tbuckley/cabot-search huggingface dataset:
Mitochondrial quality control mechanisms as molecular targets in cardiac ischemia–reperfusion injury
Authors: Jin Wang, Hao Zhou
Journal: Acta Pharmaceutica Sinica B (2020)

Mitochondrial damage is a critical contributor to cardiac ischemia/reperfusion (I/R) injury. Mitochondrial quality control (MQC) mechanisms, a series of adaptive responses that preserve mitochondrial structure and function, ensure cardiomyocyte survival and cardiac function after I/R injury. MQC includes mitochondrial fission, mitochondrial fusion, mitophagy and mitochondria-dependent cell death. The interplay among these responses is linked to pathological changes such as redox imbalance, calcium overload, energy metabolism disorder, signal transduction arrest, the mitochondrial unfolded protein response and endoplasmic reticulum stress. Excessive mitochondrial fission is an early marker of mitochondrial damage and cardiomyocyte death. Reduced mitochondrial fusion has been observed in stressed cardiomyocytes and correlates with mitochondrial dysfunction and cardiac depression. Mitophagy allows autophagosomes to selectively degrade poorly structured mitochondria, thus maintaining mitochondrial network fitness. Nevertheless, abnormal mitophagy is maladaptive and has been linked to cell death. Although mitochondria serve as the fuel source of the heart by continuously producing adenosine triphosphate, they also stimulate cardiomyocyte death by inducing apoptosis or necroptosis in the reperfused myocardium. Therefore, defects in MQC may determine the fate of cardiomyocytes. In this review, we summarize the regulatory mechanisms and pathological effects of MQC in myocardial I/R injury, highlighting potential targets for the clinical management of reperfusion.
Covid-19: Third of surgeons do not have adequate PPE, royal college warns
Authors: Abi Rimmer
Journal: BMJ (2020)

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Bioactive antibacterial silica-based nanocomposites hydrogel scaffolds with high angiogenesis for promoting diabetic wound healing and skin repair
Authors: Yannan Li, Tianzhen Xu, Zhuolong Tu, Wentong Dai, Yumeng Xue, Chengxuan Tang, Weiyang Gao, Cong Mao, Bo Lei, Cai Lin
Journal: Theranostics (2020)

Diabetic wound repair and skin regeneration remains a worldwide challenge due to the impaired functionality of re-vascularization. Methods: This study reports a bioactive self-healing antibacterial injectable dual-network silica-based nanocomposite hydrogel scaffolds that can significantly enhance the diabetic wound healing/skin tissue formation through promoting early angiogenesis without adding any bioactive factors. The nanocomposite scaffold comprises a main network of polyethylene glycol diacrylate (PEGDA) forming scaffolds, with an auxiliary dynamic network formed between bioactive glass nanoparticles containing copper (BGNC) and sodium alginate (ALG) (PABC scaffolds). Results: PABC scaffolds exhibit the biomimetic elastomeric mechanical properties, excellent injectabilities, self-healing behavior, as well as the robust broad-spectrum antibacterial activity. Importantly, PABC hydrogel significantly promoted the viability, proliferation and angiogenic ability of endothelial progenitor cells (EPCs) in vitro. In vivo, PABC hydrogel could efficiently restore blood vessels networks through enhancing HIF-1α/VEGF expression and collagen matrix deposition in the full-thickness diabetic wound, and significantly accelerate wound healing and skin tissue regeneration. Conclusion: The prominent multifunctional properties and angiogenic capacity of PABC hydrogel scaffolds enable their promising applications in angiogenesis-related regenerative medicine.
Results from the German Chronic Kidney Disease (GCKD) study support association of relative telomere length with mortality in a large cohort of patients with moderate chronic kidney disease
Authors: Federica Fazzini, Claudia Lamina, Julia Raschenberger, Ulla T. Schultheiss, Fruzsina Kotsis, Sebastian Schönherr, Hansi Weissensteiner, Lukas Forer, Inga Steinbrenner, Heike Meiselbach, Barbara Bärthlein, Christoph Wanner, Kai-Uwe Eckardt, Anna Köttgen, Florian Kronenberg, Kai-Uwe Eckardt, Heike Meiselbach, Markus Schneider, Thomas Dienemann, Hans-Ulrich Prokosch, Barbara Bärthlein, Andreas Beck, Thomas Ganslandt, André Reis, Arif B. Ekici, Susanne Avendaño, Dinah Becker-Grosspitsch, Ulrike Alberth-Schmidt, Birgit Hausknecht, Rita Zitzmann, Anke Weigel, Gerd Walz, Anna Köttgen, Ulla T. Schultheiß, Fruzsina Kotsis, Simone Meder, Erna Mitsch, Ursula Reinhard, Jürgen Floege, Georg Schlieper, Turgay Saritas, Sabine Ernst, Nicole Beaujean, Elke Schaeffner, Seema Baid-Agrawal, Kerstin Theisen, Hermann Haller, Jan Menne, Martin Zeier, Claudia Sommerer, Rebecca Woitke, Gunter Wolf, Martin Busch, Rainer Fuß, Thomas Sitter, Claudia Blank, Christoph Wanner, Vera Krane, Antje Börner-Klein, Britta Bauer, Florian Kronenberg, Julia Raschenberger, Barbara Kollerits, Lukas Forer, Sebastian Schönherr, Hansi Weissensteiner, Peter Oefner, Wolfram Gronwald, Helena Zacharias, Matthias Schmid, Jennifer Nadal
Journal: Kidney International (2020)

