tbuckley/cabot-search huggingface dataset:
Association of Phosphodiesterase-5 Inhibitors Versus Alprostadil With Survival in Men With Coronary Artery Disease
Authors: Daniel P. Andersson, Laura Landucci, Ylva Trolle Lagerros, Alessandra Grotta, Rino Bellocco, Mikael Lehtihet, Martin J. Holzmann
Journal: Journal of the American College of Cardiology (2021)

Phosphodiesterase 5 inhibitor (PDE5i) treatment is associated with reduced mortality compared with no treatment for erectile dysfunction after myocardial infarction (MI). This study sought to investigate the association between treatment with PDE5i or alprostadil and outcomes in men with stable coronary artery disease. All Swedish men with a prior MI or revascularization who received PDE5i or alprostadil during 2006 through 2013 at >6 months after the event were included, using the Swedish Patient Register and the Swedish Prescribed Drug Register. Cox regression was used to estimate adjusted hazard ratios with 95% confidence intervals for all-cause mortality, MI, heart failure, cardiovascular mortality, noncardiovascular mortality, cardiac revascularization, peripheral arterial disease, and stroke in men treated with PDE5i versus alprostadil. This study included 16,548 men treated with PDE5i and 1,994 treated with alprostadil. The mean follow-up was 5.8 years, with 2,261 deaths (14%) in the PDE5i group and 521 (26%) in the alprostadil group. PDE5i compared with alprostadil treatment was associated with lower mortality (hazard ratio: 0.88; 95% confidence interval: 0.79 to 0.98) and with similar associations for MI, heart failure, cardiovascular mortality, and revascularization. When quintiles (q) of filled PDE5i prescriptions were compared using q1 as reference, patients in q3, q4, and q5 had lower all-cause mortality. Among alprostadil users, those in q5 had a lower all-cause mortality compared to q1. In men with stable coronary artery disease, treatment with PDE5i is associated with lower risks of death, MI, heart failure, and revascularization compared with alprostadil treatment. Although the decrease in all-cause mortality was PDE5i dose dependent, the data do not permit the inference of causality or any clinical benefits of PDE5i because of the observational study design.
Bile acid–activated macrophages promote biliary epithelial cell proliferation through integrin αvβ6 upregulation following liver injury
Authors: Adrien Guillot, Lucia Guerri, Dechun Feng, Seung-Jin Kim, Yeni Ait Ahmed, Janos Paloczi, Yong He, Kornel Schuebel, Shen Dai, Fengming Liu, Pal Pacher, Tatiana Kisseleva, Xuebin Qin, David Goldman, Frank Tacke, Bin Gao
Journal: Journal of Clinical Investigation (2021)

Cholangiopathies caused by biliary epithelial cell (BEC) injury represent a leading cause of liver failure. No effective pharmacologic therapies exist, and the underlying mechanisms remain obscure. We aimed to explore the mechanisms of bile duct repair after targeted BEC injury. Injection of intermedilysin into BEC-specific human CD59 (hCD59) transgenic mice induced acute and specific BEC death, representing a model to study the early signals that drive bile duct repair. Acute BEC injury induced cholestasis followed by CCR2+ monocyte recruitment and BEC proliferation. Using microdissection and next-generation RNA-Seq, we identified 5 genes, including Mapk8ip2, Cdkn1a, Itgb6, Rgs4, and Ccl2, that were most upregulated in proliferating BECs after acute injury. Immunohistochemical analyses confirmed robust upregulation of integrin αvβ6 (ITGβ6) expression in this BEC injury model, after bile duct ligation, and in patients with chronic cholangiopathies. Deletion of the Itgb6 gene attenuated BEC proliferation after acute bile duct injury. Macrophage depletion or Ccr2 deficiency impaired ITGβ6 expression and BEC proliferation. In vitro experiments revealed that bile acid–activated monocytes promoted BEC proliferation through ITGβ6. Our data suggest that BEC injury induces cholestasis, monocyte recruitment, and induction of ITGβ6, which work together to promote BEC proliferation and therefore represent potential therapeutic targets for cholangiopathies.
Blue poo: impact of gut transit time on the gut microbiome using a novel marker
Authors: Francesco Asnicar, Emily R Leeming, Eirini Dimidi, Mohsen Mazidi, Paul W Franks, Haya Al Khatib, Ana M Valdes, Richard Davies, Elco Bakker, Lucy Francis, Andrew Chan, Rachel Gibson, George Hadjigeorgiou, Jonathan Wolf, Timothy D Spector, Nicola Segata, Sarah E Berry
Journal: Gut (2021)

