tbuckley/cabot-search huggingface dataset:
Abstract 321: miR-125b-3p Cox20 Axis Deregulation in the Novel Combined Model of Pulmonary Fibrosis, Pulmonary Hypertension
Authors: Gregoire Ruffenach, Soban Umar, Mansoureh Eghbali
Journal: Circulation Research (2016)

Introduction: Pulmonary fibrosis (PF) is a life threatening disease characterized by lung scaring. In some cases PF is complicated by pulmonary hypertension (PH). Growing evidence demonstrates the role of oxidative stress and the implication of micro-RNAs in PF and PH but their exact role in PF associated with PH (PH-PF) remain unclear. Recently, our group developed a combined model of PF-PH in rats and demonstrated a robust up-regulation of miR125 in rats with PF-PH compared to PF. Interestingly, the cytochrome C oxidase assembly factor 20 (COX20), a protein implicated in respiratory chain complex IV structure and oxidative stress regulation, is predicted to be a target of miR125. Based on these data, we hypothesis that: upregulation of miR125 in the lungs of combined PF-PH lead to COX20 down-regulation and therefore increases oxidative stress. Methods: Wistar male rats were divided to 5 groups. The rats received either a single intra-tracheal instillation of bleomycin (2.5mg.kg -1 , PF group) or PBS in day 0 (control). Two weeks later some of the rats in PF group received MCT injection (60mg.kg -1 , PF-PH group). All the rats were sacrificed at day 35 (n=4 rats per groups). Disease severity at day 35 was assessed by direct heart catheterization and Masson trichrome staining. Real-time PCR was used to quantify expression of COX20 and gluthation peroxidase 1 (GPX1), an anti-oxidant protein. Results: PF-PH rats developed a more severe PH than PF alone (58.02±4.3 vs. 37.59±5.9mmHg,). Histological analysis revealed an increase in pulmonary fibrosis and vascular remodelling in lung of PH-PF rats compare to PF alone. Mechanistically we found COX20 was robustly downregulated in PF-PH compared to PF group (~200 fold vs. ~10 fold, in relative to control, p&lt;0.05) This drastic decrease in COX20 in PF-PH expression was concomitant with an increase in oxidative stress highlighted by reduced expression of GPX1 in PF-PH compared to PF alone (~20000 fold vs. ~400 fold, relative to control). Conclusion: Our results implicate miR-125/COX20 axis in PH-PF model and pave the way to a better understanding of PH-PF disease mechanism
Mechanisms underlying genetic susceptibility to multisystem inflammatory syndrome in children (MIS-C)
Authors: Janet Chou, Craig D. Platt, Saddiq Habiballah, Alan A. Nguyen, Megan Elkins, Sabrina Weeks, Zachary Peters, Megan Day-Lewis, Tanya Novak, Myriam Armant, Lucinda Williams, Shira Rockowitz, Piotr Sliz, David A. Williams, Adrienne G. Randolph, Raif S. Geha, Abduarahman Almutairi, Faris Jaber, Tina Banzon, Jordan Roberts, Olha Halyabar, Mindy Lo, Stacy Kahn, Lauren A. Henderson, Pui Y. Lee, Mary Beth Son, Leah Cheng
Journal: Journal of Allergy and Clinical Immunology (2021)

Multisystem inflammatory syndrome in children (MIS-C) is a pediatric complication of severe acute respiratory syndrome coronavirus 2 infection that is characterized by multiorgan inflammation and frequently by cardiovascular dysfunction. It occurs predominantly in otherwise healthy children. We previously reported haploinsufficiency of suppressor of cytokine signaling 1 (SOCS1), a negative regulator of type I and II interferons, as a genetic risk factor for MIS-C.
Impact of octreotide counterion nature on the long-term stability and release kinetics from an in situ forming depot technology
Authors: Charlotte Molinier, Marina Picot-Groz, Océane Malval, Sophie Le Lamer-Déchamps, Joël Richard, Adolfo Lopez-Noriega, Sylvestre Grizot
Journal: Journal of Controlled Release (2021)

