tbuckley/cabot-search huggingface dataset:
AFF4 regulates osteogenic differentiation of human dental follicle cells
Authors: Qingyue Xiao, Yuning Zhang, Xingying Qi, Yaqian Chen, Rui Sheng, Ruoshi Xu, Quan Yuan, Chenchen Zhou
Journal: International Journal of Oral Science (2020)

Abstract As a member of the AFF (AF4/FMR2) family, AFF4 is a transcription elongation factor that is a component of the super elongation complex. AFF4 serves as a scaffolding protein that connects transcription factors and promotes gene transcription through elongation and chromatin remodelling. Here, we investigated the effect of AFF4 on human dental follicle cells (DFCs) in osteogenic differentiation. In this study, we found that small interfering RNA-mediated depletion of AFF4 resulted in decreased alkaline phosphatase (ALP) activity and impaired mineralization. In addition, the expression of osteogenic-related genes ( DLX5 , SP7 , RUNX2 and BGLAP ) was significantly downregulated. In contrast, lentivirus-mediated overexpression of AFF4 significantly enhanced the osteogenic potential of human DFCs. Mechanistically, we found that both the mRNA and protein levels of ALKBH1, a critical regulator of epigenetics, changed in accordance with AFF4 expression levels. Overexpression of ALKBH1 in AFF4 -depleted DFCs partially rescued the impairment of osteogenic differentiation. Our data indicated that AFF4 promoted the osteogenic differentiation of DFCs by upregulating the transcription of ALKBH1 .
Three-dimensional single-cell imaging for the analysis of RNA and protein expression in intact tumour biopsies
Authors: Nobuyuki Tanaka, Shigeaki Kanatani, Dagmara Kaczynska, Keishiro Fukumoto, Lauri Louhivuori, Tomohiro Mizutani, Oded Kopper, Pauliina Kronqvist, Stephanie Robertson, Claes Lindh, Lorand Kis, Robin Pronk, Naoya Niwa, Kazuhiro Matsumoto, Mototsugu Oya, Ayako Miyakawa, Anna Falk, Johan Hartman, Cecilia Sahlgren, Hans Clevers, Per Uhlén
Journal: Nature Biomedical Engineering (2020)
Letter in response to article in journal of infection: “High SARS-CoV-2 antibody prevalence among healthcare workers exposed to COVID-19 patients”
Authors: Pedro Arriola-Villalobos, Cristina Fernandez-Perez, Mayte Ariño-Gutierrez, Jose I. Fernandez-Vigo, Blanca Benito-Pascual, Noemi Cabello-Clotet, Julio Mayol-Martinez, Jose A. Gegundez-Fernandez, David Diaz-Valle, Jose M. Benitez-del-Castillo, Julian Garcia-Feijoo
Journal: Journal of Infection (2020)
No Benefit of Concomitant Immunomodulator Therapy on Efficacy of Biologics That Are Not Tumor Necrosis Factor Antagonists in Patients With Inflammatory Bowel Diseases: A Meta-analysis
Authors: Clara Yzet, Momar Diouf, Siddarth Singh, Franck Brazier, Justine Turpin, Eric Nguyen-Khac, Jonathan Meynier, Mathurin Fumery
Journal: Clinical Gastroenterology and Hepatology (2020)
Effect of Increased Lactate Dehydrogenase A Activity and Aerobic Glycolysis on the Proinflammatory Profile of Autoimmune CD8+ T Cells in Rheumatoid Arthritis
Authors: M. Margarida Souto‐Carneiro, Karel D. Klika, Mónica T. Abreu, André P. Meyer, Rainer Saffrich, Roger Sandhoff, Richard Jennemann, Franziska V. Kraus, Lars Tykocinski, Volker Eckstein, Lina Carvalho, Mark Kriegsmann, Thomas Giese, Hanns‐Martin Lorenz, Rui A. Carvalho
Journal: Arthritis & Rheumatology (2020)

