tbuckley/cabot-search huggingface dataset:
Angiopoietins as Prognostic Markers for Future Kidney Disease and Heart Failure Events after Acute Kidney Injury
Authors: Sherry G. Mansour, Pavan K. Bhatraju, Steven G. Coca, Wassim Obeid, Francis P. Wilson, Ian B. Stanaway, Yaqi Jia, Heather Thiessen-Philbrook, Alan S. Go, T. Alp Ikizler, Edward D. Siew, Vernon M. Chinchilli, Chi-yuan Hsu, Amit X. Garg, W. Brian Reeves, Kathleen D. Liu, Paul L. Kimmel, James S. Kaufman, Mark M. Wurfel, Jonathan Himmelfarb, Samir M. Parikh, Chirag R. Parikh
Journal: Journal of the American Society of Nephrology (2022)

Significance Statement Mechanisms underlying long-term effects after AKI remain unclear. Because vessel instability is an early response to endothelial injury, the authors studied markers of blood vessel homeostasis (the plasma angiopoietins angiopoietin-1 and angiopoietin-2) in a multicenter prospective cohort that included 1503 adults, half of whom had AKI. Three months after hospitalization, the highest quartile of plasma angiopoietin-1:angiopoietin-2 ratio compared with the lowest quartile associated with 72% less risk of CKD progression, 94% less risk of heart failure, and 82% less risk of death among those with AKI; those without AKI exhibited similar but less pronounced reductions in risk of heart failure and mortality. Angiopoietins may serve as a common pathway to explain the progression of kidney and heart disease after AKI and may point to potential future interventions. Background The mechanisms underlying long-term sequelae after AKI remain unclear. Vessel instability, an early response to endothelial injury, may reflect a shared mechanism and early trigger for CKD and heart failure. Methods To investigate whether plasma angiopoietins, markers of vessel homeostasis, are associated with CKD progression and heart failure admissions after hospitalization in patients with and without AKI, we conducted a prospective cohort study to analyze the balance between angiopoietin-1 (Angpt-1), which maintains vessel stability, and angiopoietin-2 (Angpt-2), which increases vessel destabilization. Three months after discharge, we evaluated the associations between angiopoietins and development of the primary outcomes of CKD progression and heart failure and the secondary outcome of all-cause mortality 3 months after discharge or later. Results Median age for the 1503 participants was 65.8 years; 746 (50%) had AKI. Compared with the lowest quartile, the highest quartile of the Angpt-1:Angpt-2 ratio was associated with 72% lower risk of CKD progression (adjusted hazard ratio [aHR], 0.28; 95% confidence interval [CI], 0.15 to 0.51), 94% lower risk of heart failure (aHR, 0.06; 95% CI, 0.02 to 0.15), and 82% lower risk of mortality (aHR, 0.18; 95% CI, 0.09 to 0.35) for those with AKI. Among those without AKI, the highest quartile of Angpt-1:Angpt-2 ratio was associated with 71% lower risk of heart failure (aHR, 0.29; 95% CI, 0.12 to 0.69) and 68% less mortality (aHR, 0.32; 95% CI, 0.15 to 0.68). There were no associations with CKD progression. Conclusions A higher Angpt-1:Angpt-2 ratio was strongly associated with less CKD progression, heart failure, and mortality in the setting of AKI.
Inhibiting serotonin signaling through HTR2B in visceral adipose tissue improves obesity-related insulin resistance
Authors: Won Gun Choi, Wonsuk Choi, Tae Jung Oh, Hye-Na Cha, Inseon Hwang, Yun Kyung Lee, Seung Yeon Lee, Hyemi Shin, Ajin Lim, Dongryeol Ryu, Jae Myoung Suh, So-Young Park, Sung Hee Choi, Hail Kim
Journal: Journal of Clinical Investigation (2021)