Telomere length is known to be inversely associated with aging and has been proposed as a marker for aging-related diseases. Telomere attrition can be accelerated by oxidative stress and inflammation, both commonly present in patients with chronic kidney disease. Here, we investigated whether relative telomere length is associated with mortality in a large cohort of patients with chronic kidney disease stage G3 and A1-3 or G1-2 with overt proteinuria (A3) at enrollment. Relative telomere length was quantified in peripheral blood by a quantitative PCR method in 4,955 patients from the GCKD study, an ongoing prospective observational cohort. Complete four-year follow-up was available from 4,926 patients in whom we recorded 354 deaths. Relative telomere length was a strong and independent predictor of all-cause mortality. Each decrease of 0.1 relative telomere length unit was highly associated with a 14% increased risk of death (hazard ratio1.14 [95% confidence interval 1.06-1.22]) in a model adjusted for age, sex, baseline eGFR, urine albumin/creatinine ratio, diabetes mellitus, prevalent cardiovascular disease, LDL-cholesterol, HDL-cholesterol, smoking, body mass index, systolic and diastolic blood pressure, C-reactive protein and serum albumin. This translated to a 75% higher risk for those in the lowest compared to the highest quartile of relative telomere length. The association was mainly driven by 117 cardiovascular deaths (1.20 [1.05-1.35]) as well as 67 deaths due to infections (1.27 [1.07-1.50]). Thus, our findings support an association of shorter telomere length with all-cause mortality, cardiovascular mortality and death due to infections in patients with moderate chronic kidney disease.
Modulation of Wnt and Activin/Nodal supports efficient derivation, cloning and suspension expansion of human pluripotent stem cells
Authors: Zongyong Ai, Baohua Niu, Kui Duan, Chenyang Si, Sile Wang, Lifeng Xiang, Xiaoqing Zhu, Qingyuan Zhu, Chun Feng, Yu Yin, Shumei Zhao, Ruize Kong, Weizhi Ji, Tianqing Li
Journal: Biomaterials (2020)
Using single-operator cholangioscopy for endoscopic evaluation of indeterminate biliary strictures: results from a large multinational registry
Authors: Majid A. Almadi, Takao Itoi, Jong Ho Moon, Mahesh K. Goenka, Dong Wan Seo, Rungsun Rerknimitr, James Y. Lau, Amit P. Maydeo, Jong Kyun Lee, Nam Q. Nguyen, Saad K. Niaz, Randhir Sud, Tiing Leong Ang, Abdulrahman Aljebreen, Benedict M. Devereaux, Rakesh Kochhar, Jörg Reichenberger, Ichiro Yasuda, Arthur J. Kaffes, Masayuki Kitano, Joyce Peetermans, Pooja G. Goswamy, Matthew J. Rousseau, D. Nageshwar Reddy, Sundeep Lakhtakia, Yun Nah Lee, Vijay Kumar Rai, Kentaro Kamada, Reina Tanaka, Ryosuke Tonozuka, Akihiko Tsuchida, Tae Jun Song, Mohan K. Ramchandani
Journal: Endoscopy (2020)

