tbuckley/cabot-search huggingface dataset:
Prediabetes, Diabetes, and the Risk of All-Cause and Cause-Specific Mortality in a Japanese Working Population: Japan Epidemiology Collaboration on Occupational Health Study
Authors: Zobida Islam, Shamima Akter, Yosuke Inoue, Huan Hu, Keisuke Kuwahara, Tohru Nakagawa, Toru Honda, Shuichiro Yamamoto, Hiroko Okazaki, Toshiaki Miyamoto, Takayuki Ogasawara, Naoko Sasaki, Akihiko Uehara, Makoto Yamamoto, Takeshi Kochi, Masafumi Eguchi, Taiki Shirasaka, Makiko Shimizu, Satsue Nagahama, Ai Hori, Teppei Imai, Akiko Nishihara, Kentaro Tomita, Tomofumi Sone, Maki Konishi, Isamu Kabe, Tetsuya Mizoue, Seitaro Dohi
Journal: Diabetes Care (2021)

Prediabetes has been suggested to increase risk for death; however, the definitions of prediabetes that can predict death remain elusive. We prospectively investigated the association of multiple definitions of prediabetes with the risk of death from all causes, cardiovascular disease (CVD), and cancer in Japanese workers.The study included 62,785 workers who underwent a health checkup in 2010 or 2011 and were followed up for death from 2012 to March 2019. Prediabetes was defined according to fasting plasma glucose (FPG) or glycated hemoglobin (HbA1c) values or a combination of both using the American Diabetes Association (ADA) or World Health Organization (WHO)/International Expert Committee (IEC) criteria. The Cox proportional hazards regression model was used to investigate the associations.Over a 7-year follow-up, 229 deaths were documented. Compared with normoglycemia, prediabetes defined according to ADA criteria was associated with a higher risk of all-cause mortality (hazard ratio [HR] 1.53; 95% CI 1.12-2.09) and death due to cancer (HR 2.37; 95% CI 1.45-3.89) but not with death due to CVD. The results were materially unchanged when prediabetes was defined according to ADA FPG, ADA HbA1c, WHO FPG, or combined WHO/IEC criteria. Diabetes was associated with the risk of all-cause, CVD, and cancer deaths.In a cohort of Japanese workers, FPG- and HbA1c-defined prediabetes, according to ADA or WHO/IEC, were associated with a significantly increased risk of death from all causes and cancer but not CVD.
Alternatively Spliced Form of Angiopoietin-2 as a New Vascular Rheostat
Authors: Miki Kamiyama, Hellmut G. Augustin
Journal: Cancer Research (2021)

Abstract Angiopoietin (ANPGT)–TIE signaling serves as a critical regulator of vessel maturation controlling vascular quiescence, maintenance, and homeostasis (primarily through ANGPT1–TIE2 signaling), as well as enabling vascular plasticity and responsiveness to exogenous cytokines (primarily through antagonistically acting ANGPT2). An alternatively spliced form of ANGPT2 (ANGPT2443) was first reported 20 years ago. Yet, little is known to this day about its biological functions. In this issue of Cancer Research, Kapiainen and colleagues report an elegant series of experiments adding to the complexity and contextuality of ANGPT–TIE signaling. The authors studied the function of ANGPT2443 in cellular experiments as well as in a genetic model in vivo, revealing that it is proteolytically cleaved into a lower molecular weight isoform (termed ANGPT2DAP) that lacks the superclustering domain necessary for multimer formation. When compared with full-length ANGPT2, ANGPT2443 and ANGPT2DAP showed lower binding affinity to α5β1 integrin, but were more potent inhibitors of ANGPT1–TIE2 signaling. Functionally, ANGPT2443 impaired vessel enlargement and vein morphogenesis during postnatal retinal angiogenesis. Tumor experiments in Angpt2443-expressing mice showed enhanced destabilization of the lung vasculature, with varying effects on metastasis. Taken together, the study provides important insight into the significance of ANGPT2 alternative splicing and identifies ANGPT2443 and ANGPT2DAP as a biological rheostat of ANGPT1–TIE2 signaling. Future work will need to characterize the relative ratios and functional contributions of the ANGPT2 variants in different pathophysiologic settings. See related article by Kapiainen et al., p. 129
Where should ascitic drains be placed? Revisiting anatomical landmarks for paracentesis
Authors: Keith Siau, Naomi Robson, Steven Bollipo
Journal: Gut (2021)