Insulin resistance is a cornerstone of obesity-related complications such as type 2 diabetes, metabolic syndrome, and nonalcoholic fatty liver disease. A high rate of lipolysis is known to be associated with insulin resistance, and inhibiting adipose tissue lipolysis improves obesity-related insulin resistance. Here, we demonstrate that inhibition of serotonin (5-hydroxytryptamine [5-HT]) signaling through serotonin receptor 2B (HTR2B) in adipose tissues ameliorates insulin resistance by reducing lipolysis in visceral adipocytes. Chronic high-fat diet (HFD) feeding increased Htr2b expression in epididymal white adipose tissue, resulting in increased HTR2B signaling in visceral white adipose tissue. Moreover, HTR2B expression in white adipose tissue was increased in obese humans and positively correlated with metabolic parameters. We further found that adipocyte-specific Htr2b-knockout mice are resistant to HFD-induced insulin resistance, visceral adipose tissue inflammation, and hepatic steatosis. Enhanced 5-HT signaling through HTR2B directly activated lipolysis through phosphorylation of hormone-sensitive lipase in visceral adipocytes. Moreover, treatment with a selective HTR2B antagonist attenuated HFD-induced insulin resistance, visceral adipose tissue inflammation, and hepatic steatosis. Thus, adipose HTR2B signaling could be a potential therapeutic target for treatment of obesity-related insulin resistance.
51P Testing patterns and outcomes of different EGFR-positive metastatic non-small cell lung cancer (NSCLC) patients in a Canadian real-world setting
Authors: D.J. Boyne, T. Jarada, A. Yusuf, D.E. O'Sullivan, L.X.Y. Hu, D.R. Brenner, E. Abbie, J.B. Rose, K. Eaton, E.M. Ewara, W.Y. Cheung
Journal: Annals of Oncology (2022)
Exploratory Study of NPC-0501 Trial: Optimal Cisplatin Dose of Concurrent and Induction/Adjuvant Chemotherapy for Locoregionally Advanced Nasopharyngeal Carcinoma
Authors: Wai-Tong Ng, Cheuk-Wai Choi, Barton But, Roger K.C. Ngan, Stewart Tung, Ashley C. Cheng, Dora L.W. Kwong, Tai-Xiang Lu, Anthony T.C. Chan, Harry Yiu, Sarah Lee, Frank Wong, Kam-Tong Yuen, Richard J. Chappell, Anne W.M. Lee
Journal: Clinical Cancer Research (2022)

The current recommendation for patients with locoregionally advanced nasopharyngeal carcinoma (NPC) is cisplatin-based induction chemotherapy (IC) or adjuvant chemotherapy (AC) plus concurrent chemoradiotherapy (CRT). However, data on the optimal platinum doses for each phase of combined regimens are lacking.742 patients with NPC in the NPC-0501 trial treated with CRT plus IC/AC and irradiated with intensity-modulated radiotherapy (IMRT) were analyzed. The optimal platinum dose to achieve the best overall survival (OS) in the concurrent and induction/adjuvant phases was studied.Evaluation of the whole series shows the optimal platinum dose was 160 mg/m2 in the concurrent and 260 mg/m2 in the induction/adjuvant phase. Repeating the analyses on 591 patients treated with cisplatin throughout (no replacement by carboplatin) confirmed the same results. The cohort with optimal platinum doses in both phases had better OS than the cohort suboptimal in both phases (stage III: 90% vs. 75%; stage IVA-B: 80% vs. 56%, at 5-year). Multivariable analyses confirmed optimal platinum doses in both phases versus suboptimal dose in each phase are significant independent factors for OS, with HR of 0.61 [95% confidence interval (CI), 0.41-0.91] and 0.67 (95% CI, 0.48-0.94), respectively. Treatment sequence was statistically insignificant after adjusting for platinum doses.Both concurrent and IC/AC are needed for locoregionally advanced NPC, even for patients irradiated by IMRT; the concurrent platinum dosage could be set at ≥160 mg/m2 when coupled with adequate induction/adjuvant dosage at ≥260 mg/m2 (or at least ≥240 mg/m2). To achieve these optimal dosages, IC-CRT at conventional fractionation is favored.
Knowledge prior to belief: Is extended better than enacted?
Authors: Mirko Farina, Andrea Lavazza
Journal: Behavioral and Brain Sciences (2021)

