tbuckley/cabot-search huggingface dataset:
Renin–Angiotensin–Aldosterone System Blockers and the Risk of Covid-19
Authors: Giuseppe Mancia, Federico Rea, Monica Ludergnani, Giovanni Apolone, Giovanni Corrao
Journal: New England Journal of Medicine (2020)

BackgroundA potential association between the use of angiotensin-receptor blockers (ARBs) and angiotensin-converting–enzyme (ACE) inhibitors and the risk of coronavirus disease 2019 (Covid-19) has not been well studied.MethodsWe carried out a population-based case–control study in the Lombardy region of Italy. A total of 6272 case patients in whom infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was confirmed between February 21 and March 11, 2020, were matched to 30,759 beneficiaries of the Regional Health Service (controls) according to sex, age, and municipality of residence. Information about the use of selected drugs and patients' clinical profiles was obtained from regional databases of health care use. Odds ratios and 95% confidence intervals for associations between drugs and infection, with adjustment for confounders, were estimated by means of logistic regression.ResultsAmong both case patients and controls, the mean (±SD) age was 68±13 years, and 37% were women. The use of ACE inhibitors and ARBs was more common among case patients than among controls, as was the use of other antihypertensive and non-antihypertensive drugs, and case patients had a worse clinical profile. Use of ARBs or ACE inhibitors did not show any association with Covid-19 among case patients overall (adjusted odds ratio, 0.95 [95% confidence interval {CI}, 0.86 to 1.05] for ARBs and 0.96 [95% CI, 0.87 to 1.07] for ACE inhibitors) or among patients who had a severe or fatal course of the disease (adjusted odds ratio, 0.83 [95% CI, 0.63 to 1.10] for ARBs and 0.91 [95% CI, 0.69 to 1.21] for ACE inhibitors), and no association between these variables was found according to sex.ConclusionsIn this large, population-based study, the use of ACE inhibitors and ARBs was more frequent among patients with Covid-19 than among controls because of their higher prevalence of cardiovascular disease. However, there was no evidence that ACE inhibitors or ARBs affected the risk of COVID-19. Quick Take Inhibitors of the Renin–Angiotensin–Aldosterone System and Covid-19 1m 58s
Near-infrared nerve-binding fluorophores for buried nerve tissue imaging
Authors: Lei G. Wang, Connor W. Barth, Catherine H. Kitts, Mubark D. Mebrat, Antonio R. Montaño, Broderick J. House, Meaghan E. McCoy, Alexander L. Antaris, S. N. Galvis, Ian McDowall, Jonathan M. Sorger, Summer L. Gibbs
Journal: Science Translational Medicine (2020)

Small-molecule near-infrared nerve contrast agents were developed to enable nerve visualization at depth, improving nerve-sparing during surgery.
The Pathogenesis of Atherosclerosis
Authors: Russell Ross, John A. Glomset
Journal: New England Journal of Medicine (1976)

Atherosclerosis is an arterial disease that is recognized to be the chief cause of death in the United States and in Western Europe.1 Its importance as a principal cause of myocardial and cerebral infarction and thrombosis has been appreciated for many years. Nevertheless, its cause and pathogenesis remain unsolved. A major problem is that the disease progresses insidiously for many years before symptoms develop, making it difficult to follow the early development of the disease in individual patients, and to relate causally the several types of lesion that have been described. For the same reason, identification . . .
Pressure support reduces inspiratory effort and dyspnea during exercise in chronic airflow obstruction.
Authors: F Maltais, H Reissmann, S B Gottfried
Journal: American Journal of Respiratory and Critical Care Medicine (1995)

