tbuckley/cabot-search huggingface dataset:
Targeting γ-secretase triggers the selective enrichment of oligomeric APP-CTFs in brain extracellular vesicles from Alzheimer cell and mouse models
Authors: Inger Lauritzen, Anaïs Bécot, Alexandre Bourgeois, Raphaëlle Pardossi-Piquard, Maria-Grazia Biferi, Martine Barkats, Fréderic Checler
Journal: Translational Neurodegeneration (2019)

Abstract Background We recently demonstrated an endolysosomal accumulation of the β-secretase-derived APP C-terminal fragment (CTF) C99 in brains of Alzheimer disease (AD) mouse models. Moreover, we showed that the treatment with the γ-secretase inhibitor (D6) led to further increased endolysosomal APP-CTF levels, but also revealed extracellular APP-CTF-associated immunostaining. We here hypothesized that this latter staining could reflect extracellular vesicle (EV)-associated APP-CTFs and aimed to characterize these γ-secretase inhibitor-induced APP-CTFs. Methods EVs were purified from cell media or mouse brains from vehicle- or D6-treated C99 or APP swedish expressing cells/mice and analyzed for APP-CTFs by immunoblot. Combined pharmacological, immunological and genetic approaches (presenilin invalidation and C99 dimerization mutants (GXXXG)) were used to characterize vesicle-containing APP-CTFs. Subcellular APP-CTF localization was determined by immunocytochemistry. Results Purified EVs from both AD cell or mouse models were enriched in APP-CTFs as compared to EVs from control cells/brains. Surprisingly, EVs from D6-treated cells not only displayed increased C99 and C99-derived C83 levels but also higher molecular weight (HMW) APP-CTF-immunoreactivities that were hardly detectable in whole cell extracts. Accordingly, the intracellular levels of HMW APP-CTFs were amplified by the exosomal inhibitor GW4869. By combined pharmacological, immunological and genetic approaches, we established that these HMW APP-CTFs correspond to oligomeric APP-CTFs composed of C99 and/or C83. Immunocytochemical analysis showed that monomers were localized mainly to the trans -Golgi network, whereas oligomers were confined to endosomes and lysosomes, thus providing an anatomical support for the selective recovery of HMW APP-CTFs in EVs. The D6-induced APP-CTF oligomerization and subcellular mislocalization was indeed due to γ-secretase blockade, since it similarly occurred in presenilin-deficient fibroblasts. Further, our data proposed that besides favoring APP-CTF oligomerization by preventing C99 proteolysis, γ-secretase inhibiton also led to a defective SorLA-mediated retrograde transport of HMW APP-CTFs from endosomal compartments to the TGN. Conclusions This is the first study to demonstrate the presence of oligomeric APP-CTFs in AD mouse models, the levels of which are selectively enriched in endolysosomal compartments including exosomes and amplified by γ-secretase inhibition. Future studies should evaluate the putative contribution of these exosome-associated APP-CTFs in AD onset, progression and spreading.
A Horizon Scan of Emerging Global Biological Conservation Issues for 2020
Authors: William J. Sutherland, Maria P. Dias, Lynn V. Dicks, Helen Doran, Abigail C. Entwistle, Erica Fleishman, David W. Gibbons, Rosie Hails, Alice C. Hughes, Jonathan Hughes, Ruth Kelman, Xavier Le Roux, Becky LeAnstey, Fiona A. Lickorish, Luke Maggs, James W. Pearce-Higgins, Lloyd S. Peck, Nathalie Pettorelli, Jules Pretty, Mark D. Spalding, Femke H. Tonneijck, Jonathan Wentworth, Ann Thornton
Journal: Trends in Ecology & Evolution (2019)
肺腺癌における上皮成長因子受容体、K-ras、METおよび肝細胞増殖因子の状況に関する分子レベルでの包括的解析[含 コメント]
Authors: Takamitsu Onitsuka, Hidetaka Uramoto, Kenji Ono
Journal: Journal of Thoracic Oncology (2010)
Ученый-физиолог Василий Михайлович Архангельский: от ассистента до ректора
Authors: M.P. Chaban, Z.I. Shevtsova, V.V. Gaponov
Journal: GASTROENTEROLOGY (2019)

