate (with a cocoa content of 70% or greater). Further information on dietary sources of flavonoids can be obtained from the US Department of Agriculture flavonoid database.[7]

Parsley[edit]
Parsley, both fresh and dried, contains flavones.[7]

Blueberries[edit]
Blueberries are a dietary source of anthocyanidins.[7][8]

Black tea[edit]
Black tea is a rich source of dietary flavan-3-ols.[7]

Citrus[edit]
The citrus flavonoids include hesperidin (a glycoside of the flavanone hesperetin), quercitrin, rutin (twoglycosides of the flavonol quercetin), and the flavone tangeritin.

Wine[edit]
Main article: Polyphenols in wine
Cocoa[edit]
Main article: Health effects of chocolate
Flavonoids exist naturally in cocoa, but because they can be bitter, they are often removed from chocolate, even dark chocolate.[9] Although flavonoids are present in milk chocolate, milk may interfere with their absorption;[10][11] however this conclusion has been questioned.[12]

Peanut[edit]
Peanut (red) skin contains significant polyphenol content, including flavonoids.[13][14]

Food source Flavones Flavonols Flavanones
Red onion 0 4 - 100 0
Parsley, fresh 24 - 634 8 - 10 0
Thyme, fresh 56 0 0
Lemon juice, fresh 0 0 - 2 2 - 175
[15]

Dietary intake[edit]

Mean flavonoid intake in mg/d per country, the pie charts show the relative contribution of different types of flavonoids.[16]
Food composition data for flavonoids were provided by the USDA database on flavonoids.[7] In the United States NHANES survey, mean flavonoid intake was 190 mg/d in adults, with flavan-3-ols as the main contributor.[17] In the European Union, based on data from EFSA, mean flavonoid intake was 140 mg/d, although there were considerable differences between individual countries.[16]


Data is based on mean flavonoid intake of all countries included in the 2011 EFSA Comprehensive European Food Consumption Database.[16]
The main type of flavonoids consumed in the EU and USA were flavan-3-ols, mainly from tea, while intake of other flavonoids was considerably lower.[16][17]

Research[edit]
Though there is ongoing research into the potential health benefits of individual flavonoids, neither theFood and Drug Administration (FDA) nor the European Food Safety Authority (EFSA) has approved any health claim for flavonoids or approved any flavonoids as pharmaceutical drugs.[18][19][20] Moreover, several companies have been cautioned by the FDA over misleading health claims.[21][22][23][24]

In vitro[edit]
Flavonoids have been shown to have a wide range of biological and pharmacological activities in in vitrostudies. Examples include anti-allergic,[25] anti-inflammatory,[25][26] antioxidant,[26] anti-microbial(antibacterial,[27][28] antifungal,[29][30] and antiviral[29][30]), anti-cancer,[26][31] and anti-diarrheal activities.[32]Flavonoids have also been shown to inhibit topoisomerase enzymes[33][34] and to induce DNA mutations in the mixed-lineage leukemia (MLL) gene in in vitro studies.[35] However, in most of the above cases no follow up in vivo or clinical research has been performed, leaving it impossible to say if these activities have any beneficial or detrimental effect on human health. Biological and pharmacological activities which have been investigated in greater depth are described below.

Antioxidant[edit]
Research at the Linus Pauling Institute and the European Food Safety Authority shows that flavonoids are poorly absorbed in the human body (less than 5%), with most of what is absorbed being quickly metabolized and excreted.[20][36][37] These findings suggest that flavonoids have negligible systemic antioxidant activity, and that the increase in antioxidant capacity of blood seen after consumption of flavonoid-rich foods is not caused directly by flavonoids, but is due to production of uric acid resulting from flavonoid depolymerizationand excretion.[38]

Inflammation[edit]
Inflammation has been implicated as a possible origin of numerous local and systemic diseases, such ascancer,[39] cardiovascular disorders,[40] diabetes mellitus,[41] and celiac disease.[42]

Preliminary studies indicate that flavonoids may affect anti-inflammatory mechanisms via their ability to inhibit reactive oxygen or nitrogen compounds.[43] Flavonoids have also been proposed to inhibit the pro-inflammatory activity of enzymes involved in free radical production, such as cyclooxygenase, lipoxygenaseor inducible nitric oxide synthase,[43][44] and to modify intracellular signaling pathways in immune cells,[43] or in brain cells after a stroke.[45]

Procyanidins, a class of flavonoids, have been shown in preliminary research to have anti-inflammatory mechanisms including modulation of thearachidonic acid pathway, inhibition of gene transcription, expression and activity of inflammatory enzymes, as well as secretion of anti-inflammatory mediators.[46]

Cancer[edit]
Clinical studies investigating the relationship between flavonoid consumption and cancer prevention/development are conflicting for most types of cancer, probably because most studies are retrospective in design and use a small sample size.[47] Two apparent exceptions are gastric carcinomaand smoking-related cancers. Dietary flavonoid intake is associated with reduced gastric carcinoma risk in women,[48] and reduced aerodigestive tract cancer risk in smokers.[49]

Cardiovascular diseases[edit]
Among the most intensively studied of general human disorders possibly affected by dietary flavonoids, preliminary cardiovascular diseaseresearch has revealed the following mechanisms under investigation in patients or normal subjects:[50][51][52][53][54]

inhibit coagulation, thrombus formation or platelet aggregation
reduce risk of atherosclerosis
reduce arterial blood pressure and risk of hypertension
reduce oxidative stress and related signaling pathways in blood vessel cells
modify vascular inflammatory mechanisms
improve endothelial and capillary function
modify blood lipid levels
regulate carbohydrate and glucose metabolism
modify mechanisms of aging
Listed on the clinical trial registry of the US National Institutes of Health (July 2016) are 48 human studies completed or underway to study the dietary effects of plant flavonoids on cardiovascular diseases.[55]

However, population-based studies have failed to show a strong beneficial effect[56] which might be due to the considerably lower intake in the habitual diet of those investigated.

Antibacterial[edit]
Flavonoids have been shown to have (a) direct antibacterial activity, (b) synergistic activity with antibiotics, and (c) the ability to suppress bacterialvirulence factors in numerous in vitro and a limited number of in vivo studies.[27][57] Noteworthy among the in vivo studies[58][59][60] is the finding that oral quercetin protects guinea pigs against the Group 1 carcinogen Helicobacter pylori.[60] Researchers from the European Prospective Investigation into Cancer and Nutrition have speculated this may be one reason why dietary flavonoid intake is associated with reduced gastric carcinoma risk in European women.[61] Additional in vivo and clinical research is needed to determine if flavonoids could be used as pharmaceutical drugs for the treatment of bacterial infection, or whether dietary flavonoid intake offers any protection against infection.

Synthesis, detection, quantification, and semi-synthetic alterations[edit]
Color spectrum[edit]
Flavonoid synthesis in plants is induced by light color spectrums at both high and low energy radiations. Low energy radiations are accepted byphytochrome, while high energy radiations are accepted by carotenoids, flavins, cryptochromes in addition to phytochromes. Thephotomorphogenic process of phytochome-mediated flavonoid biosynthesis has been observed in Amaranthus, barley, maize, Sorghum and turnip. Red light promotes flavonoid synthesis.[62]

Availability through microorganisms[edit]
Several recent research articles have demonstrated the efficient production of flavonoid molecules from genetically engineered microorganisms.[63][64][65]

Tests for detection[edit]
Shinoda test
Four pieces of magnesium filings are added to the ethanolic extract followed by few drops of concentrated hydrochloric acid. A pink or red colour indicates the presence of flavonoid.[66] Colours varying from orange to red indicated flavones, red to crimson indicated flavonoids, crimson to magenta indicated flavonones.

Sodium hydroxide test
About 5 mg of the compound is dissolved in water, warmed and filtered. 10% aqueous sodium hydroxide is added to 2 ml of this solution. This produces a yellow coloration. A change in color from yellow to colorless on addition of dilute hydrochloric acid is an indication for the presence of flavonoids.[67]

p-Dimethylaminocinnamaldehyde test
A colorimetric assay based upon the reaction of A-rings with the chromogen p-dimethylaminocinnamaldehyde (DMACA) has been developed for flavanoids in beer that can be compared with the vanillin procedure.[68]

Quantification[edit]
Lamaison and Carnet have designed a test for the determination of the total flavonoid content of a sample (AlCI3 method). After proper mixing of the sample and the reagent, the mixture is incubated for 10 minutes at ambient temperature and the absorbance of the solution is read at 440 nm. Flavonoid content is expressed in mg/g of quercetin.[69]

Semi-synthetic alterations[edit]
Immobilized Candida antarctica lipase can be used to catalyze the regioselective acylation of flavonoids.[70]

See also[edit]
Phytochemical
List of antioxidants in food
List of phytochemicals in food
Phytochemistry
Secondary metabolites
Homoisoflavonoids, related chemicals with a 16 carbons skeleton
References[edit]
Jump up^ McNaught, Alan D; Wilkinson, Andrew; IUPAC (1997), "IUPAC Compendium of Chemical Terminology", IUPAC Compendium of Chemical Terminology (2 ed.), Oxford: Blackwell Scientific, ISBN 0-9678550-9-8, doi:10.1351/goldbook.F02424
Jump up^ "The Gold Book". 2009. ISBN 0-9678550-9-8.doi:10.1351/goldbook. Retrieved 16 September 2012. |chapter=ignored (help)
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Jump up^ Ververidis F, Trantas E, Douglas C, Vollmer G, Kretzschmar G, Panopoulos N (October 2007). "Biotechnology of flavonoids and other phenylpropanoid-derived natural products. Part I: Chemical diversity, impacts on plant biology and human health". Biotechnology Journal. 2(10): 1214–34. PMID 17935117. doi:10.1002/biot.200700084.
Jump up^ Isolation of a UDP-glucose: Flavonoid 5-O-glucosyltransferase gene and expression analysis of anthocyanin biosynthetic genes in herbaceous peony (Paeonia lactiflora Pall.). Da Qiu Zhao, Chen Xia Han, Jin Tao Ge and Jun Tao, Electronic Journal of Biotechnology, 15 November 2012, Volume 15, Number 6, doi:10.2225/vol15-issue6-fulltext-7
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Jump up^ "The devil in the dark chocolate". Lancet. 370 (9605): 2070. 2007.PMID 18156011. doi:10.1016/S0140-6736(07)61873-X.
Jump up^ Serafini M, Bugianesi R, Maiani G, Valtuena S, De Santis S, Crozier A (2003). "Plasma antioxidants from chocolate". Nature. 424 (6952): 1013. Bibcode:2003Natur.424.1013S. PMID 12944955.doi:10.1038/4241013a.
Jump up^ Serafini M, Bugianesi R, Maiani G, Valtuena S, De Santis S, Crozier A (2003). "Nutrition: milk and absorption of dietary flavanols". Nature.424 (6952): 1013. Bibcode:2003Natur.424.1013S. PMID 12944955.doi:10.1038/4241013a.
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Jump up^ de Camargo AC, Regitano-d'Arce MA, Gallo CR, Shahidi F (2015)."Gamma-irradiation induced changes in microbiological status, phenolic profile and antioxidant activity of peanut skin". Journal of Functional Foods. 12: 129–143. doi:10.1016/j.jff.2014.10.034.
Jump up^ Chukwumah Y, Walker LT, Verghese M (2009). "Peanut skin color: a biomarker for total polyphenolic content and antioxidative capacities of peanut cultivars". Int J Mol Sci. 10 (11): 4941–52. PMC 2808014 Freely accessible.PMID 20087468. doi:10.3390/ijms10114941.
Jump up^ "Flavonoids - Linus Pauling Institute - Oregon State University". Retrieved 26 February 2016.
^ Jump up to:a b c d Vogiatzoglou, A; Mulligan, A. A.; Lentjes, M. A.; Luben, R. N.; Spencer, J. P.; Schroeter, H; Khaw, K. T.; Kuhnle, G. G. (2015)."Flavonoid intake in European adults (18 to 64 years)". PLoS ONE. 10(5): e0128132. PMC 4444122 Freely accessible. PMID 26010916.doi:10.1371/journal.pone.0128132.
^ Jump up to:a b Chun, O. K.; Chung, S. J.; Song, W. O. (2007). "Estimated dietary flavonoid intake and major food sources of U.S. Adults". The Journal of Nutrition. 137 (5): 1244–52. PMID 17449588.
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^ Jump up to:a b González-Segovia R, Quintanar JL, Salinas E, Ceballos-Salazar R, Aviles-Jiménez F, Torres-López J (2008). "Effect of the flavonoid quercetin on inflammation and lipid peroxidation induced by Helicobacter pylori in gastric mucosa of guinea pig". Journal of Gastroenterology. 43(6): 441–447. PMID 18600388. doi:10.1007/s00535-008-2184-7.
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Further reading[edit]
Andersen, Ø.M. / Markham, K.R. (2006). Flavonoids: Chemistry, Biochemistry and Applications. CRC Press. ISBN 978-0-8493-2021-7
Grotewold, Erich (2007). The Science of Flavonoids. Springer. ISBN 978-0-387-74550-3
Comparative Biochemistry of the Flavonoids, by J.B. Harborne, 1967 (Google Books)
The systematic identification of flavonoids, by T.J. Mabry, K.R. Markham and M.B. Thomas, 1970, doi:10.1016/0022-2860(71)87109-0
External links[edit]
Micronutrient Information Center – Flavonoids, Linus Pauling Institute, Oregon State University, Corvallis, 2015
Databases[edit]
USDA Database for the Flavonoid Content of Selected Foods, Release 3.1 (December 2013); data for 506 foods in the 5 subclasses of flavonoids provided in a separate PDF updated May 2014

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182
6948891480
alsfakia@gmail.com
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Wed Jun 21, 2017 21:15
  Immature human DCs efficiently translocate endocytosed antigens into the cytosol for proteasomal processing
updated on Thu Jun 22, 2017 01:41 by Alexandros G. Sfakianakis via Allergy Rhinology Immunology Asthma
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Publication date: August 2017
Source:Molecular Immunology, Volume 88
Author(s): Renato B. Baleeiro, Peter Walden
Cross-presentation of endocytosed antigen is essential for induction of CD8 effector T cell responses and a hallmark of dendritic cells (DCs). The mode of antigen processing in this context is controversial and some models imply translocation of the antigen from the endosomes into the cytosol. To test this hypothesis we made use of the pro-apoptotic properties of cytochrome c when in the cytosol, and confirmed that it indeed triggered apoptosis of human immature DCs but only at high concentrations. Proteasome inhibitors reduced the required concentration of cytochrome c thousand-fold, indicating that protein translocated into the cytosol is rapidly degraded by proteasomes. Mature DCs were also susceptible to cytochrome c-triggered apoptosis at high concentrations but proteasome inhibitors did not increase their sensitivity. Other cross-presenting cells such as B cells and monocytes were not sensitive to cytochrome c at all, indicating that they do not shuttle internalized antigen into the cytosol. Thus, processing of internalized antigens seems to follow different pathways depending on cell type and, in case of DCs, maturation state. Immature DCs appear to have a unique capacity to shuttle external antigen into the cytosol for proteasomal processing, which could explain their efficiency in antigen cross-presentation.



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Wed Jun 21, 2017 21:15
  Hypoxia-induced ADAM 17 expression is mediated by RSK1-dependent C/EBPβ activation in human lung fibroblasts
updated on Thu Jun 22, 2017 01:41 by Alexandros G. Sfakianakis via Allergy Rhinology Immunology Asthma
Publication date: August 2017
Source:Molecular Immunology, Volume 88
Author(s): Jing-Yun Chen, Chien-Huang Lin, Bing-Chang Chen
Hypoxia was identified as a mediator of lung fibrosis in patients with chronic obstructive asthma (COA). Overexpression of a disintegrin and metalloproteinase 17 (ADAM 17) and connective tissue growth factor (CTGF) leads to development of tissue fibrosis. However, the signaling pathway in hypoxia-induced ADAM 17 expression remains poorly defined. In this study, we investigated the roles that ribosomal S-6 kinase 1 (RSK1)/CCAAT/enhancer-binding protein β (C/EBPβ)-dependent ADAM 17 expression plays in hypoxia-induced CTGF expression in human lung fibroblasts. We observed that hypoxia caused increases in ADAM 17 expression and ADAM 17-luciferase activity in WI-38 cells. Hypoxia-induced CTGF-luciferase activity and CTGF expression were reduced in cells transfected with small interfering (si)RNA of ADAM 17 in WI-38 cells. Moreover, hypoxia-induced ADAM 17 expression was reduced by RSK1 siRNA and C/EBPβ siRNA. Hypoxia caused time-dependent increases in RSK1 phosphorylation at Thr359/Ser363. Exposure of cells to hypoxia resulted in increased C/EBPβ phosphorylation at Thr266 and C/EBPβ-luciferase activity in time-dependent manners, and these effects were suppressed by RSK1 siRNA. Hypoxia induced recruitment of C/EBPβ to the ADAM 17 promoter. Furthermore, CTGF-luciferase activity induced by hypoxia was attenuated by RSK1 siRNA and C/EBPβ siRNA. These results suggest that hypoxia instigates the RSK1-dependent C/EBPβ signaling pathway, which in turn initiates binding of C/EBPβ to the ADAM 17 promoter and ultimately induces ADAM 17 expression in human lung fibroblasts. Moreover, RSK1/C/EBPβ-dependent ADAM 17 expression is involved in hypoxia-induced CTGF expression. Our results suggest possible therapeutic approaches for treating hypoxia-mediated lung fibrosis in COA.

Graphical abstract
image



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Wed Jun 21, 2017 19:10
  Rheumatoid arthritis: from basic findings and clinical manifestations to future therapies
updated on Thu Jun 22, 2017 01:41 by Alexandros G. Sfakianakis via Allergy Rhinology Immunology Asthma
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Wed Jun 21, 2017 14:40
  LILRB receptor-mediated regulation of myeloid cell maturation and function
updated on Wed Jun 21, 2017 19:06 by Alexandros G. Sfakianakis via Allergy Rhinology Immunology Asthma
Abstract
The leukocyte immunoglobulin-like receptor (LILR) family comprises a set of paired immunomodulatory receptors expressed among human myeloid and lymphocyte cell populations. While six members of LILR subfamily A (LILRA) associate with membrane adaptors to signal via immunoreceptor tyrosine-based activating motifs (ITAM), LILR subfamily B (LILRB) members signal via multiple cytoplasmic immunoreceptor tyrosine-based inhibitory motifs (ITIM). Ligand specificity of some LILR family members has been studied in detail, but new perspective into the immunoregulatory aspects of this receptor family in human myeloid cells has been limited. LILRB receptors and the murine ortholog, paired immunoglobulin-like receptor B (PIRB), have been shown to negatively regulate maturation pathways in myeloid cells including mast cells, neutrophils, dendritic cells, as well as B cells. Our laboratory further demonstrated in mouse models that PIRB regulated functional development of myeloid-derived suppressor cell and the formation of a tumor-permissive microenvironment. Based on observations from the literature and our own studies, our laboratory is focusing on how LILRs modulate immune homeostasis of human myeloid cells and how these pathways may be targeted in disease states. Integrity of this pathway in tumor microenvironments, for example, permits a myeloid phenotype that suppresses antitumor adaptive immunity. This review presents the evidence supporting a role of LILRs as myeloid cell regulators and ongoing efforts to understand the functional immunology surrounding this family.



