tbuckley/cabot-search huggingface dataset:
Post-Discharge Bleeding and Mortality Following Acute Coronary Syndromes With or Without PCI
Authors: Guillaume Marquis-Gravel, Frederik Dalgaard, Aaron D. Jones, Yuliya Lokhnygina, Stefan K. James, Robert A. Harrington, Lars Wallentin, Philippe Gabriel Steg, Renato D. Lopes, Robert F. Storey, Shaun G. Goodman, Kenneth W. Mahaffey, Pierluigi Tricoci, Harvey D. White, Paul W. Armstrong, E. Magnus Ohman, John H. Alexander, Matthew T. Roe
Journal: Journal of the American College of Cardiology (2020)
Longevity and replenishment of human liver-resident memory T cells and mononuclear phagocytes
Authors: Laura J. Pallett, Alice R. Burton, Oliver E. Amin, Sergio Rodriguez-Tajes, Amit A. Patel, Nekisa Zakeri, Anna Jeffery-Smith, Leo Swadling, Nathalie M. Schmidt, Anna Baiges, Amir Gander, Dominic Yu, David Nasralla, Farid Froghi, Satheesh Iype, Brian R. Davidson, Douglas Thorburn, Simon Yona, Xavier Forns, Mala K. Maini
Journal: The Journal of Experimental Medicine (2020)

The human liver contains specialized subsets of mononuclear phagocytes (MNPs) and T cells, but whether these have definitive features of tissue residence (long-term retention, lack of egress) and/or can be replenished from the circulation remains unclear. Here we addressed these questions using HLA-mismatched liver allografts to discriminate the liver-resident (donor) from the infiltrating (recipient) immune composition. Allografts were rapidly infiltrated by recipient leukocytes, which recapitulated the liver myeloid and lymphoid composition, and underwent partial reprogramming with acquisition of CD68/CD206 on MNPs and CD69/CD103 on T cells. The small residual pool of donor cells persisting in allografts for over a decade contained CX3CR1hi/CD163hi/CD206hi Kupffer cells (KCs) and CXCR3hi tissue-resident memory T cells (TRM). CD8+ TRM were found in the local lymph nodes but were not detected egressing into the hepatic vein. Our findings inform organ transplantation and hepatic immunotherapy, revealing remarkably long-lived populations of KCs and TRM in human liver, which can be additionally supplemented by their circulating counterparts.
SARS-CoV-2 detection, viral load and infectivity over the course of an infection
Authors: Kieran A. Walsh, Karen Jordan, Barbara Clyne, Daniela Rohde, Linda Drummond, Paula Byrne, Susan Ahern, Paul G. Carty, Kirsty K. O'Brien, Eamon O'Murchu, Michelle O'Neill, Susan M. Smith, Máirín Ryan, Patricia Harrington
Journal: Journal of Infection (2020)
How to Quantify and Interpret Treatment Effects in Comparative Clinical Studies of COVID-19
Authors: Zachary R. McCaw, Lu Tian, Jason L. Vassy, Christine Seel Ritchie, Chien-Chang Lee, Dae Hyun Kim, Lee-Jen Wei
Journal: Annals of Internal Medicine (2020)

Clinical trials of treatments for coronavirus disease 2019 (COVID-19) draw intense public attention. More than ever, valid, transparent, and intuitive summaries of the treatment effects, including efficacy and harm, are needed. In recently published and ongoing randomized comparative trials evaluating treatments for COVID-19, time to a positive outcome, such as recovery or improvement, has repeatedly been used as either the primary or key secondary end point. Because patients may die before recovery or improvement, data analysis of this end point faces a competing risk problem. Commonly used survival analysis techniques, such as the Kaplan-Meier method, often are not appropriate for such situations. Moreover, almost all trials have quantified treatment effects by using the hazard ratio, which is difficult to interpret for a positive event, especially in the presence of competing risks. Using 2 recent trials evaluating treatments (remdesivir and convalescent plasma) for COVID-19 as examples, a valid, well-established yet underused procedure is presented for estimating the cumulative recovery or improvement rate curve across the study period. Furthermore, an intuitive and clinically interpretable summary of treatment efficacy based on this curve is also proposed. Clinical investigators are encouraged to consider applying these methods for quantifying treatment effects in future studies of COVID-19.
Activation of a mitochondrial apoptosis pathway induced by calcitriol in combination with ketoconazole and dexamethasone in human prostate cancer PC-3 cells
Authors: Wei-Dong Yu, Yingyu Ma, Rui-xian Kong, Donald L. Trump, Candace S. Johnson
Journal: Cancer Research (2006)