Abstract Background Peroral cholangioscopy (POCS) of indeterminate biliary strictures aims to achieve a diagnosis through visual examination and/or by obtaining targeted biopsies under direct visualization. In this large, prospective, multinational, real-life experience of POCS-guided evaluation of indeterminate biliary strictures, we evaluated the performance of POCS in this difficult-to-manage patient population. Methods This prospective registry enrolled patients, with indeterminate biliary strictures across 20 centers in Asia, the Middle East, and Africa. The primary end points were the ability to visualize the lesion, obtain histological sampling when intended, and an assessment of the diagnostic accuracy of POCS for malignant strictures. Patients were followed for 6 months after POCS or until a definitive malignant diagnosis was made, whichever occurred first. Results 289 patients underwent 290 POCS procedures with intent to biopsy in 182 cases. The stricture/filling defect was successfully visualized in 286/290 (98.6 %), providing a visual diagnostic impression in 253/290 (87.2 %) and obtaining adequate biopsies in 169/182 (92.9 %). Procedure-related adverse events occurred in 5/289 patients (1.7 %). POCS influenced patient management principally by elucidating filling defects or the causes of bile duct stricture or dilation. The visual impression of malignancy showed 86.7 % sensitivity, 71.2 % specificity, 65.8 % positive and 89.4 % negative predictive value, and 77.2 % overall accuracy compared with final diagnosis. Histological POCS-guided samples showed 75.3 % sensitivity, 100 % specificity, 100 % positive and 77.1 % negative predictive value, and 86.5 % overall accuracy. Conclusion In this large, real-life, prospective series, POCS was demonstrated to be an effective and safe intervention guiding the management of patients with indeterminate biliary strictures.
The Distribution of Body Fluids In Congestive Heart Failure
Authors: J. R. ELKINTON, R. D. SQUIRES
Journal: Circulation (1951)

The pathogenesis of congestive heart failure is discussed. Experimental evidence is cited to support the thesis that abnormalities in the distribution of body fluids may affect circulatory and renal function, and hence may be a cause as well as an effect in the complex sequence of events leading to the congestive state. Emphasis is placed upon alterations in cellular metabolism which may lead to such disturbances in body fluids and so through various mechanisms, cellular, humoral, and circulatory, may modify the volume regulation of the body.
Assessing the Burden of Nondeferrable Major Uro-oncologic Surgery to Guide Prioritisation Strategies During the COVID-19 Pandemic: Insights from Three Italian High-volume Referral Centres
Authors: Riccardo Campi, Daniele Amparore, Umberto Capitanio, Enrico Checcucci, Andrea Salonia, Cristian Fiori, Andrea Minervini, Alberto Briganti, Marco Carini, Francesco Montorsi, Sergio Serni, Francesco Porpiglia
Journal: European Urology (2020)
Retraction Note: Disruption of the Bcr-Abl/Hsp90 protein complex: a possible mechanism to inhibit Bcr-Abl-positive human leukemic blasts by novobiocin
Authors: L. X. Wu, J. H. Xu, K. Z. Zhang, Q. Lin, X. W. Huang, C. X. Wen, Y. Z. Chen
Journal: Leukemia (2020)

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Cardiomyocyte Maturation
Authors: Yuxuan Guo, William T. Pu
Journal: Circulation Research (2020)

