tbuckley/cabot-search huggingface dataset:
Combinatorial CRISPR/Cas9 Screening Reveals Epistatic Networks of Interacting Tumor Suppressor Genes and Therapeutic Targets in Human Breast Cancer
Authors: Xiaoyu Zhao, Jinyu Li, Zhimin Liu, Scott Powers
Journal: Cancer Research (2021)

The majority of cancers are driven by multiple genetic alterations, but how these changes collaborate during tumorigenesis remains largely unknown. To gain mechanistic insights into tumor-promoting genetic interactions among tumor suppressor genes (TSG), we conducted combinatorial CRISPR screening coupled with single-cell transcriptomic profiling in human mammary epithelial cells. As expected, different driver gene alterations in mammary epithelial cells influenced the repertoire of tumor suppressor alterations capable of inducing tumor formation. More surprisingly, TSG interaction networks were comprised of numerous cliques-sets of three or four genes such that each TSG within the clique showed oncogenic cooperation with all other genes in the clique. Genetic interaction profiling indicated that the predominant cooperating TSGs shared overlapping functions rather than distinct or complementary functions. Single-cell transcriptomic profiling of CRISPR double knockouts revealed that cooperating TSGs that synergized in promoting tumorigenesis and growth factor independence showed transcriptional epistasis, whereas noncooperating TSGs did not. These epistatic transcriptional changes, both buffering and synergistic, affected expression of oncogenic mediators and therapeutic targets, including CDK4, SRPK1, and DNMT1. Importantly, the epistatic expression alterations caused by dual inactivation of TSGs in this system, such as
Abstract 11062: The δC Isoform of Ca <sup>2+</sup> /Calmodulin-Dependent Protein Kinase II (camk2) Regulates Cardiac Metabolic Substrate Switching in Mice
Authors: Alireza Saadatmand, Mark E Pepin, Matthias Dewenter, Uwe Haberkorn, Johannes Backs
Journal: Circulation (2021)

Introduction: Ca 2+ /calmodulin-dependent protein kinase II (CaMK2) is a recognized driver of pathological cardiac remodeling and heart failure, but its role in the metabolic reprogramming of heart failure remains unclear, as do the molecular processes that trigger this pathologic switch. Hypothesis: Myocardial CaMKIIδ drives the pathological remodeling of cardiac metabolic substrate preference. Methods and Results: Adeno-associated viral (ssAAV9) overexpression of constitutively-active cytosolic (CaMK2δC) and nuclear (CaMK2δB) CaMK2δ isoforms, as well as the catalytic PKA subunit (PKAca), were created under the control of the cardiac troponin-T promoter and introduced via tail-vein injection into 12-week old mice (1 x 10 12 v.g., n = 5). In vivo metabolic phenotyping via 18-fluorodeoxyglucose ( 18 FDG)-based positron emission tomography (PET) revealed a 3.4-fold (P = 0.02) higher glucose uptake among mice receiving ssAAV9-TnnT-CaMK2δC commensurate with cardiac CaMK2δC expression. In contrast, no differences were seen in glucose uptake following AAV overexpression of cardiac CaMK2δB or PKAca relative to luciferase control vector. Echocardiography subsequently revealed a 14.6% decrease in left ventricular ejection fraction at 6 weeks following CaMK2δC overexpression (P = 0.047), whereas no changes were seen following CaMK2δB or PKAca overexpression in systolic or diastolic cardiac parameters. Conversely, transcriptomic analysis of hearts from mice lacking cardiac CaMK2δC expression revealed disproportionate up-regulation of fatty acid oxidative genes (P &lt; 0.001). Conclusion: Taken together, these preliminary findings implicate CaMK2δC as a crucial regulator of the cardiac metabolic reprogramming that likely precedes the hemodynamic manifestations of cardiac dysfunction in heart failure.
Abstract P220: Low Levels Of Endogenous Estrogen Are Associated With Elevated Risk Of Cardiovascular Disease Mortality In Young And Middle-Aged Men In The United States
Authors: Duke Appiah, Sujata Luitel, Chike C Nwabuo, Imo A Ebong, Stephen J Winters
Journal: Circulation (2022)