4041  1,25-dihydroxycholecalciferol (calcitriol) has significant antiproliferative activity in vitro and in vivoin a number of tumor models. We demonstrated that ketoconazole, an inhibitor of CYP24, the enzyme that catalyzes calcitriol catabolism, synergizes with calcitriol and dexamethasone (dex) as measured by the median dose effect using the human prostate cancer PC-3 cell line. This combination also demonstrates significantly greater in vivo activity in the PC-3 model as compared to any agent alone. To examine enhanced apoptotic effects, we examined the caspase-8/caspase-6 and the caspase-9/caspase-3/PARP pathways. Immunoblot analyses show no significant changes in cleavage of caspase-9, caspase-3 and the downstream effector PARP in the cells treated with calcitriol/ketoconazole/dex. Cytochrome c was present in the mitochondria with the combination and each agent alone, however, no cytochrome c was detected in the cytosolic fraction. Increased expression of apoptosis-inducing factor (AIF) was observed when cells were treated with the calcitriol, ketoconazole and dex three -drug combination as compared to any agent alone in both the cytosol and nuclear extract fraction. The release of AIF from the mitochondria without detectable increase in cytosolic cytochrome c suggests that the caspase-9/caspase-3/PARP pathway is not likely involved in apoptosis. Treatment of PC-3 cells with calcitriol/ketoconazole/dex was associated with a significant increase in the cleavage/activation of caspase-8, caspase-6 and cleavage of Bid to form tBid. An increase in cleavage of nuclear lamin A, a major target of caspase-6 was also observed with calcitriol/ketoconazole/dex as compared to any agent alone. In addition, cleavage of nuclear lamin A activated the process of nuclear condensation and apoptosis. Therefore, these data demonstrated the involvement of the mitochondrial apoptosis pathway through over-expression of apoptosis-inducing factor during calcitriol/ketoconazole/dex-induced apoptosis of the PC-3 prostate cancer cell line. This work supported by NIH grants CA67267, CA95045 and CA85142.
Regression Discontinuity Design
Authors: Matthew L. Maciejewski, Anirban Basu
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
Recent insights for the emerging COVID-19: Drug discovery, therapeutic options and vaccine development
Authors: Yuefei Zhu, Jia Li, Zhiqing Pang
Journal: Asian Journal of Pharmaceutical Sciences (2020)

SARS-CoV-2 has been marked as a highly pathogenic coronavirus of COVID-19 disease into the human population, causing over 5.5 million confirmed cases worldwide. As COVID-19 has posed a global threat with significant human casualties and severe economic losses, there is a pressing demand to further understand the current situation and develop rational strategies to contain the drastic spread of the virus. Although there are no specific antiviral therapies that have proven effective in randomized clinical trials, currently, the rapid detection technology along with several promising therapeutics for COVID-19 have mitigated its drastic transmission. Besides, global institutions and corporations have commenced to parse out effective vaccines for the prevention of COVID-19. Herein, the present review will give exhaustive details of extensive researches concerning the drug discovery and therapeutic options for COVID-19 as well as some insightful discussions of the status of COVID-19.
Aldolase B suppresses hepatocellular carcinogenesis by inhibiting G6PD and pentose phosphate pathways
Authors: Min Li, Xuxiao He, Weixing Guo, Hongming Yu, Shicheng Zhang, Ningning Wang, Guijun Liu, Rina Sa, Xia Shen, Yabo Jiang, Yufu Tang, Yujuan Zhuo, Chunzhao Yin, Qiaochu Tu, Nan Li, Xiaoqun Nie, Yu Li, Zhimin Hu, Hanwen Zhu, Jianping Ding, Zi Li, Te Liu, Fan Zhang, He Zhou, Shengxian Li, Jiang Yue, Zheng Yan, Shuqun Cheng, Yongzhen Tao, Huiyong Yin
Journal: Nature Cancer (2020)
Targeting the Notch and TGF-β signaling pathways to prevent retinal fibrosis <i>in vitro</i> and <i>in vivo</i>
Authors: Jiawen Fan, Weiyong Shen, So-Ra Lee, Ashish Easow Mathai, Rui Zhang, Gezhi Xu, Mark C Gillies
Journal: Theranostics (2020)

