tbuckley/cabot-search huggingface dataset:
An <i>In Vivo</i> CRISPR Screening Platform for Prioritizing Therapeutic Targets in AML
Authors: Shan Lin, Clément Larrue, Nastassja K. Scheidegger, Bo Kyung A. Seong, Neekesh V. Dharia, Miljan Kuljanin, Caroline S. Wechsler, Guillaume Kugener, Amanda L. Robichaud, Amy Saur Conway, Thelma Mashaka, Sarah Mouche, Biniam Adane, Jeremy A. Ryan, Joseph D. Mancias, Scott T. Younger, Federica Piccioni, Lynn H. Lee, Mark Wunderlich, Anthony Letai, Jérôme Tamburini, Kimberly Stegmaier
Journal: Cancer Discovery (2021)

CRISPR-Cas9-based genetic screens have successfully identified cell type-dependent liabilities in cancer, including acute myeloid leukemia (AML), a devastating hematologic malignancy with poor overall survival. Because most of these screens have been performed in vitro using established cell lines, evaluating the physiologic relevance of these targets is critical. We have established a CRISPR screening approach using orthotopic xenograft models to validate and prioritize AML-enriched dependencies in vivo, including in CRISPR-competent AML patient-derived xenograft (PDX) models tractable for genome editing. Our integrated pipeline has revealed several targets with translational value, including SLC5A3 as a metabolic vulnerability for AML addicted to exogenous myo-inositol and MARCH5 as a critical guardian to prevent apoptosis in AML. MARCH5 repression enhanced the efficacy of BCL2 inhibitors such as venetoclax, further highlighting the clinical potential of targeting MARCH5 in AML. Our study provides a valuable strategy for discovery and prioritization of new candidate AML therapeutic targets. SIGNIFICANCE: There is an unmet need to improve the clinical outcome of AML. We developed an integrated in vivo screening approach to prioritize and validate AML dependencies with high translational potential. We identified SLC5A3 as a metabolic vulnerability and MARCH5 as a critical apoptosis regulator in AML, both of which represent novel therapeutic opportunities.This article is highlighted in the In This Issue feature, p. 275.
Abstract P100: Changes In Adiponectin But Not Tnfα Predict Changes In Insulin Sensitivity Following Health Behavior Intervention Among Latino Youth
Authors: Armando Pena, Abigail Colburn, Eucharia C Nwabichie, Dorothy D Sears, Sonia Vega Lopez, Micah Olson, Stephanie Ayers, William Knowler, Gabriel Shaibi
Journal: Circulation (2022)

