tbuckley/cabot-search huggingface dataset:
Alterations of the Mdm2 C-Terminus Differentially Impact Its Function <i>In Vivo</i>
Authors: Vinod Pant, Neeraj K. Aryal, Shunbin Xiong, Gilda P. Chau, Natalie W. Fowlkes, Guillermina Lozano
Journal: Cancer Research (2022)

Murine double minute 2 (Mdm2) is the principal E3-ubiquitin ligase for p53 and contains a C2H2C4 type RING domain wherein the last cysteine residue is followed by an evolutionarily conserved 13 amino acid C-terminal tail. Previous studies have indicated that integrity of the C-terminal tail is critical for Mdm2 function. Recently, a mutation extending the MDM2 length by five amino acids was identified and associated with enhanced p53 response in fibroblasts and premature aging in a human patient. To investigate the importance of the conserved Mdm2 C-terminal length on p53 regulatory function in vivo, we engineered three novel mouse alleles using CRISPR-Cas9 technology. Genetic studies with these murine models showed that curtailing Mdm2 C-terminal length by even a single amino acid leads to p53-dependent embryonic lethality. Extension of the Mdm2 C-terminal length by five amino acids (QLTCL) yielded viable mice that are smaller in size, exhibit fertility problems, and have a shortened life span. Analysis of early passage mouse embryonic fibroblasts indicated impaired Mdm2 function correlates with enhanced p53 activity under stress conditions. Furthermore, analysis in mice showed tissue-specific alterations in p53 target gene expression and enhanced radiosensitivity. These results confirm the physiological importance of the evolutionarily conserved Mdm2 C-terminus in regulating p53 functions.This in vivo study highlights that alterations to the C-terminus of Mdm2 perturb its regulation of the tumor suppressor p53.
Representation and misrepresentation of knowledge
Authors: Mikkel Gerken
Journal: Behavioral and Brain Sciences (2021)

I argue for three points: First, evidence of the primacy of knowledge representation is not evidence of primacy of knowledge. Second, knowledge-oriented mindreading research should also focus on misrepresentations and biased representations of knowledge. Third, knowledge-oriented mindreading research must confront the problem of the gold standard that arises when disagreement about knowledge complicates the interpretation of empirical findings.
Abstract P195: Title
Authors: Junichi Ishigami, Mayank M Kansal, Rupal Mehta, Anand Srivastava, Mahboob Rahman, Mirela A Dobre, Sadeer Al-Kindi, Alan S Go, Sankar Navaneethan, Jing Chen, Jiang He, Zeenat Y Bhat, Bernard Jaar, Lawrence J Appel, Kuni Matsushita
Journal: Circulation (2022)

Background: A bidirectional relationship between cardiovascular disease and chronic kidney disease (CKD) is well-recognized, but the association of cardiac dysfunction and structure with the risk of CKD progression has not been systematically evaluated in a CKD population. Methods: We analyzed Chronic Renal Insufficiency Cohort participants who underwent an echocardiogram at baseline. We evaluated the association of left ventricular mass index (LVMI), left ventricular ejection fraction (EF), left atrial area (LAA), and peak tricuspid regurgitation (TR) velocity with CKD progression, defined as ≥50% decline in estimated glomerular filtration rate (eGFR) or incident end-stage kidney disease. A secondary outcome was annual eGFR slope. We used multivariable Cox models and mixed-effects models for these outcomes, respectively. Results: Among 3,025 eligible patients, mean age was 59 (SD 11) years, 54% were men, 46% had diabetes, and mean eGFR was 43 (17) ml/min/1.73m 2 . Higher LVMI, LAA, peak TR velocity, and lower EF were each significantly associated with an increased risk of CKD progression. Corresponding HRs for the highest vs. lowest quartiles [lowest vs. highest for EF] were 2.38 (95% CI, 1.87-3.03), 1.51 (1.21-1.88), 1.57 (1.20-2.06), and 1.22 (1.02-1.47) (Table). Participants in the highest quartile (vs. lowest quartile) of LVMI and peak TR velocity had a significantly faster eGFR decline (i.e., ΔeGFR slope per year, -0.33 [95% CI, -0.43 to -0.22] and -0.33 [-0.46 to -0.20] ml/min/1.73m 2 , respectively) (Table). In contrast, EF and LAA were not associated with eGFR slopes (p for linear trend &gt;0.05). Conclusions: While echo-based parameters of cardiac structure and function were generally associated with increased risk of CKD progression, only higher LVMI and peak TR velocity were independently associated with faster eGFR decline in slope analyses. Our findings may indicate different mechanisms associated with adverse kidney outcomes based on cardiac structural and functional phenotypes.
Agrin Loss in Barrett's Esophagus-Related Neoplasia and Its Utility as a Diagnostic and Predictive Biomarker
Authors: Steffen Rickelt, Azfar Neyaz, Charlene Condon, Charles A. Whittaker, Ali H. Zaidi, Martin S. Taylor, Genevieve Abbruzzese, Anthony R. Mattia, Lawrence Zukerberg, Stuti G. Shroff, Omer H. Yilmaz, Osman Yilmaz, Elizabeth Y. Wu, Won-Tak Choi, Blair A. Jobe, Robert D. Odze, Deepa T. Patil, Vikram Deshpande, Richard O. Hynes
Journal: Clinical Cancer Research (2021)

