tbuckley/cabot-search huggingface dataset:
NFATc1 signaling drives chronic ER stress responses to promote NAFLD progression
Authors: Muhammad Umair Latif, Geske Elisabeth Schmidt, Sercan Mercan, Raza Rahman, Christine Silvia Gibhardt, Ioana Stejerean-Todoran, Kristina Reutlinger, Elisabeth Hessmann, Shiv K Singh, Abdul Moeed, Abdul Rehman, Umer Javed Butt, Hanibal Bohnenberger, Philipp Stroebel, Sebastian Christopher Bremer, Albrecht Neesse, Ivan Bogeski, Volker Ellenrieder
Journal: Gut (2022)

Objectives Non-alcoholic fatty liver disease (NAFLD) can persist in the stage of simple hepatic steatosis or progress to steatohepatitis (NASH) with an increased risk for cirrhosis and cancer. We examined the mechanisms controlling the progression to severe NASH in order to develop future treatment strategies for this disease. Design NFATc1 activation and regulation was examined in livers from patients with NAFLD, cultured and primary hepatocytes and in transgenic mice with differential hepatocyte-specific expression of the transcription factor ( Alb-cre, NFATc1 c.a . and NFATc1 Δ/Δ ). Animals were fed with high-fat western diet (WD) alone or in combination with tauroursodeoxycholic acid (TUDCA), a candidate drug for NAFLD treatment. NFATc1-dependent ER stress-responses, NLRP3 inflammasome activation and disease progression were assessed both in vitro and in vivo. Results NFATc1 expression was weak in healthy livers but strongly induced in advanced NAFLD stages, where it correlates with liver enzyme values as well as hepatic inflammation and fibrosis. Moreover, high-fat WD increased NFATc1 expression, nuclear localisation and activation to promote NAFLD progression, whereas hepatocyte-specific depletion of the transcription factor can prevent mice from disease acceleration. Mechanistically, NFATc1 drives liver cell damage and inflammation through ER stress sensing and activation of the PERK-CHOP unfolded protein response (UPR). Finally, NFATc1-induced disease progression towards NASH can be blocked by TUDCA administration. Conclusion NFATc1 stimulates NAFLD progression through chronic ER stress sensing and subsequent activation of terminal UPR signalling in hepatocytes. Interfering with ER stress-responses, for example, by TUDCA, protects fatty livers from progression towards manifest NASH.
Mechanistic convergence of the TIGIT and PD-1 inhibitory pathways necessitates co-blockade to optimize anti-tumor CD8+ T cell responses
Authors: Karl L. Banta, Xiaozheng Xu, Avantika S. Chitre, Amelia Au-Yeung, Chikara Takahashi, William E. O’Gorman, Thomas D. Wu, Stephanie Mittman, Rafael Cubas, Laetitia Comps-Agrar, Amit Fulzele, Eric J. Bennett, Jane L. Grogan, Enfu Hui, Eugene Y. Chiang, Ira Mellman
Journal: Immunity (2022)