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Wed Jun 21, 2017 01:21
  Atopic dermatitis is associated with anxiety, depression, and suicidal ideation, but not with hospitalization or suicide
updated on Wed Jun 21, 2017 05:47 by Alexandros G. Sfakianakis via Allergy Rhinology Immunology Asthma
Abstract
Background
Atopic dermatitis (AD) has been linked with psychiatric disease in adults. However, the exact relationship and its consequences have been insufficiently studied. Our aim in this study was to assess the association between depression, anxiety and AD in adults, and examine the risk of hospitalization and suicide.

Methods
We utilized questionnaire data from a large general population study with data on social habits and psychiatric symptoms to compare prevalences of depression, anxiety, suicidal ideation, and anxiety attacks, in adults with and without a history of AD. Additionally we used nationwide hospital/clinic registry and prescription data to examine the risk of anxiety and depression in Danish adults with mild and moderate-severe AD, as well as the risk of hospitalization and suicide.

Results
In the general population study, those with AD reported clinician-diagnosed depression and anxiety more often than non-AD subjects, and had an increased prevalence of suicidal ideation and depressive symptoms. In the health registry study, moderate-severe AD patients had increased risk of antidepressant and anxiolytic medication use, while patients with mild AD only had increased risk of anxiolytic medication use. There was no increased risk of hospitalization or outpatient contacts due to depression or anxiety, or risk of suicide in AD patients.

Conclusions
Depression, anxiety, and suicidal ideation are more common among AD individuals, but do not to lead to psychiatric consultations, hospitalization, or suicide.

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Tue Jun 20, 2017 21:55
  A prospective microbiome-wide association study of food sensitization and food allergy in early childhood
updated on Wed Jun 21, 2017 05:47 by Alexandros G. Sfakianakis via Allergy Rhinology Immunology Asthma
Abstract
Background
Alterations in the intestinal microbiome are prospectively associated with the development of asthma; less is known regarding the role of microbiome alterations in food allergy development.

Methods
Intestinal microbiome samples were collected at age 3-6 months in children participating in the follow-up phase of an interventional trial of high dose Vitamin D given during pregnancy. At age 3, sensitization to foods (milk, egg, peanut, soy, wheat, walnut) was assessed. Food allergy was defined as caretaker report of healthcare provider-diagnosed allergy to the above foods prior to age 3 with evidence of IgE sensitization. Analysis was performed using Phyloseq and DESeq2; p-values were adjusted for multiple comparisons.

Results
Complete data were available for 225 children; there were 87 cases of food sensitization and 14 cases of food allergy. Microbial diversity measures did not differ between food sensitization and food allergy cases and controls. The genera Haemophilus (log2 fold change -2.15, p=0.003), Dialister (log2 fold change -2.22, p=0.009), Dorea (log2 fold change -1.65, p=0.02) and Clostridium (log2 fold change -1.47, p=0.002) were underrepresented among subjects with food sensitization. The genera Citrobacter (log2 fold change -3.41, p=0.03), Oscillospira (log2 fold change -2.80, p=0.03), Lactococcus (log2 fold change -3.19, p=0.05) and Dorea (log2 fold change -3.00, p=0.05) were underrepresented among subjects with food allergy.

Conclusions
The temporal association between bacterial colonization and food sensitization and allergy suggests that the microbiome may have a causal role in the development of food allergy. Our findings have therapeutic implications for the prevention and treatment of food allergy.

This article is protected by copyright. All rights reserved.



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Tue Jun 20, 2017 21:10
  Effect of C1-INH on ischemia/reperfusion injury in a porcine limb ex vivo perfusion model
updated on Wed Jun 21, 2017 05:47 by Alexandros G. Sfakianakis via Allergy Rhinology Immunology Asthma
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Publication date: August 2017
Source:Molecular Immunology, Volume 88
Author(s): Mai M. Abdelhafez, Jane Shaw, Damian Sutter, Jonas Schnider, Yara Banz, Hansjörg Jenni, Esther Voegelin, Mihai A. Constantinescu, Robert Rieben
Revascularization of an amputated limb within 4–6h is essential to avoid extensive ischemia/reperfusion (I/R) injury leading to vascular leakage, edema and tissue necrosis. I/R injury is a pathological inflammatory condition that occurs during reperfusion of an organ or tissue after prolonged ischemia. It is characterized by a complex crosstalk between endothelial cell activation and the activation of plasma cascades. Vasculoprotective pharmacological intervention to prevent I/R injury might be an option to prolong the time window between limb amputation and successful replantation. We used C1-easterase inhibitor (C1-INH) in this study because of its known inhibitory effects on the activation of the complement, coagulation and kinin cascades. Forelimbs of 8 large white pigs were amputated, subjected to ischemia, and then reperfused with autologous whole blood. All limbs were exposed to 9h of cold ischemia at 4°C. After 2h of cold ischemia the limbs were either perfused with of C1-INH (1U/ml in hydroxyethyl starch, n=8) or hydroxyethyl starch alone (n=7). After completion of the 9-h ischemia period, all limbs were ex vivo perfused with heparinized autologous whole blood for 12h using a pediatric heart lung machine to simulate in vivo revascularization. Our results show that I/R injury in the control group led to a significant elevation of tissue deposition of IgG and IgM, complement C3b/c, C5b-9 and MBL. Also, activation of the kinin system was significantly increased, namely bradykinin in plasma, and expression of bradykinin receptors 1 and 2 in tissue. In addition, markers for endothelial integrity like expression of CD31, VE-cadherin and heparan sulfate proteoglycans were decreased in reperfused tissue. Limb I/R injury also led to activation of the coagulation cascade with a significant elevation of fibrin and thrombin deposition and increased fibrinogen-like protein-2 expression. C1-INH treated limbs showed much less activation of plasma cascades and better protection of endothelial integrity compared to the reperfused control limbs. In conclusion, the use of the cytoprotective drug C1-INH significantly reduced I/R injury by protecting the vascular endothelium as well as the muscle tissue from deposition of immunoglobulins, complement and fibrin.



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Tue Jun 20, 2017 21:10
  RAG2 involves the Igκ locus demethylation during B cell development
updated on Wed Jun 21, 2017 05:47 by Alexandros G. Sfakianakis via Allergy Rhinology Immunology Asthma
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Publication date: August 2017
Source:Molecular Immunology, Volume 88
Author(s): Caijun Wu, Yanying Dong, Xiaohui Zhao, Ping Zhang, Mingzhe Zheng, Hua Zhang, Shichang Li, Yaofeng Jin, Yunfeng Ma, Huixun Ren, Yanhong Ji
The genes encoding the immunoglobulin κ light chain are assembled during B cell development by V(D)J recombination. For efficient rearrangement, the Igκ locus must undergo a series of epigenetic changes. One such epigenetic mark is DNA methylation. The mechanism that the Igκ locus is selectively demethylated at the pre-B cell stage has not previously been characterized. Here, we employed bisulfite DNA-modification assays to analyze the methylation status of the Igκ locus in primary pre-B cells from RAG-deficient mice with pre-rearranged Igh knock-in allele. We observed that the Igκ locus was hypermethylated in RAG2-deficient pre-B cells but hypomethylated in RAG1-deficient pre-B cells, indicating that wild-type (WT) RAG2 involves the Igκ locus demethylation in a RAG1-independent manner prior to rearrangement. We generated a series of RAG2 mutants between residue 350 and 383. We showed that these mutants mediated the Igκ rearrangement but failed to regulate the Igκ gene demethylation. We further analyzed that these mutants could increase RAG recombinase activity in vivo. We conclude that residues 350–383 region are responsible for endogenous Igκ locus demethylation at pre-B cells. We propose that WT RAG2 has an intrinsic function to regulate the Igκ locus demethylation.



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Tue Jun 20, 2017 21:10
  Advantages of targeting B cell receptor complex to treat B-cell derived autoimmune diseases and lymphomas
updated on Wed Jun 21, 2017 05:47 by Alexandros G. Sfakianakis via Allergy Rhinology Immunology Asthma
Publication date: August 2017
Source:Molecular Immunology, Volume 88
Author(s): Jemal Adem, Mine Eray, Jonna Eeva, Ulla Nuutinen, Jukka Pelkonen
Antibodies produced by B-cells provide protection from infectious agents. However, impaired cell death signaling pathways in B-cells can lead to cancer, immunodeficiency or autoimmune diseases. B-cell signaling molecules such as CD20, CD19, Btk, and BAFF-R are targeted by therapeutic drugs and used to treat B-cell derived lymphomas or autoimmune diseases. Nevertheless, B-cells could develop resistance to these therapeutic drugs or the therapeutic drugs may have off-target effects. For instance, repeated rituximab (anti-CD20 antibody) treatment may lead to the loss of its target cell surface molecule, CD20. In addition, in B-cell malignancies, loss of CD19 expression has been observed. Another target molecule, Btk is expressed not only in B-cells but also in mast cells, macrophages, and dendritic cells. Thus, targeting Btk could negatively regulate the functions of innate immunity. The expression of BAFF-R is thought to be restricted to B-cells but it is also expressed on T-cells. Targeting BAFF-R, therefore, may lead to depletion of T-cells in addition to B-cells. B cell receptor (BCR) expression and signaling, however, are critically important for development, differentiation and survival of B-cells. Moreover, BCR is exclusively expressed on B-cells, which makes it an excellent target to avoid off-target effects.



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Tue Jun 20, 2017 21:10
  IL-18/IL-15/IL-12 synergy induces elevated and prolonged IFN-γ production by ex vivo expanded NK cells which is not due to enhanced STAT4 activation
updated on Wed Jun 21, 2017 05:47 by Alexandros G. Sfakianakis via Allergy Rhinology Immunology Asthma
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Publication date: August 2017
Source:Molecular Immunology, Volume 88
Author(s): Evan Lusty, Sophie M. Poznanski, Karen Kwofie, Talveer S. Mandur, Dean A. Lee, Carl D. Richards, Ali A. Ashkar
The synergistic effect of IL-18/IL-15/IL-12 stimulation potently activates NK cells, inducing high levels of IFN-γ production. As a result of this potent stimulatory effect, NK cell pre-activation with IL-18/IL-15/IL-12 is being developed as a cancer immunotherapy. Ex vivo expansion of NK cells enables the efficient generation of large numbers of NK cells for wide-scale and repeated therapeutic use, and is thus an important source of NK cells for clinical application. However, the effects of IL-18/IL-15/IL-12 stimulation on ex vivo expanded NK cells have not yet been assessed. Thus, the present study assessed the effects of IL-18/IL-15/IL-12 stimulation on NK cells expanded ex vivo using K562-based artificial antigen presenting cells expressing membrane-bound IL-21. We report that ex vivo expanded NK cells stimulated with IL-18/IL-15/IL-12 produce high levels of IFN-γ and TNFα, have potent cytotoxicity, and maintain prolonged IFN-γ production following removal of stimulation. IL-18/IL-15/IL-12 stimulation induces a phenotypically unique IFN-γ-producing population with reduced CD16 expression and greater CD25 expression as compared to stimulated IFN-γ- NK cells and unstimulated NK cells. We elucidate that the mechanism of synergy for induction and maintenance of IFN-γ production is not due to a further enhancement of STAT4 activation compared to stimulation with IL-12 alone. Furthermore, we demonstrate that the synergistic increase in IFN-γ is not solely under translational regulation, as elevated levels of IFN-γ mRNA contribute to the synergistic increase in IFN-γ. Overall, this study characterizes the response of ex vivo expanded NK cells to IL-18/IL-15/IL-12 stimulation and supports the use of ex vivo expanded NK cells as a feasible and efficient source of IL-18/IL-15/IL-12 pre-activated NK cells for adoptive transfer in cancer immunotherapies.



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Tue Jun 20, 2017 20:49
  Critical biological parameters modulate affinity as a determinant of function in T-cell receptor gene-modified T-cells
updated on Wed Jun 21, 2017 05:47 by Alexandros G. Sfakianakis via Allergy Rhinology Immunology Asthma
Abstract
T-cell receptor (TCR)-pMHC affinity has been generally accepted to be the most important factor dictating antigen recognition in gene-modified T-cells. As such, there is great interest in optimizing TCR-based immunotherapies by enhancing TCR affinity to augment the therapeutic benefit of TCR gene-modified T-cells in cancer patients. However, recent clinical trials using affinity-enhanced TCRs in adoptive cell transfer (ACT) have observed unintended and serious adverse events, including death, attributed to unpredicted off-tumor or off-target cross-reactivity. It is critical to re-evaluate the importance of other biophysical, structural, or cellular factors that drive the reactivity of TCR gene-modified T-cells. Using a model for altered antigen recognition, we determined how TCR–pMHC affinity influenced the reactivity of hepatitis C virus (HCV) TCR gene-modified T-cells against a panel of naturally occurring HCV peptides and HCV-expressing tumor targets. The impact of other factors, such as TCR–pMHC stabilization and signaling contributions by the CD8 co-receptor, as well as antigen and TCR density were also evaluated. We found that changes in TCR–pMHC affinity did not always predict or dictate IFNγ release or degranulation by TCR gene-modified T-cells, suggesting that less emphasis might need to be placed on TCR–pMHC affinity as a means of predicting or augmenting the therapeutic potential of TCR gene-modified T-cells used in ACT. A more complete understanding of antigen recognition by gene-modified T-cells and a more rational approach to improve the design and implementation of novel TCR-based immunotherapies is necessary to enhance efficacy and maximize safety in patients.



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Tue Jun 20, 2017 13:59
  Primary Prevention of Food Allergy
updated on Tue Jun 20, 2017 18:24 by Alexandros G. Sfakianakis via Allergy Rhinology Immunology Asthma
Abstract
Purpose of Review
This article summarises recent developments on the prevention of food allergy in terms of the 5 D's of the development of food allergy: dry skin, diet, dogs, dribble, and vitamin D.

Recent Findings
While several advances have improved our understanding of the development of food allergy, few preventive strategies have been implemented beyond changes in infant feeding guidelines. These now state that the introduction of allergenic solids such as peanuts should occur in the first year of life.

Summary
Results from randomised controlled trials on other allergenic solids, vitamin D supplementation, BCG immunisation at birth and eczema prevention are eagerly anticipated in order to inform further preventative strategies.



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Tue Jun 20, 2017 13:59
  Review of Physical Urticarias and Testing Methods
updated on Tue Jun 20, 2017 18:24 by Alexandros G. Sfakianakis via Allergy Rhinology Immunology Asthma
Abstract
Purpose of Review
This review aims to update the information available on the prevalence, clinical picture, diagnostic methods, and treatment of urticarias induced by external physical stimuli.

Recent Findings
Physical urticarias are present in up to 5% of the general population, and in 10 to 50% of patients with chronic urticaria. Recent investigations have provided evidence that the presence of physical urticaria alone or when comorbid with chronic spontaneous urticaria is associated with a worse prognosis and duration.

Summary
Most frequent subtypes of physical urticaria are dermographism and delayed pressure urticaria. The diagnosis is established through specific provocation tests and the management encompasses avoidance measures, pharmacologic therapy with nonsedating antihistamines, and alternative medications in refractory cases.



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Tue Jun 20, 2017 13:59
  Role of Obesity in Asthma: Mechanisms and Management Strategies
updated on Tue Jun 20, 2017 18:24 by Alexandros G. Sfakianakis via Allergy Rhinology Immunology Asthma
Abstract
Purpose of Review
Obesity is a commonly reported comorbidity in asthma, particularly in severe asthma. Obese asthmatics are highly symptomatic with a poor quality of life, despite using high-dose inhaled corticosteroids. While the clinical manifestations have been documented, the aetiologies of obese-asthma remain unclear.

Recent Findings
Several potential mechanisms have been proposed, including poor diet quality, physical inactivity and consequent accrual of excess adipose tissue. Each of these factors independently activates inflammatory pathways, potentially exerting effects in the airways. Because the origins of obesity are multifactorial, it is now believed there are multiple obese-asthma phenotypes, with varied aetiologies and clinical consequences.

Summary
In this review, we will describe the clinical implications of obesity in people with asthma, our current understanding of the mechanisms driving this association and describe recently proposed obese-asthma phenotypes. We will then discuss how asthma management is complicated by obesity, and provide graded recommendations for the management of obesity in this population.



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Tue Jun 20, 2017 13:59
  Accumulated evidence on Helicobacter pylori infection and the risk of asthma
updated on Tue Jun 20, 2017 18:24 by Alexandros G. Sfakianakis via Allergy Rhinology Immunology Asthma
Publication date: Available online 19 June 2017
Source:Annals of Allergy, Asthma & Immunology
Author(s): Cheng Chen, Pengcheng Xun, Cari Tsinovoi, Ka He
BackgroundHelicobacter pylori (H pylori) infection has been suggested to be related to a decreased risk of asthma, but findings in the literature are inconsistent.ObjectiveTo quantitatively summarize the existing evidence on the association between H pylori infection and asthma risk.MethodsThe PubMed database was searched for observational studies of H pylori infection in relation to the risk of asthma published in English through May 2017. Measurements of association were pooled using a meta-analytic approach and expressed as odds ratios (ORs) with 95% confidence intervals (95% CIs).ResultsTwenty-four studies were identified in this meta-analysis, including 8 case-control studies composed of 1,247 cases and 2,410 controls, and 16 cross-sectional studies composed of 50,290 participants (4,185 cases and 46,105 noncases). The average H pylori infection rates were 40.01% and 48.74% in case-control and cross-sectional studies, respectively. Five studies subcategorized H pylori infection according to CagA status, in which 59.37% of H pylori–infected participants were identified as having CagA positivity. Helicobacter pylori infection was significantly inversely associated with the risk of asthma in case-control studies (OR 0.83, 95% CI 0.71–0.98) but was borderline significant in cross-sectional studies (OR 0.88, 95% CI 0.76–1.02). The observed inverse association persisted for CagA-positive H pylori infection (OR 0.77, 95% CI 0.63–0.93, P for interaction = .03) but not for CagA-negative strains (OR 1.08, 95% CI 0.66–1.78). No significant difference was observed across age or region subgroups.ConclusionThe accumulated evidence supports that H pylori infection, especially CagA-positive H pylori infection, is inversely associated with the risk of asthma.



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Tue Jun 20, 2017 13:59
  Distribution, subtype population, and IgE positivity of mast cells in chronic rhinosinusitis with nasal polyps
updated on Tue Jun 20, 2017 18:24 by Alexandros G. Sfakianakis via Allergy Rhinology Immunology Asthma
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Publication date: Available online 19 June 2017
Source:Annals of Allergy, Asthma & Immunology
Author(s): Shintaro Baba, Kenji Kondo, Maho Suzukawa, Ken Ohta, Tatsuya Yamasoba
BackgroundChronic rhinosinusitis with nasal polyps (CRSwNP) has been categorized into 2 subtypes in the Asian population: eosinophilic chronic rhinosinusitis (ECRS; similar to CRSwNP in Western countries) and non-ECRS (characterized by inflammation dominated by T-helper cell type 1). The pathogenesis of CRSwNP and the role of mast cells are poorly understood.ObjectiveTo investigate the distribution, phenotypes, and immunoglobulin E (IgE) positivity of mast cells in these 2 subtypes of CRSwNP.MethodsWe collected nasal tissue from patients with CRSwNP and control subjects. The mRNA for mast cell proteases tryptase and chymase was measured using real-time polymerase chain reaction, and the distribution of each type of protease-positive mast cell was examined using immunohistochemistry and immunofluorescence. IgE distribution on mast cells was determined using double-immunofluorescent staining for IgE and tryptase.ResultsExpression of tryptase mRNA was significantly increased in nasal polyps from patients with the 2 subtypes of CRSwNP compared with controls. Immunohistochemistry showed increased numbers of tryptase-positive mast cells in the epithelium, glands, and submucosa of ECRS polyps, whereas the number of tryptase- and chymase-positive mast cells was increased in the glands and submucosa of non-ECRS polyps. IgE-positive mast cells were abundant in the epithelial, glandular, and submucosal regions of ECRS polyps but few were detected in non-ECRS polyps.ConclusionThe present study demonstrates that the distribution, subtype population, and IgE positivity of mast cells is different between ECRS and non-ECRS nasal polyps. Our results suggest a role for IgE-mediated mast cell activation in the pathogenesis of ECRS.



