tbuckley/cabot-search huggingface dataset:
Abstract 43: SIRT1 Enhances Oxidized Low-density Lipoprotein Induced Autophagy in Human Valve Interstitial Cells
Authors: Huadong Li, Jiawei Shi, Weihua Qiao, Nianguo Dong, Gangjian Qin
Journal: Circulation Research (2016)

Objectives: Sirt1, an NAD + -dependent class III deacetylase, has been shown to regulate autophagy during cardiac remodeling. Its role in calcific aortic valve disease has not been studied. Methods: Aortic valve samples were collected from patients with calcific aortic valve diseases complicated with hyper-lipidemia (at the time of heart valve replacement) (CAVD group), and from patients with dilated cardiomyopathy with non-calcified valves and a normal blood lipid profile (at the time of heart transplantation) (control group); the expression and distribution of calcification and Sirt1 in the aortic valves were analyzed by immuno-histochemical staining and Western blotting. In addition, primary human valvular intersititial cells (VICs) were isolated from normal valves in control group, and their response to DiI-ox-LDL treatments was analyzed in the presence of adenovirus-mediated Sirt1 over-expression (Ad-SIRT1) and Sirt1 inhibitor EX527, followed by assessments of the levels of reactive oxygen species (ROS), autophagy, apoptosis and calcification with biochemical methods. Results: The H&amp;E, Masson, Von Kossa and α-SMA immuno-fluorescence staining showed that the aortic valves in CAVD group were thickened by excessive elastin, collagen expression and calcium deposition, which was associated with an elevated expression of osteocalcin and a reduced expression of Sirt1, as compared to control group. In vitro, the primary VICs were incubated with different concentrations (25, 50 and 100μg/mL) of ox-LDL for 48 h. ROS levels increased in an ox-LDL dose dependent manner. In addition, ox-LDL treatment led to a slight increase in the level of LC3 and Beclin-1, autophagic death-related hMOF and acetyl-histone H4, and a significant decrease in the level of Sirt1 through Western blotting. Interestingly, co-treatment of VICs with EX527 further increased ROS generation and expression of Caspase 3, Bax, and β-Catenin, while Sirt1 over-expression by Ad-SIRT1 resulted in increased expression of LC3 and Beclin-1, decreased expression of Caspase 3, Bax, Wnt3a and β-Catenin and reduced ROS generation. Conclusion: Our data suggest that Sirt1 may play a protective role in ox-LDL-induced VIC autophagy and heart valve calcification.
The impact of disability on performance in a high-stakes postgraduate surgical examination: a retrospective cohort study
Authors: R Ellis, J Cleland, DSG Scrimgeour, AJ Lee, PA Brennan
Journal: Journal of the Royal Society of Medicine (2021)

Despite rising numbers of doctors in the workforce with disabilities, little is known about the impact of disabilities on postgraduate performance. To ensure all groups are treated fairly in surgical training, it is essential to know whether any attainment differences exist in markers of surgical performance. To address this gap, we assessed the impact of disabilities on performance on the Intercollegiate Membership of the Royal College of Surgeons examination (MRCS).Retrospective cohort study.Secondary care.All UK MRCS candidates attempting Part A (n = 9600) and Part B (n = 4560) between 2007 and 2017 with linked disability data in the UK Medical Education Database (https://www.ukmed.ac.uk) were included.Chi-square tests and correlation coefficients established univariate associations with MRCS performance, while multiple logistic regressions identified independent predictors of success.Though MRCS Part B pass rates were similar (p = 0.339), candidates with registered disabilities had significantly lower first-attempt Part A pass rates (46.3% vs. 59.8%, p < 0.001). Candidates with disabilities also performed less well in examinations taken throughout school and medical school, and after adjusting for prior academic performance and sociodemographic predictors of success, logistic regression found that candidates with disabilities were no less likely to pass MRCS than their peers (odds ratio 1.04, 95% confidence interval 0.66 to 1.62). No significant variation was found in MRCS performance between type of disability or degree of limitations caused by disability (p > 0.05).Although candidates with registered disabilities performed less well in formal, written examinations, our data indicate that they are as likely to pass MRCS at first attempt as their peers who achieved similar grades at high school and medical school. In order to enable equity in career progression, further work is needed to investigate the causes of attainment differences in early career assessments.
GSAP regulates lipid homeostasis and mitochondrial function associated with Alzheimer’s disease
Authors: Peng Xu, Jerry C. Chang, Xiaopu Zhou, Wei Wang, Michael Bamkole, Eitan Wong, Karima Bettayeb, Lu-Lin Jiang, Timothy Huang, Wenjie Luo, Huaxi Xu, Angus C. Nairn, Marc Flajolet, Nancy Y. Ip, Yue-Ming Li, Paul Greengard
Journal: The Journal of Experimental Medicine (2021)