Dual blockade of the PD-1 and TIGIT coinhibitory receptors on T cells shows promising early results in cancer patients. Here, we studied the mechanisms whereby PD-1 and/or TIGIT blockade modulate anti-tumor CD8+ T cells. Although PD-1 and TIGIT are thought to regulate different costimulatory receptors (CD28 and CD226), effectiveness of PD-1 or TIGIT inhibition in preclinical tumor models was reduced in the absence of CD226. CD226 expression associated with clinical benefit in patients with non-small cell lung carcinoma (NSCLC) treated with anti-PD-L1 antibody atezolizumab. CD226 and CD28 were co-expressed on NSCLC infiltrating CD8+ T cells poised for expansion. Mechanistically, PD-1 inhibited phosphorylation of both CD226 and CD28 via its ITIM-containing intracellular domain (ICD); TIGIT's ICD was dispensable, with TIGIT restricting CD226 co-stimulation by blocking interaction with their common ligand PVR (CD155). Thus, full restoration of CD226 signaling, and optimal anti-tumor CD8+ T cell responses, requires blockade of TIGIT and PD-1, providing a mechanistic rationale for combinatorial targeting in the clinic.
A comprehensive assessment of long-term SARS-CoV-2–specific adaptive immune memory in convalescent COVID-19 Solid Organ Transplant recipients
Authors: Alexandre Favà, Laura Donadeu, Thomas Jouve, José Gonzalez-Costello, Laura Lladó, Carolina Santana, Néstor Toapanta, Manuel Lopez, Vincent Pernin, Carme Facundo, Nuria Serra Cabañas, Olivier Thaunat, Marta Crespo, Laura Llinàs-Mallol, Ignacio Revuelta, Nuria Sabé, Alexander Rombauts, Laura Calatayud, Carmen Ardanuy, Juliana Esperalba, Candela Fernandez, Juan J. Lozano, Rosemarie Preyer, Kevin Strecker, Carlos Couceiro, Elena García-Romero, Alba Cachero, Maria Meneghini, Alba Torija, Moglie Le Quintrec, Edoardo Melilli, Josep Maria Cruzado, Carolina Polo, Francesc Moreso, Elena Crespo, Oriol Bestard
Journal: Kidney International (2022)
IST HYBRID ABLATION IMPACT ON QUALITY OF LIFE, ANXIETY, AND DEPRESSION
Authors: Rishi Ajeet Charate, Adnan Ahmed, Dhanunjaya R. Lakkireddy, Jalaj Garg, Ahmed Romeya, Peter Hong-Sik Park, Rangarao V. Tummala, Scott Koerber, Chandrasekhar R. Vasamreddy, Alap P. Shah, Poojita Shivamurthy, Donita Atkins, Sudharani Bommana, Luigi Di Biase, Amin Al-Ahmad, Andrea Natale, Rakesh Gopinathannair, Carlo DeAsmundis, Mark LaMeier, Justin Vanmeeteren, Yashi Awasthi, Frazier Ken
Journal: Journal of the American College of Cardiology (2022)
NATRIURESIS IS LOWER IN BLACK PATIENTS WITH ACUTE HEART FAILURE: A POST HOC ANALYSIS OF ROSE-AHF
Authors: Jeffrey Wang, Yuxuan Chen, Alexis K. Okoh, Apoorva Gangavelli, Aditi Nayak, Rebecca S. Steinberg, Tola Ebunlomo, Krishan Patel, Yi-An Ko, Jeffrey M. Testani, Alanna A. Morris
Journal: Journal of the American College of Cardiology (2022)
COMPARISON OF ANGIOGRAPHIC/FLOW-DERIVED PRESSURE GRADIENTS ACROSS CORONARY STENOSES COMPARED TO PRESSURE-WIRE DERIVED GRADIENTS-AN UPDATED SYSTEMATIC REVIEW AND META-ANALYSIS
Authors: Rebecca Easly-Merski, Debabrata Mukherjee, Vladimir Lakhter, Shengxian Tu, Saurav Chatterjee
Journal: Journal of the American College of Cardiology (2022)
HEALTH STATUS IN PATIENTS WITH ATTR CARDIAC AMYLOIDOSIS RECEIVING TAFAMIDIS: RESPONDER ANALYSES FROM ATTR-ACT
Authors: Brett Wesley Sperry, Mazen A. Hanna, Jose Nativi-Nicolau, Mathew S. Maurer, Michelle Stewart, Kathleen Wyrwich, Alexandra Barsdorf, Heli Kapadia, Libby Floden, John A. Spertus
Journal: Journal of the American College of Cardiology (2022)
Regulatory guidelines and preclinical tools to study the biodistribution of RNA therapeutics
Authors: P. Vervaeke, S.E. Borgos, N.N. Sanders, F. Combes
Journal: Advanced Drug Delivery Reviews (2022)