Abstract In this commentary, we argue that Phillips et al.'s findings can be used to provide new important insights in the debate between externalists’ theories of cognition. In particular, we claim that the results presented in this target article may offer us the conceptual palette needed for a sustained defence of an extended account of cognition over an enactive one.
Mental health among patients with non‐Hodgkin lymphoma: A Danish nationwide study of psychotropic drug use in 8750 patients and 43 750 matched comparators
Authors: Andreas Kiesbye Øvlisen, Lasse Hjort Jakobsen, Kristian Hay Kragholm, René Ernst Nielsen, Peter de Nully Brown, Rasmus Bo Dahl‐Sørensen, Henrik Frederiksen, Nikolaj Mannering, Pär Lars Josefsson, Ahmed Ludvigsen Al‐Mashhadi, Judit Mészáros Jørgensen, Andriette Dessau‐Arp, Michael Roost Clausen, Robert Schou Pedersen, Christian Torp‐Pedersen, Marianne Tang Severinsen, Tarec Christoffer El‐Galaly
Journal: American Journal of Hematology (2022)

Psychological distress following cancer diagnosis may lead to mental health complications including depression and anxiety. Non-Hodgkin lymphomas (NHLs) include indolent and aggressive subtypes for which treatment and prognosis differ widely. Incident use of psychotropic drugs (PDs-antidepressants, antipsychotics, and anxiolytics) and its correlation to lymphoma types can give insights into the psychological distress these patients endure. In this prospective matched cohort study, we used nationwide population-based registries to investigate the cumulative risk of PD use in NHL patients compared to a sex- and age-matched cohort from the Danish background population. In addition, contact patterns to psychiatric departments and incident intentional self-harm or completed suicide were explored. In total, 8750 NHL patients and 43 750 matched comparators were included (median age 68; male:female ratio 1.6). Median follow-up was 7.1 years. Two-year cumulative risk of PD use was higher in NHL patients (16.4%) as compared to the matched comparators (5.1%, p < .01); patients with aggressive NHL subtypes had the highest incidence. Prescription rates were higher in the first years after diagnosis but approached the rate of the matched population 5 years into survivorship in aggressive NHLs, whereas patients with indolent subtypes continued to be at higher risk. NHL patients had a slightly higher two-year risk of suicide/intentional self-harm (0.3%) as compared to the matched comparators (0.2%, p = .01). These results demonstrate that mental health complications among NHL patients are frequent. Routine assessment for symptoms of depression and anxiety should be consider as part of standard follow-up of NHL patients.
Abstract EP32: Low Density Lipoprotein Cholesterol Associations With The Risk Of Coronary Heart Disease And Stroke Among Middle-aged Japanese Workers: Analysis Using Inverse Probability Weighting
Authors: Abubakr A Al-shoaibi, Yuanying Li, Chifa Chiang, Yoshihisa Hirakawa, Zean Song, KM Saif-Ur-Rahman, Shimoda Masako, Matsunaga Masaaki, Atsuko Aoyama, Koji Tamakoshi, Atsuhiko Ota, Hiroshi Yatsuya
Journal: Circulation (2022)