В статье представлен жизненный путь ученого-физиолога Василия Михайловича Архангельского. Его профессиональная деятельность: от ассистента до профессора, заведующего кафедрами физиологии и биохимии Днепропетровского университета и Днепропетровской медицинской академии, директора НИИ физиологии. Впервые представлена информация о его участии в создании Днепропетровского украинского университета во время оккупации.
Cardio-renal Exosomes in Myocardial Infarction Serum Regulate Proangiogenic Paracrine Signaling in Adipose Mesenchymal Stem Cells
Authors: Lei Gao, Shuya Mei, Shuning Zhang, Qing Qin, Hao Li, Yiteng Liao, Huimin Fan, Zhongmin Liu, Hongming Zhu
Journal: Theranostics (2019)

Rationale: Mesenchymal stem cells (MSCs) play important roles in tissue repair and regeneration. However, the molecular mechanisms underlying MSCs activation remain largely unknown, thus hindering their clinical translation. Exosomes are small vesicles that act as intercellular messengers, and their potential for stem cell activation in pathological conditions has not been fully characterized yet. Here, we aim to investigate whether serum exosomes are involved in the remote activation of MSCs after myocardial infarction (MI). Methods: We established MI mouse model by ligating the left anterior descending branch of the coronary artery. Afterwards, serum exosomes were isolated from control (Con Exo) and MI mice (MI Exo) by differential centrifugation. Exosomes were characterized through transmission electron microscopy and nanoparticle tracking analysis. The cell proliferation rate was evaluated by CCK-8 and EdU incorporation assays. Exosomal miRNA and protein levels were assessed using qRT-PCR and western blotting, respectively. VEGF levels in the supernatant and serum were quantified by ELISA. Matrigel plug and tube formation assays were used to evaluate angiogenesis. To explore miR-1956 roles, overexpression and knock-down experiments were performed using mimic and inhibitor, respectively. Finally, miR-1956 target genes were confirmed using the luciferase reporter assay. Results: Both types of exosomes exhibited typical characteristics and could be internalized by adipose-derived MSCs (ADMSCs). MI Exo enhanced ADMSCs proliferation through the activation of ERK1/2. Gain- and loss-of-function studies allowed the validation of miR-1956 (enriched in MI Exo) as the functional messenger that stimulates ADMSCs-mediated angiogenesis and paracrine VEGF signaling, by downregulating Notch-1. Finally, we found that the ischemic myocardium and kidney may be the main sources that release serum exosomes after MI. Conclusions: Cardio-renal exosomes deliver miR-1956 and activate paracrine proangiogenic VEGF signaling in ADMSCs after MI; this process also involves Notch-1, which functions as the core mediator.
Natriuretic Peptide Levels Correlate with Pulmonary Pressures and Prospective Mortality in SCD: Use of This Biomarker To Identify Prevalence and Mortality of Pulmonary Hypertension in the MSH Cohort.
Authors: Roberto Machado, Martin Steinberg, Duane Bonds, Samir Ballas, William Blackwelder, Bruce Barton, Myron Waclawiw, Oswaldo Castro, Mark Gladwin
Journal: Blood (2005)
Tumor Necrosis Factor-α Contributes to Microenvironmental up- Regulation of NF-κB Activity in Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia: Implication for a Novel Therapeutic Target.
Authors: Hui-Jen Tsai, Seiichiro Kobayashi, Kiyoko Itoh, Takaomi Ishida, Kazuo Umezawa, Arinobu Tojo
Journal: Blood (2008)
Ten-Hour Time-Restricted Eating Reduces Weight, Blood Pressure, and Atherogenic Lipids in Patients with Metabolic Syndrome
Authors: Michael J. Wilkinson, Emily N.C. Manoogian, Adena Zadourian, Hannah Lo, Savannah Fakhouri, Azarin Shoghi, Xinran Wang, Jason G. Fleischer, Saket Navlakha, Satchidananda Panda, Pam R. Taub
Journal: Cell Metabolism (2019)
The Promethean fire
Authors: P McCrory
Journal: British Journal of Sports Medicine (2004)

See page 11 for Editorial warm up.