The success of the messenger RNA-based COVID-19 vaccines of Moderna and Pfizer/BioNTech marks the beginning of a new chapter in modern medicine. However, the rapid rise of mRNA therapeutics has resulted in a regulatory framework that is somewhat lagging. The current guidelines either do not apply, do not mention RNA therapeutics, or do not have widely accepted definitions. This review describes the guidelines for preclinical biodistribution studies of mRNA/siRNA therapeutics and highlights the relevant differences for mRNA vaccines. We also discuss the role of in vivo RNA imaging techniques and other assays to fulfill and/or complement the regulatory requirements. Specifically, quantitative whole-body autoradiography, microautoradiography, mass spectrometry-based assays, hybridization techniques (FISH, bDNA), PCR-based methods, in vivo fluorescence imaging, and in vivo bioluminescence imaging, are discussed. We conclude that this new and rapidly evolving class of medicines demands a multi-layered approach to fully understand its biodistribution and in vivo characteristics.
AMC-070: Lenalidomide Is Safe and Effective in HIV-Associated Kaposi Sarcoma
Authors: Erin G. Reid, Kelly Shimabukuro, Page Moore, Richard F. Ambinder, Jack D. Bui, Semi Han, Otoniel Martínez-Maza, Dirk P. Dittmer, David Aboulafia, Elizabeth Yu Chiao, Toby Maurer, Robert Baiocchi, Ronald Mitsuyasu, William Wachsman
Journal: Clinical Cancer Research (2022)

Abstract Purpose: Kaposi sarcoma (KS), an endothelial cell tumor associated with KS herpesvirus (KSHV), remains among the most common malignancies occurring with HIV infection (HIV-KS). As an oral anti-inflammatory, antiangiogenic, and immunomodulatory agent, lenalidomide is potentially an attractive alternative to standard chemotherapy for KS. Experimental Design: The primary objectives of this phase I/II trial were to determine the maximum tolerated dose (MTD) and response rates for lenalidomide in HIV-KS. Secondary objectives included correlating response with natural killer (NK) and T-cell subsets, plasma cytokines, viral copy number, and KSHV gene expression in biopsies. Four dose levels of oral lenalidomide taken 21 consecutive days of 28-day cycles were evaluated in adults with HIV-KS on antiretroviral therapy with controlled viremia. Results: Fifteen and 23 participants enrolled in phases I and II, respectively, 76% of whom had received prior KS therapy. The MTD was not reached, declaring 25 mg as the recommended phase II dose (RP2D). The most frequent adverse events were neutropenia, fatigue, leukopenia, and diarrhea. Of the 25 evaluable participants receiving RP2D, 60% responded. Correlative studies performed in a subset of participants demonstrated a significant increase in proportions of blood T cells with T-regulatory phenotype, and plasma cytokines trended toward a less inflammatory pattern. Clinical response was associated with loss of KSHV transcription. Conclusions: Lenalidomide is active in HIV-KS. The most common adverse events were manageable. With 60% of participants receiving RP2D obtaining a partial response and &amp;lt;10% discontinuing due to adverse events, the response and tolerability to lenalidomide support its use in HIV-KS. See related commentary by Henry and Maki, p. 2485
Global evidence of expressed sentiment alterations during the COVID-19 pandemic
Authors: Jianghao Wang, Yichun Fan, Juan Palacios, Yuchen Chai, Nicolas Guetta-Jeanrenaud, Nick Obradovich, Chenghu Zhou, Siqi Zheng
Journal: Nature Human Behaviour (2022)

