Related ArticlesNon-Reflex Defense Mechanisms of Upper Airway Mucosa: Possible Clinical Application. Physiol Res. 2020 Mar 27;69(Suppl 1):S55-S67 Authors: Pedan H, Janosova V, Hajtman A, Calkovsky V Abstract The sinonasal mucosa has an essential role in defense mechanisms of the upper respiratory tract. The innate immune system presents the primary defense against noxious microorganisms followed by induction of the adaptive immune mechanisms as a...
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Related ArticlesUpper Airway Cough Syndrome in Pathogenesis of Chronic Cough. Physiol Res. 2020 Mar 27;69(Suppl 1):S35-S42 Authors: Lucanska M, Hajtman A, Calkovsky V, Kunc P, Pecova R Abstract Cough is one of the most important defensive reflexes. However, extensive non- productive cough is a harmful mechanism leading to the damage of human airways. Cough is initiated by activation of vagal afferents in the airways. The site of their convergence...
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Related ArticlesEffect of HIV-1 TAT Peptide Fusion on 5' mRNA Cap Analogs Cell Membrane Permeability and Translation Inhibition. Bioconjug Chem. 2020 Mar 31;: Authors: Piecyk K, Pietrow P, Arnold T, Worch R, Korneeva NL, Jankowska-Anyszka M Abstract The development of targeted anticancer drugs has been one of the most challenging goals of current research. Eukaryotic translation initiation factor 4E (eIF4E) is an oncogene that stimulates mRNA translation...
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Related ArticlesFrequent Headaches: Evaluation and Management. Am Fam Physician. 2020 Apr 01;101(7):419-428 Authors: Walling A Abstract Most frequent headaches are typically migraine or tension-type headaches and are often exacerbated by medication overuse. Repeated headaches can induce central sensitization and transformation to chronic headaches that are intractable, are difficult to treat, and cause significant morbidity and costs. A complete...
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Related ArticlesCommentary on: Crudele GDL, Merelli VG, Vener C, Milani S, Cattaneo C. The frequency of cranial base fractures in lethal head trauma. J Forensic Sci doi: 10.1111/1556-4029.14149. Epub 2019 Aug 21. J Forensic Sci. 2020 01;65(1):343 Authors: Hu J, Zheng N, Liang M PMID: 31792966 [PubMed - indexed for MEDLINE]
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Related ArticlesCommentary on: Zhuo Y, Wang X, Wu J, Zhang S, Deng H, Liu W, et al. Simultaneous quantitative determination of amphetamines, opiates, ketamine, cocaine and metabolites in human hair: application to forensic cases of drug abuse. J Forensic Sci doi: 10.1111/1556-4029.14179. Epub 2019 Sep 9. J Forensic Sci. 2020 03;65(2):664 Authors: Hu J, Zheng N, Liang M PMID: 31651991 [PubMed - indexed for MEDLINE]
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Single-sided deafness and cochlear implantation in congenital and acquired hearing loss in children.
Related ArticlesSingle-sided deafness and cochlear implantation in congenital and acquired hearing loss in children. Clin Otolaryngol. 2019 03;44(2):138-143 Authors: Ramos Macías Á, Borkoski-Barreiro SA, Falcón González JC, de Miguel Martínez I, Ramos de Miguel Á Abstract OBJECTIVE: To determine the audiological and clinical results of cochlear implantation in children below the age of 12 years old with congenital and acquired single-sided deafness....
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This paper is number 7 in a series developed through a partnership between ISIMM and NordiQC with the purpose of reporting research assessing the performance characteristics of immunoassays in an external proficiency testing program. The authors declare no conflict of interest. Reprints: Christian Thomsen, MD, Department of Pathology, Aalborg University Hospital, Ladegaardsgade 3, Aalborg DK-9000, Denmark (e-mail: christian.t@rn.dk). Received February 24, 2020 Accepted March 1, 2020 This...
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Abstract Anti-angiogenesis effect of ascorbic acid (AA) is still controversial. However, most of the scientific evidence suggests that AA has anti-angiogenesis effects on a number of test systems, including laboratory animals, human beings, and their derived cell lines. The information provided in this paper suggests that AA may be a hopeful angiostatic agent for the treatment of cancer.