Most readers will be aware that publishing of medical journals is undergoing a sea change at present. The traditional ‘reader pays’ subscription, with a growing pile of journals neatly filed on the bookshelf, is what most sports medicine practitioners would be most familiar with. The coming tidal wave is of online only journals with free open access using an ‘author pays’ system.

Journals will need to adapt to these new developments. It is either evolve or perish like the dodo. For our journal, the coming year heralds a number of changes, many of which fit into a long term strategy of journal online evolution.

First, the dramatic increase in manuscript submissions means that we need to increase our ability to publish more papers or face unacceptable delay-to-publication times. Over the past twelve months, we have seen a 60% increase in manuscript submissions—far outstripping the growth seen in our ‘competitor’ journals within the field of sports medicine. Over time this will mean an increased number of submissions but, necessarily, this will mean that our rejection rate will also rise. This will no doubt cause some …
Abstract 13779: TAS2R38 Haplotype Predicts Vegetable Consumption in Community Dwelling Adults at Risk for Cardiovascular Disease
Authors: Jennifer L Smith, Steve Estus, Terry A Lennie, Debra K Moser, Misook Lee L Chung, Gia Mudd-Martin
Journal: Circulation (2019)

Introduction: Choosing a heart healthy diet is one way to reduce cardiovascular disease (CVD) risk. Taste is an important factor in food choice. Genetic variants that affect taste may be associated...
Decreased Responsiveness of Mature Dendritic Cells from Cord Blood to Chemotaxis Induced by CXCR4 Ligand CXCL12, and CCR7 Ligand CCL19 May Explain Lowered GVHD Associated with Cord Blood Tranplantation.
Authors: Geling Li, Myung-Kwan Han, Hal E. Broxmeyer
Journal: Blood (2005)
Itching for the right treatment
Authors: Karen Mate
Journal: British Journal of Dermatology (2019)

Linked Article: Cenzer et al. Br J Dermatol 2020; 182:763–769. Audio S1 Author audio Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
Selective Expression of the Immunoregulatory Lectin, Galectin-1, in Precursor B Cell Acute Lymphoblastic Leukemias (ALLs) with MLL Rearrangements
Authors: Przemyslaw Juszczynski, Scott J. Rodig, Kunihiko Takeyama, Jing Ouyang, Jorg Faber, Scott Armstrong, Jeffery L. Kutok, Margaret A. Shipp
Journal: Blood (2008)
Reduced Intensity Allogeneic Transplantation for Non-Hodgkin’s Lymphoma: Extended Follow-Up of an Alemtuzumab-Containing Regimen.
Authors: Kirsty J. Thomson, Emma C. Morris, Don Milligan, Gordon Cook, Jim Cavet, Charles Craddock, Ann Hunter, Steve Schey, Anne Parker, Anthony H. Goldstone, David C. Linch, Karl S. Peggs, Stephen Mackinnon
Journal: Blood (2005)
支持与反对：社会保险——是英国卫生保健的正确前进方向吗？
Authors: 刘智
Journal: BMJ (2003)

