tbuckley/cabot-search huggingface dataset:
Atractylenolide-I covalently binds to CYP11B2, selectively inhibits aldosterone synthesis, and improves hyperaldosteronism
Authors: Wenjuan Liu, Zhenqiang Li, Simeng Chu, Xiaoyao Ma, Xiaoying Wang, Min Jiang, Gang Bai
Journal: Acta Pharmaceutica Sinica B (2021)

Hyperaldosteronism is a common disease that is closely related to endocrine hypertension and other cardiovascular diseases. Cytochrome P450 11B2 (CYP11B2), an important enzyme in aldosterone (ALD) synthesis, is a promising target for the treatment of hyperaldosteronism. However, selective inhibitors targeting CYP11B2 are still lacking due to the high similarity with CYP11B1. In this study, atractylenolide-I (AT-I) was found to significantly reduce the production of ALD but had no effect on cortisol synthesis, which is catalyzed by CYP11B1. Chemical biology studies revealed that due to the presence of Ala320, AT-I is selectively bound to the catalytic pocket of CYP11B2, and the C8/C9 double bond of AT-I can be epoxidized, which then undergoes nucleophilic addition with the sulfhydryl group of Cys450 in CYP11B2. The covalent binding of AT-I disrupts the interaction between heme and CYP11B2 and inactivates CYP11B2, leading to the suppression of ALD synthesis; AT-I shows a significant therapeutic effect for improving hyperaldosteronism.
Antimicrobial Therapy and Respiratory Hospitalization or Death in Adults With Idiopathic Pulmonary Fibrosis
Authors: Ching-Yi Chen, Cheng-Yi Wang, Chih-Cheng Lai
Journal: JAMA (2021)

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IASLC肺癌病期分類プロジェクト:肺癌TNM分類次版(第7版)におけるT desriptor修正の提案
Authors: Rami-Porta R, Ball D, Crowley J, Giroux Dj, Jett J, Travis Wd, Tsuboi M, Vallieres E, Goldstraw P
Journal: Journal of Thoracic Oncology (2007)
Race in Medicine — Genetic Variation, Social Categories, and Paths to Health Equity
Authors: Michele K. Evans, Joseph L. Graves, Ruth S. Shim, Sarah A. Tishkoff, Winfred W. Williams
Journal: New England Journal of Medicine (2021)

Race in Medicine In this video roundtable, moderated by Dr. Michele Evans, experts from a range of clinical and biomedical backgrounds analyze and discuss complex questions about race in medicine, ...
Abstract 9580: Stabilization of CaMKII-phosphorylated RyR2 By Dantrolene Prevents the Development of Age-related Cardiomyopathy in CaMKIIδc Transgenic Mice
Authors: Yoko Sufu-Shimizu, Shinichi Okuda, Yoko Okamoto, Takayoshi Kato, Hitoshi Uchinoumi, Tetsuro Oda, Shigeki Kobayashi, Takeshi Yamamoto, Masafumi Yano
Journal: Circulation (2019)

Backgrounds: Calcium/calmodulin-dependent protein kinase II (CaMKII) has been reported to be one of the important factors for the alteration of calcium handling in heart failure, presumably mediate...
Role of total lung stress on the progression of early COVID-19 pneumonia
Authors: Silvia Coppola, Davide Chiumello, Mattia Busana, Emanuele Giola, Paola Palermo, Tommaso Pozzi, Irene Steinberg, Stefano Roli, Federica Romitti, Stefano Lazzari, Simone Gattarello, Michela Palumbo, Peter Herrmann, Leif Saager, Michael Quintel, Konrad Meissner, Luigi Camporota, John J. Marini, Stefano Centanni, Luciano Gattinoni
Journal: Intensive Care Medicine (2021)