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Purpose: To determine the contributions to hearing aid benefit of patient-reported outcomes and audiologic measures. Methods: Independent review was conducted on audiologic and patient-reported outcomes of hearing aid benefit collected in the course of a middle ear implant FDA clinical trial. Unaided and aided data were extracted from the preoperative profiles of 95 experienced hearing aid users, and the relationships between a patient-reported outcome and audiologic measures were assessed. The following...
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Abstract U.S. Latinos face multiple inter-related barriers to access health and social services. Researchers and practitioners have called upon community-based participatory research (CBPR) to address such challenges and health disparities, with the community health worker—or promotoras—model evidencing positive outcomes. What is less clear, however, are the promising strategies to support the development of a multisystem, community-based promotoras program. In response, the current...
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Genomic analysis of lung adenocarcinomas has revealed that the MGA gene, which encodes a heterodimeric partner of the MYC-interacting protein MAX, is significantly mutated or deleted in lung adenocarcinomas. Most of the mutations are loss of function for MGA, suggesting that MGA may act as a tumor suppressor. Here, we characterize both the molecular and cellular role of MGA in lung adenocarcinomas and illustrate its functional relevance in the MYC pathway. Although MGA and MYC interact with the same...
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Breast tumors are heterogeneous and composed of different subpopulation of cells, each with dynamic roles that can change with stage, site, and microenvironment. Cellular heterogeneity is, in part, due to cancer stem–like cells (CSC) that share properties with stem cells and are associated with treatment resistance. CSCs rewire metabolism to meet energy demands of increased growth and biosynthesis. O-GlcNAc transferase enzyme (OGT) uses UDP-GlcNAc as a substrate for adding O-GlcNAc moieties to nuclear...
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The antibody–drug conjugate trastuzumab-emtansine (T-DM1) offers an additional treatment option for patients with HER2-amplified tumors. However, primary and acquired resistance is a limiting factor in a significant subset of patients. Hypoxia, a hallmark of cancer, regulates the trafficking of several receptor proteins with potential implications for tumor targeting. Here, we have investigated how hypoxic conditions may regulate T-DM1 treatment efficacy in breast cancer. The therapeutic effect of...
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High-grade sarcomas are metastatic and pose a serious threat to patient survival. Undifferentiated pleomorphic sarcoma (UPS) is a particularly dangerous and relatively common sarcoma subtype diagnosed in adults. UPS contains large quantities of extracellular matrix (ECM) including hyaluronic acid (HA), which is linked to metastatic potential. Consistent with these observations, expression of the HA receptor, hyaluronan-mediated motility receptor (HMMR/RHAMM), is tightly controlled in normal tissues...
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EGFR-mutated lung cancer accounts for a significant proportion of lung cancer cases worldwide. For these cases, osimertinib, a third-generation EGFR tyrosine kinase inhibitor, is extensively used as a first-line or second-line treatment. However, lung cancer cells acquire resistance to osimertinib in 1 to 2 years. Thus, a thorough clarification of resistance mechanisms to osimertinib is highly anticipated. Recent next-generation sequencing (NGS) of lung cancer samples identified several genetically...
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The signaling lymphocytic activation molecule family 3 (SLAMF3) is a member of the immunoglobulin superfamily expressed on T, B, and natural killer cells and modulates the activation and cytotoxicity of these cells. SLAMF3 is also expressed on plasma cells from patients with multiple myeloma (MM), although its role in MM pathogenesis remains unclear. This study found that SLAMF3 is highly and constitutively expressed on MM cells regardless of disease stage and that SLAMF3 knockdown/knockout suppresses...
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Immune dysfunction is critical in pathogenesis of cutaneous T-cell lymphoma (CTCL). Few studies have reported abnormal cytokine profile and dysregulated T-cell functions during the onset and progression of certain types of lymphoma. However, the presence of IL9-producing Th9 cells and their role in tumor cell metabolism and survival remain unexplored. With this clinical study, we performed multidimensional blood endotyping of CTCL patients before and after standard photo/chemotherapy and revealed...