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Tue Jun 20, 2017 13:59
  Mycoplasma pneumoniae and health outcomes in children with asthma
updated on Tue Jun 20, 2017 18:24 by Alexandros G. Sfakianakis via Allergy Rhinology Immunology Asthma
S10811206.gif

Publication date: Available online 19 June 2017
Source:Annals of Allergy, Asthma & Immunology
Author(s): Pamela R. Wood, Jordan C. Kampschmidt, Peter H. Dube, Marianna P. Cagle, Paola Chaparro, Norma S. Ketchum, Thirumalai R. Kannan, Harjinder Singh, Jay I. Peters, Joel B. Baseman, Edward G. Brooks
BackgroundAcute infections with Mycoplasma pneumoniae (Mp) have been associated with worsening asthma in children. Mp can be present in the respiratory tract for extended periods; it is unknown whether the long-term persistence of Mp in the respiratory tract affects long-term asthma control.ObjectiveTo determine the effect of Mp on asthma control.MethodsWe enrolled 31 pediatric subjects 3 to 10 years of age with persistent asthma who completed up to 8 visits over a 24-month period. We detected Mp by antigen capture and polymerase chain reaction. Primary outcome measurements included symptom scores, quality of life, medication scores, oral corticosteroid use, health care usage, school absences, and exhaled breath condensate pH.ResultsLow levels of Mp community-acquired respiratory distress syndrome toxin were detected in 20 subjects (64.5%) at enrollment. Subjects with Mp positivity at a given visit had a .579 probability of remaining Mp positive at the subsequent visit, whereas those with Mp negativity had a .348 probability of becoming Mp positive at the following visit. The incidence of Mp overall was higher in the spring and summer months. Overall, we found no significant relation between the detection of Mp and worse outcome measurements at the same visit or at subsequent visits.ConclusionThe long-term persistence of Mp in the respiratory tract is common in children with asthma. However, the detection of Mp was not associated significantly with worse asthma symptoms, quality of life, health care usage, school absences, or exhaled breath condensate pH in this pediatric asthma cohort.



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Tue Jun 20, 2017 13:59
  Economic evaluation of epinephrine auto-injectors for peanut allergy
updated on Tue Jun 20, 2017 18:24 by Alexandros G. Sfakianakis via Allergy Rhinology Immunology Asthma
Publication date: Available online 19 June 2017
Source:Annals of Allergy, Asthma & Immunology
Author(s): Marcus Shaker, Katherine Bean, Marylee Verdi
BackgroundThree commercial epinephrine auto-injectors were available in the United States in the summer of 2016: EpiPen, Adrenaclick, and epinephrine injection, USP auto-injector.ObjectiveTo describe the variation in pharmacy costs among epinephrine auto-injector devices in New England and evaluate the additional expense associated with incremental auto-injector costs.MethodsDecision analysis software was used to evaluate costs of the most and least expensive epinephrine auto-injector devices for children with peanut allergy. To evaluate regional variation in epinephrine auto-injector costs, a random sample of New England national and corporate pharmacies was compared with a convenience sample of pharmacies from 10 Canadian provinces.ResultsAssuming prescriptions written for 2 double epinephrine packs each year (home and school), the mean costs of food allergy over the 20-year model horizon totaled $58,667 (95% confidence interval [CI] $57,745–$59,588) when EpiPen was prescribed and $45,588 (95% CI $44,873–$46,304) when epinephrine injection, USP auto-injector was prescribed. No effectiveness differences were evident between groups, with 17.19 (95% CI 17.11–17.27) quality-adjusted life years accruing for each subject. The incremental cost per episode of anaphylaxis treated with epinephrine over the model horizon was $12,576 for EpiPen vs epinephrine injection, USP auto-injector. EpiPen costs were lowest at Canadian pharmacies ($96, 95% CI $85–$107). There was price consistency between corporate and independent pharmacies throughout New England by device brand, with the epinephrine injection, USP auto-injector being the most affordable device.ConclusionCost differences among epinephrine auto-injectors were significant. More expensive auto-injector brands did not appear to provide incremental benefit.



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Tue Jun 20, 2017 12:59
  Autoimmune diabetes induced by PD-1 inhibitor—retrospective analysis and pathogenesis: a case report and literature review
updated on Tue Jun 20, 2017 18:24 by Alexandros G. Sfakianakis via Allergy Rhinology Immunology Asthma
Abstract
Anti-PD-1 antibody treatment is approved in advanced melanoma and provides median overall survival over 24 months. The main treatment-related side effects are immune-related adverse events, which include rash, pruritus, vitiligo, thyroiditis, diarrhoea, hepatitis and pneumonitis. We report a case of autoimmune diabetes related to nivolumab treatment. A 73-year-old man was treated in second line with nivolumab at 3 mg/kg every two weeks for metastatic melanoma. At 6 weeks of treatment, he displayed diabetic ketoacidosis. Nivolumab was withheld 3.5 weeks and insulin therapy was initiated, enabling a normalization of glycaemia and the disappearance of symptoms. Laboratory investigations demonstrated the presence of islet cell autoantibodies, while C-peptide was undetectable. Retrospective explorations on serum banked at week 0 and 3 months before the start of nivolumab, already showed the presence of autoantibodies, but normal insulin, C-peptide secretion and glycaemia. Partial response was obtained at month 3, and nivolumab was then resumed at the same dose. The clinical context and biological investigations before, at and after nivolumab initiation suggest the autoimmune origin of this diabetes, most likely induced by anti-PD-1 antibody in a predisposed patient. The role of PD-1/PD-L1 binding is well known in the pathogenesis of type 1 diabetes. Therefore, this rare side effect can be expected in a context of anti-PD-1 treatment. Glycaemia should be monitored during PD-1/PD-L1 blockade. The presence of autoantibodies before treatment could identify individuals at risk of developing diabetes, but systematic titration may not be relevant considering the rarity of this side effect.



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Tue Jun 20, 2017 08:28
  The absence of CD56 expression can differentiate papillary thyroid carcinoma from other thyroid lesions
updated on Tue Jun 20, 2017 12:54 by Alexandros G. Sfakianakis via Allergy Rhinology Immunology Asthma
http://orlhealth.blogspot.com/2017/06/the-absence-of-cd56-expression-can.html

The neural cell adhesion molecule CD56 is an antigen important for the differentiation of the follicular epithelium. Recent studies have reported low or absent expression of CD56 in papillary thyroid carcinoma (PTC) and its presence in normal thyroid tissue, benign thyroid lesions, and most follicular non-PTC tumors. Aim: We wish to estimate the value of CD56 in the differentiation of PTC (including follicular variant-PTC [FV-PTC]) from other nontumoral lesions and follicular thyroid neoplasias. Settings and Design: This was a retrospective, case–control study. Subjects and Methods: We analyzed the expression of CD56 in normal thyroid follicular tissue, 15 nonneoplastic thyroid lesions (nodular hyperplasia, Graves' disease, and chronic lymphocytic thyroiditis/Hashimoto), and 38 thyroid follicular cell neoplasms (25 cases of PTC). The immunohistochemical reactions were performed on sections stained with anti-CD56 antibody. Statistical Analysis Used: We used the Chi-square test, values of P< 0.05 being considered statistically significant. Risk analysis was applied on these studied groups, by calculating the odds ratio (OR) value. Results: Our results indicated that CD56 immunoexpression had differentiated PTC from benign nonneoplastic lesions (P = 0.002), as well as from follicular neoplasias (P = 0.046). There were no significant differences regarding CD56 expression between FV-PTC and classical PTC (P = 0.436). The immunoexpression of CD56 has differentiated PTC from other thyroid non-PTC lesions (P < 0.001), with 26.4 OR value. Conclusions: CD56 has been proved to be a useful marker in the diagnosis of PTC, including FV-PTC. Its absence can help differentiate FV-PTC from other thyroid nodules with follicular patterns.

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182
6948891480
alsfakia@gmail.com
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Tue Jun 20, 2017 00:30
  TLR-Induced Murine Dendritic Cell (DC) Activation Requires DC-Intrinsic Complement [INNATE IMMUNITY AND INFLAMMATION]
updated on Tue Jun 20, 2017 04:55 by Alexandros G. Sfakianakis via Allergy Rhinology Immunology Asthma
Induction of proinflammatory T cell immunity is augmented by innate dendritic cell (DC) maturation commonly initiated by TLR signaling. We demonstrate that ligation of TLR3, TLR4, and TLR9 induces murine DC production of complement components and local production of the anaphylatoxin C5a. In vitro, ex vivo, and in vivo analyses show that TLR-induced DC maturation, as assessed by surface phenotype, expression profiling by gene array, and functional ability to stimulate T cell responses, requires autocrine C3a receptor and C5a receptor (C3ar1/C5ar1) signaling. Studies using bone marrow chimeric animals and Foxp3-GFP/ERT2-Cre/dTomato fate-mapping mice show that TLR-initiated DC autocrine C3ar1/C5ar1 signaling causes expansion of effector T cells and instability of regulatory T cells and contributes to T cell–dependent transplant rejection. Together, our data position immune cell–derived complement production and autocrine/paracrine C3ar1/C5ar1 signaling as crucial intermediary processes that link TLR stimulation to DC maturation and the subsequent development of effector T cell responses.



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Tue Jun 20, 2017 00:30
  Enhanced Effector Functions Due to Antibody Defucosylation Depend on the Effector Cell Fc{gamma} Receptor Profile [IMMUNOTHERAPY AND VACCINES]
updated on Tue Jun 20, 2017 04:55 by Alexandros G. Sfakianakis via Allergy Rhinology Immunology Asthma
Abs of the IgG isotype are glycosylated in their Fc domain at a conserved asparagine at position 297. Removal of the core fucose of this glycan greatly increases the affinity for FcRIII, resulting in enhanced FcRIII-mediated effector functions. Normal plasma IgG contains ~94% fucosylated Abs, but alloantibodies against, for example, Rhesus D (RhD) and platelet Ags frequently have reduced fucosylation that enhances their pathogenicity. The increased FcRIII-mediated effector functions have been put to use in various afucosylated therapeutic Abs in anticancer treatment. To test the functional consequences of Ab fucosylation, we produced V-gene–matched recombinant anti-RhD IgG Abs of the four different subclasses (IgG1–4) with and without core fucose (i.e., 20% fucose remaining). Binding to all human FcR types and their functional isoforms was assessed with surface plasmon resonance. All hypofucosylated anti-RhD IgGs of all IgG subclasses indeed showed enhanced binding affinity for isolated FcRIII isoforms, without affecting binding affinity to other FcRs. In contrast, when testing hypofucosylated anti-RhD Abs with FcRIIIa-expressing NK cells, a 12- and 7-fold increased erythrocyte lysis was observed with the IgG1 and IgG3, respectively, but no increase with IgG2 and IgG4 anti-RhD Abs. Notably, none of the hypofucosylated IgGs enhanced effector function of macrophages, which, in contrast to NK cells, express a complex set of FcRs, including FcRIIIa. Our data suggest that the beneficial effects of afucosylated biologicals for clinical use can be particularly anticipated when there is a substantial involvement of FcRIIIa-expressing cells, such as NK cells.



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Tue Jun 20, 2017 00:30
  Access Guide to Antigen Receptor Genes [PILLARS OF IMMUNOLOGY]
updated on Tue Jun 20, 2017 04:55 by Alexandros G. Sfakianakis via Allergy Rhinology Immunology Asthma
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Tue Jun 20, 2017 00:30
  In This Issue [IN THIS ISSUE]
updated on Tue Jun 20, 2017 04:55 by Alexandros G. Sfakianakis via Allergy Rhinology Immunology Asthma
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Tue Jun 20, 2017 00:30
  Pillars Article: A Role for Histone Acetylation in the Developmental Regulation of V(D)J Recombination. Science. 2000. 287: 495-498 [PILLARS OF IMMUNOLOGY]
updated on Tue Jun 20, 2017 04:55 by Alexandros G. Sfakianakis via Allergy Rhinology Immunology Asthma
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Tue Jun 20, 2017 00:30
  T Follicular Helper Cell-Derived IL-4 Is Required for IgE Production during Intestinal Helminth Infection [INFECTIOUS DISEASE AND HOST RESPONSE]
updated on Tue Jun 20, 2017 04:55 by Alexandros G. Sfakianakis via Allergy Rhinology Immunology Asthma
IgE production plays a crucial role in protective as well as pathogenic type 2 immune responses. Although the cytokine IL-4 is required for the development of IgE-producing plasma cells, the source of IL-4 and cellular requirements for optimal IgE responses remain unclear. Recent evidence suggests that T follicular helper (Tfh) cells are the primary producer of IL-4 in the reactive lymph node during type 2 immune responses. As Tfh cells are also required for the development of plasmablasts derived from germinal center and extrafollicular sources, we hypothesized that this cell subset is essential for the IgE plasmablast response. In this study, we show that during intestinal helminth infection, IL-4 derived from Tfh cells is required for IgE class switching and plasmablast formation. Notably, early IgE class switching did not require germinal center formation. Additionally, Tfh cell–derived IL-4 was required to maintain the Th2 response in the mesenteric lymph nodes of infected mice. Collectively, our results indicate that IL-4–producing Tfh cells are central orchestrators of the type 2 immune response in the reactive lymph nodes during parasitic helminth infection.



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Tue Jun 20, 2017 00:30
  Inducing Mucosal IgA: A Challenge for Vaccine Adjuvants and Delivery Systems [BRIEF REVIEWS]
updated on Tue Jun 20, 2017 04:55 by Alexandros G. Sfakianakis via Allergy Rhinology Immunology Asthma
Mucosal IgA or secretory IgA (SIgA) are structurally equipped to resist chemical degradation in the harsh environment of mucosal surfaces and enzymes of host or microbial origin. Production of SIgA is finely regulated, and distinct T-independent and T-dependent mechanisms orchestrate Ig α class switching and SIgA responses against commensal and pathogenic microbes. Most infectious pathogens enter the host via mucosal surfaces. To provide a first line of protection at these entry ports, vaccines are being developed to induce pathogen-specific SIgA in addition to systemic immunity achieved by injected vaccines. Mucosal or epicutaneous delivery of vaccines helps target the inductive sites for SIgA responses. The efficacy of such vaccines relies on the identification and/or engineering of vaccine adjuvants capable of supporting the development of SIgA alongside systemic immunity and delivery systems that improve vaccine delivery to the targeted anatomic sites and immune cells.



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Tue Jun 20, 2017 00:30
  Single-Cell RNA Sequencing Reveals Expanded Clones of Islet Antigen-Reactive CD4+ T Cells in Peripheral Blood of Subjects with Type 1 Diabetes [SYSTEMS IMMUNOLOGY]
updated on Tue Jun 20, 2017 04:55 by Alexandros G. Sfakianakis via Allergy Rhinology Immunology Asthma
The significance of islet Ag-reactive T cells found in peripheral blood of type 1 diabetes (T1D) subjects is unclear, partly because similar cells are also found in healthy control (HC) subjects. We hypothesized that key disease-associated cells would show evidence of prior Ag exposure, inferred from expanded TCR clonotypes, and essential phenotypic properties in their transcriptomes. To test this, we developed single-cell RNA sequencing procedures for identifying TCR clonotypes and transcript phenotypes in individual T cells. We applied these procedures to analysis of islet Ag-reactive CD4+ memory T cells from the blood of T1D and HC individuals after activation with pooled immunodominant islet peptides. We found extensive TCR clonotype sharing in Ag-activated cells, especially from individual T1D subjects, consistent with in vivo T cell expansion during disease progression. The expanded clonotype from one T1D subject was detected at repeat visits spanning >15 mo, demonstrating clonotype stability. Notably, we found no clonotype sharing between subjects, indicating a predominance of "private" TCR specificities. Expanded clones from two T1D subjects recognized distinct IGRP peptides, implicating this molecule as a trigger for CD4+ T cell expansion. Although overall transcript profiles of cells from HC and T1D subjects were similar, profiles from the most expanded clones were distinctive. Our findings demonstrate that islet Ag-reactive CD4+ memory T cells with unique Ag specificities and phenotypes are expanded during disease progression and can be detected by single-cell analysis of peripheral blood.



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Tue Jun 20, 2017 00:30
  Macrophage-Mediated Inflammation in Normal and Diabetic Wound Healing [BRIEF REVIEWS]
updated on Tue Jun 20, 2017 04:55 by Alexandros G. Sfakianakis via Allergy Rhinology Immunology Asthma
The healing of cutaneous wounds is dependent on the progression through distinct, yet overlapping phases of wound healing, including hemostasis, inflammation, proliferation, and resolution/remodeling. The failure of these phases to occur in a timely, progressive fashion promotes pathologic wound healing. The macrophage (M) has been demonstrated to play a critical role in the inflammatory phase of tissue repair, where its dynamic plasticity allows this cell to mediate both tissue-destructive and -reparative functions. The ability to understand and control both the initiation and the resolution of inflammation is critical for treating pathologic wound healing. There are now a host of studies demonstrating that metabolic and epigenetic regulation of gene transcription can influence M plasticity in wounds. In this review, we highlight the molecular and epigenetic factors that influence M polarization in both physiologic and pathologic wound healing, with particular attention to diabetic wounds.



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Tue Jun 20, 2017 00:30
  The Influence of MHC Class II on B Cell Defects Induced by Invariant Chain/CD74 N-Terminal Fragments [IMMUNE SYSTEM DEVELOPMENT]
updated on Tue Jun 20, 2017 04:55 by Alexandros G. Sfakianakis via Allergy Rhinology Immunology Asthma
The invariant chain (CD74) mediates assembly and targeting of MHC class II (MHCII) complexes. In endosomes, CD74 undergoes sequential degradation by different proteases, including cathepsin S (CatS) and the intramembrane protease signal peptide peptidase-like 2a (SPPL2a). In their absence, CD74 N-terminal fragments (NTFs) accumulate. In SPPL2a–/– B cells, such an NTF impairs endosomal trafficking and BCR signal transduction. In mice, this leads to a loss of splenic B cells beyond the transitional stage 1. To gain insight into CD74 determinants and the role of MHCII, we compared B cells from CatS–/–, SPPL2a–/–, and SPPL2a-MHCII double-deficient mice. We assessed differentiation of B cells in bone marrow and spleen and analyzed their endosomal morphology, BCR expression, and signal transduction. We demonstrate that MHCII is dispensable for the B cell phenotype of SPPL2a–/– mice, further supporting a CD74-intrinsic effect. Despite significant vacuolization of endosomal compartments similar to SPPL2a–/– B cells, CatS–/– traditional stage 1 B cells show unimpaired degradation of endocytic cargo, have intact BCR signaling, and do not exhibit any relevant defects in maturation. This could indicate that CD74 NTF–induced structural changes of endosomes are not directly involved in these processes. We further found that the block of CD74 degradation in CatS–/– B cells is incomplete, so that NTF levels are significantly lower than in SPPL2a–/– B cells. This suggests a dose dependency and threshold for the CD74 NTF–associated impairment of B cell signaling and maturation. In addition, different functional properties of the longer, MHCII-bound CD74 NTF could contribute to the milder phenotype of CatS–/– B cells.



