tbuckley/cabot-search huggingface dataset:
AB0709 SERUM IL-12/23 AND IL-17 LEVELS IN PATIENTS WITH SPONDYLOARTHRITIS WERE NOT INFLUENCED BY TNF-BLOCKADE
Authors: M. Murakami, N. Nishimoto
Journal: Annals of the Rheumatic Diseases (2020)

Background: Spondyloarthritis (SpA) refers to a heterogeneous group of disorders with clinical features that can include axial and peripheral arthritis, inflammatory bowel disease, uveitis, and psoriasis. Several cytokines including interleukin (IL)-12/23, IL-17 and tumor necrosis factor (TNF) are involved in pathogenesis of SpA. It is assumed that TNF is the upstream cytokine in the cytokine cascade (Schett, et al., 2013). Objectives: To investigate whether TNF inhibitors decrease serum IL-12/23 and IL-17 levels in patients with SpA. Methods: Serum were obtained from 23 SpA patients (AS, 10 patients; PsA, 13 patients) enrolled in this study, at baseline, 24 and 48 weeks of TNF inhibitor treatment. Serum IL-12/23 and IL17 levels were measured using LEGEND MAX Human IL-12/IL-23 (p40) ELISA Kit (BioLegend) and Human IL-17A ELISA kit (Invitrogen), respectively. IL-6 levels, the other downstream cytokine, was measured using Lumipulse G600II (FUJIREBIO) as a control. Results: Any significant reduction in IL-12/23 levels (143.9±143.6 pg/mL at baseline, 156.3±117.1 pg/mL at 24 weeks and 139.3±118.1 pg/mL at 48 weeks), as well as that in IL-17 levels (13.6±51.9 pg/mL at baseline, 12.3±41.4 pg/mL at 24 weeks and 11.6±39.2 pg/mL at 48 weeks) were not observed in 23 SpA patients. On the other hand, serum IL-6 levels were significantly decreased after treatment (4.0±4.2 pg/mL at baseline; 1.8±1.4 pg/mL, p=0.002 , at 24 weeks; 1.6±1.9 pg/mL, p=0.0002 at 48 weeks. Pain-VAS was significantly reduced at 24 and 48 weeks compared with that at baseline. No significant differences in serum levels of analyzed cytokines were observed in the AS group compared with the PsA group at baseline (IL-12/23 levels: 110.8±70.0 vs.169.3±180.3 pg/mL, p=0.28 ; IL-17 levels: 26.8±78.6 vs. 3.4±7.6pg/mL, p=0.08 ). Conclusion: TNF inhibitors did not alter serum IL-12/23 and IL-17 levels but reduced IL-6 levels in patients with SpA. These results imply that IL-12/23 and IL-17 expression might be regulated by alternative pathways. References: [1]Schett, et al. Toward a cytokine-based disease taxonomy. Nat Med. 2013 Jul; 19 (7):822-4 Disclosure of Interests: Miho Murakami Grant/research support from: Chugai, Eisai, Consultant of: Chugai, Norihiro Nishimoto Grant/research support from: Chugai, Eisai, Consultant of: Chugai, Speakers bureau: Chugai, Eisai, AYUMI, Mitsubishi Tanabe, AbbVie, Novartis, Nippon Kayaku, TOWA, Astellas, Kyowa Kirin
Berberine mediates root remodeling in an immature tooth with apical periodontitis by regulating stem cells from apical papilla differentiation
Authors: Yujia Cui, Jing Xie, Yujie Fu, Chuwen Li, Liwei Zheng, Dingming Huang, Changchun Zhou, Jianxun Sun, Xuedong Zhou
Journal: International Journal of Oral Science (2020)