Objective CD8+ T cells contribute to rheumatoid arthritis (RA) by releasing proinflammatory and cytolytic mediators, even in a challenging hypoxic and nutrient‐poor microenvironment such as the synovial membrane. This study was undertaken to explore the mechanisms through which CD8+ T cells meet their metabolic demands in the blood and synovial membrane of patients with RA. Methods Purified blood CD8+ T cells from patients with RA, patients with psoriatic arthritis (PsA), and patients with spondyloarthritis (SpA), as well as healthy control subjects, and CD8+ T cells from RA synovial membrane were stimulated in medium containing 13 C‐labeled metabolic substrates in the presence or absence of metabolic inhibitors, under conditions of normoxia or hypoxia. The production of metabolic intermediates was quantified by 1 H‐nuclear magnetic resonance. The expression of metabolic enzymes, transcription factors, and immune effector molecules was assessed at both the messenger RNA (mRNA) and protein levels. CD8+ T cell functional studies were performed. Results RA blood CD8+ T cells met their metabolic demands through aerobic glycolysis, production of uniformly 13 C‐enriched lactate in the RA blood (2.6 to 3.7–fold higher than in patients with SpA, patients with PsA, and healthy controls; P &lt; 0.01), and induction of glutaminolysis. Overexpression of Warburg effect–linked enzymes in all RA CD8+ T cell subsets maintained this metabolic profile, conferring to the cells the capacity to proliferate under hypoxia and low‐glucose conditions. In all RA CD8+ T cell subsets, lactate dehydrogenase A (LDHA) was overexpressed at the mRNA level ( P &lt; 0.03 versus controls; n = 6 per group) and protein level ( P &lt; 0.05 versus controls; n = 17 RA patients, n = 9 controls). In RA blood, inhibition of LDHA with FX11 led to reductions in lipogenesis, migration and proliferation of CD8+ T cells, and CD8+ T cell effector functions, while production of reactive oxygen species was increased by 1.5‐fold ( P &lt; 0.03 versus controls). Following inhibition of LDHA with FX11, RA CD8+ T cells lost their capacity to induce healthy B cells to develop a proinflammatory phenotype. Similar metabolic alterations were observed in RA CD8+ T cells from the synovial membrane. Conclusion Remodeling glucose and glutamine metabolism in RA CD8+ T cells by targeting LDHA activity can reduce the deleterious inflammatory and cytolytic contributions of these cells to the development of autoimmunity.
Venetoclax and hypomethylating agents in <scp><i>FLT3</i></scp>‐mutated acute myeloid leukemia
Authors: Ibrahim Aldoss, Jianying Zhang, Matthew Mei, Monzr M Al Malki, Shukaib Arslan, Dat Ngo, Ahmed Aribi, Haris Ali, Karamjeet Sandhu, Amandeep Salhotra, Paul Koller, Samer Khaled, Andrew Artz, David Snyder, Ryotaro Nakamura, Stephen J Forman, Anthony S. Stein, Guido Marcucci, Vinod Pullarkat
Journal: American Journal of Hematology (2020)