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Breast cancer is the most common cancer among American women and a major cause of mortality. To identify metabolic pathways as potential targets to treat metastatic breast cancer, we performed metabolomics profiling on the breast cancer cell line MDA-MB-231 and its tissue-tropic metastatic subclones. Here, we report that these subclones with increased metastatic potential display an altered metabolic profile compared with the parental population. In particular, the mitochondrial serine and one-carbon...
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Deregulated RNA-binding proteins (RBP), such as Argonaute 2 (AGO2), mediate tumor-promoting transcriptomic changes during carcinogenesis, including hepatocellular carcinoma (HCC). While AGO2 is well characterized as a member of the RNA-induced silencing complex (RISC), which represses gene expression through miRNAs, its role as a bona fide RBP remains unclear. In this study, we investigated AGO2's role as an RBP that regulates the MYC transcript to promote HCC. Using mRNA and miRNA arrays from patients...
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Lack of durable response to cytotoxic chemotherapy is a major contributor to the dismal outcomes seen in pancreatic ductal adenocarcinoma (PDAC). Extensive tumor desmoplasia and poor vascular supply are two predominant characteristics which hinder the delivery of chemotherapeutic drugs into PDAC tumors and mediate resistance to therapy. Previously, we have shown that STAT3 is a key biomarker of therapeutic resistance to gemcitabine treatment in PDAC, which can be overcome by combined inhibition of...
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Fusion genes can be oncogenic drivers in a variety of cancer types and represent potential targets for targeted therapy. The BRAF gene is frequently involved in oncogenic gene fusions, with fusion frequencies of 0.2%–3% throughout different cancers. However, BRAF fusions rarely occur in the same gene configuration, potentially challenging personalized therapy design. In particular, the impact of the wide variety of fusion partners on the oncogenic role of BRAF during tumor growth and drug response...
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Multiple myeloma had been successfully treated by combining lenalidomide and bortezomib with reports suggesting benefits of such a combination even in relapsed/refractory cases. Recently, it was demonstrated that Ikaros degradation by lenalidomide happens via proteasome-dependent pathway and this process is critical for the eradication of myeloma cells. On the basis of this, an antagonistic effect should be observed if a combination of both these agents were used, which however is not the observation...
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Circulating tumor DNA (ctDNA) has recently emerged as a minimally invasive "liquid biopsy" tool in precision medicine. ctDNA-genomic DNA fragments that are released into the bloodstream after the active secretion of microvesicles or tumor cell lysis reflects tumor evolution and the genomic alterations present in primary and/or metastatic tumors. Notably, ctDNA analysis might allow the stratification of patients, the monitoring of the therapeutic response, and the establishment of an opportunity for...
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Background: To date, information on laser treatment of accidental tattoos is limited. Objectives: This study analyzes the efficacy and safety of quality-switched ruby, quality-switched Nd:YAG and picosecond lasers in the treatment of accidental hyperpigmentation in a larger patient cohort. To date, there is limited information on laser therapy of accidental hyperpigmentation. Methods: We conducted a retrospective systematic single-center analysis on 70 patients, which presented with accidental hyperpigmentation...
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Abstract Purpose of Review To summarize the current available treatments for stage I rectal cancer and the evidence that supports them. Recent Findings Radical surgery, or total mesorectal excision (TME) without neoadjuvant therapy, reports excellent oncologic outcomes, with 5-year disease-free survival of approximately 95%. Alternative therapies...
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Up to 50% of patients with uveal melanoma (UM) develop metastatic disease, for which there is no effective systemic treatment. This study aimed to evaluate the safety and efficacy of the orally available protein kinase C inhibitor, AEB071, in patients with metastatic UM, and to perform genomic profiling of metastatic tumor samples, with the aim to propose combination therapies. Patients with metastatic UM (n = 153) were treated with AEB071 in a phase I, single-arm study. Patients received total daily...