There is an unmet need for identifying novel biomarkers in Barrett's esophagus that could stratify patients with regards to neoplastic progression. We investigate the expression patterns of extracellular matrix (ECM) molecules in Barrett's esophagus and Barrett's esophagus-related neoplasia, and assess their value as biomarkers for the diagnosis of Barrett's esophagus-related neoplasia and to predict neoplastic progression. Gene-expression analyses of ECM matrisome gene sets were performed using publicly available data on human Barrett's esophagus, Barrett's esophagus-related dysplasia, esophageal adenocarcinoma (ADCA) and normal esophagus. Immunohistochemical expression of basement membrane (BM) marker agrin (AGRN) and p53 was analyzed in biopsies of Barrett's esophagus-related neoplasia from 321 patients in three independent cohorts. Differential gene-expression analysis revealed significant enrichment of ECM matrisome gene sets in dysplastic Barrett's esophagus and ADCA compared with controls. Loss of BM AGRN expression was observed in both Barrett's esophagus-related dysplasia and ADCA. The mean AGRN loss in Barrett's esophagus glands was significantly higher in Barrett's esophagus-related dysplasia and ADCA compared with non-dysplastic Barrett's esophagus (NDBE; P < 0.001; specificity = 82.2% and sensitivity = 96.4%). Loss of AGRN was significantly higher in NDBE samples from progressors compared with non-progressors (P < 0.001) and identified patients who progressed to advanced neoplasia with a specificity of 80.2% and sensitivity of 54.8%. Moreover, the combination of AGRN loss and abnormal p53 staining identified progression to Barrett's esophagus-related advanced neoplasia with a specificity and sensitivity of 86.5% and 58.7%. We highlight ECM changes during Barrett's esophagus progression to neoplasia. BM AGRN loss is a novel diagnostic biomarker that can identify patients with NDBE at increased risk of developing advanced neoplasia.
Cellular senescence and the skeleton: pathophysiology and therapeutic implications
Authors: Sundeep Khosla, Joshua N. Farr, David G. Monroe
Journal: Journal of Clinical Investigation (2022)

Cellular senescence is a fundamental aging mechanism that is currently the focus of considerable interest as a pathway that could be targeted to ameliorate aging across multiple tissues, including the skeleton. There is now substantial evidence that senescent cells accumulate in the bone microenvironment with aging and that targeting these cells prevents age-related bone loss, at least in mice. Cellular senescence also plays important roles in mediating the skeletal fragility associated with diabetes mellitus, radiation, and chemotherapy. As such, there are ongoing efforts to develop "senolytic" drugs that kill senescent cells by targeting key survival mechanisms in these cells without affecting normal cells. Because senescent cells accumulate across tissues with aging, senolytics offer the attractive possibility of treating multiple age-related comorbidities simultaneously.
Correction: Splicing Patterns in <i>SF3B1</i>-Mutated Uveal Melanoma Generate Shared Immunogenic Tumor-Specific Neoepitopes
Journal: Cancer Discovery (2022)