Abstract FMS‐like tyrosine kinase 3 ( FLT3 ) mutations are prevalent in acute myeloid leukemia (AML), and their presence confers adverse risk. FLT3 ‐mutated ( FLT3m ) AML is a challenging leukemia to manage, particularly in older and unfit patients as well as patients with relapsed/refractory (r/r) disease. We retrospectively analyzed the outcomes of 50 FLT3m AML patients (17 treatment‐naïve, 33 r/r) treated with venetoclax (VEN) and hypomethylating agents (HMA). The overall CR/CRi rate with VEN‐HMA was 60% (94% in treatment‐naïve AML and 42% in r/r AML). Early (60‐days) treatment related mortality was 2%. The r/r AML setting was an independent predictor of lower complete response (OR: 0.08; 95%CI: 0.00‐0.60, P = .03). Cytogenetics‐molecular risk, concurrent mutations, the type of FLT3 mutation (ITD vs TKD), the ITD allelic ratio, the type of HMA, age, prior exposure to HMA and receipt of prior allogeneic transplant did not independently impact response or leukemia‐free survival (LFS). Concurrent IDH mutations were associated with lower CR/CRi ( P = .01), while ASXL1 or TET2 mutations showed a non‐significant association toward higher CR/CRi ( P = .07, for both). However, none of the concurrent mutations were an independent predictor for response when adjusted to AML setting. In conclusion, VEN‐HMA is associated with encouraging efficacy in FLT3m AML among both newly diagnosed unfit and r/r patients.
Nasopharyngeal Haemophilus and local immune response during infant respiratory syncytial virus infection
Authors: Meghan H. Shilts, Christian Rosas-Salazar, Kedir N. Turi, Devi Rajan, Seesandra V. Rajagopala, Megan F. Patterson, Tebeb Gebretsadik, Larry J. Anderson, R. Stokes Peebles, Tina V. Hartert, Suman R. Das
Journal: Journal of Allergy and Clinical Immunology (2020)

ethnicity-stratified analyses revealed that the effect in Latinos was driven mainly by Mexicans and other Latinos (see Table E7 in this article's Online Repository at www.jacionline.org).In conclusion, the SNP rs67622929 was associated with severe asthma exacerbations in African Americans and Latinos and showed regulatory effects over DNASE1L3 expression.
Young patients with heart failure: clinical characteristics and outcomes. Data from the Swedish Heart Failure, National Patient, Population and Cause of Death Registers
Authors: Carmen Basic, Annika Rosengren, Urban Alehagen, Ulf Dahlström, Magnus Edner, Michael Fu, Masuma Novak, Tatiana Zverkova Sandström, Maria Schaufelberger
Journal: European Journal of Heart Failure (2020)

Aims The prevalence and hospitalizations of patients with heart failure (HF) aged &lt;55 years have increased in Sweden during the last decades. We aimed to compare characteristics of younger and older patients with HF, and examine survival in patients &lt;55 years compared with matched controls. Methods and results All patients ≥18 years in the Swedish Heart Failure Register from 2003 to 2014 were included. Data were merged with National Patient and Cause of Death Registers. Among 60 962 patients, 3752 (6.2%) were &lt;55 years, and were compared with 7425 controls from the Population Register. Compared with patients ≥55 years, patients &lt;55 years more frequently had registered diagnoses of obesity, dilated cardiomyopathy, congenital heart disease, and an ejection fraction &lt;40% (9.8% vs. 4.7%, 27.2% vs. 5.5%, 3.7% vs. 0.8%, 67.9% vs. 45.1%, respectively; all P &lt; 0.001). One‐year all‐cause mortality was 21.2%, 4.2%, and 0.3% in patients ≥55 years, patients &lt;55 years, and controls &lt;55 years, respectively (all P &lt; 0.001). Patients &lt;55 years had a five times higher mortality risk compared with controls [hazard ratio (HR) 5.48, 95% confidence interval (CI) 4.45–6.74]; the highest HR was in patients 18–34 years (HR 38.3, 95% CI 8.70–169; both P &lt; 0.001). At the age of 20, the estimated life‐years lost was up to 36 years for 50% of patients, with declining estimates with increasing age. Conclusion Patients with HF &lt;55 years had different comorbidities than patients ≥55 years. The highest mortality risk relative to that of controls was among the youngest patients.
Response by Jackson et al to Letter Regarding Article, “Effects of Sacubitril-Valsartan Versus Valsartan in Women Compared With Men With Heart Failure and Preserved Ejection Fraction: Insights From PARAGON-HF”
Authors: Alice M. Jackson, Pardeep S. Jhund, Scott D. Solomon, John J.V. McMurray
Journal: Circulation (2020)
Response to: ‘Cutaneous adverse events with febuxostat after previous reactions to allopurinol: comment on the artcile by Singh and Clevland’ by Quills<i>et al</i>
Authors: Jasvinder A Singh
Journal: Annals of the Rheumatic Diseases (2020)

Response to: 'Cutaneous adverse events with febuxostat after previous reactions to allopurinol: comment on the
New GP partners in England can now access “golden hello” of up to £20 000
Authors: Gareth Iacobucci
Journal: BMJ (2020)

A new incentive scheme offering new GP partners in England a one off “golden hello” payment of up to £20 000 (€21 000; $25 000) has come into force.