The generation of acylated impurities has represented an important hurdle in the development of long acting injectables for therapeutic peptides using biocompatible polymers with a polyester moiety. We investigated here an in situ forming depot (ISFD) technology that uses polyethylene glycol - polyester copolymers and a solvent exchange mechanism to promote depot formation. This technology has shown promise in formulating small molecules as well as therapeutic proteins. In the present work, using the well-known somatostatin analog octreotide acetate (OctAc) as a model molecule, we evaluated this delivery platform to release therapeutic peptides. Peptide acylation was found to be pronounced in the formulation, while it was very limited once the depot was formed and during the release process. The octreotide acylation pattern was fully characterized by LC-MS/MS. Moreover, it was demonstrated that exchanging the acetate anion with more hydrophobic counterions like pamoate or lauryl sulfate allowed to greatly improve the peptide stability profile, as well as the formulation release performance. Finally, the in vivo evaluation through pharmacokinetics studies in rat of these new octreotide salts in ISFD formulations showed that octreotide was quantifiable up to four weeks post-administration with a high bioavailability and an acceptable initial burst.
A public health approach to gambling regulation: countering powerful influences
Authors: May C I van Schalkwyk, Mark Petticrew, Rebecca Cassidy, Peter Adams, Martin McKee, Jennifer Reynolds, Jim Orford
Journal: The Lancet Public Health (2021)

Often portrayed as a harmless leisure activity in the UK, gambling is being increasingly recognised as a public health concern. However, a gambling policy system that explicitly tackles public health concerns and confronts the dependencies and conflicts of interest that undermine the public good is absent in the UK. Although there is a window of opportunity to change the gambling policy system, with the UK Government's launch of a review of the Gambling Act 2005, the adoption of a comprehensive and meaningful public health approach is not guaranteed. Too often, government policy has employed discourses that align more closely with those of the gambling industry than with those of the individuals, families, and communities affected by the harms of gambling. In view of the well described commercial determinants of health and corporate behaviour, an immense effort will be needed to shift the gambling discourse to protect public health. In this Viewpoint, we seek to advance this agenda by identifying elements that need challenging and stimulating debate.
A Worldwide Pharmacoepidemiologic Update on Drug‐Induced Antineutrophil Cytoplasmic Antibody–Associated Vasculitis in the Era of Targeted Therapies
Authors: Samuel Deshayes, Charles Dolladille, Anaël Dumont, Nicolas Martin Silva, Basile Chretien, Hubert De Boysson, Joachim Alexandre, Achille Aouba
Journal: Arthritis & Rheumatology (2021)

The literature supporting the role of a specific drug in the onset of drug-induced antineutrophil cytoplasmic antibody-associated vasculitis (AAV) mainly relies on case reports or short series and implicates old treatments. The advent of new treatments may have modified the epidemiology of these adverse drug reactions. This study was undertaken to update the list of drugs associated with AAV by using a pharmacovigilance-based data mining approach.We collected data on adverse drug reactions reported using the Medical Dictionary for Regulatory Activities preferred term "anti-neutrophil cytoplasmic antibody positive vasculitis" up to November 2020 from the World Health Organization pharmacovigilance database (VigiBase). For each retrieved drug, a case-noncase analysis was performed, and disproportionate reporting was calculated by using the information component (IC). A positive IC025 value, which is the lower end of the 95% credibility interval, was considered significant.A total of 483 deduplicated individual case safety reports of drug-induced AAV involving 15 drugs with an IC025 >0 were retrieved. Of the individuals with drug-induced AAV for whom data on sex were available (n = 371), 264 (71.2%) were women. The median age at onset of drug-induced AAV was 62 years (quartile 1 [Q1]-Q3 45-72 years), and the median time from the introduction of the suspected drug to the onset of drug-induced AAV was 9 months (Q1-Q3 1-36 months). Drug-induced AAV was considered serious in 472 (98.1%), and was fatal in 43 (8.9%), of 481 cases. The drugs associated with the highest disproportionate reporting were hydralazine, propylthiouracil, thiamazole, sofosbuvir, minocycline, carbimazole, mirabegron, and nintedanib.Our findings strengthen the evidence of an association of AAV with previously suspected drugs, but also identify 3 new drugs that may cause drug-induced AAV. Particular attention should be given to these drugs by prescribers and in experimental studies.
Changes in Hospitalizations at US Safety-Net Hospitals Following Medicaid Expansion
Authors: Karen E. Lasser, Zhixiu Liu, Meng-Yun Lin, Michael K. Paasche-Orlow, Amresh Hanchate
Journal: JAMA Network Open (2021)

