tbuckley/cabot-search huggingface dataset:
Divergent Trajectories of Cardiovascular Risk Factors in the Years Before Pregnancy in Women With and Without Gestational Diabetes Mellitus: A Population-Based Study
Authors: Ravi Retnakaran, Baiju R. Shah
Journal: Diabetes Care (2020)

OBJECTIVE Women who develop gestational diabetes mellitus (GDM) have an elevated lifetime risk of cardiovascular disease, which has been attributed to an adverse cardiovascular risk factor profile that is apparent even within the first year postpartum. Given its presence in the early postpartum, we hypothesized that this adverse cardiovascular risk factor profile may develop over time in the years before pregnancy. RESEARCH DESIGN AND METHODS With population-based administrative databases, we identified all nulliparous women in Ontario, Canada, who had singleton pregnancies between January 2011 and December 2016 and two or more measurements of the following analytes between 2007 and the start of pregnancy: A1C, fasting glucose, random glucose, lipids, and transaminases. This population consisted of 8,047 women who developed GDM and 93,114 women who did not. RESULTS The two most recent pregravid tests were performed at a median of 0.61 years and 1.86 years before pregnancy, respectively. Women who went on to develop GDM had higher pregravid A1C, fasting glucose, random glucose, LDL cholesterol, triglycerides, and ALT and lower HDL cholesterol than their peers (all P &amp;lt; 0.0001). Notably, in the years before pregnancy, women who went on to develop GDM had higher annual increases than their peers in A1C (1.9-fold higher) (difference 0.0089%/year [95% CI 0.0043–0.0135]) and random glucose (4.3-fold), greater annual decrease in HDL cholesterol (5.5-fold), and lesser annual decline in LDL cholesterol (0.4-fold) (all P ≤ 0.0002). During this time, fasting glucose and triglycerides increased in women who developed GDM but decreased in their peers (both P &amp;lt; 0.0001). CONCLUSIONS The adverse cardiovascular risk factor profile of women with GDM evolves over time in the years before pregnancy.
Prevalence of Cardiovascular Risk Factors and Incidence of Venous and Arterial Thrombosis in Non-Splenectomized Immune Thrombocytopenia Adult Patients in Sweden and France. Results from Two Nationwide Studies
Authors: Charlotta Ekstrand, Bérangère Baricault, Marie Linder, Margaux Lafaurie, Laurent Sailler, Maryse Lapeyre-Mestre, Helle Kieler, Shahram Bahmanyar, Guillaume Moulis
Journal: Blood (2017)
Race Disparities in the COVID-19 Pandemic—Solutions Lie in Policy, Not Biology
Authors: L. Ebony Boulware
Journal: JAMA Network Open (2020)

Baligh R. Yehia, MD, MPP; Angela Winegar, PhD; Richard Fogel, MD; Mohamad Fakih, MD, MPH; Allison Ottenbacher, PhD; Christine Jesser, ScD; Angelo Bufalino, PhD; Ren-Huai Huang, PhD; Joseph Cacchione, MD
Pregnancy and Access to Treatment for Opioid Use Disorder
Authors: Magdalena Cerdá, Noa Krawczyk
Journal: JAMA Network Open (2020)

Stephen W. Patrick, MD, MPH, MS; Michael R. Richards, MD, PhD; William D. Dupont, PhD; Elizabeth McNeer, MS; Melinda B. Buntin, PhD; Peter R. Martin, MD, MSc; Matthew M. Davis, MD, MAPP; Corey S. Davis, JD, MSPH; Katherine E. Hartmann, MD, PhD; Ashley A. Leech, PhD; Kim S. Lovell, MPH, MBA; Bradley D. Stein, MD, PhD; William O. Cooper, MD, MPH
Abstract LB-020: The replication factor MCM10 maintains breast cancer stem-like cells that constitutively experience c-Myc-driven replication stress
Authors: Noriko Gotoh
Journal: Cancer Research (2020)