Introduction: Low density lipoprotein cholesterol (LDL-C) is an established causal factor for coronary heart disease (CHD) and ischemic stroke. A positive linear association between LDL-C and risk of CHD or ischemic stroke was reported from western populations but among Japanese the evidence still insufficient especially on the risk of ischemic stroke. This study used a longitudinal data from the Aichi Worker’s Cohort Study to explore the associations of LDL-C levels with the incidence of CHD, and stroke subtypes. Methods: Pooled data of 6325 adults (5001 men and 1324 women) who responded to the second (2002) and third (2007) wave surveys of the study were used for the current analysis. Propensity scores for LDL-C categories were generated using multinomial logistic regression that included age, sex, smoking, alcohol drinking, physical activity, body mass index, high-density lipoprotein cholesterol, triglycerides, history of diabetes and hypertension, antihypertensive medication, taking dyslipidemia medication and survey year. Hazard ratios (HRs) and the 95% confidence intervals (95% CIs) were estimated from inverse probability weighted (IPW) cox proportional hazards model for LDL-C categories associations with risks of CHD, stroke and its subtypes, and CVD. We also used restricted cubic spline to examine the possible nonlinear relationship. Results: During a median of 14 years of follow-up, 73 strokes (40 ischemic stroke, 30 hemorrhagic stroke and 3 unknown) and 60 CHD were observed. In comparison with LDL-C &lt; 120 mg/ dl, LDL-C ≥160 mg/dl was significantly associated with the increased risk of CVD (HR 1.79, 95% CI: 1.12-2.86) and CHD (HR 3.82, 95% CI: 1.80-8.06), but not with stroke (HR 1.05, 95% CI: 0.54-2.06), hemorrhagic stroke (HR 0.47, 95% CI: 0.13-1.67) or ischemic stroke (HR 1.56, 95% CI: 0.66-3.68). The results of restricted cubic spline analysis showed that the risks of CVD and CHD gradually increased from LDL-C of 120 mg/dl. On the other hand, the risk of ischemic stroke was flat until around LDL-C of 160 mg/dl and then increased afterward. The risk of hemorrhagic stroke was flat from LDL-C of 120 mg/dl or above, but showed an increased risk trend towards lower levels of LDL-C. Conclusions: Based on this recent, long-term prospective study among middle-aged Japanese workers and by applying the IPW method to adjust for several confounding variables, we found that LDL-C was linearly and positively associated with CHD incidence while higher LDL-C levels tended to be at an increased risk of ischemic stroke, though non-significant.
Severe COVID-19-associated variants linked to chemokine receptor gene control in monocytes and macrophages
Authors: Bernard S. Stikker, Grégoire Stik, Antoinette F. van Ouwerkerk, Lianne Trap, Salvatore Spicuglia, Rudi W. Hendriks, Ralph Stadhouders
Journal: Genome biology (2022)

Abstract Genome-wide association studies have identified 3p21.31 as the main risk locus for severe COVID-19, although underlying mechanisms remain elusive. We perform an epigenomic dissection of 3p21.31, identifying a CTCF-dependent tissue-specific 3D regulatory chromatin hub that controls the activity of several chemokine receptor genes. Risk SNPs colocalize with regulatory elements and are linked to increased expression of CCR1 , CCR2 and CCR5 in monocytes and macrophages. As excessive organ infiltration of inflammatory monocytes and macrophages is a hallmark of severe COVID-19, our findings provide a rationale for the genetic association of 3p21.31 variants with elevated risk of hospitalization upon SARS-CoV-2 infection.
Safety and immunogenicity of an AS03-adjuvanted SARS-CoV-2 recombinant protein vaccine (CoV2 preS dTM) in healthy adults: interim findings from a phase 2, randomised, dose-finding, multicentre study
Authors: Saranya Sridhar, Arnel Joaquin, Matthew I Bonaparte, Agustin Bueso, Anne-Laure Chabanon, Aiying Chen, Roman M Chicz, David Diemert, Brandon J Essink, Bo Fu, Nicole A Grunenberg, Helene Janosczyk, Michael C Keefer, Doris M Rivera M, Ya Meng, Nelson L Michael, Sonal S Munsiff, Onyema Ogbuagu, Vanessa N Raabe, Randall Severance, Enrique Rivas, Natalya Romanyak, Nadine G Rouphael, Lode Schuerman, Lawrence D Sher, Stephen R Walsh, Judith White, Dalia von Barbier, Guy de Bruyn, Richard Canter, Marie-Helene Grillet, Maryam Keshtkar-Jahromi, Marguerite Koutsoukos, Denise Lopez, Roger Masotti, Sandra Mendoza, Catherine Moreau, Maria Angeles Ceregido, Shelly Ramirez, Ansoyta Said, Fernanda Tavares-Da-Silva, Jiayuan Shi, Tina Tong, John Treanor, Carlos A Diazgranados, Stephen Savarino
Journal: The Lancet Infectious Diseases (2022)