Maturation is the last phase of heart development that prepares the organ for strong, efficient, and persistent pumping throughout the mammal's lifespan. This process is characterized by structural, gene expression, metabolic, and functional specializations in cardiomyocytes as the heart transits from fetal to adult states. Cardiomyocyte maturation gained increased attention recently due to the maturation defects in pluripotent stem cell-derived cardiomyocyte, its antagonistic effect on myocardial regeneration, and its potential contribution to cardiac disease. Here, we review the major hallmarks of ventricular cardiomyocyte maturation and summarize key regulatory mechanisms that promote and coordinate these cellular events. With advances in the technical platforms used for cardiomyocyte maturation research, we expect significant progress in the future that will deepen our understanding of this process and lead to better maturation of pluripotent stem cell-derived cardiomyocyte and novel therapeutic strategies for heart disease.
Evaluation of Ixekizumab Treatment for Patients With Pityriasis Rubra Pilaris
Authors: Dylan Haynes, Jennifer L. Strunck, Christina A. Topham, Alex G. Ortega-Loayza, Gail Kent, Pamela B. Cassidy, Ronghua Hu, Keith Choate, Zhiping Wang, Yuangang Liu, Teri M. Greiling
Journal: JAMA Dermatology (2020)

Pityriasis rubra pilaris is a rare and disabling cutaneous disease that is frequently recalcitrant to conventional therapies and appears to involve interleukin (IL)-17 overexpression.To investigate the clinical response and safety of ixekizumab in treating pityriasis rubra pilaris.Single-arm, investigator-initiated trial conducted in adult patients with moderate to severe pityriasis rubra pilaris at a single-center academic university from June 2018 to January 2020. A total of 41 patients were screened, 12 were enrolled, and 11 completed the full duration of therapy. A referred, consecutive sample was used during participant selection. The treatment period and primary outcome occurred over 24 weeks with additional patient follow-up through 36 weeks.Subcutaneous administration of ixekizumab, a humanized IgG4 antibody that binds IL-17A, at the US Food and Drug Administration-approved dosing schedule for treatment of psoriasis for 24 weeks.The primary outcome was the mean change in Psoriasis Area and Severity Index at 24 weeks. Secondary outcomes included change in affected body surface area, quality of life, induction of sustained remission, and association of improvement with CARD14 genetic variations and cutaneous cytokine expression.A total of 12 white patients (mean [SD] age, 49.8 [15.1] years; 8 male [67%]) were enrolled between June 2018 and April 2019, with 11 completing the full course of intervention. The mean (SEM) improvements in Psoriasis Area and Severity Index, affected body surface area, and Dermatology Life Quality Index were 15.2 (2.1) (P < .0001), 29.8% (9.3%) (P = .009), and 9.5 (2.5) (P = .004), respectively. The 4 participants with the most improvement in Psoriasis Area and Severity Index at week 24 stayed in remission at week 36 (defined as lack of increase in Psoriasis Area and Severity Index from week 24 through week 36), off therapy. Relative dermal IL-17A expression decreased by a 1.9 log-fold change. No participants had known pathogenic CARD14 variations. There were no serious adverse events.In this single-armed trial, ixekizumab was associated with reduced clinical signs and symptoms of pityriasis rubra pilaris in a subset of patients, including those in whom other systemic therapies have failed.ClinicalTrials.gov Identifier: NCT03485976.
Complication risk despite preventive endoscopic measures in patients undergoing endoscopic mucosal resection of large duodenal adenomas
Authors: Andreas Probst, Simone Freund, Lukas Neuhaus, Alanna Ebigbo, Georg Braun, Stefan Goelder, Tobias Weber, Bruno Märkl, Matthias Anthuber, Helmut Messmann
Journal: Endoscopy (2020)