Abstract Cancer stem-like cells (CSCs) are thought to be responsible for recurrence of tumors and poor prognosis due to their higher tumor-initiating capacity and resistance against chemotherapeutic agents, although the underlying mechanisms remain unclear. Here, we uncover a critical role of the replication factor mini-chromosome maintenance protein 10 (MCM10) in enabling breast cancer-derived CSCs to deal with constitutively accumulating DNA replication stress. Transcriptomic analysis of patient-derived breast cancer cells revealed that c-Myc downstream target genes and replication stress response genes were highly upregulated in CSC-enriched spheroid cells. Upregulated c-Myc enhanced the transcriptional activity especially at nucleoli, leading to DNA replication stress caused by collision of transcription and replication machineries. MCM10, one of the most upregulated factors in CSCs, showed important roles for enabling cells to survive under such condition through activating dormant origins. MCM10 depletion decreased tumorigenesis, tumor sphere-forming capacity, expression levels of stemness markers, and tumor-initiating capacity, suggesting that elevated MCM10 levels are vital for CSC survival and proliferation. On the other hand, overexpression of MCM10 helped cells to proliferate in medium containing hydroxyurea (HU), a chemotherapeutic agent that induces replication stress. We therefore conclude MCM10 plays critical roles for cancer cell proliferation under DNA replication stress, which is more pronounced in CSCs with upregulated c-Myc activity and in cells treated with chemotherapeutic agents, and propose to target MCM10 for therapy of both CSCs and other cancer cells. Citation Format: Noriko Gotoh. The replication factor MCM10 maintains breast cancer stem-like cells that constitutively experience c-Myc-driven replication stress [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-020.
Deprescribing Proton Pump Inhibitors—Reply
Authors: Emily G. McDonald, Todd C. Lee
Journal: JAMA Internal Medicine (2020)

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Yes‐Associated Protein Is Crucial for Constitutive Androstane Receptor‐Driven Hepatocyte Proliferation But Not for Induction of Drug Metabolism Genes in Mice
Authors: Bharat Bhushan, Laura Molina, Kelly Koral, John W. Stoops, Wendy M. Mars, Swati Banerjee, Anne Orr, Shirish Paranjpe, Satdarshan P. Monga, Joseph Locker, George K. Michalopoulos
Journal: Hepatology (2020)

Background and Aims Constitutive androstane receptor (CAR) agonists, such as 1,4‐bis [2‐(3,5‐dichloropyridyloxy)] benzene (TCPOBOP), are known to cause robust hepatocyte proliferation and hepatomegaly in mice along with induction of drug metabolism genes without any associated liver injury. Yes‐associated protein (Yap) is a key transcription regulator that tightly controls organ size, including that of liver. Our and other previous studies suggested increased nuclear localization and activation of Yap after TCPOBOP treatment in mice and the potential role of Yap in CAR‐driven proliferative response. Here, we investigated a direct role of Yap in CAR‐driven hepatomegaly and hepatocyte proliferation using hepatocyte‐specific Yap‐knockout (KO) mice. Approach and Results Adeno‐associated virus 8‐thyroxine binding globulin promoter‐Cre recombinase vector was injected to Yap‐floxed mice for achieving hepatocyte‐specific Yap deletion followed by TCPOBOP treatment. Yap deletion did not decrease protein expression of CAR or CAR‐driven induction of drug metabolism genes (including cytochrome P450 [Cyp] 2b10, Cyp2c55, and UDP‐glucuronosyltransferase 1a1 [Ugt1a1]). However, Yap deletion substantially reduced TCPOBOP‐induced hepatocyte proliferation. TCPOBOP‐driven cell cycle activation was disrupted in Yap‐KO mice because of delayed (and decreased) induction of cyclin D1 and higher expression of p21, resulting in decreased phosphorylation of retinoblastoma protein. Furthermore, the induction of other cyclins, which are sequentially involved in progression through cell cycle (including cyclin E1, A2, and B1), and important mitotic regulators (such as Aurora B kinase and polo‐like kinase 1) was remarkably reduced in Yap‐KO mice. Microarray analysis revealed that 26% of TCPOBOP‐responsive genes that were mainly related to proliferation, but not to drug metabolism, were altered by Yap deletion. Yap regulated these proliferation genes through alerting expression of Myc and forkhead box protein M1, two critical transcriptional regulators of CAR‐mediated hepatocyte proliferation. Conclusions Our study revealed an important role of Yap signaling in CAR‐driven hepatocyte proliferation; however, CAR‐driven induction of drug metabolism genes was independent of Yap.
RAGE and TLR4 differentially regulate airway hyperresponsiveness: Implications for COPD
Authors: Venkata Sita Rama Raju Allam, Alen Faiz, Maggie Lam, Senani N. H. Rathnayake, Benedikt Ditz, Simon D. Pouwels, Corry‐Anke Brandsma, Wim Timens, Pieter S. Hiemstra, Gaik W. Tew, Margaret Neighbors, Michele Grimbaldeston, Maarten van den Berge, Sheila Donnelly, Simon Phipps, Jane E. Bourke, Maria B. Sukkar
Journal: Allergy (2020)

