tbuckley/cabot-search huggingface dataset:
RNF168 regulates R-loop resolution and genomic stability in BRCA1/2-deficient tumors
Authors: Parasvi S. Patel, Karan Joshua Abraham, Kiran Kumar Naidu Guturi, Marie-Jo Halaby, Zahra Khan, Luis Palomero, Brandon Ho, Shili Duan, Jonathan St-Germain, Arash Algouneh, Francesca Mateo, Samah El Ghamrasni, Haithem Barbour, Daniel R. Barnes, Jonathan Beesley, Otto Sanchez, Hal K. Berman, Grant W. Brown, None El Bachir Affar, Georgia Chenevix-Trench, Antonis C. Antoniou, Cheryl H. Arrowsmith, Brian Raught, Miquel Angel Pujana, Karim Mekhail, Anne Hakem, Razqallah Hakem
Journal: Journal of Clinical Investigation (2021)

Germline mutations in BRCA1 and BRCA2 (BRCA1/2) genes considerably increase breast and ovarian cancer risk. Given that tumors with these mutations have elevated genomic instability, they exhibit relative vulnerability to certain chemotherapies and targeted treatments based on poly (ADP-ribose) polymerase (PARP) inhibition. However, the molecular mechanisms that influence cancer risk and therapeutic benefit or resistance remain only partially understood. BRCA1 and BRCA2 have also been implicated in the suppression of R-loops, triple-stranded nucleic acid structures composed of a DNA:RNA hybrid and a displaced ssDNA strand. Here, we report that loss of RNF168, an E3 ubiquitin ligase and DNA double-strand break (DSB) responder, remarkably protected Brca1-mutant mice against mammary tumorigenesis. We demonstrate that RNF168 deficiency resulted in accumulation of R-loops in BRCA1/2-mutant breast and ovarian cancer cells, leading to DSBs, senescence, and subsequent cell death. Using interactome assays, we identified RNF168 interaction with DHX9, a helicase involved in the resolution and removal of R-loops. Mechanistically, RNF168 directly ubiquitylated DHX9 to facilitate its recruitment to R-loop-prone genomic loci. Consequently, loss of RNF168 impaired DHX9 recruitment to R-loops, thereby abrogating its ability to resolve R-loops. The data presented in this study highlight a dependence of BRCA1/2-defective tumors on factors that suppress R-loops and reveal a fundamental RNF168-mediated molecular mechanism that governs cancer development and vulnerability.
Factors Associated with Severe Non-Alcoholic Steatohepatitis According to the FLIP Algorithm / SAF Score in Adults with Obesity from a Bariatric Center In Peru
Authors: Jorge L. Salazar-Alarcón, Alexandro J. Berrospi-San Martín, Gian F. Maldonado-Basurto, Carlos J. Toro-Huamanchumo, Gustavo Salinas-Sedo
Journal: Metabolism (2021)
Innate cell microenvironments in lymph nodes shape the generation of T cell responses during type I inflammation
Authors: Joseph M. Leal, Jessica Y. Huang, Karan Kohli, Caleb Stoltzfus, Miranda R. Lyons-Cohen, Brandy E. Olin, Michael Gale, Michael Y. Gerner
Journal: Science Immunology (2021)

Microanatomical organization of innate immune cells within lymph nodes (LNs) is critical for the generation of adaptive responses. In particular, steady-state LN-resident dendritic cells (Res cDCs) are strategically localized to intercept lymph-draining antigens. Whether myeloid cell organization changes during inflammation and how that might affect the generation of immune responses are unknown. Here, we report that during type I, but not type II, inflammation after adjuvant immunization or viral infection, antigen-presenting Res cDCs undergo CCR7-dependent intranodal repositioning from the LN periphery into the T cell zone (TZ) to elicit T cell priming. Concurrently, inflammatory monocytes infiltrate the LNs via local blood vessels, enter the TZ, and cooperate with Res cDCs by providing polarizing cytokines to optimize T cell effector differentiation. Monocyte infiltration is nonuniform across LNs, generating distinct microenvironments with varied local innate cell composition. These spatial microdomains are associated with divergent early T cell effector programming, indicating that innate microenvironments within LNs play a critical role in regulating the quality and heterogeneity of T cell responses. Together, our findings reveal that dynamic modulation of innate cell microenvironments during type I inflammation leads to optimized generation of adaptive immune responses to vaccines and infections.
Forging a new path: an endoscopic jejunojejunostomy
Authors: Daniel Hogan, Maheep Sangha, Paul Lee, Evin McCabe, Petros Benias
Journal: Endoscopy (2021)