Abstract Once pulp necrosis or apical periodontitis occurs on immature teeth, the weak root and open root apex are challenging to clinicians. Berberine (BBR) is a potential medicine for bone disorders, therefore, we proposed to apply BBR in root canals to enhance root repair in immature teeth. An in vivo model of immature teeth with apical periodontitis was established in rats, and root canals were filled with BBR, calcium hydroxide or sterilized saline for 3 weeks. The shape of the roots was analyzed by micro-computed tomography and histological staining. In vitro, BBR was introduced into stem cells from apical papilla (SCAPs). Osteogenic differentiation of stem cells from apical papilla was investigated by alkaline phosphatase activity, mineralization ability, and gene expression of osteogenic makers. The signaling pathway, which regulated the osteogenesis of SCAPs was evaluated by quantitative real time PCR, Western blot analysis, and immunofluorescence. In rats treated with BBR, more tissue was formed, with longer roots, thicker root walls, and smaller apex diameters. In addition, we found that BBR promoted SCAPs osteogenesis in a time-dependent and concentration-dependent manner. BBR induced the expression of β-catenin and enhanced β-catenin entering into the nucleus, to up-regulate more runt-related nuclear factor 2 downstream. BBR enhanced root repair in immature teeth with apical periodontitis by activating the canonical Wnt/β-catenin pathway in SCAPs.
Frequent mutations in the amino-terminal domain of BCL7A impair its tumor suppressor role in DLBCL
Authors: Carlos Baliñas-Gavira, María I. Rodríguez, Alvaro Andrades, Marta Cuadros, Juan Carlos Álvarez-Pérez, Ángel F. Álvarez-Prado, Virginia G. de Yébenes, Sabina Sánchez-Hernández, Elvira Fernández-Vigo, Javier Muñoz, Francisco Martín, Almudena R. Ramiro, José A. Martínez-Climent, Pedro P. Medina
Journal: Leukemia (2020)
Clinical Genomics in Critically Ill Infants and Children
Authors: F. Lucy Raymond
Journal: JAMA (2020)

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
Natural products as LSD1 inhibitors for cancer therapy
Authors: Yuan Fang, Chao Yang, Zhiqiang Yu, Xiaochuan Li, Qingchun Mu, Guochao Liao, Bin Yu
Journal: Acta Pharmaceutica Sinica B (2020)

Natural products generally fall into the biologically relevant chemical space and always possess novel biological activities, thus making them a rich source of lead compounds for new drug discovery. With the recent technological advances, natural product-based drug discovery is now reaching a new era. Natural products have also shown promise in epigenetic drug discovery, some of them have advanced into clinical trials or are presently being used in clinic. The histone lysine specific demethylase 1 (LSD1), an important class of histone demethylases, has fundamental roles in the development of various pathological conditions. Targeting LSD1 has been recognized as a promising therapeutic option for cancer treatment. Notably, some natural products with different chemotypes including protoberberine alkaloids, flavones, polyphenols, and cyclic peptides have shown effectiveness against LSD1. These natural products provide novel scaffolds for developing new LSD1 inhibitors. In this review, we mainly discuss the identification of natural LSD1 inhibitors, analysis of the co-crystal structures of LSD1/natural product complex, antitumor activity and their modes of action. We also briefly discuss the challenges faced in this field. We believe this review will provide a landscape of natural LSD1 inhibitors.
Genome-wide whole blood transcriptome profiling in a large European cohort of systemic sclerosis patients
Authors: Lorenzo Beretta, Guillermo Barturen, Barbara Vigone, Chiara Bellocchi, Nicolas Hunzelmann, Ellen De Langhe, Ricard Cervera, Maria Gerosa, László Kovács, Rafaela Ortega Castro, Isabel Almeida, Divi Cornec, Carlo Chizzolini, Jacques-Olivier Pers, Zuzanna Makowska, Ralf Lesche, Martin Kerick, Marta Eugenia Alarcón-Riquelme, Javier Martin
Journal: Annals of the Rheumatic Diseases (2020)