As of 1 July, eligible participants can now access a sum of up to £20 000 (for a full time GP), a contribution towards on-costs (overheads) of up to £4 000 (for a full time GP) to support their establishment as a partner, and up to £3 000 in a training fund to develop non-clinical partnership skills.

The move, first announced in February 2020, …
Attenuating the Epidermal Growth Factor Receptor–Extracellular Signal‐Regulated Kinase–Sex‐Determining Region Y‐Box 9 Axis Promotes Liver Progenitor Cell‐Mediated Liver Regeneration in Zebrafish
Authors: Juhoon So, Minwook Kim, Seung‐Hoon Lee, Sungjin Ko, Daniel A. Lee, Hyewon Park, Mizuki Azuma, Michael J. Parsons, David Prober, Donghun Shin
Journal: Hepatology (2020)

Background and Aims The liver is a highly regenerative organ, but its regenerative capacity is compromised in severe liver injury settings. In chronic liver diseases, the number of liver progenitor cells (LPCs) correlates proportionally to disease severity, implying that their inefficient differentiation into hepatocytes exacerbates the disease. Moreover, LPCs secrete proinflammatory cytokines; thus, their prolonged presence worsens inflammation and induces fibrosis. Promoting LPC‐to‐hepatocyte differentiation in patients with advanced liver disease, for whom liver transplantation is currently the only therapeutic option, may be a feasible clinical approach because such promotion generates more functional hepatocytes and concomitantly reduces inflammation and fibrosis. Approach and Results Here, using zebrafish models of LPC‐mediated liver regeneration, we present a proof of principle of such therapeutics by demonstrating a role for the epidermal growth factor receptor (EGFR) signaling pathway in differentiation of LPCs into hepatocytes. We found that suppression of EGFR signaling promoted LPC‐to‐hepatocyte differentiation through the mitogen‐activated ERK kinase (MEK)‐extracellular signal‐regulated kinase (ERK)–sex‐determining region Y‐box 9 (SOX9) cascade. Pharmacological inhibition of EGFR or MEK/ERK promoted LPC‐to‐hepatocyte differentiation as well as genetic suppression of the EGFR‐ERK‐SOX9 axis. Moreover, Sox9b overexpression in LPCs blocked their differentiation into hepatocytes. In the zebrafish liver injury model, both hepatocytes and biliary epithelial cells contributed to LPCs. EGFR inhibition promoted the differentiation of LPCs regardless of their origin. Notably, short‐term treatment with EGFR inhibitors resulted in better liver recovery over the long term. Conclusions The EGFR‐ERK‐SOX9 axis suppresses LPC‐to‐hepatocyte differentiation during LPC‐mediated liver regeneration. We suggest EGFR inhibitors as a proregenerative therapeutic drug for patients with advanced liver disease.
Tescalcin is an unfavorable prognosis factor that regulats cell proliferation and survival in hepatocellular carcinoma patients
Authors: Zhong‐Guo Zhou, Jin‐Bin Chen, Rong‐Xin Zhang, Ling Ye, Jun‐Cheng Wang, Yang‐Xun Pan, Xiao‐Hui Wang, Wen‐Xuan Li, Yao‐Jun Zhang, Li Xu, Min‐Shan Chen
Journal: Cancer Communications (2020)