Rationale: The Notch and transforming growth factor-β (TGFβ) signaling pathways are two intracellular mechanisms that control fibrosis in general but whether they play a major role in retinal fibrosis is less clear. Here we study how these two signaling pathways regulate Müller cell-dominated retinal fibrosis in vitro and in vivo. Methods: Human MIO-M1 Müller cells were treated with Notch ligands and TGFβ1, either alone or in combination. Western blots were performed to study changes in γ-secretase proteases, Notch downstream effectors, endogenous TGFβ1, phosphorylated Smad3 (p-Smad3) and extracellular matrix (ECM) proteins. We also studied the effects of RO4929097, a selective γ-secretase inhibitor, on expression of ECM proteins after ligand stimulation. Müller cell viability was studied by AlamarBlue and cytotoxicity by lactate cytotoxicity assays. Finally, we studied changes in Notch and TGFβ signaling and tested the effect of intravitreal injections of the Notch pathway inhibitor RO4929097 on retinal fibrosis resulted from Sodium iodate (NaIO3)-induced retinal injury in mice. We also studied the safety of intravitreal injections of RO4929097 in normal mice. Results: Treatment of Müller cells with Notch ligands upregulated γ-secretase proteases and Notch downstream effectors, with increased expression of endogenous TGFβ1, TGFβ receptors and p-Smad3. TGFβ1 upregulated the expression of proteins associated with both signaling pathways in a similar manner. Notch ligands and TGFβ1 had additive effects on overexpression of ECM proteins in Müller cells which were inhibited by RO4929097. Notch and TGFβ ligands stimulated Müller cell proliferation which was inhibited by RO4929097 without damaging the cells. NaIO3-induced retinal injury activated both Notch and TGFβ signaling pathways in vivo. Intravitreal injection of RO4929097 prevented Müller cell gliosis and inhibited overexpression of ECM proteins in this murine model. We found no safety concerns for up to 17 days after an intravitreal injection of RO4929097. Conclusions: Inhibiting Notch signaling might be an effective way to prevent retinal fibrosis. This study is of clinical significance in developing a treatment for preventing fibrosis in proliferative vitreoretinopathy, proliferative diabetic retinopathy and wet age-related macular degeneration.
Treatment of HIV-associated primary CNS lymphoma with antiretroviral therapy, rituximab, and high-dose methotrexate
Authors: Kathryn Lurain, Thomas S. Uldrick, Ramya Ramaswami, Mark N. Polizzotto, Priscila H. Goncalves, Anaida Widell, Seth M. Steinberg, Elaine S. Jaffe, Stefania Pittaluga, Hao-Wei Wang, Constance M. Yuan, Mary Anne Tamula, Staci Martin, Pamela L. Wolters, Jomy George, Richard F. Little, Robert Yarchoan
Journal: Blood (2020)
Methotrexate: what are the true risks of treatment?
Authors: Anja Strangfeld, Gerd R Burmester
Journal: Annals of the Rheumatic Diseases (2020)

For more than three decades, low-dose methotrexate (MTX) has been the first-line treatment for patients with rheumatoid arthritis (RA). Even after the introduction of biologics/biosimilars and janus kinase (JAK)-inhibitors, MTX has maintained its importance and is used as a combination partner in the most cases.1 Clinicians are well aware of several toxicities of MTX, including constitutional symptoms (such as nausea and malaise) as well as haematological, gastrointestinal and hepatic adverse events (AEs). In the vast majority of cases, these are clinically manageable.

Despite the extensive use of MTX, we have little information about the magnitude of the adverse effects of MTX compared with placebo because, for ethical reasons, we cannot withhold effective therapy in patients with inflammatory rheumatic diseases for longer periods of time to avoid disease progression and occurrence of further comorbidities. It is therefore of utmost interest that a study has now been published in the Annals of Internal Medicine that has examined the safety profile of MTX compared with placebo in a large group of patients without inflammatory rheumatic disease.2