Biochemical, pathogenic, and human genetic data confirm that GSAP (γ-secretase activating protein), a selective γ-secretase modulatory protein, plays important roles in Alzheimer's disease (AD) and Down's syndrome. However, the molecular mechanism(s) underlying GSAP-dependent pathogenesis remains largely elusive. Here, through unbiased proteomics and single-nuclei RNAseq, we identified that GSAP regulates multiple biological pathways, including protein phosphorylation, trafficking, lipid metabolism, and mitochondrial function. We demonstrated that GSAP physically interacts with the Fe65-APP complex to regulate APP trafficking/partitioning. GSAP is enriched in the mitochondria-associated membrane (MAM) and regulates lipid homeostasis through the amyloidogenic processing of APP. GSAP deletion generates a lipid environment unfavorable for AD pathogenesis, leading to improved mitochondrial function and the rescue of cognitive deficits in an AD mouse model. Finally, we identified a novel GSAP single-nucleotide polymorphism that regulates its brain transcript level and is associated with an increased AD risk. Together, our findings indicate that GSAP impairs mitochondrial function through its MAM localization and that lowering GSAP expression reduces pathological effects associated with AD.
Exercises in Practical Physiology.
Journal: JAMA (1898)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Dietary micronutrient intakes and risk of pancreatic cancer
Authors: Donghui Li, Manal Hassan, Rabia Khan, Melissa Bondy, James Abbruzzese, Rena Day
Journal: Cancer Research (2007)

853  Epidemiological studies of pancreatic cancer have shown a protective role for diet high in fruits and vegetables, which are major sources of antioxidants. In a hospital-based case-control study conducted at M.D. Anderson Cancer Center, we evaluated the dietary factors in 524 patients with pathologically diagnosed pancreatic adenocarcinoma and 525 healthy controls. Subjects were personally interviewed for possible risk factors of pancreatic cancer. Dietary intake and supplement was evaluated in all subjects using a validated food frequency questionnaire. Odds ratios (OR) and 95% confidence interval (95% CI) were estimated by unconditional logistic regression with adjustment for demographics and significant risk factors of pancreatic cancer observed in this study population (smoking, history of diabetes, family history of cancer, and heavy alcohol consumption). Quintile analysis of micronutrients showed a protective effect of higher intakes of vitamins C, E, and lutein/zeaxanthin from both food and dietary supplement (Table 1). On the other hand, an increased risk of pancreatic cancer was associated with a higher intake of food vitamin B12, retinol, calcium, and sodium (Table 1). These preliminary observations support the notion that dietary intake of antioxidants reduce the risk of pancreatic cancer. (Supported by NIH grants RO1 CA98380 and SPORE P20 101936).  Table 1. Quintile Analysis of Micronutrient Intake and Risk of Pancreatic Cancer
Abstract 15680: Metabolomic Profiling of Engineered Skeletal Myobundles Identifies a Plasma Biomarker for Statin Associated Musculoskeletal Symptoms (SAMS)
Authors: Yiling Liu, Anandita Ananthakumar, Will Thompson, Rachel Myers, Rima Kaddurah-Daouk, Laura Dubois, George A Truskey, Deepak Voora
Journal: Circulation (2019)

Introduction: SAMS are common, increase cardiovascular morbidity, and most patients have normal creatine kinase (CK) levels. Hypothesis: Metabolomic profiling of skeletal muscle “myobundles” and th...
Ultrapotent miniproteins targeting the SARS-CoV-2 receptor-binding domain protect against infection and disease
Authors: James Brett Case, Rita E. Chen, Longxing Cao, Baoling Ying, Emma S. Winkler, Max Johnson, Inna Goreshnik, Minh N. Pham, Swathi Shrihari, Natasha M. Kafai, Adam L. Bailey, Xuping Xie, Pei-Yong Shi, Rashmi Ravichandran, Lauren Carter, Lance Stewart, David Baker, Michael S. Diamond
Journal: Cell Host & Microbe (2021)