Background: While endogenous estrogen deficiency in men due to inactivating mutations of the aromatase gene results in profound metabolic dysfunction, evidence for the association of estradiol with cardiovascular disease (CVD) in men overall is inconsistent, with most studies performed among older men or patients with CVD. We investigated the association of total estradiol (E2) or free estradiol (FE2) and CVD mortality in a nationally representative sample of US men. Hypothesis: Low levels of E2 or FE2 will be associated with elevated risk of CVD mortality. Methods: Data on 954 men without CVD, cancer, diabetes and not on androgen therapy or taking anabolic steroids who participated in Phase 1 (1988 to 1991) of the third National Health and Nutrition Examination Survey and for whom E2 was measured, and were followed for mortality through to December 31, 2015 were included. Fasting serum levels of E2 were measured using competitive electrochemiluminescence immunoassays. Free estradiol was estimated from estradiol, sex hormone binding globulin, and albumin. Cox regression models were used to calculate hazard ratios (HR) and 95% confidence intervals (CI). Results: The average age of participants at baseline was 35.7 (Standard deviation (SD) ±11.6) years with 11% and 6% of them reporting Black and Hispanic race and ethnicity, respectively. During a median follow-up of 25.2 years, 40 CVD deaths were recorded, with the cumulative incidence greater among men with low E2 or FE2 (Figure). Controlling for baseline age, race/ethnicity, education, systolic blood pressure, body mass index, physical activity, smoking status, alcohol intake, HDL cholesterol, c-reactive protein and total testosterone levels, a 1 log SD decrease in E2 (HR: 2.38, 95%CI: 1.11-5.00) or FE2 (HR: 1.96, 95%CI: 1.03-3.70) was associated with elevated CVD mortality. Conclusions: In this nationally representative sample of U.S young and middle-aged men, low levels of total estradiol or free estradiol were associated with elevated risk for CVD mortality.
Proteolysis-targeting chimeras (PROTACs) in cancer therapy
Authors: Xinyi Li, Wenchen Pu, Qingquan Zheng, Min Ai, Song Chen, Yong Peng
Journal: Molecular Cancer (2022)

Abstract Proteolysis-targeting chimeras (PROTACs) are engineered techniques for targeted protein degradation. A bifunctional PROTAC molecule with two covalently-linked ligands recruits target protein and E3 ubiquitin ligase together to trigger proteasomal degradation of target protein by the ubiquitin-proteasome system. PROTAC has emerged as a promising approach for targeted therapy in various diseases, particularly in cancers. In this review, we introduce the principle and development of PROTAC technology, as well as the advantages of PROTACs over traditional anti-cancer therapies. Moreover, we summarize the application of PROTACs in targeting critical oncoproteins, provide the guidelines for the molecular design of PROTACs and discuss the challenges in the targeted degradation by PROTACs.
Abstract P118: Longitudinal Work Hour Patterns Associated With Hypertension Risk
Authors: Tia S Lal, Sadie H Conway, Ruosha Li, William B Perkison, Feng Zhang, David Aguilar
Journal: Circulation (2022)

