tbuckley/cabot-search huggingface dataset:
Can Total Nephron Number Predict Progressive CKD after Radical Nephrectomy?
Authors: Jean Seibel, Jean-Michel Rebibou, Mathieu Legendre
Journal: Journal of the American Society of Nephrology (2020)

The histologic assessment of the nontumoral kidney parenchyma is recommended in kidney cancer management. This analysis allows an estimation of CKD risk in patients with favorable cancer-related prognosis and whose survival is correlated with progression toward ESKD.1 Denic et al.2 identify several predictive features of CKD progression by analyzing large wedges of nontumoral kidney parenchyma among patients with kidney cancer. Other than larger glomerular size and nephrosclerosis, the authors focused on the larger cortex per glomerulus as an independent predictor of progressive CKD. This observation emphasizes the clinical relevance of glomerular density as a witness of the total nephron mass. However, the significant inter-individual variability in kidney size requires to relate the glomerular density to the cortical volume, resulting in an estimation of the total nephron number, which in our opinion is a more accurate marker of kidney health than the glomerular density alone. The initial assessment of patients with kidney cancer generally includes a pre-treatment abdominal computed tomography, which allows us to estimate the total cortical volume of the nontumoral kidney. In patients without underlying kidney disease, the cortical volume of the healthy kidney combined with the glomerular density estimation assessed in the nontumoral parenchyma provides an accurate evaluation of the total nephron number of the concerned kidney.3 This method is on the basis of the hypothesis of a homogeneous repartition of the glomeruli between two similar-sized kidneys (not taking the tumor into account). The total nephron number is probably a crucial determinant of CKD progression after the removal of half of the nephron mass, reflecting the adaptation capacities of the remaining kidney due to the increased filtered load per glomerulus.4 Considering its relevance, the total nephron number should be more commonly measured to predict progressive CKD. Disclosures J. Rebibou reports other interests/relationships with French Society of Nephrology Dialysis and Transplantation and ISN. All remaining authors have nothing to disclose. Funding None.
Screening for Asymptomatic Carotid Artery Stenosis
Authors: Alex H. Krist, Karina W. Davidson, Carol M. Mangione, Michael J. Barry, Michael Cabana, Aaron B. Caughey, Katrina Donahue, Chyke A. Doubeni, John W. Epling, Martha Kubik, Gbenga Ogedegbe, Lori Pbert, Michael Silverstein, Melissa A. Simon, Chien-Wen Tseng, John B. Wong
Journal: JAMA (2021)

<h3>Importance</h3> Carotid artery stenosis is atherosclerotic disease that affects extracranial carotid arteries. Asymptomatic carotid artery stenosis refers to stenosis in persons without a history of ischemic stroke, transient ischemic attack, or other neurologic symptoms referable to the carotid arteries. The prevalence of asymptomatic carotid artery stenosis is low in the general population but increases with age. <h3>Objective</h3> To determine if its 2014 recommendation should be reaffirmed, the US Preventive Services Task Force (USPSTF) commissioned a reaffirmation evidence review. The reaffirmation update focused on the targeted key questions on the potential benefits and harms of screening and interventions, including revascularization procedures designed to improve carotid artery blood flow, in persons with asymptomatic carotid artery stenosis. <h3>Population</h3> This recommendation statement applies to adults without a history of transient ischemic attack, stroke, or other neurologic signs or symptoms referable to the carotid arteries. <h3>Evidence Assessment</h3> The USPSTF found no new substantial evidence that could change its recommendation and therefore concludes with moderate certainty that the harms of screening for asymptomatic carotid artery stenosis outweigh the benefits. <h3>Recommendation</h3> The USPSTF recommends against screening for asymptomatic carotid artery stenosis in the general adult population. (D recommendation)
Coupling control of cell proliferation and nucleotide metabolism through MYC, E2F1 and their target genes
Authors: Yen-Chun Liu, Karen Zeller, Jesse Handler, Cheng Ran Lisa Huang, Chi Dang
Journal: Cancer Research (2007)