英国国家医疗卫生服务体系(NHS)在当前成本不断上升的情况下正在努力满足患者的需求。现行的资本体系是否需要改变?David G Green和Benedict Irvine赞成以社会保障为基础的体系,而Martin McKee和他的同事则认为以税务为基础的体系更加公平。 支持对卫生保健的筹资机制进行比较,结果存在争议。然而我们认为以下6个问题可以帮助我们使这些争议有据可依。我们相信英国政府应该给予社会保险这一问题较目前更为严肃认真的关注。
Genomic Characterization of a Pediatric Cohort with Non-Malignant Lymphoproliferative Disorders
Authors: Olive S. Eckstein, Nitya Gulati, Lisa Forbes, Erin Peckham-Gregory, Nmazuo Wudo Ozuah, M. Cecilia Poli, Tiphanie Vogel, Emily M Mace, Jordan S Orange, Jason Caldwell, Stephen Jolles, Fracesco Saettini, Hey J Chong, Asbjørg Stray-Pedersen, Helen E. Heslop, Kala Kamdar, Robert A. Krance, Swati Naik, Tami D John, Rayne H. Rouce, Donna Muzny, Shalini Jhangiani, Richard Gibbs, Zeynep Coban-Akdemir, James Lupski, Kenneth L. McClain, Carl E. Allen, Ivan Chinn
Journal: Blood (2019)
Abstract 14348: Deleterious Effect of IL-23/IL-17A Axis and γδT Cells in Left Ventricular Remodeling after Myocardial Infarction in Rodent
Authors: Xiaoxiang Yan, Takashi Shichita, Yoshinori Katsumata, Tomohiro Matsuhashi, Hideyuki Ito, Kentaro Ito, Atsushi Anzai, Jin Endo, Yuichi Tamura, Kensuke Kimura, Jun Fujita, Ken Shinmura, Weifeng Shen, Akihiko Yoshimura, Keiichi Fukuda, Motoaki Sano
Journal: Circulation (2012)

Abstract Background: Left ventricular (LV) remodeling leads to chronic heart failure and is a main determinant of morbidity and mortality after myocardial infarction (MI). At the present time, ther...
Mobilization of Normal Mouse Progenitors and Acute Promyelocytic Leukemia (APL) Cells with Inhibitors of CXCR4 and VLA-4 in Splenectomized and Unsplenectomized Mice.
Authors: Pablo A. Ramirez, Matthew Holt, Michael P. Rettig, Julie Ritchey, John F. DiPersio
Journal: Blood (2007)
Bile salt metabolism is not the only factor contributing to<i>Clostridioides</i>(<i>Clostridium</i>)<i>difficile</i>disease severity in the murine model of disease
Authors: Caitlin A. Jukes, Umer Zeeshan Ijaz, Anthony Buckley, Janice Spencer, June Irvine, Denise Candlish, Jia V. Li, Julian R. Marchesi, Gillian Douce
Journal: Gut Microbes (2019)

Susceptibility of patients to antibiotic-associated C. difficile disease is intimately associated with specific changes to gut microbiome composition. In particular, loss of microbes that modify bile salt acids (BSA) play a central role; primary bile acids stimulate spore germination whilst secondary bile acids limit C. difficile vegetative growth. To determine the relative contribution of bile salt (BS) metabolism on C. difficile disease severity, we treated mice with three combinations of antibiotics prior to infection. Mice given clindamycin alone became colonized but displayed no tissue pathology while severe disease, exemplified by weight loss and inflammatory tissue damage occurred in animals given a combination of five antibiotics and clindamycin. Animals given only the five antibiotic cocktails showed only transient colonization and no disease. C. difficile colonization was associated with a reduction in bacterial diversity, an inability to amplify bile salt hydrolase (BSH) sequences from fecal DNA and a relative increase in primary bile acids (pBA) in cecal lavages from infected mice. Further, the link between BSA modification and the microbiome was confirmed by the isolation of strains of Lactobacillus murinus that modified primary bile acids in vitro, thus preventing C. difficile germination. Interestingly, BSH activity did not correlate with disease severity which appeared linked to alternations in mucin, which may indirectly lead to increased exposure of the epithelial surface to inflammatory signals. These data confirm the role of microbial metabolic activity in protection of the gut and highlights the need for greater understanding the function of bacterial communities in disease prevention.
Cancer Susceptibility Mutations in Patients With Urothelial Malignancies
Authors: Maria I. Carlo, Vignesh Ravichandran, Preethi Srinavasan, Chaitanya Bandlamudi, Yelena Kemel, Ozge Ceyhan-Birsoy, Semanti Mukherjee, Diana Mandelker, Joshua Chaim, Andrea Knezevic, Satshil Rana, Zarina Fnu, Kelsey Breen, Angela G. Arnold, Aliya Khurram, Kaitlyn Tkachuk, Catharine K. Cipolla, Ashley Regazzi, A. Ari Hakimi, Hikmat Al-Ahmadie, Guido Dalbagni, Karen A. Cadoo, Michael F. Walsh, Min-Yuen Teo, Samuel A. Funt, Jonathan A. Coleman, Bernard H. Bochner, Gopa Iyer, David B. Solit, Zsofia K. Stadler, Liying Zhang, Jonathan E. Rosenberg, Barry S. Taylor, Mark E. Robson, Michael F. Berger, Joseph Vijai, Dean F. Bajorin, Kenneth Offit
Journal: Journal of Clinical Oncology (2019)