Background: Pediatric obesity is characterized by an imbalance in pro- and anti-inflammatory markers that are associated with cardiometabolic diseases. Adiponectin (Adpn), an anti-inflammatory marker, is associated with insulin sensitivity, while tumor necrosis factor-alpha (TNFα) has been associated with insulin resistance among youth with obesity. However, it is unknown whether longitudinal changes in Adpn or TNFα predict changes in insulin sensitivity among high-risk youth. Methods: A total of 73 Latino youth with obesity (age 13.3±1.4 y, Female 40.3%, BMIz 2.2±0.3) were enrolled in either a lifestyle intervention or usual care. Given that there were no between-group differences in changes in insulin sensitivity at 6-months, groups were combined for the present analysis. Fasting serum samples were used to measure high-molecular weight Adpn and TNFα before and after intervention. Insulin sensitivity was estimated by the whole-body insulin sensitivity index (WBISI) using insulin and glucose concentrations from a 75-g, 2-h oral glucose tolerance test. Baseline associations were analyzed using Pearson correlations. Linear regression was used to analyze whether changes in Adpn or TNFα predict changes in WBISI, adjusting for age, sex, and intervention assignment. Data from linear regressions are presented as betas (β) and standard errors (SE). Results: At baseline, WBISI was positively and significantly associated with Adpn (r=0.296, p=0.015) but not with TNFα (r=-0.171, p=0.168), adjusting for age and sex. Increases in Adpn were associated with increases in WBISI, whereby for every 1 μg/dL increase in Adpn, there was a 0.7 unit increase in WBISI (SE=0.3, p=0.027). Changes in TNFα did not significantly predict changes in WBISI (β=0.1, SE=0.5, p=0.915). Conclusion: Changes in Adpn but not TNFα were associated with changes in insulin sensitivity following intervention among Latino youth with obesity. Whether Adpn is the mechanism by which health behavior changes increase insulin sensitivity warrants further investigation among high-risk youth populations.
77TiP TRUST-II: A global phase II study for taletrectinib in ROS1 fusion-positive lung cancer and other solid tumors
Authors: M. Nagasaka, S. Sugawara, C-M. Choi, T. Okamoto, N. Yanagitani, K. Nosaki, T. Takahashi, Y. Fujiwara, H. Hayashi, J. Khoury, J. Nieva, A.E. Gabayan, L.E. Raez, H. Chen, A. Dimou, N. Pennell, G. Liu, S-H.I. Ou, T. Seto, Y. Ohe
Journal: Annals of Oncology (2022)
Abstract 10354: Socioeconomic Status and Differences in Trends of Atrial Fibrillation Hospitalizations Among Black and Non-Black Adults in the United States
Authors: Chaitanya Rojulpote, Shivaraj Patil, Abhijit Bhattaru, Karthik Gonuguntla, Kashyap Kela, Abdul Ahad Ehsan Sheikh, Tapan Buch, Pranjal K BORUAH
Journal: Circulation (2021)

Introduction: Socioeconomic status (SES) and race is closely interlinked. There is limited data regarding trends of atrial fibrillation (AF) hospitalizations in black and non-black adults based on SES. Methods: We queried the National Inpatient Sample database from January 2004 to December 2018 to identify patients admitted with AF. We used ICD-9-CM and ICD-10-CM diagnosis codes to identify all patients who were ≥18 years of age and hospitalized with a primary discharge diagnosis of AF. Our cohort was categorized into black and non-black groups, and SES using median household income (MHI) as a surrogate, into low SES (MHI 0-50) and high SES (MHI 51-100). AF hospitalizations per 1 million US population were calculated using US census population ≥18 years of age for each year. We estimated AF hospitalizations per 1 million blacks and non-blacks and trends in AF hospitalizations of black and non-black adults stratified by SES utilizing MHI. Cochran Armitage Test was utilized to estimate temporal trends. Results: Total admissions for AF per 1 million adults in the US population has increased (Figure 1). Among patients hospitalized with AF, the proportion of black adults is increasing. In those of low SES, both black and non-black patients have had increases in AF hospitalizations. However, in those of high SES, non-black patients have had steady improvement while black patients have remained at about the same rate of hospitalizations from 2004 to 2018 (Figure 2). Conclusions: Trends of AF hospitalizations have increased or not improved in low and high MHI-SES black adults, respectively. Identifying causes of these health disparities can improve healthcare quality in black adults with AF.
28P Dose determination and pharmacokinetics (PK) of pralsetinib: Results from the phase I ARROW study
Authors: J.F. Gainor, M. Taylor, S-H.I. Ou, E. Garralda, M.S. Brose, J. Parepally, H. Zhang, C. Rahal, A. Zalutskaya, V. Subbiah
Journal: Annals of Oncology (2022)
Abstract MP44: Adolescent Team Sports Participation, Adiposity, And Inflammation Among Young Adult Child Maltreatment Survivors
Authors: Alison L Cammack, Shakira F Suglia
Journal: Circulation (2022)