The analysis of annotated transcripts from genome-wide expression studies may help to understand the pathogenesis of complex diseases, such as systemic sclerosis (SSc). We performed a whole blood (WB) transcriptome analysis on RNA collected in the context of the European PRECISESADS project, aiming at characterising the pathways that differentiate SSc from controls and that are reproducible in geographically diverse populations.Samples from 162 patients and 252 controls were collected in RNA stabilisers. Cases and controls were divided into a discovery (n=79+163; Southern Europe) and validation cohort (n=83+89; Central-Western Europe). RNA sequencing was performed by an Illumina assay. Functional annotations of Reactome pathways were performed with the Functional Analysis of Individual Microarray Expression (FAIME) algorithm. In parallel, immunophenotyping of 28 circulating cell populations was performed. We tested the presence of differentially expressed genes/pathways and the correlation between absolute cell counts and RNA transcripts/FAIME scores in regression models. Results significant in both populations were considered as replicated.Overall, 15 224 genes and 1277 functional pathways were available; of these, 99 and 225 were significant in both sets. Among replicated pathways, we found a deregulation in type-I interferon, Toll-like receptor cascade, tumour suppressor p53 protein function, platelet degranulation and activation. RNA transcripts or FAIME scores were jointly correlated with cell subtypes with strong geographical differences; neutrophils were the major determinant of gene expression in SSc-WB samples.We discovered a set of differentially expressed genes/pathways validated in two independent sets of patients with SSc, highlighting a number of deregulated processes that have relevance for the pathogenesis of autoimmunity and SSc.
Predicting 5- and 10-Year Mortality Risk in Older Adults With Diabetes
Authors: Kevin N. Griffith, Julia C. Prentice, David C. Mohr, Paul R. Conlin
Journal: Diabetes Care (2020)

Several diabetes clinical practice guidelines suggest that treatment goals may be modified in older adults on the basis of comorbidities, complications, and life expectancy. The long-term benefits of treatment intensification may not outweigh short-term risks for patients with limited life expectancy. Because of the uncertainty of determining life expectancy for individual patients, we sought to develop and validate prognostic indices for mortality in older adults with diabetes.We used a prevalence sample of veterans with diabetes who were aged ≥65 years on 1 January 2006 (N = 275,190). Administrative data were queried for potential predictors that included patient demographics, comorbidities, procedure codes, laboratory values and anthropomorphic measurements, medication history, and previous health service utilization. Logistic least absolute shrinkage and selection operator regressions were used to identify variables independently associated with mortality. The resulting odds ratios were then weighted to create prognostic indices of mortality over 5 and 10 years.Thirty-seven predictors of mortality were identified: 4 demographic variables, prescriptions for insulin or sulfonylureas or blood pressure medications, 6 biomarkers, previous outpatient and inpatient utilization, and 22 comorbidities/procedures. The prognostic indices showed good discrimination, with C-statistics of 0.74 and 0.76 for 5- and 10-year mortality, respectively. The indices also demonstrated excellent agreement between observed outcome and predictions, with calibration slopes of 1.01 for both 5- and 10-year mortality.Prognostic indices obtained from administrative data can predict 5- and 10-year mortality in older adults with diabetes. Such a tool may enable clinicians and patients to develop individualized treatment goals that balance risks and benefits of treatment intensification.
Role of Patatin-Like Phospholipase Domain–Containing 3 Gene for Hepatic Lipid Content and Insulin Resistance in Diabetes
Authors: Oana P. Zaharia, Klaus Strassburger, Birgit Knebel, Yuliya Kupriyanova, Yanislava Karusheva, Martin Wolkersdorfer, Kálmán Bódis, Daniel F. Markgraf, Volker Burkart, Jong-Hee Hwang, Jörg Kotzka, Hadi Al-Hasani, Julia Szendroedi, Michael Roden, M. Roden, H. Al-Hasani, V. Burkart, A.E. Buyken, J. Eckel, G. Geerling, J.H. Hwang, C. Herder, A. Icks, K. Jandeleit-Dahm, S. Kahl, J. Kotzka, O. Kuss, E. Lammert, S. Trenkamp, W. Rathmann, J. Szendroedi, D. Ziegler
Journal: Diabetes Care (2020)