Urothelial cancers (UCs) have a substantial hereditary component, but, other than their association with Lynch syndrome, the contribution of genetic risk factors to UC pathogenesis has not been systematically defined. We sought to determine the prevalence of pathogenic/likely pathogenic (P/LP) germline variants in patients with UC and identify associated clinical factors.Overall, 586 patients with UC underwent prospective, matched tumor-normal DNA sequencing. Seventy-seven genes associated with cancer predisposition were analyzed; allele frequencies were compared with publicly available database.P/LP germline variants were identified in 80 (14%) of 586 individuals with UC. The most common P/LP variants in high- or moderate-penetrance genes were BRCA2 (n = 9; 1.5%), MSH2 (n = 8; 1.4%), BRCA1 (n = 8; 1.4%), CHEK2 (n = 6; 1.0%), ERCC3 (n = 4; 0.7%), and NBN and RAD50 (n = 3; 0.5% each). Sixty-six patients (83%) had germline P/LP variants in DNA-damage repair (DDR) genes, of which 28 (42%) had biallelic inactivation. Patients with P/LP variants were more commonly diagnosed at an early age (22% v 6% in those without variants; P = .01). BRCA2 and MSH2 were significantly associated with an increased risk for UC (odds ratio, 3.7 [P = .004] and 4.6 [P = .001], respectively). Current clinical guidelines for referral for genetic testing failed to identify 6 (26%) patients with high-penetrance variants.Clinically significant P/LP germline variants in DDR genes frequently are present in patients with advanced UC. The presence of DDR germline variants could guide cancer screening for patients and their families and serve as predictive biomarkers of response to targeted or immunotherapies. Family history-based criteria to identify patients with hereditary UC susceptibility are insensitive. Broader germline testing in UC, particularly in those of young ages, should be considered.
Post‐discharge haemodilution, congestion, and clinical outcomes among patients hospitalized for heart failure with reduced ejection fraction: results from the EVEREST trial
Authors: Ankeet S. Bhatt, Muthiah Vaduganathan, Ravi B. Patel, Gregg C. Fonarow, Haris P. Subacius, Marvin A. Konstam, Faiez Zannad, Javed Butler, Stephen J. Greene
Journal: European Journal of Heart Failure (2019)
Using Patient Preferences to Determine Noninferiority Margins in Trials
Authors: Eric J. Feuer, Reshma Jagsi, Iris Lansdorp-Vogelaar
Journal: JAMA (2019)

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Interaction of Stem Cells and Their Niche: Behavior and Gene Expression Profiles of CD34+/CD38− Cells upon Co-Cultivation with AFT024.
Authors: Wolfgang Wagner, Rainer Saffrich, Ute Wirkner, Volker Eckstein, Jonathon Blake, Alexandra Ansorge, Christian Schwager, Katrin Miesala, Wilhelm Ansorge, Anthony D. Ho
Journal: Blood (2004)
Authors’ reply to Shaw
Authors: Deborah Cohen, Hannah Barnes
Journal: BMJ (2019)

Shaw fails to recognise why journalists have been drawn into reporting on interventions and research in transgender health.12