In the original version of this article (1), the middle and right headings in Fig. 2A were inverted by the compositor during production of the paper. Figure 2A has been corrected in the latest online HTML and PDF versions of the article. The publisher regrets the error.No disclosures were reported.
Abstract P087: Distinct Associations Between Abdominal Muscle Density And Area With N-terminal Pro-b-type Natriuretic Peptide Among Mesa Participants
Authors: Maira Tristao Parra, Isaac Sada, Rebecca Gold, Amelia Eastman, Chantal A Vella, Candice Price, Iva Miljkovic, Matthew A Allison
Journal: Circulation (2022)

N-terminal pro-B-type natriuretic peptide (NT-proBNP) is used to identify cardiac stress, manage, and treat cardiac disease progression, and diagnose heart failure (HF). Notably, this peptide is paradoxically lower in HF patients who are obese. In this regard, a growing body of evidence has investigated its association with body composition, but the relationship between NT-proBNP and muscle quality is unknown. Therefore, we investigated the associations between abdominal muscle volume and density with NT-proBNP. We conducted a cross-sectional analysis of participants from the MESA Abdominal Body Composition, Inflammation, and Cardiovascular Disease (ABC) ancillary study. At exams 2 and 3, participants underwent abdominal computed tomography (CT) scans and had venous blood drawn. Images were analyzed using software (MIPAV 41.2), and Hounsfield units (HU) were used to determine the density of muscle groups of interest (total abdominal muscle [oblique, rectus abdominus, paraspinus muscles, psoas], stabilization muscles [oblique, rectus abdominus, paraspinus muscle] and, psoas muscle). NT-proBNP was log-transformed due to the skewed distribution of the variable. Fat, lean, and total tissue areas were measured in square centimeters. Multivariable linear regression models were used to test the associations between muscle quantity and quality (area and density), separately, with adjustment for age, sex, race/ethnicity, diabetes, smoking, hypertension, moderate-to-vigorous (MVPA), sedentary behavior, height, subcutaneous fat, visceral fat, visceral fat density, leptin, adiponectin, CRP, IL-6, and TNF-alpha. We included 1,489 participants with a mean age 64.8 (9.6) years, and 51.6% were female. The majority were non-Hispanic White (42%), followed by Hispanics (26%), African Americans (18%), and Chinese Americans (14%). After full adjustment, stabilization muscle density was inversely associated with NT-proBNP (β = -0.024, 95% CI: -0.038, -0.010). The results were similar for total abdominal muscle density (β = -0.026, 95% CI: -0.042, -0.010) and psoas muscle density (β = -0.013, 95% CI: -0.026, -0.001). For the latter, addition of muscle area as a covariate attenuated the association β = -0.011, 95% CI: -0.025, 0.002). After minimal adjustment, multivariable models of total abdominal muscle and psoas muscle areas for NT-proBNP were inversely associated but became non-significant with the addition of inflammation biomarkers (leptin, adiponectin, CRP, IL- 6, and TNF-alpha) and muscle density. Area of stabilization muscles and NT-proBNP were not significantly associated. Abdominal muscle area and NT-proBNP were not consistently associated, whereas abdominal muscle density and NT-proBNP were robustly inversely associated independently of muscle area, sociodemographic characteristics, cardiovascular risk factors, and inflammation biomarkers.
Abstracts for the Society of Nuclear Medicine and Molecular Imaging, Greater New York and New England Chapters, 34th Annual Northeast Regional Scientific Meeting, Greenwich, CT
Journal: Clinical Nuclear Medicine (2022)

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Concerns Remain Regarding the Association of Sitting Time and Physical Activity With Cancer Survivorship
Authors: Yicheng Zhang, Jin Zhang, Peiming Sun
Journal: JAMA Oncology (2022)