Introduction: Evidence shows a positive correlation between work hour (WH) duration and incident hypertension (HTN). However, little is known about the association between longitudinal WH patterns and the risk of incident HTN. Hypothesis: We hypothesized that the greatest risk of HTN would be observed in consistently long WH patterns and that age, sex, and ethnicity would modify the relationship between WH patterns and incident HTN. Methods: We utilized a representative sample of 10,338 U.S. adults from the Panel Study of Income Dynamics who reported weekly WH for a minimum of five years between 1985-2017 and did not have a history of HTN prior to reporting five years of WH data. Latent class linear mixed modeling was used to identify distinct longitudinal WH trajectory patterns. Weighted Cox proportional hazards model was used to examine the association between WH patterns and incident HTN, adjusting for age, sex, ethnicity, education, number of children, BMI, and smoking status after backwards step-down selection. We also tested for statistical interactions between WH patterns and baseline age, sex, and ethnicity. Results: Over a mean follow-up of 18.6 years, four WH trends were identified: steady (66.1%), increasing (12.1%), quickly decreasing (8.7%), and gradually decreasing (13.0%). Only age (p&lt;0.001) modified the association between WH patterns and incident HTN. In age-stratified analyses, adults aged 18-29 showed no significant association between WH patterns and HTN. In adults aged 30-39, a gradually decreasing WH trend showed lower HTN risk compared to those working steady hours (HR=0.51; 95% CI: 0.39-0.66). Among those ≥40 years, increasing (HR=0.59; 95% CI: 0.39-0.89), quickly decreasing (HR=0.49; 95% CI: 0.41-0.59) and gradually decreasing (HR=0.30; 95% CI: 0.23-0.40) WH patterns were associated with lower risk of HTN compared to those working steady hours. Conclusion: Compared to individuals working steady WH over many years, non-constant WH patterns were associated with a lower risk of incident HTN.
Vaccine effectiveness against severe acute respiratory infections (SARI) COVID-19 hospitalisations estimated from real-world surveillance data, Slovenia, October 2021
Authors: Marta Grgič Vitek, Irena Klavs, Veronika Učakar, Mojca Serdt, Maja Mrzel, Marjana Vrh, Mario Fafangel
Journal: Eurosurveillance (2022)

We estimated vaccine effectiveness (VE) against severe COVID-19 during October 2021, using Slovenian surveillance data. For people fully vaccinated with any vaccine in age groups 18–49, 50–64, ≥ 65 years, VE was 86% (95% CI: 79–90), 89% (85–91), and 77% (74–81). Among ≥ 65 year-olds fully vaccinated with mRNA vaccines, VE decreased from 93% (95% CI: 88–96) in those vaccinated ≤ 3 months ago to 43% (95% CI: 30–54) in those vaccinated ≥ 6 months ago, suggesting the need for early boosters.
Edaravone activates the GDNF/RET neurotrophic signaling pathway and protects mRNA-induced motor neurons from iPS cells
Authors: Qian Li, Yi Feng, Yingchao Xue, Xiping Zhan, Yi Fu, Gege Gui, Weiqiang Zhou, Jean-Philippe Richard, Arens Taga, Pan Li, Xiaobo Mao, Nicholas J. Maragakis, Mingyao Ying
Journal: Molecular Neurodegeneration (2022)