We investigated if the stress applied to the lung during non-invasive respiratory support may contribute to the coronavirus disease 2019 (COVID-19) progression. Single-center, prospective, cohort study of 140 consecutive COVID-19 pneumonia patients treated in high-dependency unit with continuous positive airway pressure (n = 131) or non-invasive ventilation (n = 9). We measured quantitative lung computed tomography, esophageal pressure swings and total lung stress. Patients were divided in five subgroups based on their baseline PaO2/FiO2 (day 1): non-CARDS (median PaO2/FiO2 361 mmHg, IQR [323–379]), mild (224 mmHg [211–249]), mild-moderate (173 mmHg [164–185]), moderate-severe (126 mmHg [114–138]) and severe (88 mmHg [86–99], p < 0.001). Each subgroup had similar median lung weight: 1215 g [1083–1294], 1153 [888–1321], 968 [858–1253], 1060 [869–1269], and 1127 [937–1193] (p = 0.37). They also had similar non-aerated tissue fraction: 10.4% [5.9–13.7], 9.6 [7.1–15.8], 9.4 [5.8–16.7], 8.4 [6.7–12.3] and 9.4 [5.9–13.8], respectively (p = 0.85). Treatment failure of CPAP/NIV occurred in 34 patients (24.3%). Only three variables, at day one, distinguished patients with negative outcome: PaO2/FiO2 ratio (OR 0.99 [0.98–0.99], p = 0.02), esophageal pressure swing (OR 1.13 [1.01–1.27], p = 0.032) and total stress (OR 1.17 [1.06–1.31], p = 0.004). When these three variables were evaluated together in a multivariate logistic regression analysis, only the total stress was independently associated with negative outcome (OR 1.16 [1.01–1.33], p = 0.032). In early COVID-19 pneumonia, hypoxemia is not linked to computed tomography (CT) pathoanatomy, differently from typical ARDS. High lung stress was independently associated with the failure of non-invasive respiratory support.
SARS-CoV2-specific Humoral and T-cell Immune Response After Second Vaccination in Liver Cirrhosis and Transplant Patients
Authors: Darius F. Ruether, Golda M. Schaub, Paul M. Duengelhoef, Friedrich Haag, Thomas T. Brehm, Anahita Fathi, Malte Wehmeyer, Jacqueline Jahnke-Triankowski, Leonie Mayer, Armin Hoffmann, Lutz Fischer, Marylyn M. Addo, Marc Lütgehetmann, Ansgar W. Lohse, Julian Schulze zur Wiesch, Martina Sterneck
Journal: Clinical Gastroenterology and Hepatology (2021)
P15.02 Loss of Williams Syndrome Transcription Factor (WSTF) leads to improved temozolomide sensitivity in human glioblastoma cells irrespective of MGMT expression
Authors: K Sarnow, S G Schwab, O Rio, J Mukherjee, R Bjerkvig, T A Johannessen
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND The prognosis for newly diagnosed adult glioblastoma multiforme (GBM) patients is poor even after standard therapy with a median survival of approximately 14–15 months. The DNA repair protein O 6 -methylguanine-DNA methyltransferase (MGMT) efficiently counteracts formation of the most lethal DNA adducts by temozolomide (TMZ) chemotherapy, and is thus associated with poor outcome in GBM patients. Williams Syndrome Transcription Factor (WSTF) has previously been suggested to regulate the DNA damage response pathway (DDR) in both an indirect (through chromatin remodeling together with SMARCA5 in the WICH complex) and direct manner (by phosphorylating H2AX at Tyr142). However, whether WSTF has any role in the development of resistance against chemotherapy through its ability to regulate the DDR in GBMs, is so far not known. In this study, we investigated whether loss of WSTF sensitizes different MGMT-proficient and -deficient GBM cell lines to TMZ treatment. MATERIAL AND METHODS We generated WSTF knockout clones from both MGMT-proficient (LN18, T98G) and -deficient GBM cell lines (U-251) using CRISPR/Cas9 gene-editing technology with lentiviral vectors. The PCR-based screening results combined with the T7 endonuclease mismatch assay for bi-allelic monoclonal knockouts were verified via sequencing and immunoblotting to identify candidate knockout clones. For each cell line, three knockout clones were chosen for further investigation. Colony formation assays were performed to determine the survival ability in response to TMZ treatment. Statistical analysis was performed using two-way ANOVA. RESULTS WSTF knockout clones showed a significant decrease in colony formation after TMZ-treatment compared to the corresponding WSTF-expressing control groups (non-target single guide RNA) (LN18: Clone 59 vs control: p= 0.0456, T98G: All three studied clones vs control: p &amp;lt;0.0001, U-251: Clone 7/35.1/70.2 vs control: p &amp;lt;0.0001/p= 0.0107/p= 0.0119). Furthermore, two out of three clones of T98G and U-251 (T98G Clone 13 and 128 vs control, p &amp;lt;0.0001, U-251 Clone 7 vs control, p= 0.0062; clone 70.2, p= 0.0052) showed significantly reduced plating efficiency compared to control cells. CONCLUSION WSTF is an important factor in both MGMT de- and proficient GBM cell lines for response against TMZ chemotherapy. The loss of WSTF leads to a significantly increased TMZ sensitivity in clinically relevant concentrations for all the studied cell lines. Ongoing studies are investigating the underlying mechanisms and potential alterations in the DDR pathway caused by WSTF loss.
Abstract 15667: Paroxysmal versus Non-Paroxysmal With Outcomes in Patients With Myocardial Infarction
Authors: Poonam Bhyan, Amandeep Goyal, Sameer Arora, Kishorbhai Gangani, Arman Qamar, John P Vavalle, Michael Yeung
Journal: Circulation (2019)