The Cardiovascular Inflammation Reduction Trial3 (CIRT) was a randomised, double-blind, placebo-controlled trial designed to evaluate the efficacy of MTX (target dose of 15–20 mg weekly) versus placebo in lowering the number of cardiovascular (CV) events. Both arms were carried out in combination with folic acid. Patients enrolled in the trial were required to have severe cardiovascular risks: a known history of myocardial infarction or multivessel obstructive coronary artery disease, in combination with type 2 diabetes or metabolic syndrome. The aim was to evaluate the efficacy of MTX to prevent myocardial infarction, stroke or death due to cardiovascular events. The rationale was based on previous findings in RA that had suggested a lower CV complication rate on MTX therapy.4 5 The CIRT study was terminated …
The regulatory landscape of early maize inflorescence development
Authors: Rajiv K. Parvathaneni, Edoardo Bertolini, Md Shamimuzzaman, Daniel L. Vera, Pei-Yau Lung, Brian R. Rice, Jinfeng Zhang, Patrick J. Brown, Alexander E. Lipka, Hank W. Bass, Andrea L. Eveland
Journal: Genome biology (2020)

The functional genome of agronomically important plant species remains largely unexplored, yet presents a virtually untapped resource for targeted crop improvement. Functional elements of regulatory DNA revealed through profiles of chromatin accessibility can be harnessed for fine-tuning gene expression to optimal phenotypes in specific environments.Here, we investigate the non-coding regulatory space in the maize (Zea mays) genome during early reproductive development of pollen- and grain-bearing inflorescences. Using an assay for differential sensitivity of chromatin to micrococcal nuclease (MNase) digestion, we profile accessible chromatin and nucleosome occupancy in these largely undifferentiated tissues and classify at least 1.6% of the genome as accessible, with the majority of MNase hypersensitive sites marking proximal promoters, but also 3' ends of maize genes. This approach maps regulatory elements to footprint-level resolution. Integration of complementary transcriptome profiles and transcription factor occupancy data are used to annotate regulatory factors, such as combinatorial transcription factor binding motifs and long non-coding RNAs, that potentially contribute to organogenesis, including tissue-specific regulation between male and female inflorescence structures. Finally, genome-wide association studies for inflorescence architecture traits based solely on functional regions delineated by MNase hypersensitivity reveals new SNP-trait associations in known regulators of inflorescence development as well as new candidates.These analyses provide a comprehensive look into the cis-regulatory landscape during inflorescence differentiation in a major cereal crop, which ultimately shapes architecture and influences yield potential.
Atopic dermatitis displays stable and dynamic skin transcriptome signatures
Authors: Lena Möbus, Elke Rodriguez, Inken Harder, Dora Stölzl, Nicole Boraczynski, Sascha Gerdes, Andreas Kleinheinz, Susanne Abraham, Annice Heratizadeh, Christiane Handrick, Eva Haufe, Thomas Werfel, Jochen Schmitt, Stephan Weidinger
Journal: Journal of Allergy and Clinical Immunology (2020)
Circulating IL‐4, IFNγ and IL‐17 conventional and Innate‐like T‐cell producers in adult asthma
Authors: Maria Leite‐de‐Moraes, Renata Belo, Céline Dietrich, David Soussan, Michel Aubier, Marina Pretolani
Journal: Allergy (2020)

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Increased Platelet Aggregation in Children and Adolescents with Sleep-disordered Breathing
Authors: Anna Kontos, Scott Willoughby, Kurt Lushington, James Martin, David Wabnitz, Jill Dorrian, Declan Kennedy
Journal: American Journal of Respiratory and Critical Care Medicine (2020)

Rationale: Sleep-disordered breathing (SDB) is associated with increased vascular resistance in children and adults. Persistent increased vascular resistance damages vascular endothelial cells—a marker of which is increased platelet activation.Objectives: This study compared whole-blood impedance platelet aggregation in children with clinically diagnosed SDB warranting adenotonsillectomy and healthy control subjects.Methods: Thirty children who had SDB warranting intervention clinically diagnosed by experienced pediatric otolaryngologists were recruited from adenotonsillectomy waitlists, and 20 healthy children from the community underwent overnight polysomnography to determine SDB severity (obstructive apnea–hypopnea index). Snoring frequency was collected from parents. In the morning, a fasting blood sample was taken, and whole-blood platelet aggregation was measured.Measurements and Main Results: Children with SDB exhibited increased platelet aggregation to TRAP (thrombin receptor-activating peptide) (children with SDB = 114.8 aggregation units [AU] vs. control subjects = 98.0 AU; P < 0.05) and COL antibody (96.7 vs. 82.2 AU; P < 0.05) and an increased trend in ADP antibody (82.3 vs. 69.2 AU; P < 0.07) but not aspirin dialuminate (82.1 vs. 79.5 AU; P > 0.05). No significant association was observed between either the obstructive apnea–hypopnea index and any aggregation parameter, but parental report of snoring was positively associated with TRAP aggregation (Kendall's τ-c = 0.23; P < 0.05).Conclusions: The finding of increased platelet aggregation is consistent with endothelial damage. This suggests that the profile of cardiovascular changes noted in adults with SDB may also occur in children with SDB.
Angiotensin-(1-7) inhibits the growth of human triple negative breast tumors in an orthotopic model
Authors: David Soto-Pantoja, Jyotsana Menon, Patricia Gallagher, E. Ann Tallant
Journal: Cancer Research (2008)