We welcome the recent publication of the BSG/BASL guidelines on the management of ascites in cirrhosis which will serve as a framework for patient management across the world.1 Following clinician feedback on Twitter,2 we wish to respectfully highlight concerns regarding their guidance on landmarks for therapeutic paracentesis.

Our first concern relates to the description of the landmarks. The authors recommend this to be ‘at least 8 cm (laterally) from the midline and 5 cm above the symphysis (pubis)’.1 This was predicated on three studies (two laparoscopic; one cadaveric) on the anatomical course of the inferior epigastric artery.3–5 While this approach avoids puncturing the vessel, there remains a risk of injury to underlying solid organs which can result in haemorrhage or perforation. Of note, these studies may not be generalisable to patients with distortion of …
Parkinson mice show functional and molecular changes in the gut long before motoric disease onset
Authors: Manuela Gries, Anne Christmann, Steven Schulte, Maximilian Weyland, Stephanie Rommel, Monika Martin, Marko Baller, Ralph Röth, Stefanie Schmitteckert, Marcus Unger, Yang Liu, Frederik Sommer, Timo Mühlhaus, Michael Schroda, Jean-Pierre Timmermans, Isabel Pintelon, Gudrun A. Rappold, Markus Britschgi, Hilal Lashuel, Michael D. Menger, Matthias W. Laschke, Beate Niesler, Karl-Herbert Schäfer
Journal: Molecular Neurodegeneration (2021)

Abstract Background There is increasing evidence that Parkinson’s disease (PD) might start in the gut, thus involving and compromising also the enteric nervous system (ENS). At the clinical onset of the disease the majority of dopaminergic neurons in the midbrain is already destroyed, so that the lack of early biomarkers for the disease represents a major challenge for developing timely treatment interventions. Here, we use a transgenic A30P-α-synuclein-overexpressing PD mouse model to identify appropriate candidate markers in the gut before hallmark symptoms begin to manifest. Methods Based on a gait analysis and striatal dopamine levels, we defined 2-month-old A30P mice as pre-symptomatic (psA30P), since they are not showing any motoric impairments of the skeletal neuromuscular system and no reduced dopamine levels, but an intestinal α-synuclein pathology. Mice at this particular age were further used to analyze functional and molecular alterations in both, the gastrointestinal tract and the ENS, to identify early pathological changes. We examined the gastrointestinal motility, the molecular composition of the ENS, as well as the expression of regulating miRNAs. Moreover, we applied A30P-α-synuclein challenges in vitro to simulate PD in the ENS. Results A retarded gut motility and early molecular dysregulations were found in the myenteric plexus of psA30P mice. We found that i.e. neurofilament light chain, vesicle-associated membrane protein 2 and calbindin 2, together with the miRNAs that regulate them, are significantly altered in the psA30P, thus representing potential biomarkers for early PD. Many of the dysregulated miRNAs found in the psA30P mice are reported to be changed in PD patients as well, either in blood, cerebrospinal fluid or brain tissue. Interestingly, the in vitro approaches delivered similar changes in the ENS cultures as seen in the transgenic animals, thus confirming the data from the mouse model. Conclusions These findings provide an interesting and novel approach for the identification of appropriate biomarkers in men.
Risk factors associated with the development of interstitial lung abnormalities
Authors: Ivette Buendía-Roldán, Rosario Fernandez, Mayra Mejía, Fortunato Juarez, Gustavo Ramirez-Martinez, Eduardo Montes, Ana Karem S. Pruneda, Karen Martinez-Espinosa, Aime Alarcon-Dionet, Iliana Herrera, Carina Becerril, Leslie Chavez-Galan, Mario Preciado, Annie Pardo, Moisés Selman
Journal: European Respiratory Journal (2021)