The receptor for advanced glycation end products (RAGE) and Toll-like receptor 4 (TLR4) is implicated in COPD. Although these receptors share common ligands and signalling pathways, it is not known whether they act in concert to drive pathological processes in COPD. We examined the impact of RAGE and/or TLR4 gene deficiency in a mouse model of COPD and also determined whether expression of these receptors correlates with airway neutrophilia and airway hyperresponsiveness (AHR) in COPD patients.We measured airway inflammation and AHR in wild-type, RAGE-/- , TLR4-/- and TLR4-/- RAGE-/- mice following acute exposure to cigarette smoke (CS). We also examined the impact of smoking status on AGER (encodes RAGE) and TLR4 bronchial gene expression in patients with and without COPD. Finally, we determined whether expression of these receptors correlates with airway neutrophilia and AHR in COPD patients.RAGE-/- mice were protected against CS-induced neutrophilia and AHR. In contrast, TLR4-/- mice were not protected against CS-induced neutrophilia and had more severe CS-induced AHR. TLR4-/- RAGE-/- mice were not protected against CS-induced neutrophilia but were partially protected against CS-induced mediator release and AHR. Current smoking was associated with significantly lower AGER and TLR4 expression irrespective of COPD status, possibly reflecting negative feedback regulation. However, consistent with preclinical findings, AGER expression correlated with higher sputum neutrophil counts and more severe AHR in COPD patients. TLR4 expression did not correlate with neutrophilic inflammation or AHR.Inhibition of RAGE but not TLR4 signalling may protect against airway neutrophilia and AHR in COPD.
THU0093 Rheumatoid synovia and acanthamoeba polyphaga: immunohistochemical evidence of crossreactivity
Authors: S Jeansson, T Klingen, B Roald, E Rud, T Kvien
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> <h3>Objectives</h3> The initiation event in rheumatoid arthritis (RA) may be triggered by an infection and an association to various micro-organisms has been discussed. Micro-organisms capable of persistence, such as parvovirus B19 and Epstein-Barr virus, are of special interest. Features which might be expected of any micro-organism associated with RA, such as persistence, are also found in the protozoan Acanthamoeba polyphaga (AP). The aim of the present study was by means of immunohistochemical techniques, to search for epitopes in synovial tissue from RA patients and non-RA patients reacting/crossreacting with an AP specific monoclonal antibody. <h3>Methods</h3> Patient material:Synovia and pannus was removed from the knee during arthroscopy or open joint surgery on 57 patients in a single surgical unit at Diakonhjemmet Hospital in Oslo. These patients were classified into three groups. One had a clinical diagnosis of RA (n = 30) according to the criteria of the American College of Rheumatology. The other 27 patients had degenerative joint disease (n = 17), or other inflammatory arthropathies (n = 10). The specimens were evaluated by light microscopy and immunohistochemistry. Monoclonal antibodies (MAb) against AP were produced by standard methods. A MAb reactive with the cytoplasm of AP and non-reactive with normal human skin biopsies was selected for use in immunohistochemistry. <h3>Results</h3> Synovial membranes from RA patients demonstrated a distinct immunoreactivity whereas the reactivity in non-RA patients was weak. RA patients often demonstrated reactivity in the nuclear membrane in addition to cytoplasm and nucleus. The immunereactivity in non-RA patients was restricted to cytoplasm and nucleus in endothelial cells, pericytes and fibroblasts. <h3>Conclusion</h3> Our findings indicates the presence of an epitope crossreactive between synovia and the protozoan AP. Epitopes common between micro-organisms and human tissues are possible elements in autoimmunity.
Impact of COVID-19 on Public Mental Health and the Buffering Effect of a Sense of Coherence
Authors: Sarah K. Schäfer, M. Roxanne Sopp, Christian G. Schanz, Marlene Staginnus, Anja S. Göritz, Tanja Michael
Journal: Psychotherapy and Psychosomatics (2020)