Introduction: Atrial fibrillation (AF) is commonly associated with adverse outcomes in patients with MI. However, the impact of type of AF on outcomes in MI patients remains uncertain. Hypothesis: ...
Clinical implications of Indocyanine Green Fluorescence Imaging-Guided laparoscopic lymphadenectomy for patients with gastric cancer: A cohort study from two randomized, controlled trials using individual patient data
Authors: Qing Zhong, Qi-Yue Chen, Xiao-Bo Huang, Guang-Tan Lin, Zhi-Yu Liu, Jun-Yu Chen, Hua-Gen Wang, Kai Weng, Ping Li, Jian-Wei Xie, Jian-Xian Lin, Jun Lu, Mi Lin, Ze-Ning Huang, Chao-Hui Zheng, Chang-Ming Huang
Journal: International Journal of Surgery (2021)
Chromatin remodeling due to degradation of citrate carrier impairs osteogenesis of aged mesenchymal stem cells
Authors: Andromachi Pouikli, Swati Parekh, Monika Maleszewska, Chrysa Nikopoulou, Maarouf Baghdadi, Ignacio Tripodi, Kat Folz-Donahue, Yvonne Hinze, Andrea Mesaros, David Hoey, Patrick Giavalisco, Robin Dowell, Linda Partridge, Peter Tessarz
Journal: Nature Aging (2021)

Aging is accompanied by a general decline in the function of many cellular pathways. However, whether these are causally or functionally interconnected remains elusive. Here, we study the effect of mitochondrial-nuclear communication on stem cell aging. We show that aged mesenchymal stem cells exhibit reduced chromatin accessibility and lower histone acetylation, particularly on promoters and enhancers of osteogenic genes. The reduced histone acetylation is due to impaired export of mitochondrial acetyl-CoA, owing to the lower levels of citrate carrier (CiC). We demonstrate that aged cells showed enhanced lysosomal degradation of CiC, which is mediated via mitochondrial-derived vesicles. Strikingly, restoring cytosolic acetyl-CoA levels either by exogenous CiC expression or via acetate supplementation, remodels the chromatin landscape and rescues the osteogenesis defects of aged mesenchymal stem cells. Collectively, our results establish a tight, age-dependent connection between mitochondrial quality control, chromatin and stem cell fate, which are linked together by CiC.
Differences by race in systemic oncologic end-of-life (EOL) care among patients with cancer.
Authors: Kerin B. Adelson, Xiaoliang Wang, Mustafa Ascha, Rebecca A. Miksad, Timothy N Showalter, Gregory Sampang Calip, Cary Philip Gross, Maureen Canavan
Journal: Journal of Clinical Oncology (2021)