Background: A body of literature shows that child maltreatment (CM) is associated with subsequent adiposity and inflammation, but few studies examine factors that buffer against these outcomes among survivors of CM. Child and adolescent team sports participation has been associated with positive mental and physical health outcomes, including decreased risk of obesity. However, it is unclear if these benefits extend to longer-term cardiometabolic outcomes in maltreated individuals, given that CM survivors often have impaired stress coping and may use obesogenic behaviors as a coping mechanism. The goal of this study was to assess, within a nationally representative sample of CM survivors, if sports team participation during adolescence is associated with decreased adiposity and inflammation in young adulthood. Methods: The analytic sample consisted of individuals who retrospectively self-reported CM (sexual, emotional, and physical abuse and neglect) in the National Longitudinal Study of Adolescent to Adult Health (N=3,298). We examined associations between intended team sports participation in grades 7-12 and BMI (kg/m2), waist circumference (cm), log transformed high-sensitivity C-reactive protein (hsCRP; mg/L), obesity (&gt;30 kg/m2), high waist circumference (&gt;88.9 cm for women, &gt;101.6 cm for men), and elevated hsCRP (&gt;3 mg/L) at ages 24-32 using linear regression and predictive margins. Models adjusted for age, sex, race/ethnicity, childhood household education, if raised by both biological parents, school type and size, subclinical infectious disease symptoms (hsCRP only), and BMI during adolescence. All analyses incorporated complex sample weighting. Results: 57% (1883/3298) of the sample reported plans to participate in sports teams during the school year as adolescents. The mean young adult BMI, waist circumference, and hsCRP values were 29.35 kg/m2 (SD=0.21), 98.64 cm (SD=0.50), and 4.73 mg/L (SD=0.17), respectively. In the overall sample, adolescent sports participation was inversely associated with waist circumference (B=-1.73,95% CI:-0.13, -2.13), log hsCPR (B=-0.25,95% CI:-0.13,-4.01), and elevated hsCRP (PR= 0.82,95% CI:0.74,0.92). When examining specific sports, the protective impact was especially pronounced among women who participated in track (BMI B=-2.37, 95% CI,-1.62,-3.13; waist circumference B=-5.11,95% CI:-3.14,-7.08; log hsCRP B=-.52,95% CI:-0.30,-0.74). Conclusions: There is evidence that team sports participation is associated with decreased adiposity and inflammation in men and women with histories of CM. Although intervention studies are needed to establish a causal relationship, these findings suggest that team sports participation during adolescence may help promote cardiometabolic health in survivors of CM.
Cost-Effectiveness of Coronary Artery Bypass Surgery Versus Medicine in Ischemic Cardiomyopathy: The STICH Randomized Clinical Trial
Authors: Derek S. Chew, Patricia A. Cowper, Hussein Al-Khalidi, Kevin J. Anstrom, Melanie R. Daniels, Linda Davidson-Ray, Yanhong Li, Robert E. Michler, Julio A. Panza, Ileana L. Piña, Jean L. Rouleau, Eric J. Velazquez, Daniel B. Mark
Journal: Circulation (2022)