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Elimination of Radiation-Induced Senescence in the Brain Tumor Microenvironment Attenuates Glioblastoma Recurrence
Authors: Eliot Fletcher-Sananikone, Suman Kanji, Nozomi Tomimatsu, Luis Fernando Macedo Di Cristofaro, Rahul K. Kollipara, Debabrata Saha, John R. Floyd, Patrick Sung, Robert Hromas, Terry C. Burns, Ralf Kittler, Amyn A. Habib, Bipasha Mukherjee, Sandeep Burma
Journal: Cancer Research (2021)

Glioblastomas (GBM) are routinely treated with ionizing radiation (IR) but inevitably recur and develop therapy resistance. During treatment, the tissue surrounding tumors is also irradiated. IR potently induces senescence, and senescent stromal cells can promote the growth of neighboring tumor cells by secreting factors that create a senescence-associated secretory phenotype (SASP). Here, we carried out transcriptomic and tumorigenicity analyses in irradiated mouse brains to elucidate how radiotherapy-induced senescence of non-neoplastic brain cells promotes tumor growth. Following cranial irradiation, widespread senescence in the brain occurred, with the astrocytic population being particularly susceptible. Irradiated brains showed an altered transcriptomic profile characterized by upregulation of CDKN1A (p21), a key enforcer of senescence, and several SASP factors, including HGF, the ligand of the receptor tyrosine kinase (RTK) Met. Preirradiation of mouse brains increased Met-driven growth and invasiveness of orthotopically implanted glioma cells. Importantly, irradiated p21-/- mouse brains did not exhibit senescence and consequently failed to promote tumor growth. Senescent astrocytes secreted HGF to activate Met in glioma cells and to promote their migration and invasion in vitro, which could be blocked by HGF-neutralizing antibodies or the Met inhibitor crizotinib. Crizotinib also slowed the growth of glioma cells implanted in preirradiated brains. Treatment with the senolytic drug ABT-263 (navitoclax) selectively killed senescent astrocytes in vivo, significantly attenuating growth of glioma cells implanted in preirradiated brains. These results indicate that SASP factors in the irradiated tumor microenvironment drive GBM growth via RTK activation, underscoring the potential utility of adjuvant senolytic therapy for preventing GBM recurrence after radiotherapy. SIGNIFICANCE: This study uncovers mechanisms by which radiotherapy can promote GBM recurrence by inducing senescence in non-neoplastic brain cells, suggesting that senolytic therapy can blunt recurrent GBM growth and aggressiveness.
Abstract 053: Heals Med-Tech: A Telehealth Based Behavioral Lifestyle Hypertension Control Program For High-risk African Americans Presenting At Primary Care Clinics
Authors: Amanda W Clarke, Ismail EL Moudden, Olivia M Newby, LaWanda Wood, Sunita Dodani
Journal: Circulation (2022)