Abstract Background Endoscopic mucosal resection (EMR) is the standard treatment of ampullary and nonampullary duodenal adenomas. EMR of large (10–29 mm) and giant (≥ 30 mm) lesions carries a risk of complications such as delayed bleeding and perforation. Prospective data on duodenal EMR are scarce. This study aimed to evaluate the efficacy of endoscopic procedures (clipping and coagulation of visible vessels) to prevent complications after EMR of large and giant lesions. Methods 110 patients with 118 adenomas (29 ampullary and 89 nonampullary) were included prospectively. Results 15 lesions were small (12.7 %), 68 were large (57.6 %), and 35 were giant (29.7 %). Endoscopic prevention of delayed complications was performed in 81.4 % (n = 96) of all lesions and 94.3 % (n = 33) of giant lesions. Complete resection was achieved in 111 lesions (94.1 %). Complications were 22 delayed bleedings (18.6 %), 3 intraprocedural perforations (2.5 %), 2 delayed perforations (1.7 %), and 1 stricture (0.8 %). Major complications were associated with lesions size ≥ 30 mm (28.6 % vs. 9.6 %; P = 0.02) and ampullary adenomas (27.6 % vs. 11.2 %; P = 0.07). All minor bleeding and 75 % of major bleeding episodes were treated endoscopically; 25 % of major bleedings needed radiologic embolization. Two fatal courses were observed when delayed perforation occurred after EMR of giant lesions. Residual adenoma was detected in 20.4 % at first follow-up. Conclusions EMR of giant duodenal neoplasia carries a substantial risk of major complications and recurrences. Resection technique and prevention of delayed complications need to be improved. Further measures should be evaluated in randomized studies.
MST4 kinase suppresses gastric tumorigenesis by limiting YAP activation via a non-canonical pathway
Authors: Liwei An, Pingping Nie, Min Chen, Yang Tang, Hui Zhang, Jingmin Guan, Zhifa Cao, Chun Hou, Wenjia Wang, Yun Zhao, Huixiong Xu, Shi Jiao, Zhaocai Zhou
Journal: The Journal of Experimental Medicine (2020)

Hyperactivation of YAP has been commonly associated with tumorigenesis, and emerging evidence hints at multilayered Hippo-independent regulations of YAP. In this study, we identified a new MST4-YAP axis, which acts as a noncanonical Hippo signaling pathway that limits stress-induced YAP activation. MST4 kinase directly phosphorylated YAP at Thr83 to block its binding with importin α, therefore leading to YAP cytoplasmic retention and inactivation. Due to a consequential interplay between MST4-mediated YAP phospho-Thr83 signaling and the classical YAP phospho-Ser127 signaling, the phosphorylation level of YAP at Thr83 was correlated to that at Ser127. Mutation of T83E mimicking MST4-mediated alternative signaling restrained the activity of both wild-type YAP and its S127A mutant mimicking loss of classical Hippo signal. Depletion of MST4 in mice promoted gastric tumorigenesis with diminished Thr83 phosphorylation and hyperactivation of YAP. Moreover, loss of MST4-YAP signaling was associated with poor prognosis of human gastric cancer. Collectively, our study uncovered a noncanonical MST4-YAP signaling axis essential for suppressing gastric tumorigenesis.
<scp>HLA</scp>–B27 Subtypes Predisposing to Ankylosing Spondylitis Accumulate in an Endoplasmic Reticulum–Derived Compartment Apart From the Peptide‐Loading Complex
Authors: Nadège Jah, Aude Jobart‐Malfait, Ketia Ermoza, Aurélie Noteuil, Gilles Chiocchia, Maxime Breban, Claudine André
Journal: Arthritis & Rheumatology (2020)