2112  c-Myc and E2F1 are two key transcription factors that are involved in tumorigenesis by regulating target genes involved in cell cycle progression and cell death. We recently identified target genes common to Myc and E2F1 by chromatin immunoprecipitation (ChIP) coupled with pair-end ditag sequencing analysis (ChIP-PET), computational and microarray expression studies in a MYC-inducible model of human B lymphoid tumor. We found genes, which are putatively regulated by the Myc-E2F1 transcriptional network, encoding enzymes involved in both purine and pyrimidine metabolism. Subsequent ChIP experiments with quantitative PCR characterized direct MYC and E2F1 binding to the promoter and/or first intron region of these target genes. The expression of these genes could be induced by increased MYC level but not all of them responded to decreased E2F1 level in an E2F1 knockdown study. Hence, despite of the direct binding of these two transcription factors, gene expression regulation among the nucleotide metabolism genes varies. We focused on inosine monophosphate dehydrogenase 2 (IMPDH2) involved in de novo purine synthesis and dihydroorotate dehydrogenase (DHODH) involved in pyrimidine synthesis, since overexpression of IMPDH2 appears to be a common feature in human malignancies and both enzymes have known small molecule inhibitors available for loss-of-function studies. Mycophenolic acid (MPA) inhibits IMPDH, causing S phase cell cycle arrest and delayed cell apoptosis in Myc-overexpressing B cells. On the other hand, significant cell death instead of cell cycle arrest was found by inhibiting DHODH with leflunomide. The fact that the end nucleotide product (guanosine or uracil) of each pathway could rescue both phenotypes demonstrated the specificity of the inhibitory effects. Presumably, differences in nucleotide pool depletion by the specific inhibitors led to significantly different phenotypes. To determine the potential therapeutic role of these inhibitors, we studied mycophenolic mofetil, a prodrug of MPA, and found that it significantly inhibited tumorigenesis in the P493 human B lymphoid tumor xenograft model. Since efficient nucleotide synthesis is critical to dysregulated tumor cell growth, these results link transcriptional regulation of nucleotide metabolism by factors central to tumorigenesis to small molecule inhibition and provide a solid base for potential cancer therapy targeting the nucleotide metabolism pathways in cells with dysregulated Myc or E2F1 transcriptional networks.
Modernizing Clinical Trial Eligibility Criteria: Recommendations of the ASCO-Friends of Cancer Research Performance Status Work Group
Authors: Allison Magnuson, Suanna S. Bruinooge, Harpreet Singh, Keith D. Wilner, Shadia Jalal, Stuart M. Lichtman, Paul G. Kluetz, Gary H. Lyman, Heidi D. Klepin, Mark E. Fleury, Brad Hirsch, Allen Melemed, Fernanda I. Arnaldez, Upal Basu Roy, Caroline Schenkel, Shimere Sherwood, Elizabeth Garrett-Mayer
Journal: Clinical Cancer Research (2021)

Performance status (PS) is one of the most common eligibility criteria. Many trials are limited to patients with high-functioning PS, resulting in important differences between trial participants and patient populations with the disease. In addition, existing PS measures are subjective and susceptible to investigator bias.
Insulin gene enhancer protein 1 mediates glycolysis and tumorigenesis of gastric cancer through regulating glucose transporter 4
Authors: Ting Guo, Yan‐Hua Bai, Xiao‐Jing Cheng, Hai‐Bo Han, Hong Du, Ying Hu, Shu‐Qin Jia, Xiao‐Fang Xing, Jia‐Fu Ji
Journal: Cancer Communications (2021)