Gut transit time is a key modulator of host-microbiome interactions, yet this is often overlooked, partly because reliable methods are typically expensive or burdensome. The aim of this single-arm, single-blinded intervention study is to assess (1) the relationship between gut transit time and the human gut microbiome, and (2) the utility of the 'blue dye' method as an inexpensive and scalable technique to measure transit time.We assessed interactions between the taxonomic and functional potential profiles of the gut microbiome (profiled via shotgun metagenomic sequencing), gut transit time (measured via the blue dye method), cardiometabolic health and diet in 863 healthy individuals from the PREDICT 1 study.We found that gut microbiome taxonomic composition can accurately discriminate between gut transit time classes (0.82 area under the receiver operating characteristic curve) and longer gut transit time is linked with specific microbial species such as Akkermansia muciniphila, Bacteroides spp and Alistipes spp (false discovery rate-adjusted p values <0.01). The blue dye measure of gut transit time had the strongest association with the gut microbiome over typical transit time proxies such as stool consistency and frequency.Gut transit time, measured via the blue dye method, is a more informative marker of gut microbiome function than traditional measures of stool consistency and frequency. The blue dye method can be applied in large-scale epidemiological studies to advance diet-microbiome-health research. Clinical trial registry website https://clinicaltrials.gov/ct2/show/NCT03479866 and trial number NCT03479866.
P29.02 TIP: Romiplostim for Chemo-Induced Thrombocytopenia in Adults with Solid Tumors; A P3 Randomized Placebo-Controlled Double-Blind Studies
Authors: A. Armas, G. Soff, J. Camargo, P. Bunn, C. Munoz, D. Kuter, F. Scotte, J. Park, C. Bowers
Journal: Journal of Thoracic Oncology (2021)
A Prospective Study Evaluating Changes in Histology, Clinical and Virologic Outcomes in HBV‐HIV Co‐infected Adults in North America
Authors: Richard K. Sterling, Wendy C. King, Mandana Khalili, Raymond T. Chung, Mark Sulkowski, Mamta K. Jain, Mauricio Lisker‐Melman, Marc G. Ghany, David K. Wong, Amanda S. Hinerman, Atul K. Bhan, Abdus S. Wahed, David E. Kleiner
Journal: Hepatology (2021)

Histological and clinical outcomes in HBV-HIV coinfection in the era of combination antiretroviral therapy (cART) are poorly defined.Adult patients co-infected with HBV-HIV from eight North American sites were enrolled in this National Institutes of Health (NIH)-funded prospective observational study (n = 139). Demographic, clinical, serological, and virological data were collected at entry and every 24 weeks for ≤ 192 weeks. Paired liver biopsies were obtained at study entry and at ≥ 3 years of follow-up. Biopsies were assessed by a central pathology committee using the modified Ishak scoring system. Clinical outcome rate and changes in histology are reported. Among participants with follow-up data (n = 114), median age was 49 years, 91% were male, 51% were non-Hispanic Black, and 13% had at-risk alcohol use, with a median infection of 20 years. At entry, 95% were on anti-HBV cART. Median CD4 count was 562 cells/mm3 and 93% had HIV < 400 copies/mL. HBeAg was positive in 61%, and HBV DNA was below the limit of quantification (< 20 IU/mL) in 61% and < 1,000 IU/mL in 80%. Clinical events were uncommon across follow-up: one hepatic decompensation, two HCC, no liver transplants, and one HBV-related deaths, with a composite endpoint rate of 0.61/100 person-years. Incident cirrhosis (n = 1), alanine aminotransferase flare (n = 2), and HBeAg loss (n = 13) rates were 0.40, 0.65, and 6.86 per 100 person-years, respectively. No participants had HBsAg loss. Paired biopsy (n = 62; median 3.6 years apart) revealed minimal improvement in Histologic Activity Index (median [interquartile range]: 3 [2-4] to 3 [1-3]; P = 0.02) and no significant change in fibrosis score (1 [1-2] to 1 [0-3]; P = 0.58).In a North American cohort of adults with HBV-HIV on cART with virological suppression, clinical outcomes and worsening histological disease were uncommon.
Covid-19: Health and social care workers need, want, and deserve reusable FFP3 respirators
Authors: Gillian Christina Higgins, Jasmine Ho, Eleanor Robertson, Niall McLean, Chris Horsley, James Douglas
Journal: BMJ (2021)