Spinal cord motor neurons (MNs) from human iPS cells (iPSCs) have wide applications in disease modeling and therapeutic development for amyotrophic lateral sclerosis (ALS) and other MN-associated neurodegenerative diseases. We need highly efficient MN differentiation strategies for generating iPSC-derived disease models that closely recapitulate the genetic and phenotypic complexity of ALS. An important application of these models is to understand molecular mechanisms of action of FDA-approved ALS drugs that only show modest clinical efficacy. Novel mechanistic insights will help us design optimal therapeutic strategies together with predictive biomarkers to achieve better efficacy.We induce efficient MN differentiation from iPSCs in 4 days using synthetic mRNAs coding two transcription factors (Ngn2 and Olig2) with phosphosite modification. These MNs after extensive characterization were applied in electrophysiological and neurotoxicity assays as well as transcriptomic analysis, to study the neuroprotective effect and molecular mechanisms of edaravone, an FDA-approved drug for ALS, for improving its clinical efficacy.We generate highly pure and functional mRNA-induced MNs (miMNs) from control and ALS iPSCs, as well as embryonic stem cells. Edaravone alleviates H2O2-induced neurotoxicity and electrophysiological dysfunction in miMNs, demonstrating its neuroprotective effect that was also found in the glutamate-induced miMN neurotoxicity model. Guided by the transcriptomic analysis, we show a previously unrecognized effect of edaravone to induce the GDNF receptor RET and the GDNF/RET neurotrophic signaling in vitro and in vivo, suggesting a clinically translatable strategy to activate this key neuroprotective signaling. Notably, edaravone can replace required neurotrophic factors (BDNF and GDNF) to support long-term miMN survival and maturation, further supporting the neurotrophic function of edaravone-activated signaling. Furthermore, we show that edaravone and GDNF combined treatment more effectively protects miMNs from H2O2-induced neurotoxicity than single treatment, suggesting a potential combination strategy for ALS treatment.This study provides methodology to facilitate iPSC differentiation and disease modeling. Our discoveries will facilitate the development of optimal edaravone-based therapies for ALS and potentially other neurodegenerative diseases.
Machine Learning–based Sleep Staging in Patients with Sleep Apnea Using a Single Mandibular Movement Signal
Authors: Nhat-Nam Le-Dong, Jean-Benoit Martinot, Nathalie Coumans, Valérie Cuthbert, Renaud Tamisier, Sébastien Bailly, Jean-Louis Pépin
Journal: American Journal of Respiratory and Critical Care Medicine (2021)
Ovarian Cancer–Specific <i>BRCA</i>-like Copy-Number Aberration Classifiers Detect Mutations Associated with Homologous Recombination Deficiency in the AGO-TR1 Trial
Authors: Philip C. Schouten, Lisa Richters, Daniel J. Vis, Stefan Kommoss, Ewald van Dijk, Corinna Ernst, Roelof J.C. Kluin, Frederik Marmé, Esther H. Lips, Sandra Schmidt, Esther Scheerman, Katharina Prieske, Carolien H.M. van Deurzen, Alexander Burges, Patricia C. Ewing-Graham, Dimo Dietrich, Agnes Jager, Nikolaus de Gregorio, Jan Hauke, Andreas du Bois, Petra M. Nederlof, Lodewyk F. Wessels, Eric Hahnen, Philipp Harter, Sabine C. Linn, Rita K. Schmutzler
Journal: Clinical Cancer Research (2021)

Abstract Purpose: Previously, we developed breast cancer BRCA1-like and BRCA2-like copy-number profile shrunken centroid classifiers predictive for mutation status and response to therapy, targeting homologous recombination deficiency (HRD). Therefore, we investigated BRCA1- and BRCA2-like classification in ovarian cancer, aiming to acquire classifiers with similar properties as those in breast cancer. Experimental Design: We analyzed DNA copy-number profiles of germline BRCA1- and BRCA2-mutant ovarian cancers and control tumors and observed that existing breast cancer classifiers did not sufficiently predict mutation status. Hence, we trained new shrunken centroid classifiers on this set and validated them in the independent The Cancer Genome Atlas dataset. Subsequently, we assessed BRCA1/2-like classification and obtained germline and tumor mutation and methylation status of cancer predisposition genes, among them several involved in HR repair, of 300 ovarian cancer samples derived from the consecutive cohort trial AGO-TR1 (NCT02222883). Results: The detection rate of the BRCA1-like classifier for BRCA1 mutations and promoter hypermethylation was 95.6%. The BRCA2-like classifier performed less accurately, likely due to a smaller training set. Furthermore, three quarters of the BRCA1/2-like tumors could be explained by (epi)genetic alterations in BRCA1/2, germline RAD51C mutations and alterations in other genes involved in HR. Around half of the non–BRCA-mutated ovarian cancer cases displayed a BRCA-like phenotype. Conclusions: The newly trained classifiers detected most BRCA-mutated and methylated cancers and all tumors harboring a RAD51C germline mutations. Beyond that, we found an additional substantial proportion of ovarian cancers to be BRCA-like.
Abstract P054: Plant-based Nutrition And Lifestyle Intervention To Improve Dietary Behaviors Among Black Adults In The South
Authors: Samara Sterling, Shelly-Ann Bowen
Journal: Circulation (2022)