Abstract Background Insulin gene enhancer protein 1, (ISL1), a LIM‐homeodomain transcription factor, is involved in multiple tumors and is associated with insulin secretion and metabolic phenotypes. However, the role of ISL1 in stimulating glycolysis to promote tumorigenesis in gastric cancer (GC) is unclear. In this study, we aimed to characterize the expression pattern of ISL1 in GC patients and explore its molecular biological mechanism in glycolysis and tumorigenesis. Methods We analyzed the expression and clinical significance of ISL1 in GC using immunohistochemistry and real‐time polymerase chain reaction (PCR). Flow cytometry and IncuCyte assays were used to measure cell proliferation after ISL1 knockdown. RNA‐sequencing was performed to identify differentially expressed genes, followed by Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis and Gene Set Enrichment Analysis (GSEA) to reveal key signaling pathways likely regulated by ISL1 in GC. Alteration of the glycolytic ability of GC cells with ISL1 knockdown was validated by measuring the extracellular acidification rate (ECAR) and oxygen consumption rate (OCR) and by detecting glucose consumption and lactate production. The expression of glucose transporter 4 (GLUT4) and ISL1 was assessed by Western blotting, immunohistochemistry, and immunofluorescent microscopy. The luciferase reporter activity and chromatin immunoprecipitation assays were performed to determine the transcriptional regulation of ISL1 on GLUT4. Results High levels of ISL1 and GLUT4 expression was associated with short survival of GC patients. ISL1 knockdown inhibited cell proliferation both in vitro and in vivo . KEGG analysis and GSEA for RNA‐sequencing data indicated impairment of the glycolysis pathway in GC cells with ISL1 knockdown, which was validated by reduced glucose uptake and lactate production, decreased ECAR, and increased OCR. Mechanistic investigation indicated that ISL1 transcriptionally regulated GLUT4 through binding to its promoter. Conclusion ISL1 facilitates glycolysis and tumorigenesis in GC via the transcriptional regulation of GLUT4.
Recurrent TB: a systematic review and meta-analysis of the incidence rates and the proportions of relapses and reinfections
Authors: Victor Vega, Sharon Rodríguez, Patrick Van der Stuyft, Carlos Seas, Larissa Otero
Journal: Thorax (2021)

Background A recurrent tuberculosis (TB) episode results from exogenous reinfection or relapse after cure. The use of genotyping allows the distinction between both. Methods We did a systematic review and meta-analysis, using four databases to search for studies in English, French and Spanish published between 1 January 1980 and 30 September 2020 that assessed recurrences after TB treatment success and/or differentiated relapses from reinfections using genotyping. We calculated person years of follow-up and performed random-effects model meta-analysis for estimating pooled recurrent TB incidence rates and proportions of relapses and reinfections. We performed subgroup analyses by clinical–epidemiological factors and by methodological study characteristics. Findings The pooled recurrent TB incidence rate was 2.26 per 100 person years at risk (95% CI 1.87 to 2.73; 145 studies). Heterogeneity was high (I 2 =98%). Stratified pooled recurrence rates increased from 1.47 (95% CI 0.87 to 2.46) to 4.10 (95% CI 2.67 to 6.28) per 100 person years for studies conducted in low versus high TB incidence settings. Background HIV prevalence, treatment drug regimen, sample size and duration of follow-up contributed too. The pooled proportion of relapses was 70% (95% CI 63% to 77%; I²=85%; 48 studies). Heterogeneity was determined by background TB incidence, as demonstrated by pooled proportions of 83% (95% CI 75% to 89%) versus 59% (95% CI 42% to 74%) relapse for studies from settings with low versus high TB incidence, respectively. Interpretation The risk of recurrent TB is substantial and relapse is consistently the most frequent form of recurrence. Notwithstanding, with increasing background TB incidence the proportion of reinfections increases and the predominance of relapses among recurrences decreases. PROSPERO registration number CRD42018077867
2020 ACC/AHA Guideline for the Management of Patients With Valvular Heart Disease: Executive Summary
Authors: Catherine M. Otto, Rick A. Nishimura, Robert O. Bonow, Blase A. Carabello, John P. Erwin, Federico Gentile, Hani Jneid, Eric V. Krieger, Michael Mack, Christopher McLeod, Patrick T. O’Gara, Vera H. Rigolin, Thoralf M. Sundt, Annemarie Thompson, Christopher Toly
Journal: Journal of the American College of Cardiology (2020)
Comparisons of Polyexposure, Polygenic, and Clinical Risk Scores in Risk Prediction of Type 2 Diabetes
Authors: Yixuan He, Chirag M. Lakhani, Danielle Rasooly, Arjun K. Manrai, Ioanna Tzoulaki, Chirag J. Patel
Journal: Diabetes Care (2021)

