High-throughput construction of multivalent binders and subsequent screening for biological activity represent a fundamental challenge: A linear increase of monovalent components translates to the square of possible bivalent combinations. Even high-efficiency cloning and expression methods become limiting when thousands of bispecific binders need to be screened for activity. In this study, we present an in vitro method for the efficient production of flexibly linked bispecific binding agents from...
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Abstract Objective To observe the effect of Modified Xijiao Dihuang Decoction (加味犀角地黄汤, MXDD) on rats with radiation enteritis, and explore its action mechanism. Methods Thirty female Sprague Dawley rats were divided into the control, model, dexamethasone (DXM), golden bifid (GB) and MXDD groups using random number table, 6 rats in each group. Except the...
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Abstract Objective To evaluate the effectiveness and safety of Chinese herbal external umbilicus treatment with Modified Dinggui Powder (加味丁桂散, MDGP) in patients with chronic nonbacterial prostatitis (CNP). Methods A randomized, double-blind, placebo-controlled clinical trial was conducted among 72 patients with CNP. Participants were randomly allocated to...
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Abstract Objective To study the sedative and hypnotic effects and underlying mechanisms of Polygala tenuifolia (PT) on treating aged insomnia rats. Methods Sixty Sprague-Dawley male rats were divided into 6 groups by a random number table, including control group, model group, diazepam group (0.92 mg/kg), as well as PT low-, medium- and high-dose groups (0.0875,...
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Abstract Lipopolysaccharide (LPS)-induced inflammation causes massive threatening diseases, such as sepsis, acute lung injury and multiple organ dysfunction syndrome. Efficient treatment to prevent inflammation is crucial in LPS-induced inflammatory diseases. Heat-clearing Chinese medicines (CMs) have been used to ameliorate LPS-induced inflammation in China for centuries. Heat-clearing CMs regulate inflammatory pathways, thereby inhibiting the release of inflammatory factors....
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Hiba Al-Tarcheh, Shahed Tish, Salloum Salloum, Ahed Haj IbrahimAvicenna Journal of Medicine 2020 10(2):83-88Xanthoma disseminatum (XD) is a rare and benign proliferative systemic disease that usually affects the skin and mucosal membranes with variable extent. Extensive systemic involvement can be associated with higher morbidity. There is paucity in the literature describing this rare pathological entity, and the ideal management remains controversial. In this article, we report our experience with...
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Mohamad B Sonbol, Belal M Firwana, Talal Hilal, Mohammad Hassan MuradAvicenna Journal of Medicine 2020 10(2):68-75Over the last 5 years, there have been more than 140 new drug approvals in the field of Oncology alone, all based on newly published clinical trials. These approvals have led to an ongoing change in clinical practice, offering new therapeutic options for patients. Therefore, it is important for healthcare providers to be able to appraise a clinical trial and determine its validity, understand...
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Mohammad TinawiAvicenna Journal of Medicine 2020 10(2):61-67In this brief review, the reader will find a timely update regarding some of the most commonly encountered glomerular diseases. The review will include an update on the etiology with a focus on new genetic and molecular discoveries. New classifications will be elucidated, and management will be updated in broad strokes. Illustrative pathology slides will be used as appropriate. It is critical for the reader to realize from the outset that...
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Sharon S Laing, Muhammad Alsayid, Katheryn Christiansen, Kathleen Shannon DorcyAvicenna Journal of Medicine 2020 10(2):76-82Aims: This exploratory study evaluated sociodemographic predictors of healthy eating and physical activity (PA) in a sample of working rural women and their access to and interest in using technology for health promotion. Settings and Design: This study is a cross-sectional quantitative analysis. Materials and Methods: A 32-item questionnaire was administered to a convenience...
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Omar S Obeidat, Bayan A Baniissa, Zakaria W Shkoukani, Abdullah N AlhouriAvicenna Journal of Medicine 2020 10(2):89-92Mediastinal malignancies are a commonly identified etiology in superior vena cava syndrome (SVCS), and despite the known management of chemotherapy, radiotherapy, or a combination of both, this can prove to be a dilemma during pregnancy. Reported cases of SVCS management during pregnancy are scarce. Chylopericardium is a rare entity with a myriad of causes, the most common of which...
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Mutations in Sonic hedgehog (SHH) signaling promote aberrant proliferation and tumor growth. SHH-medulloblastoma (MB) is among the most frequent brain tumors in children less than 3 years of age. Although key components of the SHH pathway are well-known, we hypothesized that new disease-modifying targets of SHH-MB might be identified from large-scale bioinformatics and systems biology analyses. Using a data-driven systems biology approach, we built a MB-specific interactome. The ATP-binding cassette...