The COVID-19 pandemic has created unprecedented burdens on people's physical health and subjective well-being. While countries worldwide have developed platforms to track the evolution of COVID-19 infections and deaths, frequent global measurements of affective states to gauge the emotional impacts of pandemic and related policy interventions remain scarce. Using 654 million geotagged social media posts in over 100 countries, covering 74% of world population, coupled with state-of-the-art natural language processing techniques, we develop a global dataset of expressed sentiment indices to track national- and subnational-level affective states on a daily basis. We present two motivating applications using data from the first wave of COVID-19 (from 1 January to 31 May 2020). First, using regression discontinuity design, we provide consistent evidence that COVID-19 outbreaks caused steep declines in expressed sentiment globally, followed by asymmetric, slower recoveries. Second, applying synthetic control methods, we find moderate to no effects of lockdown policies on expressed sentiment, with large heterogeneity across countries. This study shows how social media data, when coupled with machine learning techniques, can provide real-time measurements of affective states. Using tweets in over 100 countries, Wang et al. examine evidence of global sentiment during the COVID-19 pandemic. They find that COVID-19 outbreaks caused a decline in sentiment worldwide, and the effects of lockdowns differed across countries.
Reply
Authors: Johanna M. Kroese, Bernd W. Brandt, Mark J. Buijs, Wim Crielaard, Frank Lobbezoo, Bruno G. Loos, Egija Zaura, Laurette van Boheemen, Dirkjan van Schaardenburg, Catherine M. C. Volgenant
Journal: Arthritis & Rheumatology (2022)
Host immune responses and possible therapeutic targets for viral respiratory tract infections in susceptible populations: a narrative review
Authors: Paraskevi C. Fragkou, Charalampos D. Moschopoulos, Rieke Reiter, Thilo Berger, Chrysanthi Skevaki
Journal: Clinical Microbiology and Infection (2022)

Respiratory viruses are associated with significant global morbidity and mortality, as well as socioeconomic factors. Certain conditions and patient groups are more susceptible to develop severe viral respiratory tract infections (RTIs).To summarise the data on deregulated immune pathways that have been associated with increased susceptibility to severe viral RTIs in certain populations. We also describe the commonalities of the defective immune pathways across these susceptible populations that may represent possible targets for future therapeutic or preventative approaches.We conducted free searches in Medline, Scopus, and Google Scholar for studies focusing on potential mechanisms of immune dysfunction that may be associated with severe viral RTIs in susceptible populations with conditions including pregnancy, obesity, diabetes mellitus, hypertension, cardiovascular disease, asthma, chronic obstructive pulmonary disease (COPD), chronic kidney disease, and extremes of age. We considered preclinical/animal data, original human studies, and reviews.Innate and adaptive immune responses become quantitatively and qualitatively compromised in aging, obesity, and diabetes mellitus, with the most pronounced changes affecting T cells. Moreover, immune dysregulation by the so-called inflamm-aging results in chronic low-grade inflammation in such conditions. Increased leptin levels affect the immune system particularly in obesity, while leptin dysregulation plays a role in asthma and COPD pathogenesis. Deficient production of interferon (IFN) type I and III in response to rhinovirus contributes to asthma exacerbations. Similar attenuation of IFN production in response to influenza and rhinovirus has been documented in pregnancy. Dampened type I IFN responses have also been found in diet-induced obese mice and in obese individuals.Immunosenescence and chronic low-grade inflammation accompanying aging and a variety of chronic conditions, such as diabetes, obesity, asthma, COPD, chronic renal disease, and hypertension, contribute to the poor outcomes observed following viral respiratory infections. Commonly affected pathways may represent potential future therapeutic targets.
Increased cadmium inhalation as a possible explanation for an increased risk of rheumatoid arthritis development: comment on the article by Okamoto et al
Authors: David G. Hutchinson
Journal: Arthritis & Rheumatology (2022)

Disclosure Form Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
On-demand assembly of polymeric nanoparticles for longer-blood-circulation and disassembly in tumor for boosting sonodynamic therapy
Authors: Mei Wen, Nuo Yu, Shiwen Wu, Mengmeng Huang, Pu Qiu, Qian Ren, Meifang Zhu, Zhigang Chen
Journal: Bioactive Materials (2022)