OBJECTIVE To establish a polyexposure score (PXS) for type 2 diabetes (T2D) incorporating 12 nongenetic exposures and examine whether a PXS and/or a polygenic risk score (PGS) improves diabetes prediction beyond traditional clinical risk factors. RESEARCH DESIGN AND METHODS We identified 356,621 unrelated individuals from the UK Biobank of White British ancestry with no prior diagnosis of T2D and normal HbA1c levels. Using self-reported and hospital admission information, we deployed a machine learning procedure to select the most predictive and robust factors out of 111 nongenetically ascertained exposure and lifestyle variables for the PXS in prospective T2D. We computed the clinical risk score (CRS) and PGS by taking a weighted sum of eight established clinical risk factors and &amp;gt;6 million single nucleotide polymorphisms, respectively. RESULTS In the study population, 7,513 had incident T2D. The C-statistics for the PGS, PXS, and CRS models were 0.709, 0.762, and 0.839, respectively. Individuals in the top 10% of PGS, PXS, and CRS had 2.00-, 5.90-, and 9.97-fold greater risk, respectively, compared to the remaining population. Addition of PGS and PXS to CRS improved T2D classification accuracy, with a continuous net reclassification index of 15.2% and 30.1% for cases, respectively, and 7.3% and 16.9% for controls, respectively. CONCLUSIONS For T2D, the PXS provides modest incremental predictive value over established clinical risk factors. However, the concept of PXS merits further consideration in T2D risk stratification and is likely to be useful in other chronic disease risk prediction models.
Abstract IA018: Breaking the obesity-endometrial cancer link: Lessons from preclinical studies
Authors: Stephen D. Hursting
Journal: Clinical Cancer Research (2021)

Abstract The prevalence of obesity, an established risk factor for endometrial cancer, has increased dramatically over the past 50 years in the US and many other countries. Relative to normoweight cancer patients, obese cancer patients also often have poorer prognoses, resistance to chemotherapies, and are more likely to develop distant metastases. Recent progress on elucidating the mechanisms underlying the obesity-cancer connection suggests that obesity exerts pleomorphic effects on pathways related to tumor development and progression, and thus there are multiple opportunities for primary to tertiary prevention of obesity-related endometrial cancers. We now know that obesity can impact each of the well-established hallmarks of cancer, but obesity-associated perturbations in systemic metabolism and inflammation, and the interactions of these perturbations with cancer cell energetics and immune response, are emerging as the primary drivers of obesity-associated endometrial cancer development and progression. While additional work is needed on the mechanisms underlying the obesity-endometrial cancer link, research is also urgently needed on how to best mitigate the procancer effects of obesity on the endometrium, as well as ways to prevent obesity-associated metastatic progression and therapeutic resistance. We will thus discuss relevant dietary and lifestyle interventions that are being implemented in preclinical and clinical trials, with the ultimate goal of reducing incidence and progression of obesity-associated endometrial cancer. Citation Format: Stephen D. Hursting. Breaking the obesity-endometrial cancer link: Lessons from preclinical studies [abstract]. In: Proceedings of the AACR Virtual Special Conference: Endometrial Cancer: New Biology Driving Research and Treatment; 2020 Nov 9-10. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(3_Suppl):Abstract nr IA018.
Dapagliflozin in HFrEF Patients Treated With Mineralocorticoid Receptor Antagonists
Authors: Li Shen, Søren Lund Kristensen, Olof Bengtsson, Michael Böhm, Rudolf A. de Boer, Kieran F. Docherty, Silvio E. Inzucchi, Tzvetana Katova, Lars Køber, Mikhail N. Kosiborod, Anna Maria Langkilde, Daniel Lindholm, M. Felipe A. Martinez, Eileen O’Meara, Jose C. Nicolau, Mark C. Petrie, Piotr Ponikowski, Marc S. Sabatine, Morten Schou, Mikaela Sjöstrand, Scott D. Solomon, Pardeep S. Jhund, John J.V. McMurray
Journal: JACC Heart Failure (2021)
Resilience in Development and Psychopathology: Multisystem Perspectives
Authors: Ann S. Masten, Cara M. Lucke, Kayla M. Nelson, Isabella C. Stallworthy
Journal: Annual Review of Clinical Psychology (2021)

