Synthetic Lethal Interactions With Oncogenic KRAS

KRAS is one of the most frequently mutated genes across human cancers, including 96% of pancreatic cancers, 40% of colorectal cancers, and 35% of lung cancers. The majority of human cancer cell lines and tumors from genetically engineered mouse models harboring an oncogenic mutant KRAS allele demonstrate a strong dependence on KRAS for proliferation and survival. This KRAS dependency is a type of ‘oncogene addiction,’ a state in which cancer cells depend on signaling from a single oncogene for survival. Unfortunately, the development of clinically effective KRAS-directed cancer therapies has been unsuccessful, and KRAS-mutant cancers are refractory to standard and targeted therapies. Alternative approaches to combatting KRAS-mutant cancers are clearly needed. We postulate that oncogenic KRAS signaling induces changes in cell signaling networks that cause cells to become dependent on certain genes, termed a ‘synthetic lethal’ interaction. Identifying these selective vulnerabilities would lend insight to the pathways altered in KRAS-mutant cancers and may inform novel strategies to target KRAS-addicted cancers. In this thesis, we systematically identify candidate co-dependencies of oncogenic KRAS by analyzing genetic dependencies revealed by genome-scale RNAi screens across a large panel of cell lines. We highlight methods to facilitate candidate selection/validation and integrate analyses of gene-expression data and genome-scale CRISPR/Cas9 screens to nominate candidate co-dependencies for further study. In addition, we examine CRISPR-Cas9 screens to identify genes that modify sensitivity to small molecule MAPK pathway inhibition (MAPKi) in RAS-mutant cancers. We propose that suppression of the DOCK5-RAC1 pathway demonstrates a drug-conditional lethal interaction with small molecule MAPK pathway inhibitors in RAS-mutant cancers. We believe that these data provide a foundation for further examination of genetic co-dependencies of oncogenic KRAS and the potential synthetic lethal interaction between DOCK5-RAC1 pathway suppression and MAPKi in RAS mutant cancers

Using temporal artery biopsy to diagnose giant cell arteritis in a patient with bilateral arm ischemia

AbstractIntroductionBilateral upper extremity ischemia is an unusual presentation of vascular disease. Aetiologies include atherosclerosis as well as rheumatologic diseases. History and physical examination are often, but not always, enough to distinguish between aetiologies and guide treatment.Presentation of caseWe present the case of a female patient with findings neither typical for atherosclerotic or for rheumatologic disease who was ultimately found to have giant cell arteritis affecting her bilateral upper extremities. She underwent bilateral upper extremity bypasses using saphenous vein grafts.DiscussionThis patient presented without symptoms and laboratory findings often seen with GCA, however, biopsy revealed a definitive diagnosis. Treatment options for ischemia secondary to giant cell arteritis are not well-documented in the literature.ConclusionGiant cell arteritis can present in atypical forms, and should remain on the differential when atypical-appearing lesions are found, even in the absence of features usually associated with GCA

Human Agency in AI Configurations Supporting Organizational Decision-making

The integration of human intelligence with Artificial Intelligence (AI) is becoming increasingly essential for leveraging benefits in organizational decision-making. This necessitates to understand human-AI collaboration configurations for managing collaborative intelligence. However, existing literature on Human-AI collaboration lacks structure and is fragmented regarding what exactly human intelligence (HI) contributes to AI collaboration and how AI systems can be configured in the decision-making process. This paper undertakes an organizing literature review to consolidate insights from existing literature. We identify six types of human agency as involved in collaborative intelligence and synthesize the findings into six Human-AI collaborative configurations explained by a matrix framework. By illuminating the complexities of Human-AI collaboration, the framework sheds light on the need for a nuanced understanding of the imbricating roles of HI and AI in decision-making, with important implications for the design and implementation of AI systems for organizational decision-making

Adherence to U.S. Physical Activity and Dietary Guidelines Among A Mexican American Cohort

Purpose: The purpose of this study is to examine adherence to risk factors for chronic diseases among Mexican Americans residing along Texas / Mexico border. Method: Data was derived from the Cameron County Hispanic Cohort (CCHC), a prospective cohort study of over 2600 Mexican American adults aged 18 years and older living in a large and poor city along the Texas / Mexico border. Descriptive statistics and regression analysis were used to analyze the data. Results:The sample (67.06% female) has a mean age of 48.06 ± 15.60 years, 48.81% employed, 45.66% has less than high school education, 77.57% completed the survey in Spanish, and 31.65% has some type of public or private insurance. More than 85% of the sample were either overweight (25≤BMI Conclusions: Preventive behaviors including regular moderate to vigorous physical activity and a diet rich with fruit and vegetables are uncommon among Mexican Americans. Younger age and lower BMI were associated with meeting preventive behavior guidelines along Texas / Mexico border Mexican Americans

Sumoylation of the basic helix-loop-helix transcription factor Sharp-1 regulates recruitment of the histone methyltransferase G9a and function in myogenesis

10.1074/jbc.M113.463257Journal of Biological Chemistry2882417654-1766

HOXC8 regulates self-renewal, differentiation and transformation of breast cancer stem cells