This cross-sectional study examines whether inpatient utilization among patients with lower socioeconomic status and among those who belong to racial/ethnic minority groups changed differentially in states that expanded Medicaid following the Patient Protection and Affordable Care Act (ACA).
β2‐adrenergic agonists and doping: Where do we stand?
Authors: Olga Lourenço, Ana Cardoso, Beatriz Mónico, Jorge M. R. Gama, Henrique P. Neiva, Daniel A. Marinho
Journal: Allergy (2021)

Hostrup et al 1 kindly commented on our previous paper related to the enhancement of physical performance by β2-agonists. 2First, we would like to thank the authors for their review and acknowledge that our title and conclusions may have been misleading because, in fact, they only refer to endurance/aerobic-dominated performances.However, we were very clear that our results were based on VO2max and time to exhaustion at this intensity.We further stressed that VO2max measures do not represent a direct measure of physical performance, although VO2max is considered a variable of physical fitness and training status of each individual.We agree that we could have warned of the fact that this article only analyses efforts mainly aerobic, but, knowing that the attentive reader would check our inclusion and exclusion criteria, we chose to alert to other facts not so clear throughout the text, of the results and annexes.In our meta-analysis, only the study by Koch et al 3 favoured β2agonists (salbutamol) over placebo, when comparing VO2max, but this study included only female athletes.No other studies, which included mixed-gender populations or only male athletes, showed improved exercise performance.When evaluating time to exhaustion, one study by Collomp et al 4 favoured β2-agonists over placebo.However, these authors failed to reproduce these results in similar circumstances.
LARP7 Protects Against Heart Failure by Enhancing Mitochondrial Biogenesis
Authors: Huijing Yu, Fang Zhang, Pengyi Yan, Shasha Zhang, Yingmei Lou, Zilong Geng, Zixuan Li, Yan Zhang, Yuejuan Xu, Yanan Lu, Chen Chen, Daowen Wang, Wei Zhu, Xinyang Hu, Jian’an Wang, Tao Zhuang, Yuzhen Zhang, Gengze Wu, Junling Liu, Chunyu Zeng, William T. Pu, Kun Sun, Bing Zhang
Journal: Circulation (2021)