Background: Plant-based diets may reduce risk of cardiovascular disease (CVD) and help with weight management, particularly in communities where the burden of chronic disease is high. However, little research has been done on plant-based diet implementation in rural Black communities that are disproportionately affected with obesity/CVD. Since dietary behaviors are closely linked to cultural identity in this community, intervention strategies are needed to preserve cultural traditions while addressing lifestyle behaviors that reduce CVD risk. Methods: The Veggie &amp; Soul pilot program was a 12-week plant-based nutrition and lifestyle intervention implemented in 2020 to prioritize and educate Black adults in rural Georgia about the benefits of a healthy diet and encourage increased consumption of fruits, vegetables, and whole grains. Weekly nutrition education sessions were implemented, in addition to support groups and cooking classes. Multiple instruments for dietary assessment were collected at baseline and 12 weeks including: (1) food frequency questionnaire; (2) food behavior survey, and (3) two 24-hour dietary recalls (1 weekend and 1 weekday). Paired t-tests explored differences between baseline and 12-week measurements. Results: Twenty-four participants (22 women, 2 men) completed the intervention. Participants doubled their daily servings of fruit from baseline to 12 weeks (1.3 vs. 2.6 servings respectively; p&lt;.001) and reported a 76% increase in daily vegetable servings (1.7 vs. 3.0 servings respectively; p&lt;.001). There was also a 90% increase in daily servings of whole grain (1 vs. 1.9 servings respectively; p=0.014). Further, results showed a significant reduction in intake of nutrients to limit including cholesterol (-83%; p&lt;.001), saturated fat (-42%; p&lt;.001), sodium (-28%; p=.004), and added sugars (-54%; p-.002). At baseline, 46% of participants agreed or strongly agreed that “a diet without meat is satisfactory and nutritious.” At 12 weeks, 95% of participants agreed or strongly agreed with this statement (p&lt;.001). There was a significant increase in participant confidence in preparing healthy meals by the end of the intervention (p=.03). Median weight change was 9.6 lbs, with a decrease in both body mass index and waist circumference (p&lt;.001). Waist-hip ratio reductions were also mildly significant (p=0.058). Conclusion: Implementing a 12-week nutrition and lifestyle intervention among Black adults in the rural South improved reported dietary behaviors that may impact obesity and cardiovascular risk. Long-term interventions are needed that will promote permanent behavior changes to improve health in similar communities.
65P Blood cytokine changes in patients with advanced NSCLC receiving immunotherapy
Authors: H.L. Schindler, F. Lusky, L. Gaissmaier, L. Daniello, M. Elshiaty, F. Bozorgmehr, J. Kuon, R. Shah, M. Schneider, F. Eichhorn, P. Baum, A. Angeles, F. Janke, M. Kriegsmann, D. Kazdal, A. Stenzinger, H. Sültmann, M. Thomas, P. Christopoulos
Journal: Annals of Oncology (2022)
Actionable Tumor Alterations and Treatment Protocol Enrollment of Pediatric and Young Adult Patients With Refractory Cancers in the National Cancer Institute–Children's Oncology Group Pediatric MATCH Trial
Authors: D. Williams Parsons, Katherine A. Janeway, David R. Patton, Cynthia L. Winter, Brent Coffey, P. Mickey Williams, Sinchita Roy-Chowdhuri, Gregory J. Tsongalis, Mark Routbort, Nilsa C. Ramirez, Lauren Saguilig, Jin Piao, Todd A. Alonzo, Stacey L. Berg, Elizabeth Fox, Douglas S. Hawkins, Jeffrey S. Abrams, Margaret Mooney, Naoko Takebe, James V. Tricoli, Nita L. Seibel
Journal: Journal of Clinical Oncology (2022)

The National Cancer Institute-Children's Oncology Group Pediatric MATCH trial aimed to facilitate evaluation of molecular-targeted therapies in biomarker-selected cohorts of childhood and young adult patients with cancer by screening tumors for actionable alterations.
Correction: Hypoxia Drives Dihydropyrimidine Dehydrogenase Expression in Macrophages and Confers Chemoresistance in Colorectal Cancer
Authors: Marie Malier, Khaldoun Gharzeddine, Marie-Hélène Laverriere, Sabrina Marsili, Fabienne Thomas, Magali Court, Thomas Decaens, Gael Roth, Arnaud Millet
Journal: Cancer Research (2022)