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Blood-based liquid biopsies are considered a screening approach for early cancer detection. Sequencing technologies enable in-depth analyses of nucleic acids, including mutant cell-free (cf) DNA in the plasma. However, in the blood of patients with early-stage cancer the detection level of mutant cfDNA is relatively low, and complicated by the natural presence of noncancer cfDNA mutants attributed to aging-related processes. Consequently, analysis of methylated cfDNA patterns and alternative approaches...
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A new ecologically inspired paradigm in cancer treatment known as “adaptive therapy” capitalizes on competitive interactions between drug-sensitive and drug-resistant subclones. The goal of adaptive therapy is to maintain a controllable stable tumor burden by allowing a significant population of treatment-sensitive cells to survive. These, in turn, suppress proliferation of the less-fit resistant populations. However, there remain several open challenges in designing adaptive therapies, particularly...
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Germline nonsense and canonical splice site variants identified in disease-causing genes are generally considered as loss-of-function (LoF) alleles and classified as pathogenic. However, a fraction of such variants could maintain function through their impact on RNA splicing. To test this hypothesis, we used the alternatively spliced BRCA2 exon 12 (E12) as a model system because its in-frame skipping leads to a potentially functional protein. All E12 variants corresponding to putative LoF variants...
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Glioblastoma (GBM) responses to bevacizumab are invariably transient with acquired resistance. We profiled paired patient specimens and bevacizumab-resistant xenograft models pre- and post-resistance toward the primary goal of identifying regulators whose targeting could prolong the therapeutic window, and the secondary goal of identifying biomarkers of therapeutic window closure. Bevacizumab-resistant patient specimens and xenografts exhibited decreased vessel density and increased hypoxia versus...
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The principal unmet need in BRAFV600E-positive melanoma is lack of an adequate therapeutic strategy capable of overcoming resistance to clinically approved targeted therapies against oncogenic BRAF and/or the downstream MEK1/2 kinases. We previously discovered that copper (Cu) is required for MEK1 and MEK2 activity through a direct Cu–MEK1/2 interaction. Repurposing the clinical Cu chelator tetrathiomolybdate (TTM) is supported by efficacy in BRAFV600E-driven melanoma models, due in part to inhibition...
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Cytometry by time-of-flight (CyTOF) simultaneously measures multiple cellular proteins at the single-cell level and is used to assess intertumor and intratumor heterogeneity. This approach may be used to investigate the variability of individual tumor responses to treatments. Herein, we stratified lung tumor subpopulations based on AXL signaling as a potential targeting strategy. Integrative transcriptome analyses were used to investigate how TP-0903, an AXL kinase inhibitor, influences redundant...
22h
Pharmacologic ascorbate treatment (P-AscH−, high-dose, intravenous vitamin C) results in a transient short-term increase in the flux of hydrogen peroxide that is preferentially cytotoxic to cancer cells versus normal cells. This study examines whether an increase in hydrogen peroxide is sustained posttreatment and potential mechanisms involved in this process. Cellular bioenergetic profiling following treatment with P-AscH− was examined in tumorigenic and nontumorigenic cells. P-AscH− resulted in...
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A genetic variant on aldehyde dehydrogenase 2 (ALDH2 rs671, Glu504Lys) contributes to carcinogenesis after alcohol consumption. Somewhat conversely, the ALDH2 Lys allele also confers a protective effect against alcohol-induced carcinogenesis by decreasing alcohol consumption due to acetaldehyde-related adverse effects. Here, we applied a mediation analysis to five case–control studies for head and neck, esophageal, stomach, small intestine, and colorectal cancers, with 4,099 cases and 6,065 controls,...
22h
For maximal oncogenic activity, cellular MYC protein levels need to be tightly controlled so that they do not induce apoptosis. Here, we show how ubiquitin ligase UBR5 functions as a molecular rheostat to prevent excess accumulation of MYC protein. UBR5 ubiquitinates MYC and its effects on MYC protein stability are independent of FBXW7. Silencing of endogenous UBR5 induced MYC protein expression and regulated MYC target genes. Consistent with the tumor suppressor function of UBR5 (HYD) in Drosophila,...
22h
Invasive lobular carcinoma (ILC) accounts for 8%–14% of all breast cancer cases. The main hallmark of ILCs is the functional loss of the cell–cell adhesion protein E-cadherin. Nonetheless, loss of E-cadherin alone does not predispose mice to mammary tumor development, indicating that additional perturbations are required for ILC formation. Previously, we identified an N-terminal truncation variant of ASPP2 (t-ASPP2) as a driver of ILC in mice with mammary-specific loss of E-cadherin. Here we showed...
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Genomic rearrangements leading to the aberrant expression of ERG are the most common early events in prostate cancer and are significantly enriched for the concomitant loss of PTEN. Genetically engineered mouse models reveal that ERG overexpression alone is not sufficient to induce tumorigenesis, but combined loss of PTEN results in an aggressive invasive phenotype. Here, we show that oncogenic ERG repressed PI3K signaling through direct transcriptional suppression of IRS2, leading to reduced RTK...