We evaluated our SARS-CoV-2 prefusion spike recombinant protein vaccine (CoV2 preS dTM) with different adjuvants, unadjuvanted, and in a one-injection and two-injection dosing schedule in a previous phase 1-2 study. Based on interim results from that study, we selected a two-injection schedule and the AS03 adjuvant for further clinical development. However, lower than expected antibody responses, particularly in older adults, and higher than expected reactogenicity after the second vaccination were observed. In the current study, we evaluated the safety and immunogenicity of an optimised formulation of CoV2 preS dTM adjuvanted with AS03 to inform progression to phase 3 clinical trial.
Abstract 11838: Isosorbide Dinitrate Effect May Improve Exercise Tolerance, Venous Pressure and Liver Stiffness in Patients With Fontan Circulation (The NEET Clinical Trial)
Authors: Amee M Bigelow, Kyle W Riggs, David L Morales, Adam M Lubert, Haleh C Heydarian, Jonathan R Dillman, Andrew T Trout, Alexander R Opotowsky, David S Cooper, Yu L Wang, Clifford Chin, Joseph J Palermo, Gruschen R Veldtman, Nicholas J Ollberding, Wayne A Mays, Tarek Alsaied
Journal: Circulation (2021)

Introduction: After the Fontan operation, decreased venous capacitance (venoconstriction) and elevated central venous pressure may result in worse clinical outcomes, worse exercise capacity, and increased liver stiffness. This pilot study evaluated the acute effect of isosorbide dinitrate (ISDN), a venodilator, on exercise capacity, peripheral venous pressure (PVP), and liver stiffness in patients with Fontan circulation. Methods: In this prospective single-arm trial, 15 individuals with Fontan circulation were evaluated at baseline and after four weeks of treatment with ISDN. Cardiopulmonary exercise testing was performed to assess exercise tolerance, with a primary outcome of peak oxygen consumption (peak VO 2 ). The secondary outcome included VO 2 at the anaerobic threshold (AT VO 2 ), PVP at rest and peak exercise and liver stiffness measured by ultrasound prior to the exercise test. Repeated measure t-test was used to test for differences in outcomes in response to ISDN. Results: The mean age was 23.5 ± 9.2 years (range 11.2-30.6 years), and 10/15 (67%) were male. There was no statistically significant change in peak VO 2 from baseline (1401±428 to 1428±436 ml/min, p=0.128), but there was an improvement in AT VO 2 (1087 ± 313 to 1115 ±302 mL/min, p= 0.03). Treatment with ISDN was associated with lower peak exercise PVP (22.5 ±4.5 to 20.6 ± 2.99 mmHg, p=0.015) without a notable difference in the resting PVP (p=0.357). There was a trend towards lower liver stiffness with ISDN (2.3 ± 0.4 to 2.1 ± 0.5 m/s, p=0.079). Of the patients completing the trial, mild headache was common (67%), but there were no major adverse events. Conclusions: Treatment with ISDN for 4 weeks is well-tolerated except for headache and appears safe in patients with a Fontan circulation. ISDN therapy was associated with improvements in certain exercise and hemodynamic parameters as well as a trend towards lowering liver stiffness. Larger studies will be necessary to validate these physiologic findings and further evaluate the effects of nitrates on meaningful clinical outcomes.
A PD-1/PD-L1 Proximity Assay as a Theranostic Marker for PD-1 Blockade in Patients with Metastatic Melanoma
Authors: Isabelle Girault, Julien Adam, Shensi Shen, Séverine Roy, Caroline Brard, Sara Faouzi, Emilie Routier, Jéremy Lupu, Sarah Warren, Kristina Sorg, SuFey Ong, Pascale Morel, Jean-Yves Scoazec, Stéphan Vagner, Caroline Robert
Journal: Clinical Cancer Research (2021)