We did not set out to “investigate” the use of puberty blockers or an unpublished scientific study. We have a duty to examine claims that are brought to us that are of significant public interest—particularly when accompanied by primary documentation. Some people working in the field of gender identity are fearful of speaking about concerns they have about the evidence base. This is the very reason why …
Microneedle Patches: 3D Printed Microheater Sensor‐Integrated, Drug‐Encapsulated Microneedle Patch System for Pain Management (Adv. Healthcare Mater. 23/2019)
Authors: Mengtian Yin, Li Xiao, Qingchang Liu, Sung‐Yun Kwon, Yi Zhang, Poonam R. Sharma, Li Jin, Xudong Li, Baoxing Xu
Journal: Advanced Healthcare Materials (2019)

In article number 1901170, Xudong Li, Baoxing Xu, and co-workers present a microheater-integrated biodegradable microneedle patch system by developing a 3D printing approach of ink-solution on a curved substrate, and demonstrate that the microheater significantly enhances the delivery of encapsulated drugs from microneedles into human skin and beyond, potentially useful for fast, effective pain management.
Abstract 13476: Association of HLA-DRB3*01:01 With Heparin-Induced Thrombocytopenia
Authors: Jason H Karnes, Joshua C Denny, Robert M Cronin, Christian M Shaffer, Jonathan D Mosley, Simon A Mallal, Elizabeth J Phillips, Dan M Roden
Journal: Circulation (2015)

Introduction: Variation in the human leukocyte antigen (HLA) region is now used clinically to prevent immune-mediated adverse drug reactions. Heparin-induced thrombocytopenia (HIT) is an unpredictable, life-threatening, immune-mediated reaction to heparin treatment. Previous studies have implicated HLA-DR variants in HIT, but HLA alleles which predispose patients to HIT have not been identified. Hypothesis: Our hypothesis is that sequenced HLA alleles are associated with HIT. Methods: We identified HIT cases and heparin-exposed controls in an electronic medical record coupled to a DNA biobank. Cases were defined based on HIT antibody results, HIT risk scoring (4Ts score), and serotonin release assay results. Controls were matched to cases based on age, gender, and type of heparin exposure (unfractionated versus low molecular weight heparin). We performed high resolution, four-digit HLA sequencing for HLA-A, HLA-B, HLA-C, HLA-DR, HLA-DP, and HLA-DQ using long-read 454 FLX sequencing. We tested association of sequenced HLA alleles using conditional univariate logistic regression in a dominant model. Analysis was restricted to individuals with European ancestry and HLA alleles with a frequency greater than 0.01 (n=101). P values were corrected using a Bonferroni correction for 101 sequenced HLA alleles (alpha=4.95x10 -4 ). Results: We identified 77 HIT cases and 345 matched controls. No statistical differences were observed between cases and controls for baseline characteristics. The HLA-DRB3*01:01 allele was significantly associated with HIT (odds ratio 3.55, p=1.09x10 -4 ). No other alleles showed a significant association with HIT. Conclusions: We implicate the HLA-DRB3*01:01 allele as a risk factor for HIT. This allele represents a biologically plausible candidate for HIT, considering the previous literature implicating HLA-DR variation in HIT, the central role of HLA-DR in T cell-dependent antibody production, and the importance of T cells in HIT pathogenesis. Validation of HLA-DRB3*01:01 as a predictor of HIT pathogenesis would lead to preventive genotyping to reduce the risk of HIT.
The Efficacy and Safety of Cladribine in Combination with Cytarabine ,ATRA, G-CSF and Mitoxantrone(Claag-M Regimen)in Relapsed/Refractory AML : A Phase 1/2, Prospective, Single-Arm, Multicenter Study
Authors: Tinghua Zhang, Yinghua Xie, Limin Zhao, Xiyao Han, Yingting Lu, Jing Zhang, Yanhui Xie, Qi Zhu, Lihua Sun, Li Yang, Ligen Liu
Journal: Blood (2019)