Around 8-10% of individuals over 50 years of age present interstitial lung abnormalities (ILAs), but their risk factors are uncertain.From 817 individuals recruited in our lung ageing programme at the Mexican National Institute of Respiratory Diseases, 80 (9.7%) showed ILAs and were compared with 564 individuals of the same cohort with normal high-resolution computed tomography to evaluate demographic and functional differences, and with 80 individuals randomly selected from the same cohort for biomarkers. We evaluated MUC5B variant rs35705950, telomere length, and serum levels of matrix metalloproteinase (MMP)-1, MMP-2, MMP-3, MMP-7, MMP-8, MMP-9, MMP-12, MMP-13, interleukin (IL)-6, surfactant protein (SP)-D, α-Klotho and resistin.Individuals with ILAs were usually males (p<0.005), older than controls (p<0.0001), smokers (p=0.01), with a greater frequency of MUC5B rs35705950 (OR 3.5, 95% CI 1.3-9.4; p=0.01), and reduced diffusing capacity of the lung for carbon monoxide and oxygen saturation. Resistin, IL-6, SP-D, MMP-1, MMP-7 and MMP-13 were significantly increased in individuals with ILAs. Resistin (12±5 versus 9±4 ng·mL-1; p=0.0005) and MMP-13 (357±143 versus 298±116 pg·mL-1; p=0.004) were the most increased biomarkers. On follow-up (24±18 months), 18 individuals showed progression which was associated with gastro-oesophageal reflux disease (OR 4.1, 95% CI 1.2-12.9; p=0.02) and in females with diabetes mellitus (OR 5.3, 95% CI 1.0-27.4; p=0.01).Around 10% of respiratory asymptomatic individuals enrolled in our lung ageing programme show ILAs. Increased serum concentrations of pro-inflammatory molecules and MMPs are associated with ILAs.
Ultra-hypofractionated versus conventionally fractionated radiotherapy for prostate cancer (HYPO-RT-PC): patient-reported quality-of-life outcomes of a randomised, controlled, non-inferiority, phase 3 trial
Authors: Per Fransson, Per Nilsson, Adalsteinn Gunnlaugsson, Lars Beckman, Björn Tavelin, David Norman, Camilla Thellenberg-Karlsson, Morten Hoyer, Magnus Lagerlund, Jon Kindblom, Claes Ginman, Bengt Johansson, Kirsten Björnlinger, Mihajl Seke, Måns Agrup, Björn Zackrisson, Elisabeth Kjellén, Lars Franzén, Anders Widmark
Journal: The Lancet Oncology (2021)
Cancer Screening Test Receipt — United States, 2018
Authors: Susan A. Sabatino, Trevor D. Thompson, Mary C. White, Jean A. Shapiro, Janet de Moor, V. Paul Doria-Rose, Tainya Clarke, Lisa C. Richardson
Journal: MMWR Morbidity and Mortality Weekly Report (2021)