Abstract Background Hepatocellular carcinoma (HCC) is a major health problem and a primary cause of cancer‐related death worldwide. Although great advances have achieved recently by large‐scale high‐throughput analysis, the precise molecular mechanism underlying HCC progression remains to be clearly elucidated. We investigated the relationship between Tescalcin ( TESC ), a candidate oncogene, and clinicopathological features of HCC patients and explored the role of TECS in HCC development. Methods To identify new genes involved in HCC development, we analyzed The Cancer Genome Atlas liver cancer database, and TESC was selected for further investigation. HCC tissue microarray analysis for TESC and its association with clinicopathological features were performed to investigate its clinical significance. TESC was knocked down by using short‐hairpin RNAs. Cell proliferation was analyzed by WST‐1 assay and cell counting. Cell apoptosis was tested by fluorescence‐activated cell sorting. A subcutaneous xenograft tumor model in nude mice was established to determine the in vivo function of TESC. Affymetrix microarray was used to identify its molecular mechanism. Results TESC was significantly increased in HCC tissues compared with the adjacent normal liver tissues. High expression of TESC was detected in 61 of 172 HCC patients by tissue microarray. Large tumor (&gt; 5 cm) and elevated total bilirubin were associated with high TESC expression (both P &lt; 0.050). In multivariate analysis, TESC was identified as an independent prognostic factor for short overall survival of HCC patients. TESC knockdown impaired HCC cell growth in vitro and in vivo . TESC knockdown significantly increased cell apoptosis in HCC cell lines. Furthermore, Affymetrix microarray analysis revealed that TESC knockdown inhibited tumor proliferation‐related pathways while activated cell death‐related pathways. Conclusion TESC was identified as an independent prognostic factor for short overall survival of HCC patients, and was critical for HCC cell proliferation and survival.
<i>Salvia miltiorrhiza</i>-derived miRNAs suppress vascular remodeling through regulating OTUD7B/KLF4/NMHC IIA axis
Authors: Gao-shan Yang, Bin Zheng, Yan Qin, Jing Zhou, Zhan Yang, Xin-hua Zhang, Hong-ye Zhao, Hao-jie Yang, Jin-kun Wen
Journal: Theranostics (2020)

Objective: Abnormal proliferation and migration of vascular smooth muscle cells (VSMCs) are essential for vascular remodeling.Natural compounds with diterpene chinone or phenolic acid structure from Salvia miltiorrhiza, an eminent medicinal herb widely used to treat cardiovascular diseases in China, can effectively attenuate vascular remodeling induced by vascular injury.However, it remains unknown whether Salvia miltiorrhiza-derived miRNAs can protect VSMCs from injury by environmental stimuli.Here, we explored the role and underlying mechanisms of Salvia miltiorrhiza-derived Sal-miR-1 and 3 in the regulation of VSMC migration and monocyte adhesion to VSMCs induced by thrombin.Methods: A mouse model for intimal hyperplasia was established by the ligation of carotid artery and the injured carotid arteries were in situ-transfected with Sal-miR-1 and 3 using F-127 pluronic gel.The vascular protective effects of Sal-miR-1 and 3 were assessed via analysis of intimal hyperplasia with pathological morphology.VSMC migration and adhesion were analyzed by the wound healing, transwell membrane assays, and time-lapse imaging experiment.Using loss-and gain-of-function approaches, Sal-miR-1 and 3 regulation of OTUD7B/KLF4/NMHC IIA axis was investigated by using luciferase assay, co-immunoprecipitation, chromatin immunoprecipitation, western blotting, etc. Results: Salvia miltiorrhiza-derived Sal-miR-1 and 3 can enter the mouse body after intragastric administration, and significantly suppress intimal hyperplasia induced by carotid artery ligation.In cultured VSMCs, these two miRNAs inhibit thrombin-induced the migration of VSMCs and monocyte adhesion to VSMCs.Mechanistically, Sal-miR-1 and 3 abrogate OTUD7B upregulation by thrombin via binding to the different sites of the OTUD7B 3'UTR.Most importantly, OTUD7B downregulation by Sal-miR-1 and 3 attenuates KLF4 protein levels via decreasing its deubiquitylation, whereas decreased KLF4 relieves its repression of transcription of NMHC IIA gene and thus increases NMHC IIA expression levels.Further, increased NMHC IIA represses VSMC migration and monocyte adhesion to VSMCs via maintaining the contractile phenotype of VSMCs.Conclusions: Our studies not only found the novel bioactive components from Salvia miltiorrhiza but also clarified the molecular mechanism underlying Sal-miR-1 and 3 inhibition of VSMC migration and monocyte adhesion to VSMCs.These results add important knowledge to the pharmacological actions and bioactive components of Salvia miltiorrhiza.Sal-miR-1 and 3-regulated OTUD7B/KLF4/NMHC IIA axis may represent a therapeutic target for vascular remodeling.
Use of Adjuvant Radiotherapy in the Treatment of High-risk Cutaneous Squamous Cell Carcinoma With Perineural Invasion
Authors: Mary L. Stevenson, Maressa C. Criscito, Reason Wilken, Nicole A. Doudican, Earl Eugene Bain, Bhupesh Parashar, John A. Carucci
Journal: JAMA Dermatology (2020)