The rs738409(G) single nucleotide polymorphism (SNP) in the patatin-like phospholipase domain-containing 3 (PNPLA3) gene associates with increased risk and progression of nonalcoholic fatty liver disease (NAFLD). As the recently described severe insulin-resistant diabetes (SIRD) cluster specifically relates to NAFLD, this study examined whether this SNP differently associates with hepatic lipid content (hepatocellular lipids [HCL]) and insulin sensitivity in recent-onset diabetes.A total of 917 participants in the German Diabetes Study (GDS) underwent genotyping, hyperinsulinemic-euglycemic clamps with stable isotopic tracer dilution, and MRS.The G allele associated positively with HCL (β = 0.36, P < 0.01), independent of age, sex, and BMI across the whole cohort, but not in the individual clusters. Those with SIRD exhibited lowest whole-body insulin sensitivity compared with those with severe insulin-deficient (SIDD), moderate obesity-related (MOD), moderate age-related (MARD), and severe autoimmune diabetes (SAID) clusters (all P < 0.001). Interestingly, the SIRD group presented with higher prevalence of the rs738409(G) SNP compared with other clusters and the glucose-tolerant control group (P < 0.05). HCL was higher in the SIRD group (median 13.6% [1st quartile 5.8; 3rd quartile 19.1] compared with the MOD (6.4 % [2.1; 12.4], P < 0.05), MARD (3.0% [1.0; 7.9], P < 0.001), SAID (0.4% [0.0; 1.5], P < 0.001), and glucose-tolerant (0.9% [0.4; 4.9), P < 0.001) group. Although the PNPLA3 polymorphism did not directly associate with whole-body insulin sensitivity in SIRD, the G-allele carriers had higher circulating free fatty acid concentrations and greater adipose tissue insulin resistance compared with noncarriers (both P < 0.001).Members of the SIRD cluster are more frequently carriers of the rs738409(G) variant. The SNP-associated adipose tissue insulin resistance and excessive lipolysis may contribute to their NAFLD.
Expression and growth-promoting effect of group VIA Calcium independent phospholipase A2 in ovarian cancer
Authors: Yuanda Song, William P. Wilkins, Wenhui Hu, Karnam S. Murthy, Jing Chen, Zendra Lee, Suzanne E. Barbour, Xianjun Fang
Journal: Cancer Research (2006)

950  Angiotensin-(1-7) [Ang-(1-7)], an endogenous peptide hormone of the renin-angiotensin system, is a molecular regulator of blood pressure and natriuresis. Our previous studies showed that Ang-(1-7) inhibits the growth of vascular smooth muscle cells, cardiac myocytes and fibroblasts as well as lung and breast cancer cells in vitro and in vivo, demonstrating that the heptapeptide also regulates cell proliferation. In the present study, we examined whether one mechanism whereby Ang-(1-7) inhibits lung and breast tumor growth is by the inhibition of angiogenesis. EA.hy926 cells, a human endothelial cell line, were treated with Ang-(1-7), to determine whether the heptapeptide inhibits endothelial tube formation in vitro. EA.hy926 cells formed multiple tube-like structures after 16 h incubation on Matrigel; in contrast, Ang-(1-7) caused a marked disruption of tubule length and formation. The Ang-(1-7)-mediated reduction of tubule formation was dose-dependent with greater than 50% inhibition at 10 nM. The anti-angiogenic effect of Ang-(1-7) (54.3 ± 5.8% of control, n = 3 in triplicate) was completely blocked by the specific Ang-(1-7) receptor antagonist [D-Pro7]-Ang-(1-7) (93.0 ± 7.0% of control, n = 3 in triplicate), suggesting that these effects are mediated by a selective Ang-(1-7) receptor. [D-Pro7]-Ang-(1-7) alone did not alter tubule formation by the EA.hy926 cells. Additionally, we found that treatment of EA.hy926 with 100 nM Ang-(1-7) caused a marked reduction in 0.5% serum-stimulated cell proliferation (57.9 ± 4.2 % control, n = 4, in triplicate), as determined by 3H-thymidine incorporation. This study suggests that the anti-angiogenic properties of the heptapeptide may be due, in part, to the growth inhibition of endothelial cells. The inhibition of angiogenesis in vivo was determined using the CAM assay, to visualize vascular formation in the developing chick chorioallantoic membrane. Fertilized eggs from White Leghorn chickens were obtained from a commercial supplier and maintained in a humidified atmosphere at 37°C. On embryonic day 4, 100 nM Ang-(1-7) or cell culture media was added to the contents of the eggs and incubation was continued for 48 hours. Quantification of the branch point number showed that Ang-(1-7) administration markedly reduced neovascularization compared to the control (58.6 ± 3.6 branch points vs 29.5 ± 3.6, p
Abstract A22: Simultaneous multiparametric profiling of cell-free RNA (cfRNA) and cell-free tumor DNA (ctDNA) in advanced-stage colorectal cancer
Authors: Zheng Feng, Danyi Wang, Dennis Merkle, Jianjun Yu, Shidong Jia, Juergen Scheuenpflug
Journal: Clinical Cancer Research (2020)