Background: Homeobox genes are master regulators of cell fate during embryonic development and their expression is altered in cancer. By regulating the balance between cell proliferation and differentiation, they maintain homeostasis of normal tissues. Here, we screened the expression of homeobox genes in mammary stem cells to establish their role in stem cells transformation in breast cancer. Methods: Using a Homeobox Genes PCR array, we screened 83 homeobox genes in normal cancer breast stem/progenitor cells isolated by flow cytometry. The candidate gene HOXC8 epigenetic regulation was studied by DNA methylation and miRNA expression analyses. Self-renewal and differentiation of HOXC8-overexpressing or knockdown cells were assessed by flow cytometry and mammosphere, 3D matrigel and soft agar assays. Clinical relevance of in vitro findings were validated by bioinformatics analysis of patient datasets from TCGA and METABRIC studies. Results: In this study we demonstrate altered expression of homeobox genes in breast cancer stem/progenitor cells. HOXC8 was consistently downregulated in stem/progenitor cells of all breast molecular subtypes, thus representing an interesting tumour suppressor candidate. We show that downregulated expression of HOXC8 is associated with DNA methylation at the gene promoter and expression of miR196 family members. Functional studies demonstrated that HOXC8 gain of function induces a decrease in the CD44+/CD24-/low cancer stem cell population and proportion of chemoresistant cells, with a concomitant increase in CD24+ differentiated cells. Increased HOXC8 levels also decrease the ability of cancer cells to form mammospheres and to grow in anchorage-independent conditions. Furthermore, loss of HOXC8 in non-tumorigenic mammary epithelial cells expands the cancer stem/progenitor cells pool, increases stem cell self-renewal, prevents differentiation induced by retinoic acid and induces a transformed phenotype. Conclusions: Taken together, our study points to an important role of homeobox genes in breast cancer stem/progenitor cell function and establishes HOXC8 as a suppressor of stemness and transformation in the mammary gland lineag

A Systematic Review and Meta-Analysis Exploring Effects of Third-Wave Psychological Therapies on Hearing-Related Distress, Depression, Anxiety, and Quality of Life in People With Audiological Problems

Purpose: There is growing evidence supporting the use of third-wave psychological therapies, such as mindfulness-based interventions (MBIs) and acceptance and commitment therapy (ACT), for people with long-term or chronic physical health conditions. We conducted a systematic review and meta-analysis to critically evaluate the effectiveness of third-wave interventions for improving hearing-related distress and psychological well-being in people with audiological problems. / Method: We searched online bibliographic databases and assessed study quality. We conducted random-effects meta-analyses if at least two randomized controlled trials (RCTs) examined hearing-related distress, depression, anxiety, or quality of life in people with audiological problems. Findings of pre–post studies were summarized narratively. / Results: We identified 15 studies: six RCTs and nine pre–post studies. The methodological quality of studies was mostly poor to moderate, and sample sizes were typically small (overall n = 750). Most studies focused on tinnitus (n = 12), MBIs (n = 8), and ACT (n = 6). Statistically significant improvements in hearing-related distress were found with ACT and MBIs versus controls and other treatments at post-intervention in people with tinnitus, while improvements in depression and anxiety were only found for ACT versus controls at post-intervention. However, gains were either not maintained or not examined at follow-up, and there was no evidence for improvements in quality of life. / Conclusions: At present, there is insufficient evidence to recommend the use of third-wave interventions for improving hearing-related distress or psychological well-being in people with audiological problems. There is some evidence that ACT and MBIs may be useful in addressing hearing-related distress in people with tinnitus, but only in the short term. However, findings should be interpreted with caution given the small number of studies with generally small sample sizes and mostly poor-to-moderate methodological quality. More high-quality, adequately powered, double-blind RCTs, particularly in audiological problems other than tinnitus, are needed to draw firm conclusions and meaningful clinical recommendations

Differential expression of HERV-W in peripheral blood in multiple sclerosis and healthy patients in two different ethnic groups

Copyright © 2020 Tarlinton, Wang, Morandi, Gran, Khaiboullin, Martynova, Rizvanov and Khaiboullina. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. Overexpression of the Human endogenous retrovirus W (HERV-W) group of inherited retroviruses has been consistently linked with Multiple Sclerosis (MS). However most of the studies on this link have focused on European genetic groups with a very high risk of MS and it is not clear that this relationship holds for all ethnic groups. This study examined via qPCR the RNA expression in peripheral blood of HERV-W (the multiple sclerosis associated retrovirus variant MSRV) of MS patients and healthy controls from two ethnic groups with very different risk rates of MS. Population one was derived from the UK with a Northern European genetic background and an MS risk rate of 108/100,000, population two was derived from the republic of Tatarstan, Russian Federation, with a mixed Russian (Eastern European) and Tartar (Turkic or Volga/Urals) population with an MS risk rate of 21-31/100,000. The Russian population displayed a significantly higher basal level of expression of MSRV in both healthy and MS individuals when compared to the British control population with a trend in the Russian population towards higher expression levels in MS patients than healthy patients