Heart failure (HF) is among the leading causes of morbidity and mortality, and its prevalence continues to rise. LARP7 (La ribonucleoprotein domain family member 7) is a master regulator that governs the DNA damage response and RNAPII (RNA polymerase II) pausing pathway, but its role in HF pathogenesis is incompletely understood. We assessed LARP7 expression in human HF and in nonhuman primate and mouse HF models. To study the function of LARP7 in heart, we generated global and cardiac-specific LARP7 knockout mice. We acutely abolished LARP7 in mature cardiomyocytes by Cas9-mediated LARP7 somatic knockout. We overexpressed LARP7 in cardiomyocytes using adeno-associated virus serotype 9 and ATM (ataxia telangiectasia mutated protein) inhibitor. The therapeutic potential of LARP7-regulated pathways in HF was tested in a mouse myocardial infarction model. LARP7 was profoundly downregulated in failing human hearts and in nonhuman primate and murine hearts after myocardial infarction. Low LARP7 levels in failing hearts were linked to elevated reactive oxygen species, which activated the ATM-mediated DNA damage response pathway and promoted LARP7 ubiquitination and degradation. Constitutive LARP7 knockout in mouse resulted in impaired mitochondrial biogenesis, myocardial hypoplasia, and midgestational lethality. Cardiac-specific inactivation resulted in defective mitochondrial biogenesis, impaired oxidative phosphorylation, elevated oxidative stress, and HF by 4 months of age. These abnormalities were accompanied by reduced SIRT1 (silent mating type information regulation 2 homolog 1) stability and deacetylase activity that impaired SIRT1-mediated transcription of genes for oxidative phosphorylation and energy metabolism and dampened cardiac function. Restoring LARP7 expression after myocardial infarction by either adeno-associated virus-mediated LARP7 expression or small molecule ATM inhibitor substantially improved the function of injured heart. LARP7 is essential for mitochondrial biogenesis, energy production, and cardiac function by modulating SIRT1 homeostasis and activity. Reduction of LARP7 in diseased hearts owing to activation of the ATM pathway contributes to HF pathogenesis and restoring LARP7 in the injured heart confers myocardial protection. These results identify the ATM-LARP7-SIRT1 pathway as a target for therapeutic intervention in HF.
Infographic. ‘As easy as riding a bike’ - a narrative review of injuries and illness in road cycling
Authors: Daire Rooney, Inigo Sarriegui, Neil Heron
Journal: British Journal of Sports Medicine (2021)

The WHO recommends that adults should do at least 150 min of moderate-intensity physical activity or 75 min of vigorous physical activity per week.1 Despite this, recent statistics show that one in four adults do not meet the recommended physical activity guidelines.2 Road cycling is an effective form of exercise that can help overcome the population’s failure to meet physical activity guidelines. In addition, the popularity of cycling at an elite level continues to grow. Injuries sustained during road cycling can act as a deterrent to future participation; both at amateur and professional levels. While studies have described the most common types of injuries experienced by amateur cyclists,3 4 the findings to date …
Long‐term efficacy and safety of risankizumab for the treatment of moderate‐to‐severe plaque psoriasis: interim analysis of the LIMMitless open‐label extension trial beyond 3 years of follow‐up
Authors: K.A. Papp, M.G. Lebwohl, L. Puig, M. Ohtsuki, S. Beissert, J. Zeng, S. Rubant, R. Sinvhal, Y. Zhao, A.M. Soliman, G. Alperovich, C. Leonardi
Journal: British Journal of Dermatology (2021)

Psoriasis is a chronic inflammatory skin disease requiring prolonged treatment. New biologic therapies require long-term evaluation to assess the durability of their efficacy and safety profiles over time.To evaluate the long-term efficacy and safety of risankizumab (RZB) for the treatment of psoriasis.LIMMitless is an ongoing, phase III, open-label extension study evaluating the long-term efficacy and safety of RZB in adults with moderate-to-severe plaque psoriasis following multiple phase II/III studies. This analysis assessed efficacy through 172 weeks of continuous RZB treatment by examining the proportion of patients achieving ≥ 90% or 100% improvement in Psoriasis Area and Severity Index (PASI 90 and PASI 100), static Physician's Global Assessment of clear or almost clear (sPGA 0/1) and Dermatology Life Quality Index of no effect on quality of life (DLQI 0/1). Safety was assessed by recording adverse events (AEs) through the data cutoff date. The study is registered at ClinicalTrials.gov (identifier: NCT03047395).Of 955 patients randomized to RZB 150 mg in the base studies, 897 patients continued into LIMMitless; 799 patients were still receiving treatment in LIMMitless at the time of data cutoff for this analysis. After 172 weeks of continuous RZB treatment, 85·5% of patients achieved PASI 90, 54·4% achieved PASI 100, 85·2% achieved sPGA 0/1, and 78·4% achieved DLQI 0/1 using modified nonresponder imputation. Rates of AEs leading to discontinuation and AEs of safety interest were low with long-term treatment and comparable with those identified in the base studies.Overall, long-term continuous RZB was well tolerated and showed high and durable efficacy over 172 weeks.
Abstract 139: Role of Histone Lysine Demethylase PHF8 in Epigenetic Regulation of Embryonic Stem Cell Cardiac Differentiation
Authors: Yan Tang, Yujia Yue, Suresh K Verma, Mohsin Khan, Raj Kishore
Journal: Circulation Research (2016)