137 Background: Prior studies indicate that Black patients with cancer are more likely to receive aggressive EOL care, including chemotherapy within 14 days (d) prior to death. However, most studies are limited to specific subgroups, and it is unclear if disparities remain in the immunotherapy era. In this study, we evaluated racial differences in systemic oncologic EOL treatment among a national all-payer cohort of patients treated in routine practice. Methods: We conducted a retrospective cohort study utilizing data from the nationwide Flatiron Health electronic health record (EHR)-derived de-identified database. Patients with confirmed cancer diagnosis, with documented treatment on or after 1/1/2011 and who died between 2015 and 2019, were included. Patients with documented race of White or Black or African American were included. We defined our outcome measures as receipt of any systemic oncologic treatment within 30d or 14d prior to death, and also stratified by mono-chemotherapy (Chemo) and immunotherapy ± targeted therapy (ICI). We used mixed-level logistic regression models to assess the likelihood of receiving each treatment, compared to patients without any EOL treatment, between Black and White patients, adjusted for patient- and practice-level characteristics as fixed effects and a practice-specific random intercept. Race-specific adjusted rates were estimated using stratified analysis. Results: A total of 40,675 White and 5,150 Black patients were included in the analysis. Compared to White patients, Black patients were younger at diagnosis, were more likely to be female and have Medicaid coverage. Black patients were more likely to be treated at practices with higher patient-to-physician ratio (25.8% in highest quintile vs. 18.7%) and with a high proportion (&gt; 10%) of patients with Medicaid (38.1% vs. 31.6%). Compared to White patients within the same practice, Black patients were less likely to receive any EOL treatment within 30d (adjusted odds ratio [aOR]: 0.87; 95% CI: 0.81-0.93) or 14d (aOR: 0.87; 95% CI: 0.80-0.96). Adjusted rates of any EOL treatment within 30d prior to death were 33.8% and 37.6% among Black and White patients, respectively. When stratified by treatment types, Black patients were less likely to receive ICI within 30d prior to death, compared to White patients (aOR: 0.87; 95% CI: 0.76-1.00). Conclusions: Our findings differ from prior studies of oncologic EOL care and suggest that in contemporary practice Black patients are less likely to receive anti-cancer therapy near EOL, largely driven by lower rates of ICI use. Future research should investigate the complex causal pathway underlying observed racial differences among patient and practice-level factors.
Trajectory of COVID-19 Vaccine Hesitancy Over Time and Association of Initial Vaccine Hesitancy With Subsequent Vaccination
Authors: Aaron J. Siegler, Nicole Luisi, Eric W. Hall, Heather Bradley, Travis Sanchez, Benjamin A. Lopman, Patrick S. Sullivan
Journal: JAMA Network Open (2021)

Peter G. Szilagyi, MD, MPH; Kyla Thomas, PhD; Megha D. Shah, MD, MPH, MS; Nathalie Vizueta, PhD; Yan Cui, MD, PhD; Sitaram Vangala, MS; Arie Kapteyn, PhD
포스터전시 : 만성 B형간염(e항원 양성)에서 48주간의 클레부딘 치료 종료 시점에서의 표면항원 정량과 지속적인 생화학적, 혈청학적 관해 유지의 예측
Authors: Hwi Young Kim, Hyo Suk Lee, Byung Chul Yoo
Journal: Clinical and Molecular Hepatology (2009)
Herpes zoster infection associated with acute coronary syndrome: a population-based retrospective cohort study
Authors: Guei-Jane)、F.-C.Sung(F.-C.Sung)、C.-H.Kao(C.-H.Kao) 王駿丞(C.-C.Wang)、C.-L.Lin(C.-L.Lin)、Y.-J.Chang(Y.-J.Chang)、汪貴珍(Wang
Journal: British Journal of Dermatology (2014)
P04.05 Targeted Gene-Expression analysis during malignant transformation in primary and secondary malignant meningioma
Authors: A D Maier, A Meddis, J Haslund-Vinding, C Mirian, A Areskeviciute, P Nguyen, C Westergaard, L C Melchior, T N Munch, J Skjøth-Rasmussen, L Poulsgaard, M Ziebell, J Bartek Jr, H Broholm, F R Poulsen, T A Gerds, D Scheie, T Mathiesen
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND Malignant meningiomas comprise 2–5% of all meningiomas. The process of malignant transformation when benign meningiomas (WHO grade I-II) become malignant (WHO grade III) has not previously been investigated in sequential tumour surgeries. Upregulation of FOXM1 expression and DREAM-complex repression have shown phenotypical subgroups correlating with WHO grade and aggressiveness. We investigated the RNA expression of 30 genes central to meningioma biology and 770 genes involved in neuroinflammatory pathways in primary and secondary malignant meningioma patients who underwent one to several operations. MATERIALS AND METHODS We identified a cohort of consecutive malignant meningioma patients treated at Rigshospitalet, Copenhagen from 2000–2020 (n=51) and gathered their malignant tumours and previous WHO grade I/II tumours. The malignant cohort (MC) was counter matched with a benign cohort (BC) where patients had no recurrences during follow-up. RNA expression signatures from 140 samples from the MC and 51 samples from the BC were analysed with the Nanostring Neuroinflammation panel customized with 30 genes known to be relevant in meningioma phenotypes. RESULTS 49% of MC patients had a previous grade I/II meningioma making them secondary malignant meningioma patients. Progression-free survival calculated from first malignant surgery to first recurrence or death showed no significant difference in the primary vs. secondary patients. Preliminary results of single-gene analysis of MC tumours showed FOXM1, MYBL2, TOP2A, BIRC5 expression was higher in WHO grade III samples. Gene-expression signatures in the individual patients and gene ontology enrichment analyses are in process. CONCLUSIONS FOXM1, MYBL2, TOP2A, BIRC5 RNA expression levels seem to rise during malignant progression across patients. Gene-expression analysis using the Nanostring technology is feasible and a potentially powerful tool to distinguish meningiomas prone to malignant transformation from truly benign meningiomas.
Two-faced Janus: the dual role of macrophages in atherosclerotic calcification
Authors: Olivia J Waring, Nikolaos T Skenteris, Erik A L Biessen, Marjo M P C Donners
Journal: Cardiovascular Research (2021)