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Tue Jun 20, 2017 00:30
  Cutting Edge: Origins, Recruitment, and Regulation of CD11c+ Cells in Inflamed Islets of Autoimmune Diabetes Mice [CUTTING EDGE]
updated on Tue Jun 20, 2017 04:55 by Alexandros G. Sfakianakis via Allergy Rhinology Immunology Asthma
In NOD mice, CD11c+ cells increase greatly with islet inflammation and contribute to autoimmune destruction of pancreatic β cells. In this study, we investigated their origin and mechanism of recruitment. CD11c+ cells in inflamed islets resembled classical dendritic cells based on their transcriptional profile. However, the majority of these cells were not from the Zbtb46-dependent dendritic-cell lineage. Instead, monocyte precursors could give rise to CD11c+ cells in inflamed islets. Chemokines Ccl5 and Ccl8 were persistently elevated in inflamed islets and the influx of CD11c+ cells was partially dependent on their receptor Ccr5. Treatment with islet Ag-specific regulatory T cells led to a marked decrease of Ccl5 and Ccl8, and a reduction of monocyte recruitment. These results implicate a monocytic origin of CD11c+ cells in inflamed islets and suggest that therapeutic regulatory T cells directly or indirectly regulate their influx by altering the chemotactic milieu in the islets.



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Tue Jun 20, 2017 00:30
  The Role of Shed PrPc in the Neuropathogenesis of HIV Infection [INFECTIOUS DISEASE AND HOST RESPONSE]
updated on Tue Jun 20, 2017 04:55 by Alexandros G. Sfakianakis via Allergy Rhinology Immunology Asthma
HIV-1 enters the CNS soon after peripheral infection and causes chronic neuroinflammation and neuronal damage that leads to cognitive impairment in 40–70% of HIV-infected people. The nonpathogenic cellular isoform of the human prion protein (PrPc) is an adhesion molecule constitutively expressed in the CNS. Previously, our laboratory showed that shed PrPc (sPrPc) is increased in the cerebrospinal fluid of HIV-infected people with cognitive deficits as compared with infected people with no impairment. In this article, we demonstrate that CCL2 and TNF-α, inflammatory mediators that are elevated in the CNS of HIV-infected people, increase shedding of PrPc from human astrocytes by increasing the active form of the metalloprotease ADAM10. We show that the consequence of this shedding can be the production of inflammatory mediators, because treatment of astrocytes with rPrPc increased secretion of CCL2, CXCL-12, and IL-8. Supernatants from rPrPc-treated astrocytes containing factors produced in response to this treatment, but not rPrPc by itself, cause increased chemotaxis of both uninfected and HIV-infected human monocytes, suggesting a role for sPrPc in monocyte recruitment into the brain. Furthermore, we examined whether PrPc participates in glutamate uptake and found that rPrPc decreased uptake of this metabolite in astrocytes, which could lead to neurotoxicity and neuronal loss. Collectively, our data characterize mediators involved in PrPc shedding and the effect of this sPrPc on monocyte chemotaxis and glutamate uptake from astrocytes. We propose that shedding of PrPc could be a potential target for therapeutics to limit the cognitive impairment characteristic of neuroAIDS.



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Tue Jun 20, 2017 00:30
  Cutting Edge: Dual TCR{alpha} Expression Poses an Autoimmune Hazard by Limiting Regulatory T Cell Generation [CUTTING EDGE]
updated on Tue Jun 20, 2017 04:55 by Alexandros G. Sfakianakis via Allergy Rhinology Immunology Asthma
Despite accounting for 10–30% of the T cell population in mice and humans, the role of dual TCR-expressing T cells in immunity remains poorly understood. It has been hypothesized that dual TCR T cells pose an autoimmune hazard by allowing self-reactive TCRs to escape thymic selection. We revisited this hypothesis using the NOD murine model of type 1 diabetes. We bred NOD mice hemizygous at both TCRα and β (TCRα+/– β+/–) loci, rendering them incapable of producing dual TCR T cells. We found that the lack of dual TCRα expression skewed the insulin-specific thymocyte population toward greater regulatory T (Treg) cell commitment, resulting in a more tolerogenic Treg to conventional T cell ratio and protection from diabetes. These data support a novel hypothesis by which dual TCR expression can promote autoimmunity by limiting agonist selection of self-reactive thymocytes into the Treg cell lineage.



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Tue Jun 20, 2017 00:30
  SLC46 Family Transporters Facilitate Cytosolic Innate Immune Recognition of Monomeric Peptidoglycans [INNATE IMMUNITY AND INFLAMMATION]
updated on Tue Jun 20, 2017 04:55 by Alexandros G. Sfakianakis via Allergy Rhinology Immunology Asthma
Tracheal cytotoxin (TCT), a monomer of DAP-type peptidoglycan from Bordetella pertussis, causes cytopathology in the respiratory epithelia of mammals and robustly triggers the Drosophila Imd pathway. PGRP-LE, a cytosolic innate immune sensor in Drosophila, directly recognizes TCT and triggers the Imd pathway, yet the mechanisms by which TCT accesses the cytosol are poorly understood. In this study, we report that CG8046, a Drosophila SLC46 family transporter, is a novel transporter facilitating cytosolic recognition of TCT, and plays a crucial role in protecting flies against systemic Escherichia coli infection. In addition, mammalian SLC46A2s promote TCT-triggered NOD1 activation in human epithelial cell lines, indicating that SLC46As is a conserved group of peptidoglycan transporter contributing to cytosolic immune recognition.



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Tue Jun 20, 2017 00:30
  Aeroallergens Induce Reactive Oxygen Species Production and DNA Damage and Dampen Antioxidant Responses in Bronchial Epithelial Cells [ALLERGY AND OTHER HYPERSENSITIVITIES]
updated on Tue Jun 20, 2017 04:55 by Alexandros G. Sfakianakis via Allergy Rhinology Immunology Asthma
Exposure to environmental allergens is a major risk factor for asthma development. Allergens possess proteolytic activity that is capable of disrupting the airway epithelium. Although there is increasing evidence pointing to asthma as an epithelial disease, the underlying mechanism that drives asthma has not been fully elucidated. In this study, we investigated the direct DNA damage potential of aeroallergens on human bronchial epithelial cells and elucidated the mechanisms mediating the damage. Human bronchial epithelial cells, BEAS-2B, directly exposed to house dust mites (HDM) resulted in enhanced DNA damage, as measured by the CometChip and the staining of DNA double-strand break marker, H2AX. HDM stimulated cellular reactive oxygen species production, increased mitochondrial oxidative stress, and promoted nitrosative stress. Notably, expression of nuclear factor erythroid 2–related factor 2–dependent antioxidant genes was reduced immediately after HDM exposure, suggesting that HDM altered antioxidant responses. HDM exposure also reduced cell proliferation and induced cell death. Importantly, HDM-induced DNA damage can be prevented by the antioxidants glutathione and catalase, suggesting that HDM-induced reactive oxygen and nitrogen species can be neutralized by antioxidants. Mechanistic studies revealed that HDM-induced cellular injury is NADPH oxidase (NOX)-dependent, and apocynin, a NOX inhibitor, protected cells from double-strand breaks induced by HDM. Our results show that direct exposure of bronchial epithelial cells to HDM leads to the production of reactive oxygen and nitrogen species that damage DNA and induce cytotoxicity. Antioxidants and NOX inhibitors can prevent HDM-induced DNA damage, revealing a novel role for antioxidants and NOX inhibitors in mitigating allergic airway disease.



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Tue Jun 20, 2017 00:30
  IL-6 Signaling Regulates Small Intestinal Crypt Homeostasis [MUCOSAL IMMUNOLOGY]
updated on Tue Jun 20, 2017 04:55 by Alexandros G. Sfakianakis via Allergy Rhinology Immunology Asthma
Gut homeostasis is a tightly regulated process requiring finely tuned complex interactions between different cell types, growth factors, or cytokines and their receptors. Previous work has implicated a role for IL-6 and mucosal immune cells in intestinal regeneration following injury and in promoting inflammation and cancer. We hypothesized that IL-6 signaling could also modulate crypt homeostasis. Using mouse in vitro crypt organoid and in vivo models, this study first demonstrated that exogenous IL-6 promoted crypt organoid proliferation and increased stem cell numbers through pSTAT3 activation in Paneth cells. Immunolabeling studies showed that the IL-6 receptor was restricted to the basal membrane of Paneth cells both in vitro and in vivo and that the crypt epithelium also expressed IL-6. Either a blocking Ab to the IL-6 receptor or a neutralizing Ab to IL-6 significantly reduced in vitro basal crypt organoid proliferation and budding, and in vivo significantly reduced the number of nuclei and the number of Lgr5EGFP-positive stem cells per crypt compared with IgG-treated mice, with the number of Paneth cells per crypt also significantly reduced. Functional studies demonstrated that IL-6–induced in vitro crypt organoid proliferation and crypt budding was abrogated by the Wnt inhibitor IWP2. This work demonstrates that autocrine IL-6 signaling in the gut epithelium regulates crypt homeostasis through the Paneth cells and the Wnt signaling pathway.



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Tue Jun 20, 2017 00:30
  Airway Epithelial Cells Are Crucial Targets of Glucocorticoids in a Mouse Model of Allergic Asthma [ALLERGY AND OTHER HYPERSENSITIVITIES]
updated on Tue Jun 20, 2017 04:55 by Alexandros G. Sfakianakis via Allergy Rhinology Immunology Asthma
Although glucocorticoids (GCs) are a mainstay in the clinical management of asthma, the target cells that mediate their therapeutic effects are unknown. Contrary to our expectation, we found that GC receptor (GR) expression in immune cells was dispensable for successful therapy of allergic airway inflammation (AAI) with dexamethasone. Instead, GC treatment was compromised in mice expressing a defective GR in the nonhematopoietic compartment or selectively lacking the GR in airway epithelial cells. Further, we found that an intact GR dimerization interface was a prerequisite for the suppression of AAI and airway hyperresponsiveness by GCs. Our observation that the ability of dexamethasone to modulate gene expression in airway epithelial cells coincided with its potency to resolve AAI supports a crucial role for transcriptional regulation by the GR in this cell type. Taken together, we identified an unknown mode of GC action in the treatment of allergic asthma that might help to develop more specific therapies in the future.



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Tue Jun 20, 2017 00:30
  Comprehensive Approach for Identifying the T Cell Subset Origin of CD3 and CD28 Antibody-Activated Chimeric Antigen Receptor-Modified T Cells [NOVEL IMMUNOLOGICAL METHODS]
updated on Tue Jun 20, 2017 04:55 by Alexandros G. Sfakianakis via Allergy Rhinology Immunology Asthma
The outcome of therapy with chimeric Ag receptor (CAR)-modified T cells is strongly influenced by the subset origin of the infused T cells. However, because polyclonally activated T cells acquire a largely CD45RO+CCR7– effector memory phenotype after expansion, regardless of subset origin, it is impossible to know which subsets contribute to the final T cell product. To determine the contribution of naive T cell, memory stem T cell, central memory T cell, effector memory T cell, and terminally differentiated effector T cell populations to the CD3 and CD28–activated CAR-modified T cells that we use for therapy, we followed the fate and function of individually sorted CAR-modified T cell subsets after activation with CD3 and CD28 Abs (CD3/28), transduction and culture alone, or after reconstitution into the relevant subset-depleted population. We show that all subsets are sensitive to CAR transduction, and each developed a distinct T cell functional profile during culture. Naive-derived T cells showed the greatest rate of proliferation but had more limited effector functions and reduced killing compared with memory-derived populations. When cultured in the presence of memory T cells, naive-derived T cells show increased differentiation, reduced effector cytokine production, and a reduced reproliferative response to CAR stimulation. CD3/28-activated T cells expanded in IL-7 and IL-15 produced greater expansion of memory stem T cells and central memory T cell–derived T cells compared with IL-2. Our strategy provides a powerful tool to elucidate the characteristics of CAR-modified T cells, regardless of the protocol used for expansion, reveals the functional properties of each expanded T cell subset, and paves the way for a more detailed evaluation of the effects of manufacturing changes on the subset contribution to in vitro–expanded T cells.



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Tue Jun 20, 2017 00:30
  Occludin Expression in Epidermal {gamma}{delta} T Cells in Response to Epidermal Stress Causes Them To Migrate into Draining Lymph Nodes [ALLERGY AND OTHER HYPERSENSITIVITIES]
updated on Tue Jun 20, 2017 04:55 by Alexandros G. Sfakianakis via Allergy Rhinology Immunology Asthma
Epidermal T cells that reside in the front line of the skin play a pivotal role in stress immune surveillance. However, it is not clear whether these cells are involved in further induction of immune responses after they are activated in dysregulated epidermis. In this study, we found that activated T cells expressed occludin and migrated into draining lymph nodes in an occludin-dependent manner. Epidermal T cells in occludin-deficient mice exhibited impairments in morphology changes and motility, although they expressed activation markers at levels comparable to those in wild-type cells. Occludin deficiency weakened the induction of allergen-induced contact hypersensitivity, primarily as the result of the impaired migration of epidermal T cells. Thus, occludin expression by epidermal T cells upon activation in response to epidermal stress allows them to move, which could be important for augmentation of immune responses via collaboration with other cells.



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Tue Jun 20, 2017 00:30
  Monoclonal Invariant NKT (iNKT) Cell Mice Reveal a Role for Both Tissue of Origin and the TCR in Development of iNKT Functional Subsets [IMMUNE REGULATION]
updated on Tue Jun 20, 2017 04:55 by Alexandros G. Sfakianakis via Allergy Rhinology Immunology Asthma
Invariant NKT (iNKT) cell functional subsets are defined by key transcription factors and output of cytokines, such as IL-4, IFN-, IL-17, and IL-10. To examine how TCR specificity determines iNKT function, we used somatic cell nuclear transfer to generate three lines of mice cloned from iNKT nuclei. Each line uses the invariant Vα14Jα18 TCRα paired with unique Vβ7 or Vβ8.2 subunits. We examined tissue homing, expression of PLZF, T-bet, and RORt, and cytokine profiles and found that, although monoclonal iNKT cells differentiated into all functional subsets, the NKT17 lineage was reduced or expanded depending on the TCR expressed. We examined iNKT thymic development in limited-dilution bone marrow chimeras and show that higher TCR avidity correlates with higher PLZF and reduced T-bet expression. iNKT functional subsets showed distinct tissue distribution patterns. Although each individual monoclonal TCR showed an inherent subset distribution preference that was evident across all tissues examined, the iNKT cytokine profile differed more by tissue of origin than by TCR specificity.



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Mon Jun 19, 2017 22:34
  Cytokine Profiling in a Familial Case of Autoimmune Lymphoproliferative Syndrome with Co-mutations of FAS and MEFV
updated on Tue Jun 20, 2017 04:55 by Alexandros G. Sfakianakis via Allergy Rhinology Immunology Asthma
Pediatric Allergy, Immunology, and Pulmonology Jun 2017, Vol. 30, No. 2: 120-125.


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Mon Jun 19, 2017 22:34
  Relationship Between Vitamin D Status and Viral Pneumonia in Children
updated on Tue Jun 20, 2017 04:55 by Alexandros G. Sfakianakis via Allergy Rhinology Immunology Asthma
Pediatric Allergy, Immunology, and Pulmonology Jun 2017, Vol. 30, No. 2: 86-91.


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Mon Jun 19, 2017 22:34
  Prediction of Refractory Mycoplasma Pneumoniae Pneumonia in Pediatric Patients
updated on Tue Jun 20, 2017 04:55 by Alexandros G. Sfakianakis via Allergy Rhinology Immunology Asthma
Pediatric Allergy, Immunology, and Pulmonology Jun 2017, Vol. 30, No. 2: 92-96.


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Sat Jun 17, 2017 06:34
  Hepatitis C Virus in Pakistan: Community Education Is an Effective Weapon Against the Killer
updated on Sat Jun 17, 2017 10:35 by Alexandros G. Sfakianakis via Allergy Rhinology Immunology Asthma
Translate article
Viral Immunology , Vol. 0, No. 0.


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Fri Jun 16, 2017 19:54
  The link between morphology and complement in ocular disease
updated on Fri Jun 16, 2017 23:55 by Alexandros G. Sfakianakis via Allergy Rhinology Immunology Asthma
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Publication date: Available online 15 June 2017
Source:Molecular Immunology
Author(s): Camilla Mohlin, Kerstin Sandholm, Kristina N. Ekdahl, Bo Nilsson
The complement system is a vital component of the immune-priveliged human eye that is always active at a low-grade level, preventing harmful intraocular injuries caused by accumulation of turnover products and controlling pathogens to preserve eye homeostasis and vision. The complement system is a double-edged sword that is essential for protection but may also become harmful and contribute to eye pathology. Here, we review the evidence for the involvement of complement system dysregulation in age-related macular degeneration, glaucoma, uveitis, and neuromyelitis optica, highlighting the relationship between morphogical changes and complement system protein expression and regulation in these diseases. The potential benefits of complement inhibition in age-related macular degeneration, glaucoma, uveitis, and neuromyelitis optica are abundant, as are those of further research to improve our understanding of complement-mediated injury in these diseases.



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Fri Jun 16, 2017 19:14
  Blockade of CD112R and TIGIT signaling sensitizes human natural killer cell functions
updated on Fri Jun 16, 2017 23:55 by Alexandros G. Sfakianakis via Allergy Rhinology Immunology Asthma
Abstract
Trastuzumab is the first-line drug to treat breast cancer with high Her2 expression. However, many cancers failed to respond, largely due to their resistance to NK cell-triggered antibody-dependent cellular cytotoxicity (ADCC). Poliovirus receptor (PVR)-like molecules are known to be important for lymphocyte functions. We found that all PVR-like receptors are expressed on human NK cells, and only TIGIT is preferentially expressed on the CD16+ NK cell subset. Disrupting the interactions of PVR-like receptors with their ligands on cancer cells regulates NK cell activity. More importantly, TIGIT is upregulated upon NK cell activation via ADCC. Blockade of TIGIT or CD112R, separately or together, enhances trastuzumab-triggered antitumor response by human NK cells. Thus, our findings suggest that PVR-like receptors regulate NK cell functions and can be targeted for improving trastuzumab therapy for breast cancer.



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Fri Jun 16, 2017 15:49
  Abstracts from the 10th C1-inhibitor deficiency workshop
updated on Fri Jun 16, 2017 23:55 by Alexandros G. Sfakianakis via Allergy Rhinology Immunology Asthma
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Fri Jun 16, 2017 11:59
  Nanotechnologies for In Vitro IgE Testing
updated on Fri Jun 16, 2017 23:55 by Alexandros G. Sfakianakis via Allergy Rhinology Immunology Asthma
Abstract
Purpose of Review
This review discusses the recent advances in the development of IgE antibody assays based on nanotechnologies. IgE blood testing is an important part of the diagnostic workup of IgE-mediated hypersentivity. We also address the challenges in moving from an academic proof-of-concept to a product routinely used by allergy experts.

Recent Findings
Several nanotechnologies have been applied to the field of IgE testing: nanoparticles are used either as a support to capture analytes or as a detection tool to enhance the measurement signal. Nanofluidics allows to reduce assay time by enhancing molecular interaction.

Summary
Nanotechnologies bring forth new methods for in vitro IgE testing. Substantial advantages such as lower sample volume, shorter assay time, simplified procedures, and lower analytic sensitivity, without affecting test precision and accuracy, can be achieved thanks to nanotechnologies.