Abstract Background: It has been recognized that intratumoral heterogeneity together with therapeutic intervention-associated multiple genomic alterations added complexity for precision therapy in late-stage colorectal cancer (CRC). The clinical utility/validity of ctDNA assays have been systematically analyzed and proved under clinical settings in select cancer types with demonstrated specificity and sensitivity. Notably, cfRNA sequencing confirmed and enhanced detection sensitivity for variants with low allele frequency. In this study, plasma-based ctDNA mutation and cfRNA gene expression in patients with advanced CRC were simultaneously tested using NGS liquid biopsy panels. Methods: ctDNA and cfRNA were extracted from plasma of 25 treatment-naive patients with advanced CRC (stage III/IV), then were tested using the 600-gene PredicineATLAS ctDNA NGS assay and 180-gene PredicinePLUS cfRNA NGS assay, respectively. Various genomic alterations including single-nucleotide variation (SNV), Indel, copy number variation (CNV) and genome rearrangement are detected, along with tumor mutation burdens (TMB) evaluation/measurement. RNA-based variants and gene expression are also analyzed. Results: At ctDNA level, 96% (24/25) ctDNA samples were detected with at least 1 genomic alteration and total 265 SNV/Indels and 27 CNVs were identified across samples, including 180 genes with reported SNVs/indels and 23 genes with CNV. 20% (5/25) of the patients with RAS somatic mutations, 32% (8/25) with TP53 mutations, 8% (2/25) with APC mutations, and 8% (2/25) with PIK3CA mutations. TPM3-NTRK1 fusion was also detected in one patient. A subset of these variants detected at ctDNA level were also confirmed by cfRNA sequencing. Conclusions: Our results demonstrated the clinical utility/feasibility of simultaneous multiparametric profiling of ctDNA and cfRNA for comprehensive molecular insight/characterization in advanced-stage cancer. cfRNA-derived variant detection confirms the variants originally detected in ctDNA test and further validates the high-specificity results for report interpretation. Further investigation of exploring concordance between temporally matched tissue and plasma samples is ongoing. The ctDNA and cfRNA-based combined liquid biopsy solution provides holistic molecular overview for detecting driver mutations, monitoring efficacy/disease burden, and identifying subclonal alterations that may related to drug resistance and tumor heterogeneity. Citation Format: Zheng Feng, Danyi Wang, Dennis Merkle, Jianjun Yu, Shidong Jia, Juergen Scheuenpflug. Simultaneous multiparametric profiling of cell-free RNA (cfRNA) and cell-free tumor DNA (ctDNA) in advanced-stage colorectal cancer [abstract]. In: Proceedings of the AACR Special Conference on Advances in Liquid Biopsies; Jan 13-16, 2020; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(11_Suppl):Abstract nr A22.
Covid-19: Racism may be linked to ethnic minorities’ raised death risk, says PHE
Authors: Gareth Iacobucci
Journal: BMJ (2020)

Racism, discrimination, and social inequality may have contributed to the increased risk of death from covid-19 among ethnic minority groups, a review commissioned by the government has acknowledged. The report from Public Health England,1 published on 16 June, follows a separate PHE report on 2 June that found that people from ethnic minorities were more likely to contract and die from covid-19 but that received heavy criticism for its lack of recommendations on how to reduce the disparities.2 The second report makes some recommendations (box 1), some of which were disclosed to The BMJ last week by disgruntled stakeholders who had expected them to be published with the first report.3 Box 1 ### PHE's key recommendationsRETURN TO TEXT