Exercise training has been of limited success in patients with severe chronic airflow obstruction (CAO), in part because of the reduced ventilatory capacity and excessive dyspnea experienced. Pressure support (PS) is a new form of mechanical ventilation which can effectively assist ventilation when applied noninvasively to patients in acute respiratory failure. It was hypothesized that PS might also be used to improve exercise performance, and ultimately physical conditioning, in ambulatory patients with CAO undergoing exercise training. To begin to address this concept, the objectives of the present study were (1) to examine the feasibility of providing PS to exercising patients with CAO and (2) to determine its effects on breathing pattern, inspiratory effort, and dyspnea. Flow and volume, mouth, esophageal, and gastric pressure were measured in seven patients with severe CAO (mean FEV1 = 0.75 +/- SEM 0.09 L) performing constant workload bicycle exercise (33 +/- 6 watts) during control conditions and with the application of PS (approximately 10 cm H2O). PS increased minute ventilation as a result of changes in both tidal volume and respiratory rate. This occurred despite marked reductions in inspiratory effort, as indicated by the pressure-time integrals of esophageal (68 +/- 5% control, p < 0.0005) and transdiaphragmatic pressure (52 +/- 8% control, p < 0.0005). Using a 5-point bidirectional scale to assess changes in dyspnea, breathlessness improved significantly with the addition of PS (2.3 +/- 0.6, p < 0.05) and worsened to a similar degree when it was removed (2.1 +/- 0.5, p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
Does the concept of <i>obligation</i> develop from the inside-out or outside-in?
Authors: Marjorie Rhodes
Journal: Behavioral and Brain Sciences (2020)

Abstract Tomasello proposes that the concept of obligation develops “from the inside-out”: emerging first in experiences of shared agency and generalizing outward to shape children's broader understanding. Here I consider that obligation may also develop “from the outside-in,” emerging as a domain-specific instantiation of a more general conceptual bias to expect categories to prescribe how their members are supposed to behave.
Heme oxygenase-1 and its reaction product, carbon monoxide, prevent inflammation-related apoptotic liver damage in mice
Authors: G Sass
Journal: Hepatology (2003)

Heme oxygenase-1 (HO-1), a stress-responsive enzyme that catabolizes heme into carbon monoxide (CO), biliverdin, and iron, has previously been shown to protect grafts from ischemia/reperfusion injury and rejection. Here we investigated the protective potential of HO-1 in 5 models of immune-mediated liver injury. We found that up-regulation of endogenous HO-1 by cobalt-protoporphyrin-IX (CoPP) protected mice from apoptotic liver damage induced by anti-CD95 antibody (Ab) or d-galactosamine in combination with either anti-CD3 Ab, lipopolysaccharide (LPS), or tumor necrosis factor alpha (TNF-alpha). HO-1 induction prevented apoptotic liver injury, measured by inhibition of caspase 3 activation, although it did not protect mice from caspase-3-independent necrotic liver damage caused by concanavalin A (Con A) administration. In addition, overexpression of HO-1 by adenoviral gene transfer resulted in protection from apoptotic liver injury, whereas inhibition of HO-1 enzymatic activity by tin-protoporphyrin-IX (SnPP) abrogated the protective effect. HO-1-mediated protection seems to target parenchymal liver cells directly because CoPP treatment protected isolated primary hepatocytes from anti-CD95-induced apoptosis in vitro. Furthermore, depletion of Kupffer cells (KCs) did not interfere with the protective effect in vivo. Exogenous CO administration or treatment with the CO-releasing agent methylene chloride mimicked the protective effect of HO-1, whereas treatment with exogenous biliverdin or overexpression of ferritin by recombinant adenoviral gene transfer did not. In conclusion, HO-1 is a potent protective factor for cytokine- and CD95-mediated apoptotic liver damage. Induction of HO-1 might be of a therapeutic modality for inflammatory liver diseases.
Association of Adjuvant Chemotherapy With Overall Survival in Patients With Early-Stage Breast Cancer and 21-Gene Recurrence Scores of 26 or Higher
Authors: Sung Jun Ma, Oluwadamilola T. Oladeru, Anurag K. Singh
Journal: JAMA Network Open (2020)