Zhang and colleagues argue that single use personal protective equipment (PPE) is crucial for infection control in healthcare settings,1 but reusable options are better for the environment and healthcare systems. Organisations including the British Medical Association and Royal College of Nursing have written to the prime minister demanding FFP3 respirators to protect all healthcare workers against airborne transmission of covid-19.2 The surgical masks commonly provided do not protect staff from SARS-CoV-2 respirable aerosol, produced by breathing, speaking, or coughing.23 At least …
Progressive Multifocal Leukoencephalopathy in a Patient With Progressive Multiple Sclerosis Treated With Ocrelizumab Monotherapy
Authors: Arpan Patel, James Sul, Marc L. Gordon, Jared Steinklein, Shayna Sanguinetti, Bidyut Pramanik, Dushyant Purohit, Vahram Haroutunian, Alex Williamson, Igor Koralnik, Asaff Harel
Journal: JAMA Neurology (2021)

Progressive multifocal leukoencephalopathy (PML) is an opportunistic infection caused by the JC virus that has no proven effective treatment. Although rare cases of PML have occurred with other anti-CD20 therapies, there had been no prior cases associated with ocrelizumab.To report the first ever case of PML occurring with ocrelizumab monotherapy in a patient with progressive multiple sclerosis without prior immunomodulation.This case was reported from an academic medical center. The patient had multiple sclerosis while receiving ocrelizumab monotherapy.Ocrelizumab monotherapy.A 78-year-old man with progressive multiple sclerosis treated with ocrelizumab monotherapy for 2 years presented with 2 weeks of progressive visual disturbance and confusion. Examination demonstrated a right homonymous hemianopia, and magnetic resonance imaging revealed an enlarging nonenhancing left parietal lesion without mass effect. Cerebrospinal fluid revealed 1000 copies/mL of JC virus, confirming the diagnosis of PML. Blood work on diagnosis revealed grade 2 lymphopenia, with absolute lymphocyte count of 710/μL, CD4 of 294/μL (reference range, 325-1251/μL), CD8 of 85/μL (reference range, 90-775/μL), CD19 of 1/μL, preserved CD4/CD8 ratio (3.45), and negative HIV serology. Retrospective absolute lymphocyte count revealed intermittent grade 1 lymphopenia that preceded ocrelizumab (absolute lymphocyte count range, 800-1200/μL). The patient's symptoms progressed over weeks to involve bilateral visual loss, right-sided facial droop, and dysphasia. Ocrelizumab was discontinued and off-label pembrolizumab treatment was initiated. The patient nevertheless declined rapidly and ultimately died. PML was confirmed at autopsy.In this case report, PML occurrence was likely a result of the immunomodulatory function of ocrelizumab as well as age-related immunosenescence. This case report emphasizes the importance of a thorough discussion of the risks and benefits of ocrelizumab, especially in patients at higher risk for infections such as elderly patients.
Biomaterials Discovery: Discovery of a Novel Polymer for Xeno‐Free, Long‐Term Culture of Human Pluripotent Stem Cell Expansion (Adv. Healthcare Mater. 6/2021)
Authors: Aishah Nasir, Jordan Thorpe, Laurence Burroughs, Joris Meurs, Sara Pijuan‐Galito, Derek J. Irvine, Morgan R. Alexander, Chris Denning
Journal: Advanced Healthcare Materials (2021)