A 74-year-old man with a history of T2N1 gastric adenocarcinoma who underwent a total gastrectomy with a Roux-en-Y reconstruction presented to our institution with dysphagia. Since his surgery, the patient had several presentations to multiple area hospitals with the complaint of dysphagia to solids with vomiting, and what appeared to be intermittent food bolus obstructions. He underwent several dilations of his esophagojejunal anastomosis without improvement of his symptoms, and in fact it seemed that the greatest issue was not a stricture of the anastomosis, but rather twisting of the jejunal limbs making the blind limb the dominant lumen.
Predicting adverse outcomes due to diabetes complications with machine learning using administrative health data
Authors: Mathieu Ravaut, Hamed Sadeghi, Kin Kwan Leung, Maksims Volkovs, Kathy Kornas, Vinyas Harish, Tristan Watson, Gary F. Lewis, Alanna Weisman, Tomi Poutanen, Laura Rosella
Journal: npj Digital Medicine (2021)

Abstract Across jurisdictions, government and health insurance providers hold a large amount of data from patient interactions with the healthcare system. We aimed to develop a machine learning-based model for predicting adverse outcomes due to diabetes complications using administrative health data from the single-payer health system in Ontario, Canada. A Gradient Boosting Decision Tree model was trained on data from 1,029,366 patients, validated on 272,864 patients, and tested on 265,406 patients. Discrimination was assessed using the AUC statistic and calibration was assessed visually using calibration plots overall and across population subgroups. Our model predicting three-year risk of adverse outcomes due to diabetes complications (hyper/hypoglycemia, tissue infection, retinopathy, cardiovascular events, amputation) included 700 features from multiple diverse data sources and had strong discrimination (average test AUC = 77.7, range 77.7–77.9). Through the design and validation of a high-performance model to predict diabetes complications adverse outcomes at the population level, we demonstrate the potential of machine learning and administrative health data to inform health planning and healthcare resource allocation for diabetes management.
Developing and Validating Clinical Questionnaires
Authors: Anthony J. Rosellini, Timothy A. Brown
Journal: Annual Review of Clinical Psychology (2021)

Coinciding with the development and revision of conceptual models of psychopathology, there has been a proliferation in the number of self-report clinical questionnaires and studies evaluating their psychometric properties. Unfortunately, many clinical measures are constructed and evaluated using suboptimal methods. This review provides current guidelines for the conceptualization, development, and psychometric validation of clinical questionnaires using latent variable methods. A two-stage exploratory-confirmatory framework is provided. The exploratory stage includes item selection and revision, initial structural evaluation, and preliminary tests of concurrent validity (e.g., convergent and discriminant). The confirmatory stage involves replicating factor structure using a more restrictive model, identifying areas of model strain, conducting additional tests of concurrent and predictive validity, and evaluating measurement invariance. Recommendations are provided for (a) item generation, (b) how to use different types of exploratory and confirmatory factor models to determine structure, and (c) evaluating reliability and validity using a latent variable measurement model approach.
Abstract 1722: Intravascular Ultrasound Predictors of No-Reflow after Percutaneous Saphenous Vein Graft Intervention Using Distal Protection Devices
Authors: Young Joon Hong, Gary S. Mintz, Sang Wook Kim, Sung Yun Lee, Seok Yeon Kim, Teruo Okabe, Augusto D. Pichard, Lowell F. Satler, Ron Waksman, Kenneth M. Kent, William O. Suddath, Neil J. Weissman
Journal: Circulation (2007)