Objective It was previously shown that HLA –B27 subtypes predisposing to spondyloarthritis (SpA), i.e., B*27:02, B*27:05, and B*27:07, displayed an increased propensity to form intracellular oligomers and to accumulate at a high density in cytoplasmic vesicles, as compared to the non–SpA‐associated HLA –B*07:02 and HLA –B*27:06. This study was undertaken to characterize the nature and content of HLA –B–containing vesicles and to further examine their relevance to SpA predisposition. Methods Vesicles containing HLA –B proteins were detected in transfected HeLa cells and in cells from SpA patients or HLA –B27/human β 2 ‐microglobulin (hβ 2 m)–transgenic rats, by microscopy. The nature and content of HLA –B–containing vesicles were characterized in colocalization experiments with appropriate markers. Results The SpA‐associated HLA –B*27:04 subtype accumulated at higher levels ( P &lt; 10 −5 ) in cytoplasmic vesicles compared to HLA –B*27:06, from which it differs only by 2 substitutions, reinforcing the correlation between vesicle formation and SpA predisposition. Colocalization studies showed that those vesicles contained misfolded HLA –B heavy chain along with β 2 m and endoplasmic reticulum ( ER ) chaperones (calnexin, calreticulin, BiP, glucose‐regulated protein 94‐kd) and belonged to the ER but were distinct from the peptide‐loading complex ( PLC ). Similar vesicles were observed in immune cells from HLA –B27+ SpA patients, in greater abundance than in healthy controls ( P &lt; 0.01), and in dendritic cells from HLA –B27/hβ 2 m transgenic rats, correlating with SpA susceptibility. Conclusion Accumulation of misfolded HLA –B heavy chain along with β 2 m and ER chaperones into ER ‐derived vesicles distinct from the PLC is a characteristic feature of HLA –B27 subtypes predisposing to SpA. This phenomenon could contribute to HLA –B27 pathogenicity, via a noncanonical mechanism.
Rationalization in the pejorative sense: Cushman's account overlooks the scope and costs of rationalization
Authors: Jonathan Ellis, Eric Schwitzgebel
Journal: Behavioral and Brain Sciences (2020)

Abstract According to Cushman, rationalization occurs when a person has performed an action and then concocts beliefs and desires that would have made it rational. We argue that this isn't the paradigmatic form of rationalization. Consequently, Cushman's explanation of the function and usefulness of rationalization is less broad-reaching than he intends. Cushman's account also obscures some of rationalization's pernicious consequences.
Immunohistochemical characteristics of breast cancer in Kazakh and Russian populations
Authors: N. V. Malyshev, V. A. Kulishov, V. S. Perminov, V. B. Sirota
Journal: Journal of Clinical Oncology (2009)

e22162 Background: Ethnic differences of breast cancer were satisfactory investigated in different populations of the United States and some important findings were revealed. In other areas of the world amount of similar studies is relatively low. Our aim was to investigate the ethnical differences in the expression of standard immunohistochemical markers of breast cancer between two main nations of Kazakhstan and to reveal possible correlations between these markers and prognosis of the patients. Methods: 664 breast cancer patients, treated in Karaganda Regional Cancer Center during 2006–2007, were included in this study (222 patients of Kazakh population and 442 patients of Russian population). Immunohistochemical expression of estrogen and progesterone receptors (ER and PR) and Her2/neu was determined in all patients. Expression of steroid receptors was counted as positive if staining was presented in more than one percent of breast cancer cells. Her2/neu expression was divided in two groups: 0, 1+ - negative expression, 2+, 3+ - positive expression. The obtained data was calculated and processed by statistical program - Statistica 6.0. Results: Breast cancer in Kazakh patients demonstrated higher level of Her2/neu positive expression (31.5% versus 23.8, p&lt;0.05) and lower level of isolated ER and PR expression (36.5 versus 44.3, p=0.05). Still, breast cancer in Russian patients was more frequently associated with basal phenotype (15.2 versus 9.5, p&lt;0.05).Strong inverse correlation was observed between age of patients and Her2/neu status (p=0.0005) and direct correlation between age and positive expression of steroid receptors (p&lt;0.05). These correlations were observed in both populations. Conclusions: Breast cancer in Kazakh population was statistically significantly associated with unfavorable prognostic and predictive immunohistochemical status, such as higher expression of Her2/neu and lower expression of steroid receptors. Nevertheless elder patients were more likely to have less aggressive disease, independently from population. No significant financial relationships to disclose.