In article number 2001448 by Morgan R. Alexander, Chris Denning, and co-workers, a novel substrate for xeno-free human pluripotent stem cell (hPSC) culture is discovered using a highthroughput multigenerational polymer microarray platform approach used to rapidly test over 600 polymers. This nanoscale phase separated blend of poly(tricyclodecane-dimethanol diacrylate) and poly(butyl acrylate) (2:1 v/v) which supports hPSC expansion and differentiation after long-term serial passage can be readily applied to common tissue culture plasticware.
Protocatechuic aldehyde protects cardiomycoytes against ischemic injury via regulation of nuclear pyruvate kinase M2
Authors: Xunxun Wu, Lian Liu, Qiuling Zheng, Haiping Hao, Hui Ye, Ping Li, Hua Yang
Journal: Acta Pharmaceutica Sinica B (2021)

Rescuing cells from stress damage emerges a potential therapeutic strategy to combat myocardial infarction. Protocatechuic aldehyde (PCA) is a major phenolic acid in Chinese herb Danshen (Salvia miltiorrhiza root). This study investigated whether PCA regulated nuclear pyruvate kinase isoform M2 (PKM2) function to protect cardiomyocytes. In rats subjected to isoprenaline, PCA attenuated heart injury and protected cardiomyocytes from apoptosis. Through DARTS and CETSA assays, we identified that PCA bound and promoted PKM2 nuclear translocation in cardiomyocytes exposed to oxygen/glucose deprivation (OGD). In the nucleus, PCA increased the binding of PKM2 to β-catenin via preserving PKM2 acetylation, and the complex, in cooperation with T-cell factor 4 (TCF4), was required for transcriptional induction of genes encoding anti-apoptotic proteins, contributing to rescuing cardiomyocyte survival. In addition, PCA ameliorated mitochondrial dysfunction and prevented mitochondrial apoptosis dependent on PKM2. Consistently, PCA increased the binding of PKM2 to β-catenin, improved heart contractive function, normalized heart structure and attenuated oxidative damage in mice subjected to artery ligation, but the protective effects were lost in Pkm2-deficient heart. Together, we showed that PCA regulated nuclear PKM2 function to rescue cardiomyocyte survival via β-catenin/TCF4 signaling cascade, suggesting the potential of pharmacological intervention of PKM2 shuttle to protect the heart.
Italian Society of Interventional Cardiology ( <scp>GIse</scp> ) registry Of Transcatheter treatment of mitral valve r <scp>egurgitaTiOn</scp> ( <scp>GIOTTO</scp> ): impact of valve disease aetiology and residual mitral regurgitation after <scp>MitraClip</scp> implantation
Authors: Francesco Bedogni, Antonio Popolo Rubbio, Carmelo Grasso, Marianna Adamo, Paolo Denti, Arturo Giordano, Maurizio Tusa, Giovanni Bianchi, Federico De Marco, Antonio L. Bartorelli, Matteo Montorfano, Cosmo Godino, Rodolfo Citro, Francesco De Felice, Annalisa Mongiardo, Ida Monteforte, Emmanuel Villa, Cristina Giannini, Gabriele Crimi, Giuseppe Tarantini, Luca Testa, Corrado Tamburino
Journal: European Journal of Heart Failure (2021)
Clonal Hematopoiesis and JAK2V617F Mutations in Patients With Cardiovascular Disease
Authors: Tetsuro Yokokawa, Tomofumi Misaka, Yusuke Kimishima, Kento Wada, Keiji Minakawa, Takashi Kaneshiro, Akiomi Yoshihisa, Kazuhiko Ikeda, Yasuchika Takeishi
Journal: JACC CardioOncology (2021)
Manganese salts function as potent adjuvants
Authors: Rui Zhang, Chenguang Wang, Yukun Guan, Xiaoming Wei, Mengyin Sha, Mengran Yi, Miao Jing, Mengze Lv, Wen Guo, Jing Xu, Yi Wan, Xin-Ming Jia, Zhengfan Jiang
Journal: Cellular and Molecular Immunology (2021)