Epigenetic control mechanisms play a key role in the regulation of lineage commitment of stem/progenitor cells, while the epigenetic regulators involved in the determination of cardiomyogenic lineage are incompletely defined. Using in vitro cardiac differentiation system of mESCs with Brachyury and Nkx2.5 selection, we analyzed expression profiles of epigenetic regulators at critical stages of cardiomyogenesis by RT 2 profiler PCR arrays. To identify the potential epigenetic regulators in the cardiac lineage decision, we compared their expression levels in Brachyury + mesodermal cells with Brachyury - cells, and in Nkx2.5 + cardiac progenitor cells with the Nkx2.5 - cells, respectively. To further understand the role of these epigenetic regulators in cardiac lineage commitment, we knockout these genes and investigate their function. For example, deletion of the H3K9me2 demethylase PHF8 in mESCs did not affect self-renewal, proliferation or early ectodermal/endodermal differentiation, but it did promote the mesodermal lineage commitment with the enhanced cardiomyocyte differentiation. The effects were accompanied by a reduction in apoptosis, without significant differences between differentiating wide-type (ph8 +/Y ) and ph8 -/Y ESCs in cell cycle progression or proliferation. Functionally, PHF8 promoted the loss of a repressive mark H3K9me2 from the transcription start site of a proapoptotic gene pmaip1 and activated its transcription. These results reveal the new epigenetic control mechanism in mesodemal and cardiac differentiation and establish a link between the apoptosis and cell lineage decision as well as cardiogenesis.
Reduction in life expectancy in Brazil after COVID-19
Authors: Marcia C. Castro, Susie Gurzenda, Cassio M. Turra, Sun Kim, Theresa Andrasfay, Noreen Goldman
Journal: Nature Medicine (2021)

Brazil has been heavily affected by coronavirus disease 2019 (COVID-19). In this study, we used data on reported total deaths in 2020 and in January-April 2021 to measure and compare the death toll across states. We estimate a decline in 2020 life expectancy at birth (e0) of 1.3 years, a mortality level not seen since 2014. The reduction in life expectancy at age 65 (e65) in 2020 was 0.9 years, setting Brazil back to 2012 levels. The decline was larger for males, widening by 9.1% the female-male gap in e0. Among states, Amazonas lost 60.4% of the improvements in e0 since 2000. In the first 4 months of 2021, COVID-19 deaths represented 107% of the total 2020 figures. Assuming that death rates would have been equal to 2019 all-cause rates in the absence of COVID-19, COVID-19 deaths in 2021 have already reduced e0 in 2021 by 1.8 years, which is slightly larger than the reduction estimated for 2020 under similar assumptions.
SPARK-X: non-parametric modeling enables scalable and robust detection of spatial expression patterns for large spatial transcriptomic studies
Authors: Jiaqiang Zhu, Shiquan Sun, Xiang Zhou
Journal: Genome biology (2021)

Abstract Spatial transcriptomic studies are becoming increasingly common and large, posing important statistical and computational challenges for many analytic tasks. Here, we present SPARK-X, a non-parametric method for rapid and effective detection of spatially expressed genes in large spatial transcriptomic studies. SPARK-X not only produces effective type I error control and high power but also brings orders of magnitude computational savings. We apply SPARK-X to analyze three large datasets, one of which is only analyzable by SPARK-X. In these data, SPARK-X identifies many spatially expressed genes including those that are spatially expressed within the same cell type, revealing new biological insights.
Ethnic differences in guideline-indicated statin initiation for people with type 2 diabetes in UK primary care, 2006–2019: A cohort study
Authors: Sophie V. Eastwood, Rohini Mathur, Naveed Sattar, Liam Smeeth, Krishnan Bhaskaran, Nishi Chaturvedi
Journal: PLoS Medicine (2021)