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Darwinian evolution of tumor cells remains underexplored in childhood cancer. We here reconstruct the evolutionary histories of 56 pediatric primary tumors, including 24 neuroblastomas, 24 Wilms tumors, and 8 rhabdomyosarcomas. Whole-genome copy-number and whole-exome mutational profiling of multiple regions per tumor were performed, followed by clonal deconvolution to reconstruct a phylogenetic tree for each tumor. Overall, 88% of the tumors exhibited genetic variation among primary tumor regions....
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Tumor-associated macrophages (TAM) are important tumor-promoting cells. However, the mechanisms underlying how the tumor and its microenvironment reprogram these cells remain elusive. Here we report that lipids play a crucial role in generating TAMs in the tumor microenvironment (TME). Macrophages from both human and murine tumor tissues were enriched with lipids due to increased lipid uptake by macrophages. TAMs expressed elevated levels of the scavenger receptor CD36, accumulated lipids, and used...
22h
Identification of the molecular mechanism of action (MoA) of bioactive compounds is a crucial step for drug development but remains a challenging task despite recent advances in technology. In this study, we applied multidimensional proteomics, sensitivity correlation analysis, and transcriptomics to identify a common MoA for the anticancer compounds RITA, aminoflavone (AF), and oncrasin-1 (Onc-1). Global thermal proteome profiling revealed that the three compounds target mRNA processing and transcription,...
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Malignant features of head and neck squamous cell carcinoma (HNSCC) may be derived from the presence of stem-like cells that are characterized by uniquely high tumorigenic potential. These cancer stem cells (CSC) function as putative drivers of tumor initiation, therapeutic evasion, metastasis, and recurrence. Although they are an appealing conceptual target, CSC-directed cancer therapies remain scarce. One promising CSC target is the IL6 pathway, which is strongly correlated with poor patient survival....
22h
Enzalutamide (MDV3100) is a potent second-generation androgen receptor antagonist approved for the treatment of castration-resistant prostate cancer (CRPC) in chemotherapy-naïve as well as in patients previously exposed to chemotherapy. However, resistance to enzalutamide and enzalutamide withdrawal syndrome have been reported. Thus, reliable and integrated preclinical models are required to elucidate the mechanisms of resistance and to assess therapeutic settings that may delay or prevent the onset...
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The prognosis for pancreatic ductal adenocarcinoma (PDAC) remains poor despite decades of effort. The abundant extracellular matrix (ECM) in PDAC comprises a major fraction of the tumor mass and plays various roles in promoting resistance to therapies. However, nonselective depletion of ECM has led to poor patient outcomes. Consistent with that observation, we previously showed that individual matrisome proteins derived from stromal cells correlate with either long or short patient survival. In marked...
22h
Mammographic features influence breast cancer risk and are used in risk prediction models. Understanding how genetics influence mammographic features is important because the mechanisms through which they are associated with breast cancer are not well known. Here, using mammographic screening history and detailed questionnaire data from 56,820 women from the KARMA prospective cohort study, we investigated the association between a genetic predisposition to breast cancer and mammographic features...
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Metastasis causes most cancer-related deaths, and one poorly understood aspect of metastatic cancer is the adaptability of cells from a primary tumor to create new niches and survive in multiple, different secondary sites. We used quantitative mass spectrometry to analyze the extracellular matrix (ECM), a critical component of metastatic niches, in metastases to the brain, lungs, liver, and bone marrow, all derived from parental MDA-MB-231 triple-negative breast cancer cells. Tumor and stromal cells...
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BackgroundDespite significant attention to safety and quality in healthcare over two decades, patient harm in hospitals remains a challenge. There is now growing emphasis on continuous quality improvement, with approaches that engage front-line staff. Our objective was to determine whether a novel approach to reviewing routine clinical practice through structured conversations—map-enabled experiential review—could improve engagement of front-line staff in quality improvement activities and drive...
22h
Continuity and timely access are hallmarks of high-quality primary care and are important considerations for urgent concerns that present both during the day and after-hours. It can be especially difficult to ensure continuity of primary care after-hours in urban settings where walk-in clinics offer patients easy and convenient access. Patients of our large, multisite primary care practice in inner-city Toronto, Canada were reporting that they were not easily able to access after-hours care from...
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Abstract Background Sweet potato is easily propagated by cuttings. But the molecular biological mechanism of adventitious root formation are not yet clear. Objective To understand the molecular mechanisms of adventitious root formation from stem cuttings in sweet potato. Methods ...
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IntroductionIn the USA, transgender women are among the most vulnerable to HIV. In particular, transgender women of colour face high rates of infection and low uptake of important HIV prevention tools, including pre-exposure prophylaxis (PrEP). This paper describes the design, sampling methods, data collection and analyses of the TURNNT (‘Trying to Understand Relationships, Networks and Neighbourhoods among Transgender women of colour’) study. In collaboration with communities of transgender women...
23h
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