Despite the introduction of public health measures and spike protein-based vaccines to mitigate the COVID-19 pandemic, SARS-CoV-2 infections and deaths continue to have a global impact. Previously, we used a structural design approach to develop picomolar range miniproteins targeting the SARS-CoV-2 spike receptor-binding domain. Here, we investigated the capacity of modified versions of one lead miniprotein, LCB1, to protect against SARS-CoV-2-mediated lung disease in mice. Systemic administration of LCB1-Fc reduced viral burden, diminished immune cell infiltration and inflammation, and completely prevented lung disease and pathology. A single intranasal dose of LCB1v1.3 reduced SARS-CoV-2 infection in the lung when given as many as 5 days before or 2 days after virus inoculation. Importantly, LCB1v1.3 protected in vivo against a historical strain (WA1/2020), an emerging B.1.1.7 strain, and a strain encoding key E484K and N501Y spike protein substitutions. These data support development of LCB1v1.3 for prevention or treatment of SARS-CoV-2 infection.
Neonatal Diabetes Mellitus
Authors: M J Abramowicz, H Dorchy, E Vamos
Journal: New England Journal of Medicine (1996)

To the Editor: Since the first description of infection caused by b -lactam-resistant Streptococcus pneumoniae, the optimal empirical antibiotic therapy for patients with suspected meningitis caused by this microorganism has remained unknown.Hofmann et al. (Aug.24 issue) 1 reported a 25 percent prevalence of penicillin-resistant S. pneumoniae isolates and a 9 percent prevalence of cephalosporin-resistant isolates among 431 patients with invasive pneumococcal infections in Atlanta.The authors recommended adding vancomycin to the initial therapeutic regimen of patients with suspected pneumococcal meningitis.Their suggestion appears questionable because they did not present the susceptibility patterns of the meningeal strains or discuss morbidity and mortality, there are insufficient published data to support their recommendation, and the adjunctive use of dexamethasone may reduce the penetration of vancomycin into the cerebrospinal fluid.In addition, there have been reports in the literature on the failure of vancomycin monotherapy for S. pneumoniae meningitis. 2 Finally, it has recently been shown that the clinical outcome of patients with meningitis due to S. pneumoniae that is relatively resistant to broad-spectrum cephalosporins (minimal inhibitory concentration [MIC] of cefotaxime, Ͻ 2 m g per milliliter) is similar to that of patients infected with susceptible strains and that treatment with high doses of cefotaxime could be appropriate in this setting. 3,4 Before recommending the routine addition of vancomycin to the regimen used to treat suspected cases of S. pneumoniae meningitis, one should first demonstrate that its use is associated with a significant survival benefit.Another approach would be to reserve the use of vancomycin for infections that do not respond to b -lactam antibiotics, which would help delay the emergence of vancomycin-resistant strains of S. pneumoniae, such as we are now seeing with the strains resistant to broad-spectrum cephalosporins.
The Impact of Nursing Delirium Preventive Interventions in the ICU: A Multicenter Cluster-randomized Controlled Clinical Trial
Authors: Paul J. T. Rood, Marieke Zegers, Dharmanand Ramnarain, Matty Koopmans, Toine Klarenbeek, Esther Ewalds, Marijke S. van der Steen, Annemarie W. Oldenbeuving, Michael A. Kuiper, Steven Teerenstra, Eddy Adang, Lex M. van Loon, Annelies Wassenaar, Hester Vermeulen, Peter Pickkers, Mark van den Boogaard, Danie Pretorius, Femke van der Horst, Albertus Beishuizen, Marga Hoogendoorn
Journal: American Journal of Respiratory and Critical Care Medicine (2021)