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Fri Jun 16, 2017 11:59
  Acquired Immunity in Chronic Rhinosinusitis
updated on Fri Jun 16, 2017 23:55 by Alexandros G. Sfakianakis via Allergy Rhinology Immunology Asthma
Abstract
Chronic rhinosinusitis (CRS) is a prevalent disease that is associated with significant costs and quality of life impairments. Currently, patients are classified into subgroups based on clinical characteristics, most often the presence or absence of nasal polyps. However, despite medical and surgical treatment, many of these patients continue to have symptoms. Recent efforts have focused on gaining a more complete understanding of the inflammatory mechanisms that drive pathogenesis in CRS, and it is becoming clear that the inflammatory processes in CRS are quite complex. As our understanding of these complex phenotypes improves, it may become possible to classify patients into endotypes based on unique inflammatory patterns within the sinus mucosa. This information may also lead to the identification of appropriate targeted therapies for different endotypes. This review will discuss our current understanding of endotypes in CRS along with the unique adaptive immune responses that may contribute to these different endotypes and, finally, some potential targeted therapeutics for the next generation of CRS treatment strategies.



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Fri Jun 16, 2017 06:34
  Adjuvants for Animal Vaccines
updated on Fri Jun 16, 2017 10:35 by Alexandros G. Sfakianakis via Allergy Rhinology Immunology Asthma
Translate article
Viral Immunology , Vol. 0, No. 0.


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Thu Jun 15, 2017 21:19
  Ig-seq: Deep sequencing of the variable region of Atlantic salmon IgM heavy chain transcripts
updated on Fri Jun 16, 2017 01:20 by Alexandros G. Sfakianakis via Allergy Rhinology Immunology Asthma
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Publication date: August 2017
Source:Molecular Immunology, Volume 88
Author(s): Aleksei Krasnov, Sven Martin Jørgensen, Sergey Afanasyev
Immunoglobulin M plays a key role in systemic protection of Atlantic salmon against pathogens. Until recent, studies have focused on antigen-specific antibodies and little is known about the IgM repertoire: its size, developmental changes and responses to antigens. We report the development of deep sequencing protocol to characterize the repertoire of IgM heavy chain variable region. Its structure and changes were examined at the early stages of life and after infection with virus of cardiac myopathy. Clonotypes are identified by the V and J gene segments and amino acid sequences of CDR3, which determine the contribution of the heavy chain to the antigen binding properties. A major fraction of transcripts are functional while the rest are either sterile (transcribed from noncoding parts of Ig loci) or include stop codons. Despite marked difference in frequencies of combinations of V and J genes, the size of repertoire is large. The IgM diversity steadily increases after hatch followed with temporal reduction during smoltification and recovery after seawater transfer. Most clonotypes are present only in one fish. However multiple transcripts in uninfected fish are produced exclusively from a small fraction of shared clonotypes. While only 4.7% of clonotypes are detected in three and more fish, they comprise 35% of transcripts. Increased frequencies of most abundant clonotypes were detected in the head kidney and blood at ten weeks after viral infection and all were shared. Occurrence of the same clonotypes in multiple individuals can be explained with either their simple structure or exposure to common antigens. Complexity of CDR3 assessed by contents of non complementary nucleotides is slightly lower in shared clonotypes but difference is small. High nucleotide diversity of CDR3 with identical amino acid sequences suggests selection.



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Thu Jun 15, 2017 21:19
  A novel immune-related gene HDD1 of silkworm Bombyx mori is involved in bacterial response
updated on Fri Jun 16, 2017 01:20 by Alexandros G. Sfakianakis via Allergy Rhinology Immunology Asthma
S01615890.gif

Publication date: August 2017
Source:Molecular Immunology, Volume 88
Author(s): Kui Zhang, Guangzhao Pan, Yuzu Zhao, Xiangwei Hao, Chongyang Li, Li Shen, Rui Zhang, Jingjing Su, Hongjuan Cui
Insects have evolved an effective immune system to respond to various challenges. In this study, a novel immune-related gene, called BmHDD1, was first charactered in silkworm, Bombyx mori. BmHDD1 contained an ORF of 837bp and encoding a deduced protein of 278 amino acids. BmHDD1 was specifically expressed in hemocytes, and highly expressed at the molting and metamorphosis stages under normal physiological conditions. Our results suggested that BmHDD1 was mainly generated by hemocytes and secreted into hemolymph. Our results also showed that the expression level of BmHDD1 was significantly increased after 20E injection, which indicated that BmHDD1 might be regulated by ecdysone. More importantly, BmHDD1 was dramatically induced after injected with different types of PAMPs or bacteria, either in hemocytes or fat body. Those results suggested that BmHDD1 plays a role in developing and immunity system in silkworm, Bombyx mori.



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Thu Jun 15, 2017 14:19
  Histamine Receptor 2 Modifies iNKT Cell Activity within the Inflamed Lung
updated on Thu Jun 15, 2017 18:19 by Alexandros G. Sfakianakis via Allergy Rhinology Immunology Asthma
Abstract
Background
Histamine is a key immunoregulatory mediator and can dampen proinflammatory responses via activation of histamine receptor 2 (H2R). The aim of this study was to determine the role of H2R in modulating lung inflammatory responses.

Methods
H2R was blocked using famotidine or activated using dimaprit in both the ovalbumin (OVA) and house dust mite extract (HDM) murine models of respiratory inflammation. H2R-deficient animals and CD1d/ H2R-deficient animals were utilized to examine the CD1d presentation of lipid antigens (αGal-Cer or OCH) to invariant Natural Killer T (iNKT) cells.

Results
Famotidine treatment resulted in more severe airway disease in the OVA model, while dimaprit treatment significantly reduced disease severity. Both OVA and HDM-induced airway disease were more severe in H2R-deficient animals. Flow cytometric analysis of lung tissue from H2R-deficient animals revealed increased numbers of CD1d+ dendritic cells and increased numbers of iNKT cells. In vitro, αGal-Cer-stimulated iNKT cells from H2R-deficient mice secreted higher levels of IL-4, IL-5 and GM-CSF. In vivo, αGal-Cer or OCH administration to the lung resulted in enhanced mucus secretion, inflammatory cell recruitment and cytokine production in H2R-deficient or famotidine-treated animals, while dimaprit dampened the lung iNKT cell response to αGalCer. Removal of iNKT cells in H2R-deficient (CD1d-/-H2R-/-) animals normalized the lung response to HDM.

Conclusion
The deliberate activation of H2R, or its downstream signaling molecules, may represent a novel therapeutic target for chronic lung inflammatory diseases, especially when CD1d-mediated presentation of lipid antigens to iNKT cells are contributing to the pathology.

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Thu Jun 15, 2017 14:19
  Is the atopic march related to confounding by genetics and early life environment? A systematic review of sibship and twin data
updated on Thu Jun 15, 2017 18:19 by Alexandros G. Sfakianakis via Allergy Rhinology Immunology Asthma
Abstract
A popular hypothesis known as the atopic march proposes a set of sequential allergy and respiratory disorders in early childhood contributes enormously to the burden of disease in developed countries. Although the concept of the atopic march has been refined and strengthened by many cross-sectional and longitudinal studies linking eczema as the initial manifestation with progression to hay fever and then asthma, there is yet no definitive proof that the atopic march is the primary causal factor in childhood allergic disease. This debate is mainly related to the controversy around potential confounding of these associations by genetic and environmental factors. Family studies are ideally suited to unravelling the role of these factors. While multiple reviews have synthesised evidence from studies investigating this question, no review to date has explored specific evidence generated by twin and sibling studies to understand the aetiology of atopic march diseases. Our aim was to conduct a systematic review of twin and sibling studies that examine the allergic phenotypes that form the atopic march, to determine whether such analyses of data from these studies attempt to control for the effect confounding by shared factors, and to report estimates the magnitude of associations between multiple phenotypes. Our review suggests that (1) genetics play a bigger role predisposing eczema to hay fever and eczema to asthma than environmental factors; and (2) the link between eczema, and asthma and hay fever is independent of shared early life environmental factors and genetics.

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Thu Jun 15, 2017 10:39
  Perioperative Antibiotic Prophylaxis to Prevent Surgical Site Infections in Solid Organ Transplantation.
updated on Thu Jun 15, 2017 18:19 by Alexandros G. Sfakianakis via Allergy Rhinology Immunology Asthma
Antibiotic prophylaxis in the perioperative period is the standard of care for nearly all surgical procedures and routinely prescribed during solid organ transplantation (SOT). The primary goal of perioperative antibiotic prophylaxis is to minimize postoperative surgical site infections (SSIs). SSIs are a significant issue in SOT. Depending on the organ transplanted, SSIs occur in 3 to 53% of patients, with the highest rates observed in small bowel/multivisceral, liver, and pancreas transplant recipients. SOT recipients are also at increased risk of developing SSIs with antimicrobial-resistant organisms. In this manuscript, we describe the epidemiology and risk factors for SSIs in SOT, and examine the available literature to guide the use of different regimens for perioperative antibiotic prophylaxis for each organ. We have further addressed specific situations that are unique to each organ transplant type, such as the use of extracorporeal membrane oxygenation in thoracic organ transplantation, as well as an approach to perioperative antibiotic prophylaxis in the setting of recipient and/or donor infection prior to transplantation. We provide potential approaches to the selection, dosing, and duration of perioperative antibiotic prophylaxis for each of these clinical situations. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Thu Jun 15, 2017 10:39
  Anti-CD20 blocker Rituximab in Kidney Transplantation.
updated on Thu Jun 15, 2017 18:19 by Alexandros G. Sfakianakis via Allergy Rhinology Immunology Asthma
Rituximab is a chimeric anti-CD20 monoclonal protein used in various clinical scenarios in kidney transplant recipients. However, its evidence-based use there remains limited due to lack of controlled studies, limited sample size, short follow-up and poorly defined endpoints. Rituximab is indicated for CD20+ PTLD. It may be beneficial for treating recurrent MN and recurrent allograft ANCA vasculitis and possibly for recurrent FSGS. Rituximab, in combination with IVIG/PP, appears to decrease antibody level and increase the odds of transplantation in sensitized recipients. The role of Rituximab in ABOi transplant remains unclear, as similar outcomes are achieved without its use. Rituximab is not efficacious in ABMR/CAMR. Strict RCTs are necessary to elucidate its true role in these settings. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Thu Jun 15, 2017 06:19
  Structural Basis for CD4+ T Cell Epitope Dominance in Arbo-Flavivirus Envelope Proteins: A Meta-Analysis
updated on Thu Jun 15, 2017 10:20 by Alexandros G. Sfakianakis via Allergy Rhinology Immunology Asthma
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Viral Immunology , Vol. 0, No. 0.


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Wed Jun 14, 2017 20:46
  Demyelination, strokes, and eculizumab: Lessons from the congenital CD59 gene mutations
updated on Thu Jun 15, 2017 00:45 by Alexandros G. Sfakianakis via Allergy Rhinology Immunology Asthma
S01615890.gif

Publication date: Available online 13 June 2017
Source:Molecular Immunology
Author(s): Adi Tabib, Netanel Karbian, Dror Mevorach
Neurological symptoms of patients with p.Cys89Tyr mutation in the CD59 gene include recurrent peripheral neuropathy resembling Guillain-Barré syndrome, characterized by sensory-motor demyelinating neuropathy with secondary axonal damage and moderate enhancement of the nerve roots on spine MRI, together with recurrent strokes and retinal involvement. Three additional mutations in CD59, leading to loss of function, have been described, and overall, 12/12 (100%) of patients with any mutation presented with neurological symptoms; 11/12 (92%) patients presented with recurrent peripheral neuropathy, 6/12 (50%) with recurrent strokes, and 1/12 (8%) with retinal involvement. We review the possible thrombophilic profile associated with the mutations. In these patients, excessive intravascular hemolysis saturates scavenger mechanisms resulting in free hemoglobin in plasma that irreversibly reacts with nitric oxide to form nitrate and methemoglobin, leading to arterial thrombosis. CD59 loss of function is also one of the major thrombophilic mechanisms in patients with paroxysmal nocturnal hemoglobinuria. We then describe the relationship with demyelination. The lack of CD59 allows uncontrolled complement amplification following low-level spontaneous-, viral-, or post viral-induced complement activation, resulting in severe demyelination in the peripheral nervous system. It is interesting, and certainly encouraging, that after 3 years, following 4 patients with Cys89Tyr mutations who are treated with eculizumab, no strokes occurred and non-permanent neurological insults underwent resolution without any new neurological exacerbations.



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Wed Jun 14, 2017 12:10
  Patient and Public Outreach Initiatives in Chronic Rhinosinusitis from the Canadian Sinusitis Working Group: Support for Affected Patients and Extending an Understanding of CRS to the General Public
updated on Wed Jun 14, 2017 16:14 by Alexandros G. Sfakianakis via Allergy Rhinology Immunology Asthma
Abstract
Chronic rhinosinusitis is an important disease entity that affects patients worldwide, yet there is limited public awareness regarding the disease. The Canadian Rhinosinusitis Working Group, a group of diverse medical professionals, has made a multitude of efforts to help improve the health literacy of patients and important stakeholders, as well as the quality of life of patients with chronic rhinosinusitis. This review will aim to outline these initiatives.



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Wed Jun 14, 2017 09:00
  Recognition of Viral RNA by Pattern Recognition Receptors in the Induction of Innate Immunity and Excessive Inflammation During Respiratory Viral Infections
updated on Wed Jun 14, 2017 16:14 by Alexandros G. Sfakianakis via Allergy Rhinology Immunology Asthma
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Viral Immunology , Vol. 0, No. 0.


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Wed Jun 14, 2017 09:00
  Regional Immune Responses in the Lung After Respiratory Virus Infections
updated on Wed Jun 14, 2017 16:14 by Alexandros G. Sfakianakis via Allergy Rhinology Immunology Asthma
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Viral Immunology , Vol. 0, No. 0.


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Wed Jun 14, 2017 03:40
  Geographic distribution of phylogenetic species of the Fusarium graminearum species complex and their 8-ketotrichothecene chemotypes on wheat spikes in Iran
updated on Wed Jun 14, 2017 07:42 by Alexandros G. Sfakianakis via Allergy Rhinology Immunology Asthma
Abstract
Isolates of the Fusarium graminearum species complex (FGSC, n = 446) were collected from wheat spikes from northern and western regions of Iran with a history of Fusarium head blight (FHB) occurrences. The trichothecene mycotoxin genotypes/chemotypes, the associated phylogenetic species, and geographical distribution of these isolates were analyzed. Two phylogenetic species, Fusarium asiaticum and F. graminearum, were identified and were found to belong to sequence characterized amplified region (SCAR) groups V and I. Isolates from F. asiaticum species lineage 6 were within SCAR group V, whereas F. graminearum species lineage 7 were of SCAR group I. Of the 446 isolates assayed, 274 were F. asiaticum species predominantly of the nivalenol (NIV) genotype, while other isolates were either deoxynivalenol (DON) plus 3-acetyldeoxynivalenol (3-AcDON) or DON plus 15-acetyldeoxynivalenol (15-AcDON) genotype. Based on Tri7 gene sequences, a new subpopulation of 15-AcDON producers was observed among F. asiaticum strains in which 11-bp repeats were absent in the Tri7 sequences. The trichothecene chemotype was confirmed and quantified by high-performance liquid chromatography (HPLC) in 46 FGSC isolates. Isolates produced NIV (33.4–108.2 μg/g) and DON (64.7–473.6 μg/g) plus either 3-AcDON (51.4–142.4 μg/g) or 15-AcDON (24.1–99.3 μg/g). Among FGSC isolates, F. asiaticum produced the highest levels of trichothecenes. Using BIOCLIM based on the climate data of 20-year during 1994–2014, modelling geographical distribution of FGSC showed that F. asiaticum was restricted to warmer and humid areas with a median value of mean annual temperature of about 17.5 °C and annual rainfall of 658 mm, respectively (P < 0.05). In contrast, F. graminearum (only 15-AcDON producers) was restricted to cooler and drier areas, with a median value of the mean annual temperature of 14.4 °C and an annual rainfall of 384 mm, respectively (P < 0.05). Based on climate parameters at anthesis, the recorded distribution of F. graminearum and F. asiaticum was similar to that based on BIOCLIM parameters. Therefore, geographic differences on the wheat-growing areas in Iran have had a significant effect on distribution of FGSC and their trichothecene chemotypes.



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Wed Jun 14, 2017 00:21
  Validation of International consensus equation for acute serum total tryptase in mast cell activation: A perioperative perspective
updated on Wed Jun 14, 2017 07:42 by Alexandros G. Sfakianakis via Allergy Rhinology Immunology Asthma
Abstract
Introduction
There is no standardised method for assessing serum total mast cell tryptase (MCT) in anaphylaxis. The consensus equation (peak MCT should be>1.2x baseline tryptase+2mg/L) has been proposed to interpret acute MCT in mast cell activation syndrome (MCAS).

Aim
To validate consensus equation in a setting of perioperative anaphylaxis.

Methods
Analyses of suspected perioperative anaphylaxis during general anaesthesia (GA). Anaphylaxis was defined as per World Allergy Organisation (WAO) criteria. Timed serial MCT measurements were mapped against the consensus equation and receiver operating characteristic (ROC) curves produced.

Results
82 patients (60 females, mean age 56.5 years ± SD17.2) underwent investigation. 60 (73%) patients fulfilled WAO criteria for anaphylaxis and 22 patients did not (controls). Aetiology: 59% IgE-mediated anaphylaxis, 2% non-IgE mediated anaphylaxis, 12% anaphylaxis of unknown cause, and 27% deemed non-anaphylaxis. IgE-mediated anaphylaxis included - NMBA (35%), antibiotics (46%), chlorhexidine (8%), patent blue dye (8%) and others (8%). An acute MCT with a comparable baseline was available in 71/82 (87%) patients (60-anaphylaxis and 11-controls).The median (IQR) time from reaction to peak MCT was 1.34 (0.82-2.51) hours. Analyses confirmed that a rise in acute MCT greater than that defined by the equation had a sensitivity, specificity, positive predictive value (PPV) and negative (N) PV of 78%, 91%, 98%, and 44% respectively. The magnitude of increase in acute MCT above the threshold predicted by consensus equation was higher in the anaphylaxis group compared to controls (P=0.0001).

Conclusion
This equation has a high specificity, PPV with a moderate NPV and sensitivity in perioperative anaphylaxis.

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Tue Jun 13, 2017 20:10
  Analysis of adipose tissue immune gene expression after vaccination of rainbow trout with adjuvanted bacterins reveals an association with side effects
updated on Wed Jun 14, 2017 00:11 by Alexandros G. Sfakianakis via Allergy Rhinology Immunology Asthma
S01615890.gif

Publication date: August 2017
Source:Molecular Immunology, Volume 88
Author(s): Kimberly A. Veenstra, Tiehui Wang, Ayham Alnabulsi, Alex Douglas, K. Spencer Russell, Lincoln Tubbs, Juliette Ben Arous, Christopher J. Secombes
Most existing fish vaccines are presented in the form of oil-based emulsions delivered by intraperitoneal injection. Whilst very effective they are frequently associated with inflammatory responses that can result in clinically significant side-effects often involving the adipose tissue that is in direct contact with the vaccine. To explore the potential of immune gene expression changes in the adipose tissue of fish to be markers of vaccination efficacy or development of side-effects we have studied the response to a bacterial (Aeromonas salmonicida) vaccine administered with two different adjuvants. The first adjuvant was Montanide™ ISA 763A VG, thought to induce a mostly humoral response, and the second was Montanide™ ISA 761 VG that gives a more balanced humoral and cell mediated response. Following vaccination tissue samples were collected at days 3, 14 and 28 for RTqPCR analysis. Fifty immune genes were studied with a focus on a) pro-inflammatory associated molecules and b) adaptive immune response related molecules linked with possible Th1, Th2, Th17 and T-regulatory pathways, with the expression data analysed for associations with Speilberg post-vaccination side effect scores. The results showed that the adipose tissue is a particularly sensitive and discriminatory tissue for studying adjuvant effects. A clear upregulation of many immune genes occurred in response to both vaccine groups, which persisted over time and overlapped with the appearance of visible adhesions. Our analysis revealed a relationship between adipose tissue immune function and the development of vaccine-induced adhesions giving the potential to use immune gene expression profiling in this tissue to predict the side-effects seen.