Abstract Aluminum-containing adjuvants have been used for nearly 100 years to enhance immune responses in billions of doses of vaccines. To date, only a few adjuvants have been approved for use in humans, among which aluminum-containing adjuvants are the only ones widely used. However, the medical need for potent and safe adjuvants is currently continuously increasing, especially those triggering cellular immune responses for cytotoxic T lymphocyte activation, which are urgently needed for the development of efficient virus and cancer vaccines. Manganese is an essential micronutrient required for diverse biological activities, but its functions in immunity remain undefined. We previously reported that Mn 2+ is important in the host defense against cytosolic dsDNA by facilitating cGAS-STING activation and that Mn 2+ alone directly activates cGAS independent of dsDNA, leading to an unconventional catalytic synthesis of 2′3′-cGAMP. Herein, we found that Mn 2+ strongly promoted immune responses by facilitating antigen uptake, presentation, and germinal center formation via both cGAS-STING and NLRP3 activation. Accordingly, a colloidal manganese salt (Mn jelly, MnJ) was formulated to act not only as an immune potentiator but also as a delivery system to stimulate humoral and cellular immune responses, inducing antibody production and CD4 + /CD8 + T-cell proliferation and activation by either intramuscular or intranasal immunization. When administered intranasally, MnJ also worked as a mucosal adjuvant, inducing high levels of secretory IgA. MnJ showed good adjuvant effects for all tested antigens, including T cell-dependent and T cell-independent antigens, such as bacterial capsular polysaccharides, thus indicating that it is a promising adjuvant candidate.
P79.02 Updated OS and Time to Second Progression with First-Line Camrelizumab Plus Chemo vs Chemo for Advanced Non-Squamous NSCLC
Authors: C. Zhou, G. Chen, Y. Huang, J. Zhou, L. Lin, J. Feng, Z. Wang, Y. Shu, J. Shi, Y. Hu, Q. Wang, Y. Cheng, F. Wu, J. Chen, X. Lin, Y. Wang, J. Huang, J. Cui, L. Cao, Y. Liu, Y. Zhang, Y. Pan, J. Zhao, L. Wang, J. Chang, Q. Chen, X. Ren, W. Zhang, Y. Fan, Z. He, J. Fang, K. Gu, X. Dong, F. Jin, H. Gao, G. An, C. Ding, X. Jiang, J. Xiong, X. Zhou, S. Hu, P. Lu, A. Liu, S. Guo, J. Huang, C. Zhu, J. Zhao, B. Gao, Y. Chen, C. Hu, J. Zhang, H. Zhang, H. Zhao, Y. Zhou, Y. Tai
Journal: Journal of Thoracic Oncology (2021)
The link between COVID-19 and VItamin D (VIVID): A systematic review and meta-analysis
Authors: Aya Bassatne, Maya Basbous, Marlene Chakhtoura, Ola El Zein, Maya Rahme, Ghada El-Hajj Fuleihan
Journal: Metabolism (2021)

Disease severity and mortality rates due to COVID-19 infection are greater in the elderly and chronically ill patients, populations at high risk for vitamin D deficiency. Vitamin D plays an important role in immune function and inflammation. This systematic review and meta-analysis assesses the impact of vitamin D status and supplementation on COVID-19 related mortality and health outcomes.
Cross-resistance and drug sequence in prostate cancer
Authors: Stefan A.J. Buck, Stijn L.W. Koolen, Ron H.J. Mathijssen, Ronald de Wit, Robert J. van Soest
Journal: Drug Resistance Updates (2021)