This cohort study investigates the association of overall survival with receiving chemotherapy among patients with early-stage breast cancer and recurrence scores of 26 to 30 vs those with recurrence scores of 31 or greater.
Jet‐Lagged Nanoparticles Enhanced Immunotherapy Efficiency through Synergistic Reconstruction of Tumor Microenvironment and Normalized Tumor Vasculature
Authors: Zhijie Jiang, Hui Xiong, Shan Yang, Yun Lu, Yudi Deng, Jianxu Yao, Jing Yao
Journal: Advanced Healthcare Materials (2020)

Lactic acid (LA), an anaerobic glycolysis metabolite normally oversecreted by tumor cells, can inhibit the activity of T cells and stimulate the rapid proliferation and migration of tumor endothelial cells (TECs), thereby limiting the synergistic treatment efficiency of tumor immunotherapy and vascular normalization. Herein, Jet-lagged nanoparticles, apatinib (APA)-loaded TEC-targeting nanodrug (APA/MCP) and lonidamine (LND)-loaded tumor cell-targeting nanodrug (LND/MCA), are constructed to combine vascular normalization therapy and tumor cell metabolic treatment. APA/MCP can block VEGF/VEGFR2 to inhibit TEC proliferation and LND/MCA can inhibit LA efflux to remodel tumor acid metabolism. After treatment, Jet-lagged nanoparticles remarkably reduce the level of LA in tumor microenvironment (TME) through limiting LA efflux. Besides, the pericyte cell coverage ratio of tumor vasculature increased to 69%, which is significantly improved compared to the APA/MCP group (47%). Moreover, the results of in vivo pharmacodynamic studies show that after the above synergistic reconstruction of TME and normalized tumor vasculature, the therapeutic effect of programmed death 1 (PD-1) drug is improved 3-folds to that of the PD-1 group. Above all, the strategy in this paper may propose an innovative vision to facilitate the tumor immunotherapy through high-precision spatiotemporal delivery strategy of nanodrugs.
The Reaction of Articular Cartilage to Injury and Osteoarthritis
Authors: Henry J. Mankin
Journal: New England Journal of Medicine (1974)

THE principal purpose of this review is to outline the state of knowledge of the response of articular cartilage to trauma and to attempt to relate the data to osteoarthritic disease. In consideration of this subject, it seems important to define the biologic characteristics of normal articular cartilage and then to indicate the nature of the response of this tissue to injury.Normal Articular CartilageThe hyaline cartilages covering the articulating ends of the component bones of diarthrodial joints are composed of a highly specialized form of connective tissue, with biochemical and biophysical characteristics well suited to its dual role . . .
Improving exercise capacity and quality of life using non‐invasive heart failure treatments: evidence from clinical trials
Authors: Stephan von Haehling, Michael Arzt, Wolfram Doehner, Frank Edelmann, Ruben Evertz, Nicole Ebner, Christoph Herrmann‐Lingen, Tania Garfias Macedo, Michael Koziolek, Michel Noutsias, P. Christian Schulze, Rolf Wachter, Gerd Hasenfuß, Ulrich Laufs
Journal: European Journal of Heart Failure (2020)