We investigated the relationship between intravascular ultrasound (IVUS) findings and the no-reflow phenomenon in 125 patients with saphenous vein graft (SVG) lesions undergoing percutaneous corona...
Trends and Geographic Patterns in Drug and Synthetic Opioid Overdose Deaths — United States, 2013–2019
Authors: Christine L. Mattson, Lauren J. Tanz, Kelly Quinn, Mbabazi Kariisa, Priyam Patel, Nicole L. Davis
Journal: MMWR Morbidity and Mortality Weekly Report (2021)

Deaths involving synthetic opioids other than methadone (synthetic opioids), which largely consist of illicitly manufactured fentanyl; psychostimulants with abuse potential (e.g., methamphetamine); and cocaine have increased in recent years, particularly since 2013 (1,2).In 2019, a total of 70,630 drug overdose deaths occurred, corresponding to an age-adjusted rate of 21.6 per 100,000 population and a 4.3% increase from the 2018 rate (20.7) (3).CDC analyzed trends in age-adjusted overdose death rates involving synthetic opioids, psychostimulants, cocaine, heroin, and prescription opioids during 2013-2019, as well as geographic patterns in synthetic opioid-and psychostimulant-involved deaths during 2018-2019.From 2013 to 2019, the synthetic opioid-involved death rate increased 1,040%, from 1.0 to 11.4 per 100,000 age-adjusted (3,105 to 36,359).The psychostimulant-involved death rate increased 317%, from 1.2 (3,627) in 2013 to 5.0 (16,167) in 2019.In the presence of synthetic opioid coinvolvement, death rates for prescription opioids, heroin, psychostimulants, and cocaine increased.In the absence of synthetic opioid coinvolvement, death rates increased only for psychostimulants and cocaine.From 2018 to 2019, the largest relative increase in the synthetic opioid-involved death rate occurred in the West (67.9%), and the largest relative increase in the psychostimulant-involved death rate occurred in the Northeast (43.8%); these increases represent important changes in the geographic distribution of drug overdose deaths.Evidence-based prevention and response strategies including substance use disorder treatment and overdose prevention and response efforts focused on polysubstance use must be adapted to address the evolving drug overdose epidemic.Drug overdose deaths were identified in the National Vital Statistics System multiple cause-of-death mortality files* by using International Classification of Diseases, Tenth Revision (ICD-10) underlying cause-of-death codes X40-44 (unintentional), X60-64 (suicide), X85 (homicide), or Y10-14 (undetermined intent).Drug categories were defined using the following ICD-10 multiple cause-of-death codes: synthetic opioids other than methadone (T40.4),psychostimulants with abuse potential (T43.6), cocaine (T40.5),prescription opioids (T40.2 or T40.3), and heroin (T40.1).Deaths involving more
<i>Vital Signs:</i> Prevalence of Multiple Forms of Violence and Increased Health Risk Behaviors and Conditions Among Youths — United States, 2019
Authors: Corinne David-Ferdon, Heather B. Clayton, Linda L. Dahlberg, Thomas R. Simon, Kristin M. Holland, Nancy Brener, Jennifer L. Matjasko, Ashley S. D’Inverno, Leah Robin, Derrick Gervin
Journal: MMWR Morbidity and Mortality Weekly Report (2021)