The treatment landscape of advanced prostate cancer has widely expanded over the past years with androgen receptor signaling inhibitors (ARSIs) and taxane chemotherapy moving to earlier disease stages in the treatment of prostate cancer. With the increasing use of ARSIs in earlier disease stages, cross-resistance between treatments has emerged, which is a dominant impediment in current clinical practice. To overcome cross-resistance in the treatment of prostate cancer, it is of paramount importance to decipher the mechanisms of cross-resistance between ARSIs and between ARSIs and chemotherapy. Here, molecular mechanisms of resistance to the available therapies including androgen receptor (AR) splice variants, AR overexpression, AR mutations and glucocorticoid receptor upregulation are described. Based on these underlying mechanisms, clinical data of cross-resistance between ARSIs and chemotherapy have been reported. Only recently these data have been confirmed in prospective randomized trials. From these studies, it has become clear that sequential ARSI treatment has no place in the treatment of advanced prostate cancer due to emerging drug resistance. In addition, based on prospective evidence, we argue that it is worth considering an early switch to cabazitaxel treatment in case of lack of benefit on docetaxel regimen after an ARSI treatment. Based on these new insights from randomized trials, several recommendations for treatment sequence are proposed.
Molecular modification of a recombinant anti-CD3ε-directed immunotoxin by inducing terminal cysteine bridging enhances anti-GVHD efficacy and reduces organ toxicity in a lethal murine model
Authors: Daniel A. Vallera, David W. Kuroki, Angela Panoskaltsis-Mortari, Donald J. Buchsbaum, Buck E. Rogers, Bruce R. Blazar
Journal: Blood (2000)
P79.04 A Phase 2 Trial of Nivolumab and Temozolomide in Extensive Stage Small Cell Lung Cancer: Interim Efficacy Analysis.
Authors: D. Owen, L. Wei, C. Pilcher, S. Patel, B. Konda, M. Shah, S. Ferguson, B. Benner, R. Norman, W. Carson, M. Smith, S. Mori Vogt, C. Verschraegen, K. He, E. Bertino, C. Presley, P. Shields, D. Carbone, G. Otterson
Journal: Journal of Thoracic Oncology (2021)
Abstract 17038: Influence of Cardiac Workload on Vascular Pyridine Nucleotide Redox State
Authors: Marc Dwenger, Joseph Moore, Matthew A Nystoriak
Journal: Circulation (2020)

Introduction: Myocardial perfusion is enhanced during periods of elevated cardiomyocyte oxygen consumption. The coupling between blood flow and myocardial oxygen demand is mediated by redox-dependent signals, yet the influence of cardiac workload on arterial myocyte pyridine nucleotide redox status is unknown. Hypothesis: Increased cardiac workload acutely alters intramyocardial arterial myocyte [NADH] i :[NAD + ] i . Methods and Results: The genetically-encoded fluorescent biosensor Peredox-mCherry was used to monitor real-time changes in intracellular [NADH] i :[NAD] i in isolated arterial myocytes. Treatment of cells expressing Peredox-mCherry with a range of [lactate] o :[pyruvate] o resulted in significant changes in green (Ex,Em: 400, 510 nm): red (Ex,Em: 585,615 nm) fluorescence ratio (1.903 ± 0.010, 10 mM lactate, 1.072 ± 0.073, 10 mM pyruvate), affording accurate quantification of arterial myocyte [NADH] i :[NAD] i . Increased arterial myocyte [NADH] i :[NAD] i was observed in response to reductions in oxygen tension from 5% (0.0021 ± 0.0001) to 1% (0.0050 ± 0.0001; P&lt;0.05). [NADH] i :[NAD] i was not altered by direct stimulation of arterial myocytes with the beta-adrenergic agonist isoproterenol (1 μM; P = .0630). Furthermore, biosensor-expressing arterial myocytes in co-culture with human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) recapitulated the effects of elevated [lactate] o :[pyruvate] o and reduced oxygen tension, exhibiting frequency-dependent increases in [NADH] i :[NAD] I following electrical pacing (e.g., ~3.3 fold increase in 3 Hz vs. unpaced; P&lt;0.05). Consistent with these results, intramyocardial coronary arteries in mice acutely treated with dobutamine (10 mg/kg, i.p.) to drive high cardiac work exhibited significantly greater lactate:pyruvate ratio, used as a surrogate for [NADH] i :[NAD] i , compared with those in hearts treated with vehicle (3.17 ± 0.23 vs. 2.21 ± 0.11; P&lt;0.05). Conclusions: Our results indicate that acute increases in cardiac workload promote the elevation of [NADH] i :[NAD] i in intramyocardial arterial myocytes.