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Tue Jun 13, 2017 18:01
  A phase II study of ipilimumab plus temozolomide in patients with metastatic melanoma
updated on Tue Jun 13, 2017 19:54 by Alexandros G. Sfakianakis via Allergy Rhinology Immunology Asthma
Abstract
Checkpoint blockade has revolutionized the treatment of melanoma; however, it benefits only the minority of patients. Several agents have been combined with immunotherapy to improve T-cell activation and persistence including growth factor, chemotherapy, and radiation. Preclinical data suggest that temozolomide, which metabolizes to the same active compound as dacarbazine, selectively depletes regulatory T cells. This potential immunomodulatory effect of temozolomide provides rationale for combination with ipilimumab. We performed an open-label single-arm phase II study of ipilimumab plus temozolomide in the frontline setting for patients with metastatic melanoma and LDH ≤2× upper limit of normal. Ipilimumab was given at 10 mg/kg on day 1 and temozolomide 200 mg/m2 orally days 1–4 every 3 weeks for four doses followed by maintenance ipilimumab every 12 weeks plus temozolomide every 4 weeks. The primary objective of the study was 6-month PFS. A total of 64 patients were enrolled and the 6-month PFS was 45% with median OS of 24.5 months. There were 10 (15.6%) confirmed partial responses and 10 (15.6%) confirmed complete responses. Duration of response amongst responders is 35 months with 10 patients demonstrating an ongoing response at median follow-up of 20 months. There were no deaths or unexpected toxicities on study. The most common gastrointestinal side effects were nausea and constipation rather than diarrhea or colitis. These results suggest that the combination of induction ipilimumab plus temozolomide could potentially be an effective strategy to enhance antitumor activity with a manageable toxicity profile. These findings warrant further evaluation in a large prospective study.



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Tue Jun 13, 2017 14:51
  Angioedema suppressed by a combination of anti-histamine and leukotriene modifier
updated on Tue Jun 13, 2017 19:54 by Alexandros G. Sfakianakis via Allergy Rhinology Immunology Asthma
Angioedema without co-existent urticaria is due to a limited number of causes, including hereditary and acquired C1 esterase inhibitor deficiency, drug-induced angioedema or idiopathic histaminergic or non-his...

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Tue Jun 13, 2017 10:05
  Evolving Approaches in the Identification of Allograft-reactive T and B Cells in Mice and Humans.
updated on Tue Jun 13, 2017 14:02 by Alexandros G. Sfakianakis via Allergy Rhinology Immunology Asthma
Whether a transplanted allograft is stably accepted, rejected or achieves immunological tolerance is dependent on the frequency and function of alloreactive lymphocytes, making the identification and analysis of alloreactive T and B cells in transplant recipients critical for understanding mechanisms, and the prediction of allograft outcome. In animal models, tracking the fate of graft-reactive T and B cells allows investigators to uncover their biology and develop new therapeutic strategies to protect the graft. In the clinic, identification and quantification of graft-reactive T and B cells allows for the early diagnosis of immune reactivity and therapeutic intervention to prevent graft loss. In addition to rejection, probing of T and B cell fate in vivo provides insights into the underlying mechanisms of alloimmunity or tolerance that may lead to biomarkers predicting graft fate. In this review, we discuss existing and developing approaches to track and analyze alloreactive T and B cells in mice and humans and provide examples of discoveries made utilizing these techniques. These approaches include mixed lymphocyte reactions (MLRs), trans-vivo delayed-type hypersensitivity (DTH), enzyme-linked immunospot (ELISpot) assays, the use of antigen receptor transgenic lymphocytes, and utilization of peptide-MHC complex (pMHC) multimers, along with imaging techniques for static multiparameter analysis or dynamic in vivo tracking. Such approaches have already refined our understanding of the alloimmune response and are pointing to new ways to improve allograft outcomes in the clinic. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Mon Jun 12, 2017 19:40
  Phase I trial of antigen-targeted autologous dendritic cell-based vaccine with in vivo activation of inducible CD40 for advanced prostate cancer
updated on Mon Jun 12, 2017 23:37 by Alexandros G. Sfakianakis via Allergy Rhinology Immunology Asthma
Abstract
This phase I trial reports the safety and activity of BPX101, a second-generation antigen-targeted autologous antigen presenting cell (APC) vaccine in men with metastatic castration-resistant prostate cancer (mCRPC). To manufacture BPX101, APCs collected in a single leukapheresis were transduced with adenoviral vector Ad5f35 encoding inducible human (ih)-CD40, followed by incubation with protein PA001, which contains the extracellular domain of human prostate-specific membrane antigen. The ih-CD40 represents a modified chimeric version of the dendritic cell (DC) co-stimulatory molecule, CD40, which responds to a bioinert membrane-permeable activating dimerizer drug, rimiducid (AP1903), permitting temporally controlled, lymphoid-localized, DC-specific activation. Eighteen men with progressive mCRPC following ≤1 prior chemotherapy regimen were enrolled to evaluate three doses of BPX101 (4 × 106, 12.5 × 106 and 25 × 106 cells) administered intradermally every 2–4 weeks followed by rimiducid (0.4 mg/kg) intravenous (IV) infusion 24 h after each BPX101 dose. There were no dose-limiting toxicities. Immune upregulation as well as anti-tumor activity was observed with PSA declines, objective tumor regressions and robust efficacy of post-trial therapy. This novel antigen-targeted and in vivo activated immunotherapy platform may warrant further development as monotherapy and as a component of rational combinations.



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Mon Jun 12, 2017 16:25
  What's in a name?: Atopic dermatitis or atopic eczema, but not eczema alone
updated on Mon Jun 12, 2017 23:37 by Alexandros G. Sfakianakis via Allergy Rhinology Immunology Asthma
Abstract
Background
The ideal nomenclature of atopic dermatitis or atopic eczema (AD/AE) has long been contested. It is becoming increasingly clear that the disparate nomenclature of this disease may have important deleterious ramifications for clinical care, research and drug development.

Objective
To reach consensus among an international group of experts in AD/AE on the nomenclature for AD/AE.

Methods
A 3-question survey was sent to the councilors and associates of the International Eczema Council. Consensus was reached with at least 90% response and more than 90% agreement on nomenclature.

Results
Seventy-one of 77 (92.2%) IEC councilors and associates responded to the survey. Consensus was reached on the preference for the atopic prefix, i.e. AD or AE (69 of 71 [97.2%]). However, consensus was not reached preference of AD (40 [58.0%]) or AE (30 [43,5%]). Sixty-three respondents (88.7%) and 55 (77.5%) felt that the terms AD and AE were acceptable, whereas only 11 (15.5%) felt that eczema was acceptable.

Conclusions
Use of the atopic prefix, i.e. either AE or AD, is recommended. Whereas, use of the term eczema is not recommended. We encourage physicians in all specialties and in every country to shift their own use of terminology to AD or AE in writing, presentations and discussions with patients and other health care personnel as a first step.

This article is protected by copyright. All rights reserved.



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Mon Jun 12, 2017 08:54
  Modified Frailty Index Score and Perioperative Risk in Laryngectomy : The 11 Variables Included in Modified Frailty Index Assessment : History of diabetes Functional status (not independent at baseline) History of pneumonia or chronic obstructive pulmonary disease History of congestive cardiac failure History of myocardial infarction History of percutaneous coronary intervention, stent placement, or angina History of hypertension (requiring medical treatment) History of peripheral vascular disease or ischemic rest pain History of impaired sensorium History of transient ischemic attack or cerebrovascular accident History of cerebrovascular accident with neurologic deficit
updated on Mon Jun 12, 2017 12:50 by Alexandros G. Sfakianakis via Allergy Rhinology Immunology Asthma
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http://orlhealth.blogspot.com/2017/06/modified-frailty-index-score-and.html

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182
6948891480
alsfakia@gmail.com
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Mon Jun 12, 2017 08:41
  Barking Cough
updated on Mon Jun 12, 2017 12:50 by Alexandros G. Sfakianakis via Allergy Rhinology Immunology Asthma
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https://youtu.be/IgZuVo81298?t=33

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182
6948891480
alsfakia@gmail.com
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Mon Jun 12, 2017 08:39
  Bovine cough
updated on Mon Jun 12, 2017 12:50 by Alexandros G. Sfakianakis via Allergy Rhinology Immunology Asthma
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http://orlhealth.blogspot.com/2017/06/hoarse-voice-and-bovine-cough.html

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Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182
6948891480
alsfakia@gmail.com
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Mon Jun 12, 2017 08:19
  Hyperspectral X-ray transmission imaging................................3D chemical imaging
updated on Mon Jun 12, 2017 12:50 by Alexandros G. Sfakianakis via Allergy Rhinology Immunology Asthma
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http://orlhealth.blogspot.com/2017/06/hyperspectral-x-ray-transmission.html

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182
6948891480
alsfakia@gmail.com
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Mon Jun 12, 2017 08:13
  Persistent lesion hyperintensity on brain diffusion-weighted MRI
updated on Mon Jun 12, 2017 12:50 by Alexandros G. Sfakianakis via Allergy Rhinology Immunology Asthma
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http://orlhealth.blogspot.com/2017/06/persistent-lesion-hyperintensity-on.html

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182
6948891480
alsfakia@gmail.com
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Mon Jun 12, 2017 08:12
  Nausea, vomiting, loss of appetite and oliguria : haemoglobin =12.7 g/dL, indirect bilirubin =2.0 mg/dL, haptoglobin ≤6 mg/dL, platelet count =121 000/μL and schistocytes on peripheral smear.
updated on Mon Jun 12, 2017 12:50 by Alexandros G. Sfakianakis via Allergy Rhinology Immunology Asthma
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http://orlhealth.blogspot.com/2017/06/nausea-vomiting-loss-of-appetite-and.html

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182
6948891480
alsfakia@gmail.com
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Sun Jun 11, 2017 20:53
  MFHAS1 suppresses TLR4 signaling pathway via induction of PP2A C subunit cytoplasm translocation and inhibition of c-Jun dephosphorylation at Thr239
updated on Mon Jun 12, 2017 00:48 by Alexandros G. Sfakianakis via Allergy Rhinology Immunology Asthma
S01615890.gif

Publication date: August 2017
Source:Molecular Immunology, Volume 88
Author(s): Qiqing Shi, Bo Xiong, Jing Zhong, Huihui Wang, Duan Ma, Changhong Miao
TLR4, an important Toll-like receptor in innate immunity, can be activated by LPS and induce proinflammatory cytokines to resist invasion of pathogenic microorganism, but excessive inflammation can trigger tissue injury. Many genes negatively regulate TLR4 signaling pathway. Recent studies found that malignant fibrous histiocytoma amplified sequence 1 (MFHAS1) suppressed the expression of cytokine IL6 in Raw264.7 cells stimulated by LPS, but the mechanisms remained unclear. This study investigated the role of MFHAS1 in TLR4 signaling pathway and the possible mechanisms implicated. The results indicated that the expression of MFHAS1 was significantly increased in cells stimulated with LPS. Up-regulation of MFHAS1 effectively suppressed inflammatory cytokine expression in cells exposed to LPS, whereas down-regulation of MFHAS1 markedly increased inflammatory cytokines expression. Co-immunoprecipitation, pull-down and immunofluorescence tests demonstrated that MFHAS1 combined with the B and C subunits of PP2A and induced cytoplasm translocation of the C subunit, leading to decrease dephosphorylation of c-Jun at Thr239 and increase degradation of c-Jun. Reduction of c-Jun protein results in decreased AP-1 activity, which is independent of inhibition of JNK or p38MAPK phosphorylation. Taken together, these results indicate that MFHAS1 suppresses TLR4 signaling pathway through induction of PP2A C subunit cytoplasm translocation and subsequent c-Jun degradation, leading finally to decrease AP-1 activity and cytokines expression.



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Sat Jun 10, 2017 20:38
  Nicorandil modulated macrophages activation and polarization via NF-κb signaling pathway
updated on Sun Jun 11, 2017 00:38 by Alexandros G. Sfakianakis via Allergy Rhinology Immunology Asthma
S01615890.gif

Publication date: August 2017
Source:Molecular Immunology, Volume 88
Author(s): Fengyun Zhang, Yongli Xuan, Jinjin Cui, Xinxin Liu, Zhiying Shao, Bo Yu
Nicorandil, a drug with both nitrate-like and ATP-sensitive potassium (KATP) channel-activating properties, has been well demonstrated in various aspects of myocardial infarction (MI), especially in inhibiting cell apoptosis and increasing coronary flow. However, the role of nicorandil in regulating inflammation and angiogenesis following myocardial infarction is still unrevealed. In the present study, we explored the effect of nicorandil on macrophage phenotype transition and inflammation regulation and the potential underlying mechanisms. For the phenotype transition and phagocytosis ability of macrophages detection, flow cytometry analysis was used. The inflammation factors were measured with ELISA and qRT-PCR. Western blot was used to assess the levels of NF-κb and its target genes and VEGF expression. The tube formation ability of endothelial cells was examined on matrigel. We discovered that nicorandil can obviously inhibit the differentiation of monocytes into mature macrophages and decrease M1 phenotype transition both in peritoneal macrophages and cultured macrophage cell line in normal or hypoxia and serum deprivation (H/SD) conditions. Meanwhile, nicorandil can induce an anti-inflammatory M2 phenotype. Thereby, nicorandil regulated macrophages switching to M1/M2 status. Our data further showed that NF-κb and the expression of its target genes were pivotal players in the regulation of macrophages phenotype. Besides, we also showed that nicorandil can promote the tube formation and VEGF expression in endothelial cells. We concluded that nicorandil may serve as an effective modulator of NF-κb signaling pathway during the pathogenesis of MI via regulating M1/M2 status and promoting angiogenesis.



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Sat Jun 10, 2017 20:38
  Eculizumab-C5 complexes express a C5a neoepitope in vivo: Consequences for interpretation of patient complement analyses
updated on Sun Jun 11, 2017 00:38 by Alexandros G. Sfakianakis via Allergy Rhinology Immunology Asthma
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Publication date: Available online 10 June 2017
Source:Molecular Immunology
Author(s): Per H. Nilsson, Anub Mathew Thomas, Grethe Bergseth, Alice Gustavsen, Elena B. Volokhina, Lambertus P. van den Heuvel, Andreas Barratt-Due, Tom E. Mollnes
The complement system has obtained renewed clinical focus due to increasing number of patients treated with eculizumab, a monoclonal antibody inhibiting cleavage of C5 into C5a and C5b. The FDA approved indications are paroxysmal nocturnal haemoglobinuria and atypical haemolytic uremic syndrome, but many other diseases are candidates for complement inhibition. It has been postulated that eculizumab does not inhibit C5a formation in vivo, in contrast to what would be expected since it blocks C5 cleavage. We recently revealed that this finding was due to a false positive reaction in a C5a assay. In the present study, we identified expression of a neoepitope which was exposed on C5 after binding to eculizumab in vivo. By size exclusion chromatography of patient serum obtained before and after infusion of eculizumab, we document that the neoepitope was exposed in the fractions containing the eculizumab-C5 complexes, being positive in this actual C5a assay and negative in others. Furthermore, we confirmed that it was the eculizumab-C5 complexes that were detected in the C5a assay by adding an anti-IgG4 antibody as detection antibody. Competitive inhibition by anti-C5 antibodies localized the epitope to the C5a moiety of C5. Finally, acidification of C5, known to alter C5 conformation, induced a neoepitope reacting identical to the one we explored, in the C5a assays. These data are important for interpretation of complement analyses in patients treated with eculizumab.



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Sat Jun 10, 2017 19:14
  Enhanced stimulation of human tumor-specific T cells by dendritic cells matured in the presence of interferon-γ and multiple toll-like receptor agonists
updated on Sun Jun 11, 2017 00:38 by Alexandros G. Sfakianakis via Allergy Rhinology Immunology Asthma
Abstract
Dendritic cell (DC) vaccines have been demonstrated to elicit immunological responses in numerous cancer immunotherapy trials. However, long-lasting clinical effects are infrequent. We therefore sought to establish a protocol to generate DC with greater immunostimulatory capacity. Immature DC were generated from healthy donor monocytes by culturing in the presence of IL-4 and GM-CSF and were further differentiated into mature DC by the addition of cocktails containing different cytokines and toll-like receptor (TLR) agonists. Overall, addition of IFNγ and the TLR7/8 agonist R848 during maturation was essential for the production of high levels of IL-12p70 which was further augmented by adding the TLR3 agonist poly I:C. In addition, the DC matured with IFNγ, R848, and poly I:C also induced upregulation of several other pro-inflammatory and Th1-skewing cytokines/chemokines, co-stimulatory receptors, and the chemokine receptor CCR7. For most cytokines and chemokines the production was even further potentiated by addition of the TLR4 agonist LPS. Concurrently, upregulation of the anti-inflammatory cytokine IL-10 was modest. Most importantly, DC matured with IFNγ, R848, and poly I:C had the ability to activate IFNγ production in allogeneic T cells and this was further enhanced by adding LPS to the cocktail. Furthermore, epitope-specific stimulation of TCR-transduced T cells by peptide- or whole tumor lysate-loaded DC was efficiently stimulated only by DC matured in the full maturation cocktail containing IFNγ and the three TLR ligands R848, poly I:C, and LPS. We suggest that this cocktail is used for future clinical trials of anti-cancer DC vaccines.



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Sat Jun 10, 2017 18:24
  Transfer of innovation on allergic rhinitis and asthma multimorbidity in the elderly (MACVIA-ARIA) - Reference Site Twinning (EIP on AHA)
updated on Sun Jun 11, 2017 00:38 by Alexandros G. Sfakianakis via Allergy Rhinology Immunology Asthma
Abstract
The overarching goals of the European Innovation Partnership on Active and Healthy Ageing (EIP on AHA) are to enable European citizens to lead healthy, active and independent lives while ageing. The EIP on AHA includes 74 Reference Sites. The aim of this study is to transfer innovation from an App developed by the MACVIA-France EIP on AHA reference site (Allergy Diary) to other reference sites. The phenotypic characteristics of rhinitis and asthma multimorbidity in adults and the elderly will be compared using validated information and communication technology (ICT) tools (i.e. the Allergy Diary and CARAT: Control of Allergic Rhinitis and Asthma Test) in 22 Reference Sites or regions across Europe. This will improve understanding, assessment of burden, diagnosis and management of rhinitis in the elderly by comparison with an adult population. Specific objectives will: (i) assess the percentage of adults and elderly who are able to use the Allergy Diary, (ii) study phenotypic characteristics and treatment over a period of one year of rhinitis and asthma multimorbidity at baseline (cross-sectional study) and (iii) follow-up using visual analogue scale (VAS). This part of the study may provide some insight into the differences between the elderly and adults in terms of response to treatment and practice. Finally (iv) work productivity will be examined in adults.

This article is protected by copyright. All rights reserved.