Introduction: Experiencing violence, especially multiple types of violence, can have a negative impact on youths' development.These experiences increase the risk for future violence and other health problems associated with the leading causes of morbidity and mortality among adolescents and adults.Methods: Data from the 2019 national Youth Risk Behavior Survey were used to determine the prevalence of high school students' self-reported experiences with physical fighting, being threatened with a weapon, physical dating violence, sexual violence, and bullying.Logistic regression models adjusting for sex, grade, and race/ethnicity were used to test the strength of associations between experiencing multiple forms of violence and 16 self-reported health risk behaviors and conditions.Results: Approximately one half of students (44.3%) experienced at least one type of violence; more than one in seven (15.6%) experienced two or more types during the preceding 12 months.Experiencing multiple types of violence was significantly more prevalent among females than among males and among students identifying as gay, lesbian, or bisexual or not sure of their sexual identity than among heterosexual students.Experiencing violence was significantly associated with higher prevalence of all examined health risks and conditions.Relative to youths with no violence experiences, adjusted health risk and condition prevalence estimates were up to seven times higher among those experiencing two types of violence and up to 21 times higher among those experiencing three or more types of violence.Conclusions and implications for public health practice: Many youths experience multiple types of violence, with potentially lifelong health impacts.Violence is preventable using proven approaches that address individual, family, and environmental risks.Prioritizing violence prevention is strategic to promoting adolescent and adult health.
COVID-19 Vaccination Intent, Perceptions, and Reasons for Not Vaccinating Among Groups Prioritized for Early Vaccination — United States, September and December 2020
Authors: Kimberly H. Nguyen, Anup Srivastav, Hilda Razzaghi, Walter Williams, Megan C. Lindley, Cynthia Jorgensen, Neetu Abad, James A. Singleton
Journal: MMWR Morbidity and Mortality Weekly Report (2021)

Persons with underlying medical conditions were defined as those who reported having any of the following conditions: cancer; chronic kidney disease; chronic obstructive pulmonary disease (COPD); heart conditions (e.g., heart failure, coronary artery disease, or cardiomyopathies); immunocompromised state (weakened immune system) from solid organ transplant; obesity; pregnancy; sickle cell disease; smoking; and type 2 diabetes mellitus.Respondents aged 18-64 years reporting diagnosis of one or more of these conditions were classified as high-risk in the analyses.This list of underlying medical conditions does not include Down syndrome, which was added to the list on December 23, 2020.A complete list of underlying medical conditions is available at https://www.cdc.gov/coronavirus/2019-ncov/need-extraprecautions/people-with-medical-conditions.html† Other essential workers include those who conduct a range of operations and services that are essential to continued critical infrastructure viability, including staffing operations centers, maintaining and repairing critical infrastructure, operating call centers, working construction, and performing operational functions, among others.Also included are workers who support crucial supply chains and enable functions for critical infrastructure.The industries they support represent, but are not limited to, medical and health care, telecommunications, information technology systems, defense, food and agriculture, transportation and logistics, energy, water and wastewater, and law enforcement.
Sustained Postural Wide QRS Complex Tachycardia in an Intensive Care Unit Patient
Authors: Yinn Shaung Ooi, Maria Eleni Drosou, Gan-Xin Yan
Journal: JAMA Internal Medicine (2021)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Internal Medicine HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Internal Medicine journal
Pharmacogenomics of Fluoropyrimidines—A Personalized Approach for Treating and Preventing Keratinocyte Carcinomas
Authors: Ogechi Ikediobi
Journal: JAMA Dermatology (2021)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Dermatology HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Dermatology journal
Differential efficiencies to neutralize the novel mutants B.1.1.7 and 501Y.V2 by collected sera from convalescent COVID-19 patients and RBD nanoparticle-vaccinated rhesus macaques
Authors: Rong Li, Xiancai Ma, Jieyi Deng, Qier Chen, Weiwei Liu, Zhilin Peng, Yidan Qiao, Yingtong Lin, Xin He, Hui Zhang
Journal: Cellular and Molecular Immunology (2021)
Expectation and dyspnoea: the neurobiological basis of respiratory nocebo effects
Authors: Elke Vlemincx, Christian Sprenger, Christian Büchel
Journal: European Respiratory Journal (2021)