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FOLFOX is one of the most effective treatments for advanced colorectal cancer. However, cumulative oxaliplatin neurotoxicity often results in halting the therapy. Oxaliplatin functions predominantly via the formation of toxic covalent drug–DNA adducts. We hypothesize that oxaliplatin–DNA adduct levels formed in vivo in peripheral blood mononuclear cells (PBMC) are proportional to tumor shrinkage caused by FOLFOX therapy. We further hypothesize that adducts induced by subtherapeutic "diagnostic microdoses"...
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HER2 is a transmembrane tyrosine kinase receptor that mediates cell growth, differentiation, and survival. HER2 is overexpressed in approximately 20% of breast cancers and in subsets of gastric, colorectal, and esophageal cancers. Both antibody and small-molecule drugs that target HER2 and block its tyrosine kinase activity are effective in treating HER2-driven cancers. In this article, we describe the preclinical properties of tucatinib, an orally available, reversible HER2-targeted small-molecule...
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Full-length antibodies lack ideal pharmacokinetic properties for rapid targeted imaging, prompting the pursuit of smaller peptides and fragments. Nevertheless, studying the disposition properties of antibody-based imaging agents can provide critical insight into the pharmacology of their therapeutic counterparts, particularly for those coupled with potent payloads. Here, we evaluate modulation of binding to the neonatal Fc receptor (FcRn) as a protein engineering-based pharmacologic strategy to minimize...
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The CD137 receptor plays a key role in mediating immune response by promoting T cell proliferation, survival, and memory. Effective agonism of CD137 has the potential to reinvigorate potent antitumor immunity either alone or in combination with other immune-checkpoint therapies. In this study, we describe the discovery and characterization of a unique CD137 agonist, 7A5, a fully human IgG1 Fc effector-null monoclonal antibody. The biological properties of 7A5 were investigated through in vitro and...
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H-Ras is a unique isoform of the Ras GTPase family, one of the most prominently mutated oncogene families across the cancer landscape. Relative to other isoforms, though, mutations of H-Ras account for the smallest proportion of mutant Ras cancers. Yet, in recent years, there have been renewed efforts to study this isoform, especially as certain H-Ras–driven cancers, like those of the head and neck, have become more prominent. Important advances have therefore been made not only in the understanding...
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CD137 (TNFRSF9, 4-1BB) agonist antibodies (mAb) have demonstrated potent antitumor activity with memory response while causing hepatotoxicity in mouse models. In clinical trials, the degrees of liver toxicity of anti-CD137 vary from grade 4 transaminitis (urelumab) to nonexistent (utomilumab). To exploit the antitumor potential of CD137 signaling, we identified a new class of CD137 agonist mAbs with strong antitumor potency without significant transaminitis in vivo compared with CD137 agonists previously...
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Hypoxia is a major factor in tumor progression and resistance to therapies, which involves elevated levels of the transcription factor HIF1α. Here, we report that prostate tumor xenografts express high levels of HIF1α and show greatly enhanced growth in response to knockdown of the E3 ligase CHIP (C-terminus of Hsp70-interacting protein). In multiple human prostate cancer cell lines under hypoxia, taxol treatment induces the degradation of HIF1α, and this response is abrogated by knockdown of CHIP,...
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Androgen deprivation therapy and second-generation androgen receptor signaling inhibitors such as enzalutamide are standard treatments for advanced/metastatic prostate cancer. Unfortunately, most men develop resistance and relapse; signaling via insulin-like growth factor (IGF) has been implicated in castration-resistant prostate cancer. We evaluated the antitumor activity of xentuzumab (IGF ligand–neutralizing antibody), alone and in combination with enzalutamide, in prostate cancer cell lines (VCaP,...
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Natural killer (NK) cells play a pivotal role in controlling cancer. Multiple extracellular receptors and internal signaling nodes tightly regulate NK activation. Cyclin-dependent kinases of the mediator complex (CDK8 and CDK19) were described as a signaling intermediates in NK cells. Here, we report for the first time the development and use of CDK8/19 inhibitors to suppress phosphorylation of STAT1S727 in NK cells and to augment the production of the cytolytic molecules perforin and granzyme B...
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