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Sat Jun 10, 2017 18:23
  Influences of environmental bacteria and their metabolites on allergies, asthma and host microbiota
updated on Sun Jun 11, 2017 00:38 by Alexandros G. Sfakianakis via Allergy Rhinology Immunology Asthma
Abstract
The prevalence of allergic diseases and asthma has dramatically increased over the last decades, resulting in a high burden for patients and health care systems. Thus, there is an unmet need to develop preventative strategies for these diseases.

Epidemiological studies show that reduced exposure to environmental bacteria in early life (e.g birth by cesarian section, being formula-fed, growing up in an urban environment or with less contact to various persons) is associated with an increased risk to develop allergies and asthma later in life. Conversely, a reduced risk for asthma is consistently found in children growing up on traditional farms, thereby being exposed to a wide spectrum of microbes. However, clinical studies are still rare and to some extent contradicting. A detailed mechanistic understanding how environmental microbes influence the development of the human microbiome and the immune system is important to enable the development of novel preventative approaches that are based on the early modulation of the host microbiota and immunity.

In this mini-review we summarize current knowledge and experimental evidence for the potential of bacteria and their metabolites to be used for the prevention of asthma and allergic diseases.

This article is protected by copyright. All rights reserved.



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Sat Jun 10, 2017 18:23
  Spontaneous food allergy in Was-/- mice occurs independent of FcεRI-mediated mast cell activation
updated on Sun Jun 11, 2017 00:39 by Alexandros G. Sfakianakis via Allergy Rhinology Immunology Asthma
Abstract
Background
Food allergies are a growing health problem and the development of therapies that prevent disease onset is limited by the lack of adjuvant-free experimental animal models. We compared allergic sensitization in patients with food allergy or Wiskott-Aldrich syndrome (WAS) and defined whether spontaneous disease in Was-/- mice recapitulates the pathology of a conventional disease model and/or human food allergy.

Methods
Comparative ImmunoCAP ISAC microarray was performed in patients with food allergy or WAS. Spontaneous food allergy in Was-/- mice was compared to an adjuvant-based model in wild-type mice (WT-OVA/alum). Intestinal and systemic anaphylaxis was assessed and the role of the high affinity IgE Fc receptor (FcεRI) in allergic sensitization was evaluated using Was-/-Fcer1a-/- mice.

Results
Polysensitization to food was detected in both WAS and food allergic patients which was recapitulated in the Was-/- model. Oral administration of OVA in Was-/- mice induced low titers of OVA-specific IgE compared to the WT-OVA/alum model. Irrespectively, 79% of Was-/- mice developed allergic diarrhea following oral OVA challenge. Systemic anaphylaxis occurred in Was-/- mice (95%) with a mortality rate >50%. Spontaneous sensitization and intestinal allergy occurred independent of FcεRI expression on mast cells and basophils.

Conclusions
Was-/- mice provide a model of food allergy with the advantage of mimicking polysensitization and low food-antigen IgE titers as observed in humans with clinical food allergy. This model will facilitate studies on aberrant immune responses during spontaneous disease development. Our results imply that therapeutic targeting of the IgE/FcεRI activation cascade will not affect sensitization to food.

This article is protected by copyright. All rights reserved.



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Sat Jun 10, 2017 13:33
  Update on Intranasal Medications in Rhinosinusitis
updated on Sat Jun 10, 2017 17:34 by Alexandros G. Sfakianakis via Allergy Rhinology Immunology Asthma
Abstract
This review describes beneficial effects and adverse events of various intranasal medications in treating rhinosinusitis. Application of intranasal steroids has been described in treating all subtypes of adult rhinosinusitis, but reports are limited in pediatrics and mostly in acute pediatric subgroups resulted in benefits While saline irrigation is effective for patients with chronic rhinosinusitis without polyps and in pediatric acute rhinosinusitis, there is no evidence yet for saline drips and sprays. Application of intranasal antifungals and nasal irrigation with surfactant brings more harm than benefits. There is no evidence supporting the use of intranasal antibiotics. We also review influence of devices, methods, and patient head position on nasal and paranasal sinus drug delivery.



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Sat Jun 10, 2017 13:23
  TGF-β1-silenced leukemia cell-derived exosomes target dendritic cells to induce potent anti-leukemic immunity in a mouse model
updated on Sat Jun 10, 2017 17:34 by Alexandros G. Sfakianakis via Allergy Rhinology Immunology Asthma
Abstract
Tumor-derived exosomes (TEX) can induce a specific antitumor immune response and have been developed as a promising tumor vaccine. Despite promising preclinical data, TEX exhibit relatively low efficacy and limited clinical benefit in clinical trials. In the present study, we investigated whether exosomes from the TGF-β1 silenced L1210 cells (LEXTGF-β1si) can enhance the efficacy of DC-based vaccines. We silenced TGF-β1 in L1210 cells with a lentiviral shRNA vector and prepared the LEXTGF-β1si. It was shown that LEXTGF-β1si can significantly decrease TGF-β1 expression of dendritic cells (DC) and effectively promote their maturation and immune function. In addition, DC pulsed with LEXTGF-β1si (DCLEX-TGF-β1si) more effectively promoted CD4+ T cell proliferation in vitro and Th1 cytokine secretion and induced tumor-specific CTL response. This response was higher in potency compared to that noted by the other two formulations. Moreover, DCLEX-TGF-β1si inhibited tumor growth more efficiently than other formulations did as the preventive or therapeutic tumor vaccine. Accordingly, these findings revealed that DCLEX-TGF-β1si induced a more potent antigen-specific anti-leukemic immunity than DC pulsed with exosomes from non-manipulated L1210 cells. This indicated that the targeting of DC by LEXTGF-β1si may be used as a promising approach for leukemia immunotherapy.



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Sat Jun 10, 2017 07:58
  Interaction of Immunoglobulin with Cytomegalovirus-Infected Cells
updated on Sat Jun 10, 2017 11:59 by Alexandros G. Sfakianakis via Allergy Rhinology Immunology Asthma
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Viral Immunology , Vol. 0, No. 0.


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Fri Jun 09, 2017 20:55
  Beyond epithelial-to-mesenchymal transition: common suppression of differentiation programs underlies epithelial barrier dysfunction in mild, moderate and severe asthma
updated on Sat Jun 10, 2017 00:54 by Alexandros G. Sfakianakis via Allergy Rhinology Immunology Asthma
Abstract
Background
Epithelial barrier dysfunction is a central feature in the pathogenesis of allergic disease. Epithelial-to-mesenchymal transition (EMT) has been proposed as one mechanism afflicting barrier in asthma. However, genes and pathways involved in aberrant epithelial-mesenchymal signaling, and their relationship to asthma severity, are poorly understood.

Methods
We used unbiased gene network analysis to evaluate functional convergence in epithelial gene expression signatures across multiple public access transcriptomics datasets of human asthma, followed by text mining to evaluate functional marker relevance of discovered genes. We objectively confirmed these findings in epithelial brushings and primary asthmatic epithelial cells cultured in different biological contexts.

Results
We found a striking suppression of epithelial differentiation in asthma, overrepresented by insufficiency in insulin and Notch signaling, but with the absence of conventional EMT markers. We identified EFNB2, FGFR1, FGFR2, INSR, IRS2, NOTCH2, TLE1, and NTRK2 as novel markers central to dysregulation of epithelial-mesenchymal signaling, but surprisingly overlooked in asthma research. We found that this "core" signature of asthma is shared by mild, moderate, and severe forms of disease, progressing with severity. Loss of epithelial differentiation induced by insulin deprivation in normal human bronchial epithelial cells cultured in organotypic conditions closely approximated gene expression in asthmatic epithelial brushings.

Conclusions
The comparative analysis of publically available transcriptomes demonstrated that epithelial barrier dysfunction in asthma is characterized by persistent underlying de-differentiation program with complex etiology. The lasting alteration of the asthmatic epithelial cell transcriptome implicates regulation involving metabolism and epigenetics, beyond EMT driven by injury and repair in chronic inflammation.

This article is protected by copyright. All rights reserved.



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Fri Jun 09, 2017 20:55
  Non-lesional atopic dermatitis skin shares similar T-cell clones with lesional tissues
updated on Sat Jun 10, 2017 00:54 by Alexandros G. Sfakianakis via Allergy Rhinology Immunology Asthma
Abstract
Background
Atopic dermatitis (AD) is characterized by robust immune activation. Various T-cell subsets, including Th2/Th22 cells, are increased in lesional and non-lesional skin. However, there is conflicting literature on the diversity of the T-cell receptor (TCR) repertoire in lesional AD, and its relation to non-lesional skin remains unclear.

Methods
We performed high-throughput deep sequencing of the β-TCR repertoire in 29 lesional and 19 non-lesional AD biopsies, compared to 6 healthy control and 6 cutaneous T-cell lymphoma (CTCL) samples from previously published cohorts.

Results
While greater T-cell infiltrates were observed in lesional vs. non-lesional AD, TCR repertoire diversity was similar in lesional and non-lesional tissues, and absolute numbers of unique T-cell clones correlated with respective T-cell counts. Most (87%) top expanded lesional T-cell clones were shared with non-lesional tissues, and they were largely maintained after 16 weeks of successful treatment with topical triamcinolone. Nevertheless, both lesional and non-lesional AD showed a highly polyclonal TCR pattern, without evidence of oligoclonal expansion, or a preferred usage of certain V-β genes in AD skin. Size of the overall T-cell infiltrate, but not the level of clonality, correlated with mRNA levels of key inflammatory mediators (e.g. IL-13, CCL17, IL23p19, CXCL10).

Conclusion
While AD harbors a highly polyclonal T-cell receptor repertoire, and despite the lack of information on TCR antigen specificity, the sharing of top abundant clones between lesional and non-lesional skin, and their persistence after months of therapy, points to the continuous presence of potentially pathogenic skin resident memory T-cells well beyond clinically inflamed lesions.

This article is protected by copyright. All rights reserved.



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Fri Jun 09, 2017 20:54
  Mechanisms of exercise-induced bronchoconstriction in athletes: current perspectives and future challenges
updated on Sat Jun 10, 2017 00:54 by Alexandros G. Sfakianakis via Allergy Rhinology Immunology Asthma
Abstract
The evidence of exercise-induced bronchoconstriction (EIB) without asthma (EIBwA) occurring in athletes led to speculate about different endotypes inducing respiratory symptoms within athletes. Classical postulated mechanisms for bronchial obstruction in this population include the osmotic and the thermal hypotheses. More recently, the presence of epithelial injury and inflammation in the airways of athletes was demonstrated. In addition, neuronal activation has been suggested as a potential modulator of bronchoconstriction. Investigation of these emerging mechanisms are of major importance since EIB is a significant problem for both recreational and competitive athletes and is the most common chronic condition among Olympic athletes, with obvious implications for their competing performance, health and quality of life. Hereby we summarize the latest achievements in this area and identify the current gaps of knowledge so that future research heads towards better defining the etiologic factors and mechanisms involved in development of EIB in elite athletes as well as essential aspects to ultimately propose preventive and therapeutic measures.

This article is protected by copyright. All rights reserved.



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Fri Jun 09, 2017 20:54
  A possible role of stem cells in nasal polyposis
updated on Sat Jun 10, 2017 00:54 by Alexandros G. Sfakianakis via Allergy Rhinology Immunology Asthma
Abstract
Since its discovery, the understanding of stem/progenitor cells raised dramatically in the last decade. Their regenerative potential is important to develop new therapeutic applications, but the identification advanced much faster than our understanding of stem/progenitor cells. In nasal polyposis, little is known about stem cells/progenitor cells and their ability. However, the further characterization of stem cells/progenitor cells may provide new treatment options for combating nasal polyposis. This review highlights the knowledge of the current literature about stem cells/progenitor cells in nasal polyposis and how this may be exploited in the development of novel treatment strategies.

This article is protected by copyright. All rights reserved.



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Fri Jun 09, 2017 11:24
  Υπέρ Τροφές : ACAI berries powder bio Βιολογικό. Ενέργεια και αντοχή. Alfalfa Ο ΒΑΣΙΛΙΑΣ ΤΩΝ ΒΛΑΣΤΩΝ Apricot Kernels bio Πυρήνας Βερίκοκου! Aronia berries bio Η μελανόκαρπη! ASHWAGANDHA Powder Organic Το Ινδικό τσινσενγκ! Astragalus organic powder Ο ισχυρός σύμμαχος για το ανοσοποιητικό! AΜΒΡΟΣΙΑ Baobab powder Barley Grass ( Κριθαρόχορτο ) Blueberries Brahmi ( Gotu Kola) Powder Organic Cacao beans Cacao nibs Cacao powder bio Cacao Raw Butter Camu Camu Cats Claw Το νύχι της Γάτας Catuaba Το Catuaba είναι ένα βότανο που CHAGA Mushroom powder Chlorella Organic Powder Cranberries Dong Quai organic powder Enecta 10% CBD Έλαιο Κάνναβης Ginseng powder Korean panax bio Graviola powder Guarana powder bio GYNOSTEMA Organic powder He shou wu Fo–ti Hemp Protein bio Hemp Seeds bio Hemp seeds organic, αποφλοιωμένα Η καλύτερη πηγή πρωτείνης Horny Goat Incan-Golden Berries Kelp powder Kινόα οργανική Lingonberries Lucuma powder Maca powder Maca powder gelatinized bio Maitake organic powder MESQUITE meal Moringa Powder MSM Powder MUCUNA PRURIENS Powder Premium Shitake Powder Raspberry-Σμέουρα ωσμωτικά Reishi Mushroom Powder ΓΑΝΟΔΕΡΜΑ Rhodiola Rosea organic powder Rice Protein Rosehip Powder bio Sacha Inchi Oil Sacha inchi καρποί Scheden Bitter Schweden Bitter Schweden Bitter Schweden Βitter SHILAJIT Powder Shisandra Berries Suma root Super Moringa Leaves Tribulus Wheat Grass bio Αγάρ Αγάρ Βιολογική Φυσική ζελατίνη Αλόη αποξηραμένη Αλόη Οργανικός Χυμός Γαιδουραγκαθέλαιο Γανόδερμα δίρφυς Γκοτζι Μπερι Ζεόλιθος ΘΙΒΕΤΙΑΝΟ ΓΚΟΤΖΙ Ιπποφαές Κολλαγόνο με Υαλουρονικό Κολλαγόνο ΛΑΔΙ ΑΠΟ ΜΑΥΡΟ ΚΥΜΙΝΟ Λάδι Κάνναβης Οργανικό Λάδι Καρύδας Μαύρη Κορινθιακή σταφίδα Μύρτιλο Παστέλι με Φυστικοβούτυρο Πρωτε'ί'νη Aρακά οργανική Ρόδι Ρυζογκοφρέτες Σιρόπι Σφενδάμου Σπιρουλίνα Σπόροι Chia Φαγόπυρο Φυστικοβούτυρο Φυστικοβούτυρο Φυστικοβούτυρο Φυστικοβούτυρο Χαρουπόμελο Χυμός Οραγανικός από Αloe Vera Ψίλιο
updated on Fri Jun 09, 2017 15:22 by Alexandros G. Sfakianakis via Allergy Rhinology Immunology Asthma
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ACAI berries powder bio
Βιολογικό. Ενέργεια και αντοχή.
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Alfalfa
Ο ΒΑΣΙΛΙΑΣ ΤΩΝ ΒΛΑΣΤΩΝ
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Apricot Kernels bio
Πυρήνας Βερίκοκου!
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Aronia berries bio
Η μελανόκαρπη!
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Το Ινδικό τσινσενγκ!
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Barley Grass ( Κριθαρόχορτο )
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Blueberries
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Camu Camu
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Cats Claw
Το νύχι της Γάτας
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Graviola powder
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Guarana powder bio
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xaroupomelo6
Χαρουπόμελο
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Χυμός Οραγανικός από Αloe Vera
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Tue Jun 06, 2017 07:33
  Functional and phenotypic analysis of basophils allows determining distinct subtypes in patients with chronic urticaria
updated on Tue Jun 06, 2017 11:33 by Alexandros G. Sfakianakis via Allergy Rhinology Immunology Asthma
Abstract
Background
Chronic urticaria (CU) is a frequent skin disease characterized by relapsing appearance of pruritic hives. While clinical symptoms are due to the release of histamine by cutaneous mast cells, the underlying pathophysiology is still unknown. However, previous studies indicate that basophils might be of relevance. Besides, the occurrence of autoantibodies against IgE or its receptor, FcεRI, and the therapeutic efficacy of anti-IgE antibodies imply that IgE-mediated mechanisms also play an important role in CU.

Methods
Reactivity of CU patients' peripheral blood basophils (n=60) to specific anti-FcεRI and IgE-independent fMLP stimulation was determined by basophil activation test in comparison to patients suffering from IgE-mediated allergic rhinitis (n=10) and healthy controls (n=10). In addition, immunoglobulin receptor (FcεRI, FcγRII) expression and surface bound antibodies (IgE, IgG) were quantified on basophils. Furthermore, the autoreactive capacity of CU sera was evaluated and urticaria-related symptoms were assessed by both UCT and CU-Q2oL.

Results
Stimulating CU patients' basophils via FcεRI, we identified three distinct immunological phenotypes. One subgroup of patients' basophils reacted to FcεRI stimulation, whereas the others had anti-FcεRI non-reactive basophils. Among the latter a subgroup with pronounced basopenia was identified. Of note, this group was characterized by augmented serum-induced basophil activation, increased levels of autoantibodies against thyroid peroxidase and also exhibited the strongest disease impact on their quality of life.

Conclusions
CU patients can be categorized into three immunological subgroups based on their basophil reactivity and frequency. These phenotypes are associated with different clinical characteristics, pointing to basophils as important players in CU pathophysiology.

This article is protected by copyright. All rights reserved.



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Tue Jun 06, 2017 00:39
  Complement C5a Functions as a Master Switch for the pH Balance in Neutrophils Exerting Fundamental Immunometabolic Effects [INNATE IMMUNITY AND INFLAMMATION]
updated on Tue Jun 06, 2017 04:39 by Alexandros G. Sfakianakis via Allergy Rhinology Immunology Asthma
During sepsis, excessive activation of the complement system with generation of the anaphylatoxin C5a results in profound disturbances in crucial neutrophil functions. Moreover, because neutrophil activity is highly dependent on intracellular pH (pHi), we propose a direct mechanistic link between complement activation and neutrophil pHi. In this article, we demonstrate that in vitro exposure of human neutrophils to C5a significantly increased pHi by selective activation of the sodium/hydrogen exchanger. Upstream signaling of C5a-mediated intracellular alkalinization was dependent on C5aR1, intracellular calcium, protein kinase C, and calmodulin, and downstream signaling regulated the release of antibacterial myeloperoxidase and lactoferrin. Notably, the pH shift caused by C5a increased the glucose uptake and activated glycolytic flux in neutrophils, resulting in a significant release of lactate. Furthermore, C5a induced acidification of the extracellular micromilieu. In experimental murine sepsis, pHi of blood neutrophils was analogously alkalinized, which could be normalized by C5aR1 inhibition. In the clinical setting of sepsis, neutrophils from patients with septic shock likewise exhibited a significantly increased pHi. These data suggest a novel role for the anaphylatoxin C5a as a master switch of the delicate pHi balance in neutrophils resulting in profound inflammatory and metabolic changes that contribute to hyperlactatemia during sepsis.