It is claimed that the coronavirus disease 2019 (COVID-19) pandemic has had a negative impact on mental health. However, to date, prospective studies are lacking. Moreover, it is important to identify which factors modulate the stress response to the pandemic. Previously, sense of coherence (SOC) has emerged as a particularly important resistance factor.
NCCN Guidelines Insights: Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma, Version 1.2017
Authors: William G. Wierda, Andrew D. Zelenetz, Leo I. Gordon, Jeremy S. Abramson, Ranjana H. Advani, C. Babis Andreadis, Nancy Bartlett, John C. Byrd, Paolo Caimi, Luis E. Fayad, Richard I. Fisher, Martha J. Glenn, Thomas M. Habermann, Nancy Lee Harris, Francisco Hernandez-Ilizaliturri, Richard T. Hoppe, Steven M. Horwitz, Mark S. Kaminski, Christopher R. Kelsey, Youn H. Kim, Susan Krivacic, Ann S. LaCasce, Michael G. Martin, Auayporn Nademanee, Pierluigi Porcu, Oliver Press, Rachel Rabinovitch, Nishitha Reddy, Erin Reid, Kenneth Roberts, Ayman A. Saad, Erin D. Snyder, Lubomir Sokol, Lode J. Swinnen, Julie M. Vose, Joachim Yahalom, Mary A. Dwyer, Hema Sundar
Journal: Journal of the National Comprehensive Cancer Network (2017)

Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) are different manifestations of the same disease and managed in much the same way. The advent of novel CD20 monoclonal antibodies led to the development of effective chemoimmunotherapy regimens. More recently, small molecule inhibitors targeting kinases involved in a number of critical signaling pathways and a small molecule inhibitor of the BCL-2 family of proteins have demonstrated activity for the treatment of patients with CLL/SLL. These NCCN Guidelines Insights highlight important updates to the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for CLL/SLL for the treatment of patients with newly diagnosed or relapsed/refractory CLL/SLL.
SAT0122 Opioid rotation with oral morphine to oral hydromorphone in rheumatologic non cancer pain: a retrospective study
Authors: R Grilo, C Scotto Di Fazano, D Coyral, P Bertin, C Bonnet, R Treves
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> Although being a controversal debated, opioids may be an alternative therapeutic in intractable rheumatologic non-malignant pain (RNMP). Different mecanisms including receptor activity, cross over tolerance and toxic metabolits can explaine the differences in analgesic or adverse effect responses among opioids. <h3>Objectives</h3> To determinated that rotation with oral morphine to oral hydromorphone can be useful for establishing a more advantages analgesia/toxicity relationship. <h3>Methods</h3> We made retrospectivly 24 rotations in patients suffering from RNMP. Different criteria were assessed: dose of morphine and hydromorphone (mg/day), duration of treatment (days), evaluation of pain using a Visual Analogic Scale (VAS, cm) before and after rotation, and finally the causes of rotation. <h3>Results</h3> 11 rotations were made for nausea and 13 for inefficacity. There is a significant statistical decrease of VAS after rotation (test of Student). <h3>Conclusion</h3> Oral hydromorphone appeared to result in improvement of pain relief after rotation, and may provide a suitable alternative to bypass nausea. We observed an average morphine/hydromorphone ratio of 7:1, which has become the accepted standard.
Remodeling tumor immune microenvironment (TIME) for glioma therapy using multi-targeting liposomal codelivery
Authors: Zening Zheng, Jiaxin Zhang, Jizong Jiang, Yang He, Wenyuan Zhang, Xiaopeng Mo, Xuejia Kang, Qin Xu, Bing Wang, Yongzhuo Huang
Journal: Journal for ImmunoTherapy of Cancer (2020)