Abstract Endpoints of large‐scale trials in chronic heart failure have mostly been defined to evaluate treatments with regard to hospitalizations and mortality. However, patients with heart failure are also affected by very severe reductions in exercise capacity and quality of life. We aimed to evaluate the effects of heart failure treatments on these endpoints using available evidence from randomized trials. Interventions with evidence for improvements in exercise capacity include physical exercise, intravenous iron supplementation in patients with iron deficiency, and – with less certainty – testosterone in highly selected patients. Erythropoiesis‐stimulating agents have been reported to improve exercise capacity in anaemic patients with heart failure. Sinus rhythm may have some advantage when compared with atrial fibrillation, particularly in patients undergoing pulmonary vein isolation. Studies assessing treatments for heart failure co‐morbidities such as sleep‐disordered breathing, diabetes mellitus, chronic kidney disease and depression have reported improvements of exercise capacity and quality of life; however, the available data are limited and not always consistent. The available evidence for positive effects of pharmacologic interventions using angiotensin‐converting enzyme inhibitors, angiotensin receptor blockers, beta‐blockers, and mineralocorticoid receptor antagonists on exercise capacity and quality of life is limited. Studies with ivabradine and with sacubitril/valsartan suggest beneficial effects at improving quality of life; however, the evidence base is limited in particular for exercise capacity. The data for heart failure with preserved ejection fraction are even less positive, only sacubitril/valsartan and spironolactone have shown some effectiveness at improving quality of life. In conclusion, the evidence for state‐of‐the‐art heart failure treatments with regard to exercise capacity and quality of life is limited and appears not robust enough to permit recommendations for heart failure. The treatment of co‐morbidities may be important for these patient‐related outcomes. Additional studies on functional capacity and quality of life in heart failure are required.
Therapeutic Targeting of the Secreted Lysophospholipase D Autotaxin Suppresses Tuberous Sclerosis Complex-Associated Tumorigenesis
Authors: You Feng, William J. Mischler, Ashish C. Gurung, Taylor R. Kavanagh, Grigoriy Androsov, Peter M. Sadow, Zachary T. Herbert, Carmen Priolo
Journal: Cancer Research (2020)

Abstract Tuberous sclerosis complex (TSC) is an autosomal dominant disease characterized by multiorgan hamartomas, including renal angiomyolipomas and pulmonary lymphangioleiomyomatosis (LAM). TSC2 deficiency leads to hyperactivation of mTOR Complex 1 (mTORC1), a master regulator of cell growth and metabolism. Phospholipid metabolism is dysregulated upon TSC2 loss, causing enhanced production of lysophosphatidylcholine (LPC) species by TSC2-deficient tumor cells. LPC is the major substrate of the secreted lysophospholipase D autotaxin (ATX), which generates two bioactive lipids, lysophosphatidic acid (LPA) and sphingosine-1-phosphate (S1P). We report here that ATX expression is upregulated in human renal angiomyolipoma-derived TSC2-deficient cells compared with TSC2 add-back cells. Inhibition of ATX via the clinically developed compound GLPG1690 suppressed TSC2-loss associated oncogenicity in vitro and in vivo and induced apoptosis in TSC2-deficient cells. GLPG1690 suppressed AKT and ERK1/2 signaling and profoundly impacted the transcriptome of these cells while inducing minor gene expression changes in TSC2 add-back cells. RNA-sequencing studies revealed transcriptomic signatures of LPA and S1P, suggesting an LPA/S1P-mediated reprogramming of the TSC lipidome. In addition, supplementation of LPA or S1P rescued proliferation and viability, neutral lipid content, and AKT or ERK1/2 signaling in human TSC2-deficient cells treated with GLPG1690. Importantly, TSC-associated renal angiomyolipomas have higher expression of LPA receptor 1 and S1P receptor 3 compared with normal kidney. These studies increase our understanding of TSC2-deficient cell metabolism, leading to novel potential therapeutic opportunities for TSC and LAM. Significance: This study identifies activation of the ATX–LPA/S1P pathway as a novel mode of metabolic dysregulation upon TSC2 loss, highlighting critical roles for ATX in TSC2-deficient cell fitness and in TSC tumorigenesis.
Outcomes of Patients With Advanced Gastrointestinal Cancer in Relationship to Opioid Use: Findings From Eight Clinical Trials
Authors: Omar Abdel-Rahman, Hatim Karachiwala, Jacob C. Easaw
Journal: Journal of the National Comprehensive Cancer Network (2020)