Cues such as odours that do not per se evoke bronchoconstriction can become triggers of asthma exacerbations. Despite its clinical significance, the neural basis of this respiratory nocebo effect is unknown. We investigated this effect in a functional magnetic resonance imaging (fMRI) study involving 36 healthy volunteers. The experiment consisted of an experience phase in which volunteers experienced dyspnoea while being exposed to an odorous gas (“Histarinol”). Volunteers were told that Histarinol induces dyspnoea by bronchoconstriction. This was compared with another odorous gas which did not evoke dyspnoea. Dyspnoea was actually induced by a concealed, resistive load inserted into the breathing system. In a second, expectation phase, Histarinol and the control gas were both followed by an identical, very mild load. Respiration parameters were continuously recorded and participants rated dyspnoea intensity after each trial. Dyspnoea ratings were significantly higher in Histarinol compared with control conditions, both in the experience and in the expectation phase, despite identical physical resistance in the expectation phase. Insula fMRI signal matched the actual load, i.e. a significant difference between Histarinol and control in the experience phase, but no difference in the expectation phase. The periaqueductal gray showed a significantly higher fMRI signal during the expectation of dyspnoea. Finally, Histarinol-related deactivations during the expectation phase in the rostral anterior cingulate cortex mirrored similar responses for nocebo effects in pain. These findings highlight the neural basis of expectation effects associated with dyspnoea, which has important consequences for our understanding of the perception of respiratory symptoms.
Targeting mutant p53 with COTI-2: A new approach for the treatment of patients with triple-negative breast cancer?
Authors: Naoise C Synnott, David J O'Connell, John Crown, Michael J. Duffy
Journal: Journal of Clinical Oncology (2018)

e13121 Background: The identification of a targeted therapy for patients with triple-negative breast cancer (TNBC) is one of the most urgent needs in breast cancer therapeutics. Since the p53 gene is mutated in approximately 80% of TNBC, it is an attractive therapeutic target for this subset of breast cancer. COTI-2 is a new, orally available, small molecule that acts by reactivating mutant. The compound is currently undergoing phase I trials in patients with gynecological and H&N cancers. The aim of this study was to investigate COTI-2 as a new treatment for TNBC. Methods: Cell viability was determined by MTT assay. p53 protein levels were quantified by ELISA. P53 binding was measured by surface plasmon resonance (SPR). Combination index (CI) values were calculated using Calcusyn software. Results: Using a panel of 18 breast cell lines, TNBC cells were significantly more responsive to COTI-2 than non-TNBC cells (p =0.04). In contrast, response was independent of cell line ER or HER2 status. Significantly lower IC50 values were found in p53 mutant compared to p53 wild-type cells (p =0.001). Additionally, a significant inverse correlation was found between IC50 values and p53 protein levels (p= 0.035, r= -0.51), ie, the higher the endogenous p53 protein level, the more sensitive the cell line was to COTI-2. By staining with antibodies specific for correctly folded WT p53 (PAb1620) or unfolded mutant p53 (PAb240), we showed that COTI-2 bound to and induced refolding of mutant p53. Further evidence of COTI-2 binding to mutant p53 was obtained using SPR. To enhance response, COTI-2 was combined with several cytotoxic agents. Highly synergistic growth inhibition, i.e. CI < 1, was found when COTI-2 was combined with doxorubicin in 6 different cell lines. In addition, docetaxel plus COTI-2 was synergistic in 4/6 cell lines, carboplatin plus COTI-2 was synergistic in 3/6, while cisplatin plus COTI-2 was synergistic in 2/6 cell lines. Conclusions: We conclude that targeting mutant p53 with COTI-2 is a potential approach for treating p53-mutated TNBC and should now be investigated in a clinical trial. In selecting such patients for treatment, mutant p53 or high levels of p53 protein should be used as predictive biomarkers.
Dupilumab Improves Signs And Symptoms Of Severe Atopic Dermatitis In Children Aged 6–11 Years With And Without Comorbid Allergic Rhinitis
Authors: Lisa Beck, Andreas Wollenberg, Amy Paller, Elaine Siegfried, Zhen Chen, Alvina Abramova, Randy Prescilla
Journal: Journal of Allergy and Clinical Immunology (2021)