2416  Triple negative breast tumors are an aggressive form of breast cancer that predominantly affects young African-American and Hispanic women with lower socio-economic status. This form of breast cancer is correlated with a poor survival rate regardless of stage at diagnosis due to development of distant metastases. Triple negative tumors lack estrogen and progesterone receptors and have normal expression of the human epidermal growth factor receptor HER2 (ERBB2), severely limiting the therapeutic strategy for treatment. The purpose of this study was to determine whether angiotensin-(1-7) [Ang-(1-7)], an endogenous peptide hormone that activates the AT(1-7) receptor mas, can be used as a targeted chemotherapeutic agent in the treatment of triple negative breast cancer. Ang-(1-7) significantly inhibited the growth of MDA-MB-231 cells, a triple negative breast cancer cell line. More importantly, the heptapeptide significantly reduced the proliferation of human triple negative breast tumor growth in vivo, using an orthotopic model. Athymic mice with tumors resulting from injection of human MDA-MB-231 cells in the mammary fat pads were treated for 28 days with either saline or 1000 μg/kg Ang-(1-7), delivered by subcutaneous injection every 12 h. The average volume of the tumors from mice treated with the heptapeptide was approximately 3-fold less than the size of the tumors from control animals (170.8 ± 21.4 mm3 versus 546.7 ± 87.9 mm3; n = 5, p
Risk stratification in chronic hepatitis B patients for hepatocellular carcinoma surveillance: management in migrant sub-Saharan African populations
Authors: Zillah Cargill, Sarah E Brown, Geoff Dusheiko, Kosh Agarwal
Journal: Gut (2020)

We read with interest the paper by Zeng et al ,1 which provides a timely contribution to the ongoing debate on stratification and intensity of hepatocellular carcinoma (HCC) surveillance. The authors highlight the important need to identify patients with chronic hepatitis B (CHB) at high risk to prioritise HCC surveillance, not only during the waiting list disruption brought by the global COVID-19 pandemic, but also to improve surveillance strategies in the future and optimise patient uptake.

Surveillance for HCC is typically centred on a relatively imprecise clinical evidence base, reflected in the discrepancies observed between international guidelines. As these indices differ on how risk should be determined, there are significant implications for healthcare resources and the cost-effectiveness of CHB surveillance programmes. Thus, a large excess of hepatic imaging is undertaken, limiting the cost-effectiveness …
Molecular mechanisms of human herpes viruses inferring with host immune surveillance
Authors: Simon Jasinski-Bergner, Ofer Mandelboim, Barbara Seliger
Journal: Journal for ImmunoTherapy of Cancer (2020)

Several human herpes viruses (HHVs) exert oncogenic potential leading to malignant transformation of infected cells and/or tissues. The molecular processes induced by viral-encoded molecules including microRNAs, peptides, and proteins contributing to immune evasion of the infected host cells are equal to the molecular processes of immune evasion mediated by tumor cells independently of viral infections. Such major immune evasion strategies include (1) the downregulation of proinflammatory cytokines/chemokines as well as the induction of anti-inflammatory cytokines/chemokines, (2) the downregulation of major histocompatibility complex (MHC) class Ia directly as well as indirectly by downregulation of the components involved in the antigen processing, and (3) the downregulation of stress-induced ligands for activating receptors on immune effector cells with NKG2D leading the way. Furthermore, (4) immune modulatory molecules like MHC class Ib molecules and programmed cell death1 ligand 1 can be upregulated on infections with certain herpes viruses. This review article focuses on the known molecular mechanisms of HHVs modulating the above-mentioned possibilities for immune surveillance and even postulates a temporal order linking regular tumor immunology with basic virology and offering putatively novel insights for targeting HHVs.