Background Type 2 diabetes is 2–3 times more prevalent in people of South Asian and African/African Caribbean ethnicity than people of European ethnicity living in the UK. The former 2 groups also experience excess atherosclerotic cardiovascular disease (ASCVD) complications of diabetes. We aimed to study ethnic differences in statin initiation, a cornerstone of ASCVD primary prevention, for people with type 2 diabetes. Methods and findings Observational cohort study of UK primary care records, from 1 January 2006 to 30 June 2019. Data were studied from 27,511 (88%) people of European ethnicity, 2,386 (8%) people of South Asian ethnicity, and 1,142 (4%) people of African/African Caribbean ethnicity with incident type 2 diabetes, no previous ASCVD, and statin use indicated by guidelines. Statin initiation rates were contrasted by ethnicity, and the number of ASCVD events that could be prevented by equalising prescribing rates across ethnic groups was estimated. Median time to statin initiation was 79, 109, and 84 days for people of European, South Asian, and African/African Caribbean ethnicity, respectively. People of African/African Caribbean ethnicity were a third less likely to receive guideline-indicated statins than European people ( n/N [%]: 605/1,142 [53%] and 18,803/27,511 [68%], respectively; age- and gender-adjusted HR 0.67 [95% CI 0.60 to 0.76], p &lt; 0.001). The HR attenuated marginally in a model adjusting for total cholesterol/high-density lipoprotein cholesterol ratio (0.77 [95% CI 0.69 to 0.85], p &lt; 0.001), with no further diminution when deprivation, ASCVD risk factors, comorbidity, polypharmacy, and healthcare usage were accounted for (fully adjusted HR 0.76 [95% CI 0.68, 0.85], p &lt; 0.001). People of South Asian ethnicity were 10% less likely to receive a statin than European people (1,489/2,386 [62%] and 18,803/27,511 [68%], respectively; fully adjusted HR 0.91 [95% CI 0.85 to 0.98], p = 0.008, adjusting for all covariates). We estimated that up to 12,600 ASCVD events could be prevented over the lifetimes of people currently affected by type 2 diabetes in the UK by equalising statin prescribing across ethnic groups. Limitations included incompleteness of recording of routinely collected data. Conclusions In this study we observed that people of African/African Caribbean ethnicity with type 2 diabetes were substantially less likely, and people of South Asian ethnicity marginally less likely, to receive guideline-indicated statins than people of European ethnicity, even after accounting for sociodemographics, healthcare usage, ASCVD risk factors, and comorbidity. Underuse of statins in people of African/African Caribbean or South Asian ethnicity with type 2 diabetes is a missed opportunity to prevent cardiovascular events.
Real-World Outcomes of Chemoimmunotherapy in Chronic Lymphocytic Leukemia (CLL) Clinical Practice: Results from a Decade of Practice in Helsinki 2005-2015
Authors: Vesa Lindström, Tiina M Jarvinen, Juha Mehtälä, Houssem Khanfir, Rosa Juuti, Amy Leval, Marjaana Säily
Journal: Blood (2017)
Overexpression of helper T cell type 2-related molecules in the skin of patients with eosinophilic dermatosis of hematologic malignancy
Authors: Roberto Maglie, Filippo Ugolini, Francesco De Logu, Romina Nassini, Sara Simi, Pamela Nardiello, Elisa Pasqualini, Gianna Baroni, Elena Del Bianco, Daniela Massi, Emiliano Antiga
Journal: Journal of the American Academy of Dermatology (2021)