In the original version of this article (1), author Magali Court is mistakenly omitted from the author list. This error has been corrected in the latest online HTML and PDF versions of the article, and the author contributions and disclosures have been updated as necessary. The authors regret this error.
MicroRNA-30e* promotes human glioma cell invasiveness in an orthotopic xenotransplantation model by disrupting the NF-κB/IκBα negative feedback loop
Authors: Lili Jiang, Chuyong Lin, Libing Song, Jueheng Wu, Baixue Chen, Zhe Ying, Lishan Fang, Xiao Yan, Mian He, Jun Li, Mengfeng Li
Journal: Journal of Clinical Investigation (2021)

MicroRNA-30e* promotes human glioma
Inducible apelin receptor knockdown reduces differentiation efficiency and contractility of hESC-derived cardiomyocytes
Authors: Robyn G C Macrae, Maria T Colzani, Thomas L Williams, Semih Bayraktar, Rhoda E Kuc, Anna L Pullinger, William G Bernard, Emma L Robinson, Emma E Davenport, Janet J Maguire, Sanjay Sinha, Anthony P Davenport
Journal: Cardiovascular Research (2022)

Abstract Aims The apelin receptor, a G protein-coupled receptor, has emerged as a key regulator of cardiovascular development, physiology, and disease. However, there is a lack of suitable human in vitro models to investigate the apelinergic system in cardiovascular cell types. For the first time we have used human embryonic stem cell-derived cardiomyocytes (hESC-CMs) and a novel inducible knockdown system to examine the role of the apelin receptor in both cardiomyocyte development and to determine the consequences of loss of apelin receptor function as a model of disease. Methods and results Expression of the apelin receptor and its ligands in hESCs and hESC-CMs was determined. hESCs carrying a tetracycline-inducible short hairpin RNA targeting the apelin receptor were generated using the sOPTiKD system. Phenotypic assays characterized the consequences of either apelin receptor knockdown before hESC-CM differentiation (early knockdown) or in 3D engineered heart tissues as a disease model (late knockdown). hESC-CMs expressed the apelin signalling system at a similar level to the adult heart. Early apelin receptor knockdown decreased cardiomyocyte differentiation efficiency and prolonged voltage sensing, associated with asynchronous contraction. Late apelin receptor knockdown had detrimental consequences on 3D engineered heart tissue contractile properties, decreasing contractility and increasing stiffness. Conclusions We have successfully knocked down the apelin receptor, using an inducible system, to demonstrate a key role in hESC-CM differentiation. Knockdown in 3D engineered heart tissues recapitulated the phenotype of apelin receptor down-regulation in a failing heart, providing a potential platform for modelling heart failure and testing novel therapeutic strategies.
Exposure to Particle Radioactivity and Breast Cancer Risk in the Sister Study: A U.S.-Wide Prospective Cohort
Authors: Alexandra J. White, Allyson M. Gregoire, Jared A. Fisher, Danielle N. Medgyesi, Longxiang Li, Petros Koutrakis, Dale P. Sandler, Rena R. Jones
Journal: Environmental Health Perspectives (2022)
Early assessment of the clinical severity of the SARS-CoV-2 omicron variant in South Africa: a data linkage study
Authors: Nicole Wolter, Waasila Jassat, Sibongile Walaza, Richard Welch, Harry Moultrie, Michelle Groome, Daniel Gyamfi Amoako, Josie Everatt, Jinal N Bhiman, Cathrine Scheepers, Naume Tebeila, Nicola Chiwandire, Mignon du Plessis, Nevashan Govender, Arshad Ismail, Allison Glass, Koleka Mlisana, Wendy Stevens, Florette K Treurnicht, Zinhle Makatini, Nei-yuan Hsiao, Raveen Parboosing, Jeannette Wadula, Hannah Hussey, Mary-Ann Davies, Andrew Boulle, Anne von Gottberg, Cheryl Cohen
Journal: The Lancet (2022)