The STICH Randomized Clinical Trial (Surgical Treatment for Ischemic Heart Failure) demonstrated that coronary artery bypass grafting (CABG) reduced all-cause mortality rates out to 10 years compared with medical therapy alone (MED) in patients with ischemic cardiomyopathy and reduced left ventricular function (ejection fraction ≤35%). We examined the economic implications of these results.We used a decision-analytic patient-level simulation model to estimate the lifetime costs and benefits of CABG and MED using patient-level resource use and clinical data collected in the STICH trial. Patient-level costs were calculated by applying externally derived US cost weights to resource use counts during trial follow-up. A 3% discount rate was applied to both future costs and benefits. The primary outcome was the incremental cost-effectiveness ratio assessed from the US health care sector perspective.For the CABG arm, we estimated 6.53 quality-adjusted life-years (95% CI, 5.70-7.53) and a lifetime cost of $140 059 (95% CI, $106 401 to $180 992). For the MED arm, the corresponding estimates were 5.52 (95% CI, 5.06-6.09) quality-adjusted life-years and $74 894 lifetime cost (95% CI, $58 372 to $93 541). The incremental cost-effectiveness ratio for CABG compared with MED was $63 989 per quality-adjusted life-year gained. At a societal willingness-to-pay threshold of $100 000 per quality-adjusted life-year gained, CABG was found to be economically favorable compared with MED in 87% of microsimulations.In the STICH trial, in patients with ischemic cardiomyopathy and reduced left ventricular function, CABG was economically attractive relative to MED at current benchmarks for value in the United States.URL: https://www.gov; Unique identifier: NCT00023595.
Neoantigen-specific CD4+ T cells in human melanoma have diverse differentiation states and correlate with CD8+ T cell, macrophage, and B cell function
Authors: Joshua R Veatch, Sylvia M Lee, Carolyn Shasha, Naina Singhi, Julia L Szeto, Ata S Moshiri, Teresa S Kim, Kimberly Smythe, Paul Kong, Matthew Fitzgibbon, Brenda Jesernig, Shailender Bhatia, Scott S Tykodi, Evan T Hall, David R Byrd, John A Thompson, Venu G Pillarisetty, Thomas Duhen, A McGarry Houghton, Evan Newell, Raphael Gottardo, Stanley R Riddell
Journal: Cancer Cell (2022)
Effectiveness of an inactivated virus-based SARS-CoV-2 vaccine, BBV152, in India: a test-negative, case-control study
Authors: Devashish Desai, Adil Rashid Khan, Manish Soneja, Ankit Mittal, Shivdas Naik, Parul Kodan, Ayan Mandal, Ganesh Tarachand Maher, Rohit Kumar, Ayush Agarwal, Naveen R Gowda, Vikas H, Parmeshwar Kumar, Shivam Pandey, R M Pandey, Arvind Kumar, Animesh Ray, Pankaj Jorwal, Neeraj Nischal, Aashish Choudhary, Megha Brijwal, Karan Madan, Rakesh Lodha, Sanjeev Sinha, Lalit Dar, Naveet Wig, Randeep Guleria
Journal: The Lancet Infectious Diseases (2021)

BBV152 is a whole-virion inactivated SARS-CoV-2 vaccine that has been deployed in India. The results of the phase 3 trial have shown clinical efficacy of BBV152. We aimed to evaluate the effectiveness of BBV152 against symptomatic RT-PCR-confirmed SARS-CoV-2 infection.We conducted a test-negative, case-control study among employees of the All India Institute of Medical Sciences (a tertiary care hospital in New Delhi, India), who had symptoms suggestive of COVID-19 and had an RT-PCR test for SARS-CoV-2 during the peak of the second wave of the COVID-19 pandemic in India between April 15 and May 15, 2021. Cases (test-positives) and controls (test-negatives) were matched (1:1) on the basis of age and gender. The odds of vaccination with BBV152 were compared between cases and controls and adjusted for level of occupational exposure (to COVID-19), previous SARS-CoV-2 infection, and calendar time, using conditional logistic regression. The primary outcome was effectiveness of two doses of BBV152 (with the second dose received at least 14 days before testing) in reducing the odds of symptomatic RT-PCR-confirmed SARS-CoV-2 infection, expressed as (1 - odds ratio) × 100%.Between April 15 and May 15, 2021, 3732 individuals had an RT-PCR test. Of these, 2714 symptomatic employees had data on vaccination status, and 1068 matched case-control pairs were available for analysis. The adjusted effectiveness of BBV152 against symptomatic COVID-19 after two doses administered at least 14 days before testing was 50% (95% CI 33-62; p<0·0001). The adjusted effectiveness of two doses administered at least 28 days before testing was 46% (95% CI 22-62) and administered at least 42 days before testing was 57% (21-76). After excluding participants with previous SARS-CoV-2 infections, the adjusted effectiveness of two doses administered at least 14 days before testing was 47% (95% CI 29-61).This study shows the effectiveness of two doses of BBV152 against symptomatic COVID-19 in the context of a huge surge in cases, presumably dominated by the potentially immune-evasive delta (B.1.617.2) variant of SARS-CoV-2. Our findings support the ongoing roll-out of this vaccine to help control the spread of SARS-CoV-2, while continuing the emphasis on adherence to non-pharmacological measures.None.For the Hindi translation of the abstract see Supplementary Materials section.
Chronic Colitis Mimicking Malignancy on 68Ga-FAPI PET/CT
Authors: Xiao Yang, Yilin Huang, Chunru Mou, Huipan Liu, Yue Chen
Journal: Clinical Nuclear Medicine (2021)