Resilience science in psychology and related fields emerged from clinical research on risk for psychopathology in the 1970s and matured over the ensuing decades with advances in theory, methods, and knowledge. Definitions and models of resilience shifted to reflect the expanding influence of developmental systems theory and the growing need to integrate knowledge about resilience across levels and disciplines to address multisystem threats. Resilience is defined for scalability and integrative purposes as the capacity of a dynamic system to adapt successfully through multisystem processes to challenges that threaten system function, survival, or development. Striking alignment of resilience factors observed in human systems, ranging from individuals to communities, suggests the possibility of networked, multisystem protective factors that work in concert. Evidence suggests that there may be resilience factors that provide transdiagnostic protection against the effects of adverse childhood experiences on risk for psychopathology. Multisystem studies of resilience offer promising directions for future research and its applications to promote mental health and positive development in children and youth at risk for psychopathology.
Randomized Trial of a Vaccine Regimen to Prevent Chronic HCV Infection
Authors: Kimberly Page, Michael T. Melia, Rebecca T. Veenhuis, Matthew Winter, Kimberly E. Rousseau, Guido Massaccesi, William O. Osburn, Michael Forman, Elaine Thomas, Karla Thornton, Katherine Wagner, Ventzislav Vassilev, Lan Lin, Paula J. Lum, Linda C. Giudice, Ellen Stein, Alice Asher, Soju Chang, Richard Gorman, Marc G. Ghany, T. Jake Liang, Michael R. Wierzbicki, Elisa Scarselli, Alfredo Nicosia, Antonella Folgori, Stefania Capone, Andrea L. Cox
Journal: New England Journal of Medicine (2021)

A safe and effective vaccine to prevent chronic hepatitis C virus (HCV) infection is a critical component of efforts to eliminate the disease.
Abstract IA004: Challenges for future adjuvant studies and the role of immunotherapy in endometrial cancer
Authors: Remi A. Nout
Journal: Clinical Cancer Research (2021)

Abstract Adjuvant therapy for endometrial cancer (EC) is recommended based on risk factors. In current clinical practice these are mainly based on classical pathological factors such as stage, grade and presence of LVSI. The Cancer Genome Atlas Group demonstrated that EC can be divided in four distinct subgroups with impact on prognosis. This has now been shown to be feasible using surrogate markers in multiple large cohorts. Analysis of the intratumoral immune infiltrate using a machine learning image-based algorithm, found that low intraepithelial density of CD8+ cells was an independent prognostic factor for recurrence free survival. Combining intraepithelial CD8+ cell density with molecular and pathological factors improved the risk stratification model. Exploratory analysis found a significant impact within the p53abnormal and no specific molecular profile subgroups. While in intermediate to high-intermediate risk the majority has no specific molecular profile, in high risk there are more patients with POLE hypermutated tumors, p53abnormal and mismatch repair deficient tumors. The question is how to bring these molecular factors to the clinic? Molecular stratification does present additional subgroups with a rationale for targeted approaches. It does however present a challenge for trial design and feasibility, An overview of current ongoing studies using targeted therapies is provided, with a focus on immune checkpoint inhibition. Citation Format: Remi A. Nout. Challenges for future adjuvant studies and the role of immunotherapy in endometrial cancer [abstract]. In: Proceedings of the AACR Virtual Special Conference: Endometrial Cancer: New Biology Driving Research and Treatment; 2020 Nov 9-10. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(3_Suppl):Abstract nr IA004.
Right Ventricular Pressure–Volume Analysis Before and After Transcatheter Leaflet Approximation for Severe Mitral Regurgitation
Authors: Michael I. Brener, Daniel Burkhoff, Mohammad Sarraf
Journal: JAMA Cardiology (2021)

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