Background Glioblastoma (GBM) treatment is undermined by the suppressive tumor immune microenvironment (TIME). Seek for effective methods for brain TIME modulation is a pressing need. However, there are two major challenges against achieving the goal: first, to screen the effective drugs with TIME-remodeling functions and, second, to develop a brain targeting system for delivering the drugs. Methods In this study, an α7 nicotinic acetylcholine receptors (nAChRs)-binding peptide D CDX was used to modify the codelivery liposomes to achieve a ‘three-birds-one-stone’ delivery strategy, that is, multi-targeting the glioma vessel endothelium, glioma cells, and tumor-associated macrophages that all overexpressed α7 nAChRs. A brain-targeted liposomal honokiol and disulfiram/copper codelivery system (CDX-LIPO) was developed for combination therapy via regulating mTOR (mammalian target of rapamycin) pathway for remodeling tumor metabolism and TIME. Honokiol can yield a synergistic effect with disulfiram/copper for anti-GBM. Results It was demonstrated that CDX-LIPO remarkably triggered tumor cell autophagy and induced immunogenic cell death, and meanwhile, activated the tumor-infiltrating macrophage and dendritic cells, and primed T and NK (natural killer) cells, resulting in antitumor immunity and tumor regression. Moreover, CDX-LIPO promoted M1-macrophage polarization and facilitated mTOR-mediated reprogramming of glucose metabolism in glioma. Conclusion This study developed a potential combinatory therapeutic strategy by regulation of TIME and a ‘three-birds-one-stone’-like glioma-targeting drug delivery system.
Beneficial effect of anti-diabetic drugs for nonalcoholic fatty liver disease
Authors: Kyung-Soo Kim, Byung-Wan Lee
Journal: Clinical and Molecular Hepatology (2020)

Nonalcoholic fatty liver disease (NAFLD) is the most common liver disorder and is associated with various metabolic diseases, including type 2 diabetes mellitus. There are no approved drugs for NAFLD, and the only approved treatment option is weight reduction. As insulin resistance plays an important role in the development of NAFLD, many anti-diabetic drugs have been evaluated for the treatment of NAFLD. Improvement of liver enzymes has been demonstrated by many anti-diabetic drugs, but histological assessment still remains insufficient. Pioglitazone could become the first-line therapy for T2DM patients with NAFLD, based on evidence of histological improvement in patients with biopsy-proven nonalcoholic steatohepatitis (NASH). Liraglutide, another promising alternative, is not yet recommended in patients with NAFLD/NASH due to limited evidence. Therefore, well-designed randomized controlled trials should be performed in the near future to demonstrate if and how anti-diabetic drugs can play a role in the treatment of NAFLD.
FRI0090 The presence of microchimerism in systemic lupus erythematosus: preliminary data
Authors: M Mosca, M Curcio, S Lapi, R Neri, S Italia, D Totti, G Rizzo, S Bombardieri
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> The development of microchimerism after solid organ transplantation, but also after blood transfusions and during pregnancy, is no longer considered controversial. Controversy still exists on the immunological significance of this phenomenon, such for example its role on the development of tolerance to the graft, or of some autoimmune conditions such as scleroderma (SSc). In this respect several studies have showed the presence of fetal cells not only in the peripheral blood but also in the skin of SSc patients. These observations, along with epidemiological (female prevalence, onset after childbearing years) and clinical (similarities with chronic graft versus host disease) data, have led to the hypothesis that microchimerism may play a role in the aetiopathogenesis of this disease. <h3>Objectives</h3> The aim of our study was to evaluate the prevalence of microchimerism in a population of SLE patients in comparison with SSc patients followed at our Unit. <h3>Methods</h3> Anticoagulated peripheral blood was obtained from 22 female patients (13 SLE and 9 SSc) who had a previous male pregnancy followed at our Unit. Genomic DNA was isolated from anticoagulated blood using a DNA extraction kit. A specific Y-chromosome sequence was detected by amplifying DNA in a nested-polymerase chain reaction (PCR) using published primers. <h3>Results</h3> Microchimerism was present in 62% of SLE patients and 89% of patients with SSc, the mean time interval between the pregnancy and the analysis was of 27 years and no significative differences were observed between positive and negative patients. In all scleroderma patients the pregnancy occurred before the onset of the disease (onset of Raynaud's phenomenon). In SLE patients 38% of the pregnancies occurred before the onset of the disease, and 62% after the onset of the disease, however no differences in the development of microchimerism were observed. <h3>Conclusion</h3> Since the literature data report a prevalence of 33% of microchimerism in healthy controls, these preliminary data may suggest that microchimerism develops more easily in patients with various autoimmune conditions. Further studies on extended populations of CTD patients and healthy controls appear necessary, in order to look for permissive factors for its development, such for example immunosuppressive therapy or immunological abnormalities. <h3>References</h3> Evans PC, <i>et al.</i> Blood 1999;93:2033–7 Nelson JL. Lupus 1999;8:370–4 Nelson JL. Curr Opin Rheumatol. 1998;10:564–71