Background: This study assessed the patterns of opioid use among patients with advanced gastrointestinal cancers who were included in 8 clinical trials and evaluated the impact of opioid use on survival outcomes of included patients. Methods: Deidentified datasets from 8 clinical trials evaluating first-line systemic treatment of advanced gastrointestinal cancers were accessed from the Project Data Sphere platform ( ClinicalTrial.gov identifiers: NCT01124786, NCT00844649, NCT00290966, NCT00678535, NCT00699374, NCT00272051, NCT00305188, and NCT00384176). These trials evaluated patients with pancreatic carcinoma, gastric carcinoma, hepatocellular carcinoma (HCC), and colorectal carcinoma. Multivariable logistic regression analysis was used to evaluate factors predicting the use of opioids. Kaplan-Meier survival estimates were used to compare survival outcomes in each disease entity among patients who did or did not receive opioid treatment. Multivariable Cox regression analysis was then used to further assess the impact of opioid use on survival outcomes in each disease entity. Results: A total of 3,441 participants were included in the current analysis. The following factors predicted a higher probability of opioid use within logistic regression analysis: younger age at diagnosis (odds ratio [OR], 0.990; 95% CI, 0.984–0.997; P =.004), nonwhite race (OR for white vs nonwhite, 0.749; 95% CI, 0.600–0.933; P =.010), higher ECOG score (OR for 1 vs 0, 1.751; 95% CI, 1.490–2.058; P &lt;.001), and pancreatic primary site (OR for colorectal vs pancreatic, 0.241; 95% CI, 0.198–0.295; P &lt;.001). Use of opioids was consistently associated with worse overall survival (OS) in Kaplan-Meier survival estimates of each disease entity ( P =.008 for pancreatic cancer; P &lt;.001 for gastric cancer, HCC, and colorectal cancer). In multivariable Cox regression analysis, opioid use was associated with worse OS among patients with pancreatic cancer (hazard ratio [HR], 1.245; 95% CI, 1.063–1.459; P =.007), gastric cancer (HR, 1.725; 95% CI, 1.403–2.122; P &lt;.001), HCC (HR, 1.841; 95% CI, 1.480–2.290; P &lt;.001), and colorectal cancer (HR, 1.651; 95% CI, 1.380–1.975; P &lt;.001). Conclusions: Study findings suggest that opioid use is consistently associated with worse OS among patients with different gastrointestinal cancers. Further studies are needed to understand the underlying mechanisms of this observation and its potential implications.
Oral‐lung microbiome interactions in lung diseases
Authors: Manoj J. Mammen, Frank A. Scannapieco, Sanjay Sethi
Journal: Periodontology 2000 (2020)

Abstract The proximity and continuity of the oral cavity and the lower respiratory tract allows the oropharyngeal microbiome to be a major determinant of the lung microbiome. In addition, host‐pathogen interactions related to the oropharyngeal microbiome or its metabolites could propagate systemic inflammation or modulate host defense mechanisms that could affect other organs, including the lung. There is increasing appreciation of the pathophysiologic significance of the lung microbiome, not only in the classical infection‐related diseases, pneumonia, bronchiectasis, and cystic fibrosis, but also in chronic noninfectious lung diseases, such as chronic obstructive pulmonary disease, asthma, and pulmonary fibrosis. In this review, we will explore the relationship of the oral microbiome with lung diseases, such as pneumonia, chronic obstructive pulmonary disease, asthma, and cystic fibrosis.
BCG vaccination–induced emergency granulopoiesis provides rapid protection from neonatal sepsis
Authors: Byron Brook, Danny J. Harbeson, Casey P. Shannon, Bing Cai, Daniel He, Rym Ben-Othman, Freddy Francis, Joe Huang, Natallia Varankovich, Aaron Liu, Winnie Bao, Morten Bjerregaard-Andersen, Frederik Schaltz-Buchholzer, Lilica Sanca, Christian N. Golding, Kristina Lindberg Larsen, Ofer Levy, Beate Kampmann, Rusung Tan, Adrian Charles, James L. Wynn, Frank Shann, Peter Aaby, Christine S. Benn, Scott J. Tebbutt, Tobias R. Kollmann, Nelly Amenyogbe, Amy H. Lee, Tue B. Bennike, Joann Diray-Arce, Olubukola Idoko, William S. Pomat, Simon van Haren, Momoudou Cox, Alansana Darboe, Reza Falsafi, Samuel H. Hinshaw, Jorjoh Ndure, Jainaba Njie-Jobe, Matthew A. Pettengill, Arnaud Marchant, Peter C. Richmond, Rebecca Ford, Gerard Saleu, Geraldine Masiria, John Paul Matlam, Wendy Kirarock, Elishia Roberts, Mehrnoush Malek, Guzman Sanchez-Schmitz, Amrit Singh, Asimenia Angelidou, Kinga K. Smolen, Ryan R. Brinkman, Al Ozonoff, Robert E.W. Hancock, Anita H.J. van den Biggelaar, Hanno Steen, Diana Vo, Ken Kraft, Kerry McEnaney, Sofia Vignolo
Journal: Science Translational Medicine (2020)