Rationale: Delirium is common in critically ill patients and is associated with deleterious outcomes. Nonpharmacological interventions are recommended in current delirium guidelines, but their effects have not been unequivocally established. Objectives: To determine the effects of a multicomponent nursing intervention program on delirium in the ICU. Methods: A stepped-wedge cluster-randomized controlled trial was conducted in ICUs of 10 centers. Adult critically ill surgical, medical, or trauma patients at high risk of developing delirium were included. A multicomponent nursing intervention program focusing on modifiable risk factors was implemented as standard of care. The primary outcome was the number of delirium-free and coma-free days alive in 28 days after ICU admission. Measurements and Main Results: A total of 1,749 patients were included. Time spent on interventions per 8-hour shift was median (interquartile range) 38 (14-116) minutes in the intervention period and median 32 (13-73) minutes in the control period (P = 0.44). Patients in the intervention period had a median of 23 (4-27) delirium-free and coma-free days alive compared with a median of 23 (5-27) days for patients in the control group (mean difference, -1.21 days; 95% confidence interval, -2.84 to 0.42 d; P = 0.15). In addition, the number of delirium days was similar: median 2 (1-4) days (ratio of medians, 0.90; 95% confidence interval, 0.75 to 1.09; P = 0.27). Conclusions: In this large randomized controlled trial in adult ICU patients, a limited increase in the use of nursing interventions was achieved, and no change in the number of delirium-free and coma-free days alive in 28 days could be determined. Clinical trial registered with www.clinicaltrials.gov (NCT03002701).
Engineered composite tissue as a bioartificial limb graft
Authors: Bernhard J. Jank, Linjie Xiong, Philipp T. Moser, Jacques P. Guyette, Xi Ren, Curtis L. Cetrulo, David A. Leonard, Leopoldo Fernandez, Shawn P. Fagan, Harald C. Ott
Journal: Biomaterials (2015)
Endothelin-1 enhances the regenerative capability of human bone marrow-derived mesenchymal stem cells in a sciatic nerve injury mouse model
Authors: Injoo Hwang, Eun Ju Lee, Hyomin Park, Dodam Moon, Jong Nam Park, Keun Cheon Kim, Areum Cha, Hyunji Yun, Jaewon Lee, Hwan-Woo Park, Mi-Sook Chang, Hyo-Soo Kim
Journal: Biomaterials (2021)
Regenerative medicine for neurological diseases—will regenerative neurosurgery deliver?
Authors: Terry C Burns, Alfredo Quinones-Hinojosa
Journal: BMJ (2021)

Abstract Regenerative medicine aspires to transform the future practice of medicine by providing curative, rather than palliative, treatments. Healing the central nervous system (CNS) remains among regenerative medicine’s most highly prized but formidable challenges. “Regenerative neurosurgery” provides access to the CNS or its surrounding structures to preserve or restore neurological function. Pioneering efforts over the past three decades have introduced cells, neurotrophins, and genes with putative regenerative capacity into the CNS to combat neurodegenerative, ischemic, and traumatic diseases. In this review we critically evaluate the rationale, paradigms, and translational progress of regenerative neurosurgery, harnessing access to the CNS to protect, rejuvenate, or replace cell types otherwise irreversibly compromised by neurological disease. We discuss the evidence surrounding fetal, somatic, and pluripotent stem cell derived implants to replace endogenous neuronal and glial cell types and provide trophic support. Neurotrophin based strategies via infusions and gene therapy highlight the motivation to preserve neuronal circuits, the complex fidelity of which cannot be readily recreated. We specifically highlight ongoing translational efforts in Parkinson’s disease, amyotrophic lateral sclerosis, stroke, and spinal cord injury, using these to illustrate the principles, challenges, and opportunities of regenerative neurosurgery. Risks of associated procedures and novel neurosurgical trials are discussed, together with the ethical challenges they pose. After decades of efforts to develop and refine necessary tools and methodologies, regenerative neurosurgery is well positioned to advance treatments for refractory neurological diseases. Strategic multidisciplinary efforts will be critical to harness complementary technologies and maximize mechanistic feedback, accelerating iterative progress toward cures for neurological diseases.
Trajectories of mortality risk among patients with cancer and associated end-of-life utilization
Authors: Ravi B. Parikh, Manqing Liu, Eric Li, Runze Li, Jinbo Chen
Journal: npj Digital Medicine (2021)