A 40-year-old man presented with abdominal pain and diarrhea for 2 months. Abdominal CT showed thickening of the cecal wall, which was considered likely malignant. The patient was subsequently enrolled in a clinical trial of 68Ga-FAPI PET/CT study in tumors. Intense 68Ga-FAPI activity was noted in the thickened cecum, also suggestive of malignancy. However, pathological examination from biopsy rendered a diagnosis of chronic colitis.
Abstract 037: Multimorbidity Is Associated With Lower 24-hour Total Movement Activity Among US Adults
Authors: Erin E Dooley, Ligong Chen, Priya Palta, Pablo Martinez-Amezcua, Bjoern Hornikel, Paul Muntner, Cora E Lewis, Kelley P Gabriel
Journal: Circulation (2022)

Introduction: While multimorbidity (having ≥2 chronic conditions) is associated with inadequate higher intensity exercise, less is known about how multimorbidity relates to total movement accumulated throughout the day. We tested the hypothesis that multimorbidity is associated with lower 24-hr movement in a population-based study. Methods: We analyzed data from 2011-2014 National Health and Nutrition Examination Survey. A wrist-worn device (ActiGraph GT3X) captured movement over 24 hours in Monitor-Independent Movement Summary units (MIMS-units). Multimorbidity was quantified using 13 chronic conditions included in the CDC recommendations via self-report or clinical thresholds. We conducted multivariable linear regressions analyses to examine the association of each chronic condition and number of conditions with total daily MIMS-units. Models were adjusted for age, sex, race/ethnicity, education, and smoking, as well as the other chronic conditions in the model by condition type, per convention. Results: The sample included 7013 US adults aged 30+ (mean (± SE) age 53.2 ± 0.3 years, 53% female, 30% non-White). On average, participants had 2.4 (range 0-11) chronic conditions with 62% having ≥2. Those with ≥2 conditions had -1183.6 (95% CI: -1401.0, -966.2) lower daily MIMS-units. On a continuous scale, for each additional condition, movement was lower by -504.2 (95% CI: -580.4, -427.9) MIMS-units. Compared to those with 0 conditions, there was a dose-response reduction in movement with multimorbidity ( Figure ). Presence (vs absence) of obesity, diabetes, stroke, chronic kidney disease, cancer, depression, and memory problems were each associated with lower 24-hr movement activity. Conclusions: Multimorbidity is highly prevalent in US adults and associated with lower 24-hr movement. Intervention strategies focused on promotion of daily lifestyle movement may attenuate population-level multimorbidity burden. Future research should examine which co-occurring conditions contribute to low movement.
Chronic alcohol drinking persistently suppresses thalamostriatal excitation of cholinergic neurons to impair cognitive flexibility
Authors: Tengfei Ma, Zhenbo Huang, Xueyi Xie, Yifeng Cheng, Xiaowen Zhuang, Matthew J. Childs, Himanshu Gangal, Xuehua Wang, Laura N. Smith, Rachel J. Smith, Yubin Zhou, Jun Wang
Journal: Journal of Clinical Investigation (2021)