Neonatal administration of BCG vaccine rapidly increases neutrophil production to reduce mortality from sepsis.
The Association between sodium fluctuations and mortality in surgical patients requiring intensive care
Authors: R. Goodson, D. Marshall, J. Salciccioli, M. Pimentel, K. Sun, L. Anthony Celi, J. Shalhoub
Journal: International Journal of Surgery (2016)

Results: The FTM tremor scores at 6-months and 1-year showed statistically significant reduction in both conventional and DTI-guided groups.(P<0.05)The DTI-guided group showed statistically significant improvement of tremor control, compared with conventional group in 1 year.(P<0.05)The x, y and z co-ordinates in both groups showed comparable mean values.(P>0.05).Conclusions: DTI-guided DBS improves upper limb tremor control with comparable result of active electrode positioning.DTI may be considered as a future radiological guidance to improve long-term therapeutic effect.
Heat shock and HSP70 regulate 5-FU-mediated caspase-1 activation in myeloid-derived suppressor cells and tumor growth in mice
Authors: Thomas Pilot, Aurélie Fratti, Chloé Thinselin, Anaïs Perrichet, Lucie Demontoux, Emeric Limagne, Valentin Derangère, Alis Ilie, Mané Ndiaye, Elise Jacquin, Carmen Garrido, François Ghiringhelli, Fanny Chalmin, Cédric Rébé
Journal: Journal for ImmunoTherapy of Cancer (2020)

Background We have previously shown that 5-fluorouracil (5-FU) selectively kills myeloid-derived suppressor cells (MDSCs) and activates NLRP3 (NOD-leucine rich repeat and pyrin containing protein 3) inflammasome. NLRP3 activation leads to caspase-1 activation and production of IL-1β, which in turn favors secondary tumor growth. We decided to explore the effects of either a heat shock (HS) or the deficiency in heat shock protein (HSP) 70, previously shown to respectively inhibit or increase NLRP3 inflammasome activation in macrophages. Methods Caspase-1 activation was detected in vitro in MSC-2 cells by western blot and in vivo or ex vivo in tumor and/or splenic MDSCs by flow cytometry. The effects of HS, HSP70 deficiency and anakinra (an IL-1 inhibitor) on tumor growth and mice survival were studied in C57BL/6 WT or Hsp70 −/− tumor-bearing mice. Finally, Th17 polarization was evaluated by qPCR (Il17a, Rorc) and angiogenic markers by qPCR (Pecam1, Eng) and immunohistochemistry (ERG). Results HS inhibits 5-FU-mediated caspase-1 activation in vitro and in vivo without affecting its cytotoxicity on MDSCs. Moreover, it enhances the antitumor effect of 5-FU treatment and favors mice survival. Interestingly, it is associated to a decreased Th17 and angiogenesis markers in tumors. IL-1β injection is able to bypass HS+5-FU antitumor effects. In contrast, in Hsp70 −/− MDSCs, 5-FU-mediated caspase-1 activation is increased in vivo and in vitro without effect on 5-FU cytotoxicity. In Hsp70 −/− mice, the antitumor effect of 5-FU was impeded, with an increased Th17 and angiogenesis markers in tumors. Finally, the effects of 5-FU on tumor growth can be restored by inhibiting IL-1β, using anakinra. Conclusion This study provides evidence on the role of HSP70 in tuning 5-FU antitumor effect and suggests that HS can be used to improve 5-FU anticancer effect.