Screening for breast cancer, cervical cancer, and colorectal cancer (CRC) reduces mortality from these cancers.*However, screening test receipt has been below national targets with disparities observed in certain populations (1,2).National Health Interview Survey (NHIS) data from 2018 were analyzed to estimate percentages of adults up to date with U.S. Preventive Services Task Force (USPSTF) screening recommendations.Screening test receipt remained below national Healthy People 2020 (HP2020) targets, although CRC test receipt neared the target.Disparities were evident, with particularly low test receipt among persons who were uninsured or did not have usual sources of care.Continued monitoring helps assess progress toward targets and could inform efforts to promote screening and reduce barriers for underserved populations.Data from the 2018 NHIS, an annual survey of a nationally representative sample of the civilian, noninstitutionalized U.S. population, † were used to examine up-to-date breast, cervical, and colorectal cancer screening test receipt per USPSTF recommendations.Information about tests was collected from one randomly selected adult per family (final sample adult response rate was 53.1%) (3).Respondents were asked whether they had ever received each test and when they received their most recent test.Respondents with a personal history of the cancer in question were excluded from analysis for that cancer type.Percentages with Korn-Graubard confidence intervals (4) are presented overall and by sociodemographic and health care access factors.Percentages of respondents who were up to date with screening were also age-standardized to the 2000 U.S. standard population, consistent with HP2020 cancer screening * https://uspreventiveservicestaskforce.org/uspstf/recommendation/breast-cancerscreening#bootstrap-panel--5;https://uspreventiveservicestaskforce.org/uspstf/recommendation/cervical-cancer-screening#bootstrap-panel--8; https:// u s p r e v e n t i v e s e r v i c e s t a s k f o r c e .o r g / u s p s t f / r e c o m m e n d a t i o n / colorectal-cancer-screening#bootstrap-panel--5.† https://www.cdc.gov/nchs/nhis/nhis_2018_data_release.htm.measures.NHIS-imputed income files were used.NHIS data from 2005, 2008, 2010, 2013, 2015, and 2018 were used to examine differences across years in percentages of persons who were up to date with screening, according to USPSTF recommendations in effect for each year.For 2018, "up-to-date" status was defined as receipt of the following: mammography within 2 years among women aged 50-74 years for breast cancer screening; Pap test within 3 years for women aged 21-65 years or Pap test plus human papillomavirus (HPV) test (co-testing) within 5 years for women aged 30-65 years for cervical cancer screening (among women without hysterectomy);
Enhanced antitumor immunity by a novel small molecule HPK1 inhibitor
Authors: Dan You, Stephen Hillerman, Gregory Locke, Charu Chaudhry, Caitlyn Stromko, Anwar Murtaza, Yi Fan, Jennifer Koenitzer, Yali Chen, Stephanie Briceno, Rajarshi Bhadra, Elizabeth Duperret, Johnni Gullo-Brown, Chan Gao, Dandan Zhao, John Feder, Joshua Curtin, Andrew P Degnan, Godwin Kumi, Mark Wittman, Benjamin M Johnson, Karen E Parrish, Giridharan Gokulrangan, John Morrison, Michael Quigley, John T Hunt, Luisa Salter-Cid, Emma Lees, Miguel A Sanjuan, Jinqi Liu
Journal: Journal for ImmunoTherapy of Cancer (2021)

Background Hematopoietic progenitor kinase 1 (HPK1 or MAP4K1) has been demonstrated as a negative intracellular immune checkpoint in mediating antitumor immunity in studies with HPK1 knockout and kinase dead mice. Pharmacological inhibition of HPK1 is desirable to investigate the role of HPK1 in human immune cells with therapeutic implications. However, a significant challenge remains to identify a small molecule inhibitor of HPK1 with sufficient potency, selectivity, and other drug-like properties suitable for proof-of-concept studies. In this report, we identified a novel, potent, and selective HPK1 small molecule kinase inhibitor, compound K (CompK). A series of studies were conducted to investigate the mechanism of action of CompK, aiming to understand its potential application in cancer immunotherapy. Methods Human primary T cells and dendritic cells (DCs) were investigated with CompK treatment under conditions relevant to tumor microenvironment (TME). Syngeneic tumor models were used to assess the in vivo pharmacology of CompK followed by human tumor interrogation ex vivo. Results CompK treatment demonstrated markedly enhanced human T-cell immune responses under immunosuppressive conditions relevant to the TME and an increased avidity of the T-cell receptor (TCR) to recognize viral and tumor-associated antigens (TAAs) in significant synergy with anti-PD1. Animal model studies, including 1956 sarcoma and MC38 syngeneic models, revealed improved immune responses and superb antitumor efficacy in combination of CompK with anti-PD-1. An elevated immune response induced by CompK was observed with fresh tumor samples from multiple patients with colorectal carcinoma, suggesting a mechanistic translation from mouse model to human disease. Conclusion CompK treatment significantly improved human T-cell functions, with enhanced TCR avidity to recognize TAAs and tumor cytolytic activity by CD8+ T cells. Additional benefits include DC maturation and priming facilitation in tumor draining lymph node. CompK represents a novel pharmacological agent to address cancer treatment resistance.
Serum and pulmonary uric acid in pulmonary arterial hypertension
Authors: Laurent Savale, Satoshi Akagi, Ly Tu, Amélie Cumont, Raphaël Thuillet, Carole Phan, Benjamin Le Vely, Nihel Berrebeh, Alice Huertas, Xavier Jaïs, Vincent Cottin, Ari Chaouat, Cécile Tromeur, Athénaïs Boucly, Etienne Marie Jutant, Olaf Mercier, Elie Fadel, David Montani, Olivier Sitbon, Marc Humbert, Yuichi Tamura, Christophe Guignabert
Journal: European Respiratory Journal (2021)