Exposure to addictive substances impairs flexible decision making. Cognitive flexibility is mediated by striatal cholinergic interneurons (CINs). However, how chronic alcohol drinking alters cognitive flexibility through CINs remains unclear. Here, we report that chronic alcohol consumption and withdrawal impaired reversal of instrumental learning. Chronic alcohol consumption and withdrawal also caused a long-lasting (21 days) reduction of excitatory thalamic inputs onto CINs and reduced pause responses of CINs in the dorsomedial striatum (DMS). CINs are known to inhibit glutamatergic transmission in dopamine D1 receptor-expressing medium spiny neurons (D1-MSNs) but facilitate this transmission in D2-MSNs, which may contribute to flexible behavior. We discovered that chronic alcohol drinking impaired CIN-mediated inhibition in D1-MSNs and facilitation in D2-MSNs. Importantly, in vivo optogenetic induction of long-term potentiation of thalamostriatal transmission in DMS CINs rescued alcohol-induced reversal learning deficits. These results demonstrate that chronic alcohol drinking reduces thalamic excitation of DMS CINs, compromising their regulation of glutamatergic transmission in MSNs, which may contribute to alcohol-induced impairment of cognitive flexibility. These findings provide a neural mechanism underlying inflexible drinking in alcohol use disorder.
FDG PET/CT Findings of a Primary Paravertebral Liposarcoma
Authors: Rang Wang, Guohua Shen, Rong Tian
Journal: Clinical Nuclear Medicine (2021)

Liposarcoma is a soft tissue tumor that commonly appears in the retroperitoneum and the extremities. Herein, we presented the imaging findings of a 68-year-old man with a paravertebral liposarcoma involving the adjacent vertebral bodies, appendices, and ribs. MRI revealed this mass located in the left side of T9 to T10 vertebral bodies. FDG PET/CT demonstrated the mass with intense FDG uptake. Finally, the pathological findings were consistent with a diagnosis of a primary paravertebral liposarcoma.
105P A model of workflow for radiomics signature of stage III non-small cell lung cancer (NSCLC) patients (pts)
Authors: A. Ferro, G. Pasello, E. Scagliori, F. Caumo, M. Costa, S. Frega, M. Sepulcri, L. Bonanno, F. Rea, V. Guarneri, G. Gennaro
Journal: Annals of Oncology (2022)
7MO Oritinib (SH-1028) a third-generation EGFR tyrosine kinase inhibitor in locally advanced or metastatic NSCLC patients with positive EGFR T790M: Results of a single-arm phase II trial
Authors: C. Zhou, A. Xiong, J. Zhao, W. Li, M. Bi, J. Chen, K. Li, L. Miao, Y. Mao, D. Wang, C. Liu, A. Zeng, R. Li, Y. Pan, Y. Hu, X. Zhang, H. Niu, Y. Du, Y. Sun, Z. Liu
Journal: Annals of Oncology (2022)
MS4A3 Promotes Differentiation in Chronic Myeloid Leukemia By Enhancing Common β Chain Cytokine Receptor Endocytosis
Authors: Helong Zhao, Anthony D. Pomicter, Anna M. Eiring, Anca Franzini, Jonathan Ahmann, Jae-Yeon Hwang, Anna V. Senina, Bret Helton, Siddharth Iyer, Dongqing Yan, Jamshid Khorashad, Matthew S. Zabriskie, Anupriya Agarwal, Hannah M Redwine, Amber D. Bowler, Phillip M. Clair, Shannon K. McWeeney, Brian J. Druker, Jeffrey W. Tyner, Derek Stirewalt, Vivian G. Oehler, Sooryanarayana Varambally, Kristofer Berrett, Jeffrey Vahrenkamp, Jason Gertz, Katherine Varley, Jerald P. Radich, Michael W. Deininger
Journal: Blood (2021)
Intense 68Ga-FAPI-46 Activity in Lesions of Recurrent Ovarian Clear Cell Carcinoma That Were Negative on FDG PET/CT Study
Authors: Dheeratama Siripongsatian, Chetsadaporn Promteangtrong, Anchisa Kunawudhi, Peerapon Kiatkittikul, Chanisa Chotipanich
Journal: Clinical Nuclear Medicine (2022)

A 55-year-old woman with recurrent ovarian clear cell carcinoma who underwent complete surgical staging and completed chemotherapy session approximately 7 months before. She presented with increased CA-125 levels. 68Ga-FAPI-46 PET showed significantly higher tumor-to-background contrast of recurrent intra-abdominal node metastases and distant metastases, which were undetectable in the 18F-FDG PET. These findings changed the patient management. Larger studies with comparisons with other imaging modalities are required to validate the diagnostic performance.