Machine learning algorithms may address prognostic inaccuracy among clinicians by identifying patients at risk of short-term mortality and facilitating earlier discussions about hospice enrollment, discontinuation of therapy, or other management decisions. In the present study, we used prospective predictions from a real-time machine learning prognostic algorithm to identify two trajectories of all-cause mortality risk for decedents with cancer. We show that patients with an unpredictable trajectory, where mortality risk rises only close to death, are significantly less likely to receive guideline-based end-of-life care and may not benefit from the integration of prognostic algorithms in practice.
Efficacy and safety of treatments in cutaneous polyarteritis nodosa: A French observational retrospective study
Authors: Thomas Bettuzzi, Marie Jachiet, Emilie Sbidian, Laure Frumholtz, Florence Cordoliani, Luc Mouthon, François Chasset, Romain Paule, Jean-David Bouaziz, Loïc Guillevin, Benjamin Terrier, Selim Aractingi, Nicolas Dupin, Alexis Régent
Journal: Journal of the American Academy of Dermatology (2021)
心血管疾患JACCにおける内皮から間葉への移行-最新のレビュー【JST・京大機械翻訳】
Authors: C Kovacic Jason, Dimmeler Stefanie, P Harvey Richard, Finkel Toren, Aikawa Elena, Krenning Guido, H Baker Andrew
Journal: Journal of the American College of Cardiology (2019)
A Subset of Localized Prostate Cancer Displays an Immunogenic Phenotype Associated with Losses of Key Tumor Suppressor Genes
Authors: Carla Calagua, Miriam Ficial, Caroline S. Jansen, Taghreed Hirz, Luke del Balzo, Scott Wilkinson, Ross Lake, Anson T. Ku, Olga Voznesensky, David B. Sykes, Philip J. Saylor, Huihui Ye, Sabina Signoretti, Haydn Kissick, Adam G. Sowalsky, Steven P. Balk, David J. Einstein
Journal: Clinical Cancer Research (2021)

Abstract Purpose: A subset of primary prostate cancer expresses programmed death-ligand 1 (PD-L1), but whether they have a unique tumor immune microenvironment or genomic features is unclear. Experimental Design: We selected PD-L1–positive high-grade and/or high-risk primary prostate cancer, characterized tumor-infiltrating lymphocytes with multiplex immunofluorescence, and identified genomic alterations in immunogenic and nonimmunogenic tumor foci. Results: One quarter of aggressive localized prostate cancer cases (29/115) had tumor PD-L1 expression more than 5%. This correlated with increased density of CD8+ T cells, a large fraction coexpressing PD-1, versus absent PD-1 expression on sparse CD8 T cells in unselected cases. Most CD8+PD-1+ cells did not express terminal exhaustion markers (TIM3 or LAG3), while a subset expressed TCF1. Consistent with these CD8+PD-1+TCF1+ cells being progenitors, they were found in antigen-presenting cell niches in close proximity to MHC-II+ cells. CD8 T-cell density in immunogenic prostate cancer and renal cell carcinoma (RCC) was nearly identical. Shallow RB1 and BRCA2 losses, and deep deletions of CHD1, were prevalent, the latter being strongly associated with a dendritic cell gene set in The Cancer Genome Atlas. Tumor mutation burden was variable; neither high microsatellite instability nor CDK12 alterations were present. Conclusions: A subset of localized prostate cancer is immunogenic, manifested by PD-L1 expression and CD8+ T-cell content comparable with RCC. The CD8+ T cells include effector cells and exhausted progenitor cells, which may be expanded by immune checkpoint inhibitors (ICI). Genomic losses of RB1, BRCA2, and CHD1 may be drivers of this phenotype. These findings indicate that immunotherapies may be effective in biomarker-selected subpopulations of patients with localized prostate cancer.
Eye Outcomes in Veteran Affairs Diabetes Trial (VADT) After 17 Years
Authors: Nasrin Azad, Lily Agrawal, Gideon Bahn, Nicholas V. Emanuele, Peter D. Reaven, Rodney Hayward, Domenic Reda
Journal: Diabetes Care (2021)

OBJECTIVE The objective of this study was to assess the long-term role of intensive glycemic control (INT) compared with standard glycemic control in accumulated eye procedures in patients with advanced diabetes. RESEARCH DESIGN AND METHODS We compared the effect of treatment assignment on the accumulated number of eye procedures during the intervention period of the Veteran Affairs Diabetes Trial (VADT) (2000–2008) (median follow-up 5.6 years), the interim VADT follow-up study (2000–2013), and the full 17 years of VADT follow-up (2000–2017). We further analyzed data using various cardiovascular markers in two models. Model I included total cholesterol, HDL cholesterol, LDL cholesterol, triglycerides, systolic and diastolic blood pressure, and BMI. Model II included these covariates plus age and diabetic retinopathy (DR) severity score at baseline of the original trial. RESULTS The final analysis of the data showed a mild but nonsignificant increase in number of procedures and in retinal or retinal plus cataract surgery during the three periods of the study. CONCLUSIONS We found no significant benefit of INT during the original trial period in eye-related procedures, such as various procedures for DR, or during the 17 years of follow-up in cataract surgery. However, after adjusting data for some known vascular markers, the increase in the number of eye procedures with INT becomes more prevalent. This finding indicates that INT might not have a protective role in events requiring surgery in individuals with advanced diabetes.