Abstract Calcification is an independent predictor of atherosclerosis-related cardiovascular events. Microcalcification is linked to inflamed, unstable lesions, in comparison to the fibrotic stable plaque phenotype generally associated with advanced calcification. This paradox relates to recognition that calcification presents in a wide spectrum of manifestations that differentially impact plaque’s fate. Macrophages, the main inflammatory cells in atherosclerotic plaque, have a multifaceted role in disease progression. They crucially control the mineralization process, from microcalcification to the osteoid metaplasia of bone-like tissue. It is a bilateral interaction that weighs heavily on the overall plaque fate but remains rather unexplored. This review highlights current knowledge about macrophage phenotypic changes in relation to and interaction with the calcifying environment. On the one hand, macrophage-led inflammation kickstarts microcalcification through a multitude of interlinked mechanisms, which in turn stimulates phenotypic changes in vascular cell types to drive microcalcification. Macrophages may also modulate the expression/activity of calcification inhibitors and inducers, or eliminate hydroxyapatite nucleation points. Contrarily, direct exposure of macrophages to an early calcifying milieu impacts macrophage phenotype, with repercussions for plaque progression and/or stability. Macrophages surrounding macrocalcification deposits show a more reparative phenotype, modulating extracellular matrix, and expressing osteoclast genes. This phenotypic shift favours gradual displacement of the pro-inflammatory hubs; the lipid necrotic core, by macrocalcification. Parallels to bone metabolism may explain many of these changes to macrophage phenotype, with advanced calcification able to show homeostatic osteoid metaplasia. As the targeted treatment of vascular calcification developing in atherosclerosis is thus far severely lacking, it is crucial to better understand its mechanisms of development.
Inhaled corticosteroids in COPD: risk and benefits
Authors: Christer Janson
Journal: Thorax (2021)

COPD is a progressive disease where airway inflammation plays an important part. Previously, there were large expectations that regular anti-inflammatory treatment with inhaled corticosteroids (ICS) might help stop disease progression. In 2007, the much-anticipated result from the Towards a Revolution in COPD Health study (TORCH) was published.1 The primary objective of TORCH was to see if the combination of the long-acting beta-agonist (LABA) and ICS would reduce mortality among patients with COPD. The study did not find a statistically significant survival benefit of the ICS/LABA treatment compared with placebo. However, somewhat unexpectedly, they found that pneumonia was more common in the treatment arms that had received ICS. In the group with ICS/LABA, 20% of the patients had at least one event of pneumonia compared with 12% in the placebo group. That ICS increases the risk of pneumonia in COPD has been confirmed in many subsequent randomised controlled trials (RCTs) and observational studies.2–4

In an observational study in this issue of the journal, Eklof and coworkers report that ICS treatment is associated with an increased risk of having a positive culture of Pseudomonas aeruginosa in patients with COPD.5 In the study, the authors have linked data from multiple national registers with microbiological data. The study included over 21 000 patients with COPD, of whom 763 (4%) had a …