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Tue Jun 06, 2017 00:39
  RIG-I-like Receptor Triggering by Dengue Virus Drives Dendritic Cell Immune Activation and TH1 Differentiation [INFECTIOUS DISEASE AND HOST RESPONSE]
updated on Tue Jun 06, 2017 04:39 by Alexandros G. Sfakianakis via Allergy Rhinology Immunology Asthma
Dengue virus (DENV) causes 400 million infections annually and is one of several viruses that can cause viral hemorrhagic fever, which is characterized by uncontrolled immune activation resulting in high fever and internal bleeding. Although the underlying mechanisms are unknown, massive cytokine secretion is thought to be involved. Dendritic cells (DCs) are the main target cells of DENV, and we investigated their role in DENV-induced cytokine production and adaptive immune responses. DENV infection induced DC maturation and secretion of IL-1β, IL-6, and TNF. Inhibition of DENV RNA replication abrogated these responses. Notably, silencing of RNA sensors RIG-I or MDA5 abrogated DC maturation, as well as cytokine responses by DENV-infected DCs. DC maturation was induced by type I IFN responses because inhibition of IFN-α/β receptor signaling abrogated DENV-induced DC maturation. Moreover, DENV infection of DCs resulted in CCL2, CCL3, and CCL4 expression, which was abrogated after RIG-I and MDA5 silencing. DCs play an essential role in TH cell differentiation, and we show that RIG-I and MDA5 triggering by DENV leads to TH1 polarization, which is characterized by high levels of IFN-. Notably, cytokines IL-6, TNF, and IFN- and chemokines CCL2, CCL3, and CCL4 have been associated with disease severity, endothelial dysfunction, and vasodilation. Therefore, we identified RIG-I and MDA5 as critical players in innate and adaptive immune responses against DENV, and targeting these receptors has the potential to decrease hemorrhagic fever in patients.



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Tue Jun 06, 2017 00:39
  New Insights into the Role of IL-1{beta} in Experimental Autoimmune Encephalomyelitis and Multiple Sclerosis [BRIEF REVIEWS]
updated on Tue Jun 06, 2017 04:39 by Alexandros G. Sfakianakis via Allergy Rhinology Immunology Asthma
Multiple sclerosis (MS), and its animal model experimental autoimmune encephalomyelitis, are neuroinflammatory diseases driven by autoreactive pathogenic TH cells that elicit demyelination and axonal damage. How TH cells acquire pathogenicity and communicate with myeloid cells and cells of the CNS remain unclear. IL-1β is recognized to play an important role in experimental autoimmune encephalomyelitis (EAE) and perhaps MS. Clinical EAE is significantly attenuated in IL-1R–deficient and IL-1β–deficient mice, and IL-1β is found in the blood, cerebrospinal fluid, and CNS lesions of MS patients. In this article, we focus on new reports that elucidate the cellular sources of IL-1β and its actions during EAE, in both lymphoid tissues and within the CNS. Several immune cell types serve as critical producers of IL-1β during EAE, with this cytokine inducing response in both hematopoietic and nonhematopoietic cells. These findings from the EAE model should inspire efforts toward investigating the therapeutic potential of IL-1 blockade in MS.



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Tue Jun 06, 2017 00:39
  A Schistosoma japonicum Infection Promotes the Expansion of Myeloid-Derived Suppressor Cells by Activating the JAK/STAT3 Pathway [INFECTIOUS DISEASE AND HOST RESPONSE]
updated on Tue Jun 06, 2017 04:39 by Alexandros G. Sfakianakis via Allergy Rhinology Immunology Asthma
Myeloid-derived suppressor cells (MDSCs), a heterogeneous group of immune cells from the myeloid lineage, play an important part in suppression of host immune responses during many pathologic conditions, including cancer and infectious diseases. Thus, understanding the functional diversity of these cells as well as the underlying mechanisms is crucial for the development of disease control strategies. The role of MDSCs during Schistosoma japonicum infection, however, is not clear, and there is a lack of systematic study so far. In this study, we provide strong evidence that the soluble egg Ag (SEA) and schistosome worm Ag (SWA) of S. japonicum enhance the accumulation of MDSCs. Ag-induced MDSCs have more potent suppressive effects on T cell responses than do control MDSCs in both in vivo S. japonicum infection and in vitro SEA- and SWA-treated mouse bone marrow cells experiments. Interestingly, the enhanced suppressive activity of MDSCs by Ag administration was coupled with a dramatic induction of the NADPH oxidase subunits gp91phox and p47phox and was dependent on the production of reactive oxygen species. Moreover, mechanistic studies revealed that the Ag effects are mediated by JAK/STAT3 signaling. Inhibition of STAT3 phosphorylation by the JAK inhibitor JSI-124 almost completely abolished the Ag effects on the MDSCs. In summary, this study sheds new light on the immune modulatory role of SEA and SWA and demonstrates that the expansion of MDSCs may be an important element of a cellular network regulating immune responses during S. japonicum infection.



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Tue Jun 06, 2017 00:39
  Cutting Edge: Differential Fine-Tuning of IL-2- and IL-15-Dependent Functions by Targeting Their Common IL-2/15R{beta}/{gamma}c Receptor [CUTTING EDGE]
updated on Tue Jun 06, 2017 04:39 by Alexandros G. Sfakianakis via Allergy Rhinology Immunology Asthma
Interleukin 2 and IL-15 are two closely related cytokines, displaying important functions in the immune system. They share the heterodimeric CD122/CD132 receptor to deliver their signals within target cells. Their specificity of action is conferred by their α receptor chains, IL-2Rα and IL-15Rα. By combining an increased affinity for CD122 and an impaired recruitment of CD132, we have generated an original molecule named IL-2Rβ/ (CD122/CD132) inhibitor (BiG), targeting the CD122/CD132 receptor. BiG efficiently inhibited IL-15– and IL-2–dependent functions of primary cells, including CD8 T and NK cells, in vitro and in vivo. We also report a differential dynamic of action of these cytokines by highlighting a major role played by the IL-2Rα receptor. Interestingly, due to the presence of IL-2Rα, BiG had no impact on IL-2–dependent regulatory T cell proliferation. Thus, by acting as a fine switch in the immune system, BiG emphasizes the differential roles of these two cytokines.



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Tue Jun 06, 2017 00:39
  A Time- and Compartment-Specific Activation of Lung Macrophages in Hypoxic Pulmonary Hypertension [INNATE IMMUNITY AND INFLAMMATION]
updated on Tue Jun 06, 2017 04:39 by Alexandros G. Sfakianakis via Allergy Rhinology Immunology Asthma
Studies in various animal models suggest an important role for pulmonary macrophages in the pathogenesis of pulmonary hypertension (PH). Yet, the molecular mechanisms characterizing the functional macrophage phenotype relative to time and pulmonary localization and compartmentalization remain largely unknown. In this study, we used a hypoxic murine model of PH in combination with FACS to quantify and isolate lung macrophages from two compartments over time and characterize their programing via RNA sequencing approaches. In response to hypoxia, we found an early increase in macrophage number that was restricted to the interstitial/perivascular compartment, without recruitment of macrophages to the alveolar compartment or changes in the number of resident alveolar macrophages. Principal component analysis demonstrated significant differences in overall gene expression between alveolar and interstitial macrophages (IMs) at baseline and after 4 and 14 d hypoxic exposure. Alveolar macrophages at both day 4 and 14 and IMs at day 4 shared a conserved hypoxia program characterized by mitochondrial dysfunction, proinflammatory gene activation, and mTORC1 signaling, whereas IMs at day 14 demonstrated a unique anti-inflammatory/proreparative programming state. We conclude that the pathogenesis of vascular remodeling in hypoxic PH involves an early compartment-independent activation of lung macrophages toward a conserved hypoxia program, with the development of compartment-specific programs later in the course of the disease. Thus, harnessing time- and compartment-specific differences in lung macrophage polarization needs to be considered in the therapeutic targeting of macrophages in hypoxic PH and potentially other inflammatory lung diseases.



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Tue Jun 06, 2017 00:38
  Cutting Edge: ERK1 Mediates the Autocrine Positive Feedback Loop of TGF-{beta} and Furin in Glioma-Initiating Cells [CUTTING EDGE]
updated on Tue Jun 06, 2017 04:39 by Alexandros G. Sfakianakis via Allergy Rhinology Immunology Asthma
Glioblastoma is the most common and aggressive intrinsic brain tumor in adults. Self-renewing, highly tumorigenic glioma-initiating cells (GIC) have been linked to glioma invasive properties, immunomodulation, and increased angiogenesis, leading to resistance to therapy. TGF-β signaling has been associated with the tumorigenic activity of GIC. TGF-β is synthesized as a precursor molecule and proteolytically processed to the mature form by members of the family of the proprotein convertases subtilisin/kexin. In this study we report that furin is unique among the proprotein convertases subtilisin/kexin in being highly expressed in human GIC. Furin cleaves and promotes activation of pro–TGF-β1 and pro–TGF-β2, and TGF-β2 in turn increases furin levels. Notably, TGF-β2 controls furin activity in an ALK-5–dependent manner involving the ERK/MAPK pathway. We thus uncover a role of ERK1 in the regulation of furin activity by supporting a self-sustaining loop for high TGF-β activity in GIC.



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Tue Jun 06, 2017 00:38
  In This Issue [IN THIS ISSUE]
updated on Tue Jun 06, 2017 04:39 by Alexandros G. Sfakianakis via Allergy Rhinology Immunology Asthma


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Tue Jun 06, 2017 00:38
  Cutting Edge: Defective Aerobic Glycolysis Defines the Distinct Effector Function in Antigen-Activated CD8+ Recent Thymic Emigrants [CUTTING EDGE]
updated on Tue Jun 06, 2017 04:39 by Alexandros G. Sfakianakis via Allergy Rhinology Immunology Asthma
Recent thymic emigrants (RTEs) are the youngest peripheral T cells that have completed thymic selection and egress to the lymphoid periphery. RTEs are functionally distinct from their more mature but still naive T cell counterparts, because they exhibit dampened proliferation and reduced cytokine production upon activation. In this article, we show that, compared with more mature but still naive T cells, RTEs are impaired in their ability to perform aerobic glycolysis following activation. Impaired metabolism underlies the reduced IFN- production observed in activated RTEs. This failure to undergo Ag-induced aerobic glycolysis is caused by reduced mTORC1 activity and diminished Myc induction in RTEs. Critically, exogenous IL-2 restores Myc expression in RTEs, driving aerobic glycolysis and IFN- production to the level of mature T cells. These results reveal a previously unknown metabolic component to postthymic T cell maturation.



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Tue Jun 06, 2017 00:38
  B Cell Activity Is Impaired in Human and Mouse Obesity and Is Responsive to an Essential Fatty Acid upon Murine Influenza Infection [INFECTIOUS DISEASE AND HOST RESPONSE]
updated on Tue Jun 06, 2017 04:39 by Alexandros G. Sfakianakis via Allergy Rhinology Immunology Asthma
Obesity is associated with increased risk for infections and poor responses to vaccinations, which may be due to compromised B cell function. However, there is limited information about the influence of obesity on B cell function and underlying factors that modulate B cell responses. Therefore, we studied B cell cytokine secretion and/or Ab production across obesity models. In obese humans, B cell IL-6 secretion was lowered and IgM levels were elevated upon ex vivo anti-BCR/TLR9 stimulation. In murine obesity induced by a high fat diet, ex vivo IgM and IgG were elevated with unstimulated B cells. Furthermore, the high fat diet lowered bone marrow B cell frequency accompanied by diminished transcripts of early lymphoid commitment markers. Murine B cell responses were subsequently investigated upon influenza A/Puerto Rico/8/34 infection using a Western diet model in the absence or presence of docosahexaenoic acid (DHA). DHA, an essential fatty acid with immunomodulatory properties, was tested because its plasma levels are lowered in obesity. Relative to controls, mice consuming the Western diet had diminished Ab titers whereas the Western diet plus DHA improved titers. Mechanistically, DHA did not directly target B cells to elevate Ab levels. Instead, DHA increased the concentration of the downstream specialized proresolving lipid mediators (SPMs) 14-hydroxydocosahexaenoic acid, 17-hydroxydocosahexaenoic acid, and protectin DX. All three SPMs were found to be effective in elevating murine Ab levels upon influenza infection. Collectively, the results demonstrate that B cell responses are impaired across human and mouse obesity models and show that essential fatty acid status is a factor influencing humoral immunity, potentially through an SPM-mediated mechanism.



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Tue Jun 06, 2017 00:38
  Alternative Start Sites Downstream of Non-Sense Mutations Drive Antigen Presentation and Tolerance Induction to C-Terminal Epitopes [ANTIGEN RECOGNITION AND RESPONSES]
updated on Tue Jun 06, 2017 04:39 by Alexandros G. Sfakianakis via Allergy Rhinology Immunology Asthma
CTL responses to the transgene product remain an active area of concern for the gene therapy field. A patient's underlying genetic mutation may influence the qualitative nature of these potentially destructive T cell responses. Individuals with a mutation that introduces a premature termination codon (PTC) that prevents synthesis of the full-length peptide are considered more likely to mount a transgene-specific T cell response because of a lack of immune tolerance to C-terminal epitopes as a consequence of absent endogenous Ag presentation. In this article, we demonstrate that a human ornithine transcarbamylase gene containing various PTC-inducing non-sense mutations is able to generate and present epitopes downstream of the termination codon. Generation of these epitopes occurs primarily from alternative translation start sites downstream of the stop codon. Furthermore, we show that expression of these genes from adeno-associated virus vectors in C57BL/6 mice is able to induce peripheral tolerance to epitopes downstream of the PTC. These results suggest that, despite the lack of full-length endogenous protein, patients with PTC-inducing non-sense mutations may still present T cell epitopes downstream of the premature termination site that may render the subject tolerant to wild-type transgene products.



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Tue Jun 06, 2017 00:38
  Chronic Critical Illness from Sepsis Is Associated with an Enhanced TCR Response [INFECTIOUS DISEASE AND HOST RESPONSE]
updated on Tue Jun 06, 2017 04:39 by Alexandros G. Sfakianakis via Allergy Rhinology Immunology Asthma
Sepsis is characterized by a disproportionate host response to infection that often culminates in multiple organ failure. Current concepts invoke a deregulated immune reaction involving features of hyperinflammation, as well as protracted immune suppression. However, owing to the scarcity of human data, the precise origin of a long-term suppression of adaptive immunity remains doubtful. We report on an explorative clinical study of chronic critical illness (CCI) patients aimed at assessing the long-term consequences of sepsis on T cell function. Blood was drawn from 12 male CCI patients (median age 67 y, range 48–79 y) receiving continuous mechanical ventilation and renal replacement therapy in a long-term care hospital who had been treated in an external acute care hospital for severe sepsis. T cells were purified and subjected to flow cytometric immune-phenotyping and functional assays. We found that T cells from CCI patients featured higher basal levels of activation and stronger expression of the inhibitory surface receptor programmed cell death 1 compared with controls. However, T cells from CCI patients exhibited no suppressed TCR response at the level of proximal TCR signaling (activation/phosphorylation of PLC, Erk, Akt, LAT), activation marker upregulation (CD69, CD25, CD154, NUR77), IL-2 production, or clonal expansion. Rather, our data illustrate an augmented response in T cells from CCI patients in response to TCR/coreceptor (CD3/CD28) challenge. Thus, the present findings reveal that CCI sepsis patients feature signs of immune suppression but that their T cells exhibit a primed, rather than a suppressed, phenotype in their TCR response, arguing against a generalized T cell paralysis as a major cause of protracted immune suppression from sepsis.



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Tue Jun 06, 2017 00:38
  Disease-Specific Effects of Matrix and Growth Factors on Adhesion and Migration of Rheumatoid Synovial Fibroblasts [AUTOIMMUNITY]
updated on Tue Jun 06, 2017 04:39 by Alexandros G. Sfakianakis via Allergy Rhinology Immunology Asthma
In rheumatoid arthritis (RA), cartilage and bone matrix are degraded, and extracellular matrix (ECM) proteins, acting as cellular activators, are liberated. Similar to ECM proteins, matrix-bound chemokines, cytokines, and growth factors (GFs) influence functional properties of key cells in RA, especially synovial fibroblasts. The role of these molecules on attachment, migration, and proinflammatory and prodestructive activation of RASFs was analyzed. Adhesion/migration of RASFs were examined under GF-enriched (GF+) or –reduced (GF–) conditions with or without addition of matrix-associated GFs, TGF-β, and platelet-derived GF to GF– or culture supernatants. Fibroblast adhesion and alterations in proinflammatory/prodestructive properties (e.g., IL-6/matrix metalloproteinase 3-release) in response to matrix-associated molecules were compared. Effects of GF+, GF–, and other ECM components on human RASF-mediated cartilage invasion were examined in the SCID mouse model. RASF adhesion under GF– conditions was significantly lower compared with GF+ conditions (6.8- versus 8.3-fold). This effect was specific for RA because control cells showed opposite effects (e.g., osteoarthritis synovial fibroblasts [SF]; GF– versus GF+: 10.7- versus 8-fold). Addition of TGF-β to GF– increased RASF attachment (12.7-fold) compared with other matrices and components. RASF adhesion to GF+ matrix resulted in the strongest IL-6 and matrix metalloproteinase-3 release, and was even more pronounced compared with supplementation of single GFs. In vivo, GF– matrix decreased RASF-mediated cartilage invasion compared with GF+ matrix. ECM components and especially GFs when bound within ECM actively enhance RASF attraction and cartilage adhesion. This observation was specific for RASFs as a reverse behavior was observed for controls.



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Tue Jun 06, 2017 00:38
  Endothelial CD2AP Binds the Receptor ICAM-1 To Control Mechanosignaling, Leukocyte Adhesion, and the Route of Leukocyte Diapedesis In Vitro [INNATE IMMUNITY AND INFLAMMATION]
updated on Tue Jun 06, 2017 04:39 by Alexandros G. Sfakianakis via Allergy Rhinology Immunology Asthma
Inflammation is driven by excessive transmigration (diapedesis) of leukocytes from the blood to the tissue across the endothelial cell monolayer that lines blood vessels. Leukocyte adhesion, crawling, and transmigration are regulated by clustering of the endothelial mechanosensitive receptor intercellular adhesion molecule-1 (ICAM-1). Whereas several proteins are known to promote ICAM-1 function, the molecular mechanisms that limit ICAM-1–mediated adhesion to prevent excessive leukocyte transmigration remain unknown. We identify the endothelial actin-binding protein CD2-associated protein (CD2AP) as a novel interaction partner of ICAM-1. Loss of CD2AP stimulates the dynamics of ICAM-1 clustering, which facilitates the formation of ICAM-1 complexes on the endothelial cell surface. Consequently, neutrophil adhesion is increased, but crawling is decreased. In turn, this promotes the neutrophil preference for the transcellular over the paracellular transmigration route. Mechanistically, CD2AP is required for mechanosensitive ICAM-1 downstream signaling toward activation of the PI3K, and recruitment of F-actin and of the actin-branching protein cortactin. Moreover, CD2AP is necessary for ICAM-1–induced Rac1 recruitment and activation. Mechanical force applied on ICAM-1 impairs CD2AP binding to ICAM-1, suggesting that a tension-induced negative feedback loop promotes ICAM-1–mediated neutrophil crawling and paracellular transmigration. To our knowledge, these data show for the first time that the mechanoreceptor ICAM-1 is negatively regulated by an actin-binding adaptor protein, i.e., CD2AP, to allow a balanced and spatiotemporal control of its adhesive function. CD2AP is important in kidney dysfunction that is accompanied by inflammation. Our findings provide a mechanistic basis for the role of CD2AP in inflamed vessels, identifying this adaptor protein as a potential therapeutic target.



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