Less than 50% of patients with melanoma respond to anti-programmed cell death protein 1 (anti-PD-1), and this treatment can induce severe toxicity. Predictive markers are thus needed to improve the benefit/risk ratio of immune checkpoint inhibitors (ICI). Baseline tumor parameters such as programmed death ligand 1 (PD-L1) expression, CD8+ T-cell infiltration, mutational burden, and various transcriptomic signatures are associated with response to ICI, but their predictive values are not sufficient. Interaction between PD-1 and its main ligand, PD-L1, appears as a valuable target of anti-PD-1 therapy. Thus, instead of looking at PD-L1 expression only, we evaluated the predictive value of the proximity between PD-1 and its neighboring PD-L1 molecules in terms of response to anti-PD-1 therapy.PD-1/PD-L1 proximity was assessed by proximity ligation assay (PLA) on 137 samples from two cohorts (exploratory n = 66 and validation n = 71) of samples from patients with melanoma treated with anti-PD-1±anti-CTLA-4. Additional predictive biomarkers, such as PD-L1 expression (MELscore), CD8+ cells density, and NanoString RNA signature, were also evaluated.A PD-1/PD-L1 PLA model was developed to predict tumor response in an exploratory cohort and further evaluated in an independent validation cohort. This score showed higher predictive ability (AUC = 0.85 and 0.79 in the two cohorts, respectively) for PD-1/PD-L1 PLA as compared with other parameters (AUC = 0.71-0.77). Progression-free and overall survival were significantly longer in patients with high PLA values (P = 0.00019 and P < 0.0001, respectively).The proximity between PD-1 and PD-L1, easily assessed by this PLA on one formalin-fixed paraffin-embedded section, appears as a new biomarker of anti-PD-1 efficacy.
Robust normalization and transformation techniques for constructing gene coexpression networks from RNA-seq data
Authors: Kayla A. Johnson, Arjun Krishnan
Journal: Genome biology (2022)

Constructing gene coexpression networks is a powerful approach for analyzing high-throughput gene expression data towards module identification, gene function prediction, and disease-gene prioritization. While optimal workflows for constructing coexpression networks, including good choices for data pre-processing, normalization, and network transformation, have been developed for microarray-based expression data, such well-tested choices do not exist for RNA-seq data. Almost all studies that compare data processing and normalization methods for RNA-seq focus on the end goal of determining differential gene expression.Here, we present a comprehensive benchmarking and analysis of 36 different workflows, each with a unique set of normalization and network transformation methods, for constructing coexpression networks from RNA-seq datasets. We test these workflows on both large, homogenous datasets and small, heterogeneous datasets from various labs. We analyze the workflows in terms of aggregate performance, individual method choices, and the impact of multiple dataset experimental factors. Our results demonstrate that between-sample normalization has the biggest impact, with counts adjusted by size factors producing networks that most accurately recapitulate known tissue-naive and tissue-aware gene functional relationships.Based on this work, we provide concrete recommendations on robust procedures for building an accurate coexpression network from an RNA-seq dataset. In addition, researchers can examine all the results in great detail at https://krishnanlab.github.io/RNAseq_coexpression to make appropriate choices for coexpression analysis based on the experimental factors of their RNA-seq dataset.