Previous studies have suggested an association between uric acid (UA) and the severity of pulmonary arterial hypertension (PAH), but it is unknown whether UA contributes to disease pathogenesis. The aim of this study was to determine the prognostic value of circulating UA in the era of current management of PAH and to investigate the role of UA in pulmonary vascular remodelling. Serum UA levels were determined in idiopathic, heritable or anorexigen PAH at baseline and first re-evaluation in the French Pulmonary Hypertension Network. We studied protein levels of xanthine oxidase (XO) and the voltage-driven urate transporter 1 (URATv1) in lungs of control and PAH patients and of monocrotaline (MCT) and Sugen/hypoxia (SuHx) rats. Functional studies were performed using human pulmonary artery smooth muscle cells (PA-SMCs) and two animal models of pulmonary hypertension (PH). High serum UA levels at first follow-up, but not at baseline, were associated with a poor prognosis. Both the generating enzyme XO and URATv1 were upregulated in the wall of remodelled pulmonary arteries in idiopathic PAH patients and MCT and SuHx rats. High UA concentrations promoted a mild increase in cell growth in idiopathic PAH PA-SMCs, but not in control PA-SMCs. Consistent with these observations, oxonic acid-induced hyperuricaemia did not aggravate MCT-induced PH in rats. Finally, chronic treatment of MCT and SuHx rats with benzbromarone mildly attenuated pulmonary vascular remodelling. UA levels in idiopathic PAH patients were associated with an impaired clinical and haemodynamic profile and might be used as a non-invasive indicator of clinical prognosis during follow-up. Our findings also indicate that UA metabolism is disturbed in remodelled pulmonary vascular walls in both experimental and human PAH.
Abstract 403: TNFα-receptor Associated Factor 2 (TRAF2) Interaction With GRK2 Mediates βAR Desensitization to TNFα
Authors: Sromona Mukherjee, Mohan L Maradumane, Sathyamangla V Naga Prasad
Journal: Circulation Research (2017)