Background: Hypertension (HTN) related disparities have been recognized for decades among African-Americans(AAs), particularly concerning HTN control, HTN awareness, and HTN compliance, particularly among AA women.The efficacy tested HEALS Med-Tech behavioral lifestyle program offers a promising solution. We present thefindings from the first 3 months of HEALS Med-Tech intervention on BP reduction and improvement in DASH dietand exercise. Primary outcomes of interest are changes in BP, while secondary outcomes include a change in BMIand waist circumference. Methods: HEALS Med-Tech program offers 3 components: a) HEALS ( He althy Ea ting and Li ving Sp iritually) a 12-month behavioral lifestyle intervention, modified from the DASH and PREMIER programs (3-mo interventionfollowed by 9-mos of maintenance); b) Med -component provides HTN management through medications and socialsupport provided by PCP and Community Health Ambassadors; and c) Tech -component provides interactivetelehealth by mobile phone to combat barriers to healthcare access. The results were analyzed using ANOVA andregression analysis. Dietary analysis was done to obtain DASH scores from the food diaries and 24-hr dietary recalls.The program is currently in month 6 of its maintenance phase. Results: A total of 62 AA participants were enrolled and randomized to either HEALS Med-Tech or standard care(control). At the end of 3 months, HEALS Med-Tech arm showed a significant reduction in SBP (13.11 mmHg; p=0.01)and DBP (4.2 mmHg; p=0.04) compared to the standard care arm (SBP and DBP change of 7.83 mmHg and 0.32mmHg), respectively. After 12 weeks of intervention, the average DASH scores were 2.002 for HEALS and 1.592 forcontrol arm compared to 1.620 and 1.500 at baseline for HEALS and control arm, respectively. Conclusion: A multidisciplinary, community-engaged approach with telehealth component for improved access tohealthcare may be useful in fostering the acceptability of behavior change interventions among marginalized AAs.
Pregnant and Peripartum Women with COVID-19 Have High Survival with Extracorporeal Membrane Oxygenation: An Extracorporeal Life Support Organization Registry Analysis.
Authors: Erika R O'Neil, Huiming Lin, Amir A Shamshirsaz, Emily E Naoum, Peter R Rycus, Peta M A Alexander, Jamel P Ortoleva, Meng Li, Marc M Anders
Journal: American Journal of Respiratory and Critical Care Medicine (2022)
Abstract P076: Correlations In Hispanic/Latino Siblings’ Physical Activity And Sedentary Behavior: Results From The Hispanic Community Children’s Health Study/Study Of Latino Youth (SOL Youth)
Authors: Madison N LeCroy, Kelly R Evenson, Krista Perreira, Linda Van Horn, Xiaonan Xue, Linda Gallo, Martha L Daviglus, Carmen R Isasi
Journal: Circulation (2022)

Background: Hispanic/Latino youth in the United States are at an elevated risk for not meeting national guidelines for physical activity (PA). Siblings have the potential to influence each other’s PA and sedentary behavior (SB) through means such as role modeling and co-participation. However, to our knowledge, no study has examined correlations in Hispanic/Latino siblings’ PA and SB behavior using objective measures. Objective: To examine correlations in siblings’ total PA, moderate-to-vigorous physical activity (MVPA), and SB, and to explore whether social and environmental measures explain differences in siblings’ PA and SB. Methods: Hispanic/Latino 8-16-year-olds from the cross-sectional Hispanic Community Children’s Health Study/Study of Latino Youth (SOL Youth) with at least one sibling enrolled in the study were examined ( n =537). Frequency, duration, and intensity of PA were assessed using the ActiCal TM accelerometer. PA-related social and environmental measures were assessed using validated, interviewer-administered questionnaires. Mixed effects linear regression models were used with total PA, MVPA, or SB as the outcome, individual and family-level socio-demographic variables as fixed effects, and family as a random effect. Correlations between siblings’ PA and SB were assessed with intraclass correlation coefficients (ICCs). All models were examined stratified by siblings’ sex concordance and age difference. PA-related social and environmental measures were subsequently added as fixed effects. Results: Mean total PA was 257.4 counts/minutes. On average, youth spent 35.9 minutes in MVPA and 599.4 minutes (10.0 hours) in SB per day. Overall correlations in siblings’ PA and SB were slight to fair, with ICCs of 0.28 (95% CI: 0.18, 0.38), 0.31 (95% CI: 0.22, 0.39), and 0.46 (95% CI: 0.38, 0.54) for total PA, MVPA, and SB, respectively. Siblings who were all brothers had the strongest correlations in total PA (0.61 [95% CI: 0.47, 0.74]) and MVPA (0.62 [95% CI: 0.48, 0.75]) compared to siblings who were all sisters (total PA only) or of differing sexes (total PA and MVPA). Correlations in SB did not differ according to siblings’ sex concordance. Correlations in PA and SB did not differ by siblings’ age difference. Friend support for PA, the after-school PA environment, and workout equipment use at home did not explain differences in siblings’ PA or SB. Conclusions: Correlations in Hispanic/Latino siblings’ PA and SB were slight to fair, with siblings who were all brothers having the strongest correlations in PA. Future research should examine how role-modeling, caregiving responsibilities, and sibling-specific familial support contribute to similarities in siblings’ PA and SB and sex-specific differences in PA correlations.