in the setting of additional high-risk features and should be considered.Limitations of this study include its retrospective design, cohort size, treatment bias, and potential referral bias, with our findings suggesting the need for prospective, multicenter controlled trials.Our data suggest favorable outcomes of cSCC with perineural invasion treated with surgery and adjuvant radiotherapy, highlighting the potential role of adjuvant radiotherapy for patients with large-caliber perineural invasion and those with small-caliber perineural invasion in the presence of other high-risk features.
Tattoo Reaction—a Diagnostic Clue in Neurosarcoidosis
Authors: Amy J. Halliday, Dean L. Jones
Journal: JAMA Neurology (2020)

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Amphiregulin Aggravates Glomerulonephritis via Recruitment and Activation of Myeloid Cells
Authors: Simon Melderis, Julia Hagenstein, Matthias Tobias Warkotsch, Julien Dang, Georg Rudolf Herrnstadt, Christoph Benjamin Niehus, Katrin Neumann, Ulf Panzer, Carmen Berasain, Matias A. Avila, Pierre-Louis Tharaux, Gisa Tiegs, Oliver M. Steinmetz
Journal: Journal of the American Society of Nephrology (2020)

Recent studies have identified the EGF receptor (EGFR) ligand amphiregulin (AREG) as an important mediator of inflammatory diseases. Both pro- and anti-inflammatory functions have been described, but the role of AREG in GN remains unknown.The nephrotoxic nephritis model of GN was studied in AREG-/- mice after bone marrow transplantation, and in mice with myeloid cell-specific EGFR deficiency. Therapeutic utility of AREG neutralization was assessed. Furthermore, AREG's effects on renal cells and monocytes/macrophages (M/M) were analyzed. Finally, we evaluated AREG expression in human renal biopsies.Renal AREG mRNA was strongly upregulated in murine GN. Renal resident cells were the most functionally relevant source of AREG. Importantly, the observation that knockout mice showed significant amelioration of disease indicates that AREG is pathogenic in GN. AREG enhanced myeloid cell responses via inducing chemokine and colony stimulating factor 2 (CSF2) expression in kidney resident cells. Furthermore, AREG directly skewed M/M to a proinflammatory M1 phenotype and protected them from apoptosis. Consequently, anti-AREG antibody treatment dose-dependently ameliorated GN. Notably, selective abrogation of EGFR signaling in myeloid cells was sufficient to protect against nephritis. Finally, strong upregulation of AREG expression was also detected in kidneys of patients with two forms of crescentic GN.AREG is a proinflammatory mediator of GN via (1) enhancing renal pathogenic myeloid cell infiltration and (2) direct effects on M/M polarization, proliferation, and cytokine secretion. The AREG/EGFR axis is a potential therapeutic target for acute GN.