β- Adrenergic receptor (βAR), a prototypical G-protein coupled receptor (GPCR) is a key regulator of cardiac function. Loss of surface receptors (downregulation) and impaired G-protein coupling (desensitization) of βARs are hallmarks of heart failure. Desensitization occurs by phosphorylation of βAR by GRK2 in response to sympathetic overdrive leading to β-arrestin binding and its endocytosis into endosomes. Our studies indicate that TNFα induces βAR phosphorylation/desensitization in HEK 293, neonatal and adult cardiomyocyte cells via GRK2 recruitment. The TNFα induced GRK2 increase is independent of agonist or Gβγ pathway, suggesting a non-canonical mechanism of GRK2 recruitment to the plasma membrane. In conditions of obesity and type 2 diabetes which are clear risk factors for heart failure are consistently associated with significant increase in TNFα which is a known cardio-depressant. Correspondingly, β-blockers are known to be contra-indicative in obesity which we believe is due to βAR desensitization through non-canonical GRK2 recruitment to the βAR in response to elevated TNFα. However the underlying mechanisms for βAR desensitization are not known. We hypothesized that TRAF2 (TNFα-receptor associated factor 2) recruits GRK2 to the plasma membrane causing receptor phosphorylation. Using co-immunoprecipitation studies, we identified that scaffolding protein TRAF2 (responsible for TNFR signaling) interacts with GRK2 in untreated whole cell lysate. Furthermore, co-immunoprecipitation and immunoblotting show that TRAF2-GRK2 interaction is increased in the plasma membrane after 30 minutes of TNFα treatment. Immunoblotting also shows that TNF receptor 2 (TNFR2) engages more robustly with GRK2-TRAF2 complex than TNFR1, suggesting GRK2-TRAF2 dependent phosphorylation of βARs with TNFα is TNFR2 driven. Furthermore, TNFα induced βAR phosphorylation/desensitization is GRK2 dependent as significant loss in βAR phosphorylation is observed with GRK2 inhibitor paroxetine despite presence of TNFα. These observations suggest that cardiac dysfunction mediated by TNFα in conditions of obesity could occur through a novel GRK2-TRAF2-TNFR2 axis that could mediate agonist-independent βAR phosphorylation.
PR01.01 Evaluation of Circulating Tumor Cells for Non-Invasively Discerning Lung Primary from Metastasis
Authors: D. Patil, S. Limaye, D. Akolkar, P. Fulmali, P. Fulmali, A. Adhav, S. Apurwa, S. Pawar, S. Patel, R. Chougule, V. Ranjan, P. Shejwalkar, S. Khan, R. Dhasarathan, V. Datta, S. Schuster, C. Sims, P. Kumar, P. Devhare, A. Srinivasan, R. Datar
Journal: Journal of Thoracic Oncology (2021)
Clean air actions in China, PM2.5 exposure, and household medical expenditures: A quasi-experimental study
Authors: Tao Xue, Tong Zhu, Wei Peng, Tianjia Guan, Shiqiu Zhang, Yixuan Zheng, Guannan Geng, Qiang Zhang
Journal: PLoS Medicine (2021)

Background Exposure to air pollution, a leading contributor to the global burden of disease, can cause economic losses. Driven by clean air policies, the air quality in China, one of the most polluted countries, has improved rapidly since 2013. This has enabled a unique, quasi-experiment to assess the economic impact of air pollution empirically. Methods and findings Using a series of nation-scale longitudinal surveys in 2011, 2013, and 2015, we first examined the questionnaire-based medical expenditure changes before and after the policy intervention for air pollution. Using a state-of-the-art estimator of the historical concentration of particulate matters with diameter less than 2.5 μm (particulate matter (PM) 2.5 ), we further quantified the association between household medical expenditure and PM 2.5 using mixed-effect models of the repeated measurements from 26,511 households in 126 cities. Regression models suggest a robust linear association between reduced PM 2.5 and saved medical expenditures, since the association did not vary significantly across models with different covariate adjustments, subregions, or subpopulations. Each 10 μg/m 3 reduction in PM 2.5 was associated with a saving of 251.6 (95% CI: 30.8, 472.3; p -value = 0.026) Yuan in per capita annual medical expenditure. However, due to limitations in data quality (e.g., self-reported expenditures), and imperfect control for unmeasured confounders or impact from concurrent healthcare reform in China, the causality underlying our findings should be further confirmed or refuted. Conclusion In this study, we observed that compared with the PM 2.5 reduction in 2013, the PM 2.5 reduction in 2017 was associated with a saving of 552 (95% CI: 68, 1036) Yuan / (person × year), or approximately 736 billion Yuan (equivalent to 111 billion US dollar) per year nationally, which is equivalent to approximately 1% of the national gross domestic product of China.