Sonodynamic therapy (SDT) is one of the promising strategies for tumor therapy, but its application is usually hindered by fast clearance in blood-circulation, abnormal tumor microenvironment, and inefficient generation of reactive oxygen species. To solve these problems, we proposed an on-demand assembly-disassembly strategy, where the assembly is favorable for longer-blood-circulation and then the disassembly in tumor is favorable for boosting SDT. Hematoporphyrin monomethyl ether (HMME) as the model of organic sonosensitizers were conjugated with hyaluronic acid (HA). Then HA-HMME was mixed with catalase (CAT) and assembled into polymeric nanoparticles (CAT@HA-HMME NPs) with size of ∼80 nm. CAT@HA-HMME NPs exhibit good biocompatibility and a longer blood half-time (t1/2 = 4.17 h) which is obviously longer than that (∼0.82 h) of HMME molecules. After HA receptor-mediated endocytosis of cancer cells, CAT@HA-HMME NPs can be cleaved by endogenous hyaluronidase, resulting in the on-demand disassembly in tumor to release HA-HMME molecules and CAT. The CAT catalyzes the endogenous H2O2 into O2 to relieve the hypoxic microenvironment, and the released HA-HMME exhibits a higher ROS generation ability, greatly boosting SDT for the inhibition of tumor growth. Therefore, the on-demand assembly-disassembly strategy may provide some insight in the design and development of nanoagents for tumor therapy.
Multi-scale Pan-cancer Integrative Analyses Identify the STAT3-VSIR Axis as a Key Immunosuppressive Mechanism in Head and Neck Cancer
Authors: Ramachandra Katabathula, Peronne Joseph, Salendra Singh, Songzhu Zhao, Bhavna Kumar, Patricia Gaule, Quintin Pan, Matthew Old, David P. Tuck, Vinay Varadan
Journal: Clinical Cancer Research (2021)

VSIR is a novel immune checkpoint protein whose expression on tumor cells across cancers remains largely uncharacterized. Here we purposed to decode the pan-cancer biologic and clinical significance of VSIR overexpression in the tumor compartment.We performed multi-omics integrative analyses of 9,735 tumor samples to identify cancers with non-leukocytic expression of VSIR (VSIR High), followed by association with overall survival and immune cell infiltration levels. Orthogonal assessments of VSIR protein expression and lymphocytic infiltration were performed using quantitative immunofluorescence (QIF).Integrative modeling identified a subset of cancer types as being enriched for VSIR High tumors. VSIR High tumors were associated with significantly poorer overall survival in immunogenic ovarian serous adenocarcinoma (SA) and oral cavity squamous cell carcinoma (SCC). QIF assessments in an independent validation cohort confirmed overexpression of VSIR as being associated with poorer overall survival within immunogenic oral cavity SCC. VSIR overexpression was associated with lower CD4 helper T-cell infiltration in both ovarian SA and oral cavity SCC, but did not impact CD8 T-cell infiltration. VSIR overexpressing tumors in both cancer types exhibited significantly higher STAT3 signaling activity. Pharmacologic inhibition of STAT3 signaling resulted in dose-dependent reduction of VSIR expression in ovarian SA and oral cavity SCC cells.The STAT3-VSIR axis is a potentially significant immunomodulatory mechanism in oral cavity and ovarian cancers, whose activation is associated with poorer survival and an immune microenvironment marked by decreased CD4 helper T-cell activity. The role of VSIR as a tumor-intrinsic modulator of resistance to immunotherapy warrants further exploration.
AORTIC VALVE REPLACEMENT (AVR) IN A PATIENT WITH SEVERE AORTIC REGUGITATION (AR) AND LV DYSFUNCTION WITH DOUBLE AORTIC ARCH (DAA)
Authors: Prashant Tarakant Upasani, Jeewan Pillai, Gouri Garg, Syead Ameer Ahmed, Sameer Gupta, Purshotam Lal
Journal: Journal of the American College of Cardiology (2022)
Shorter Treatment for Nonsevere Tuberculosis in African and Indian Children
Authors: Anna Turkova, Genevieve H. Wills, Eric Wobudeya, Chishala Chabala, Megan Palmer, Aarti Kinikar, Syed Hissar, Louise Choo, Philippa Musoke, Veronica Mulenga, Vidya Mave, Bency Joseph, Kristen LeBeau, Margaret J. Thomason, Robert B. Mboizi, Monica Kapasa, Marieke M. van der Zalm, Priyanka Raichur, Perumal K. Bhavani, Helen McIlleron, Anne-Marie Demers, Rob Aarnoutse, James Love-Koh, James A. Seddon, Steven B. Welch, Stephen M. Graham, Anneke C. Hesseling, Diana M. Gibb, Angela M. Crook
Journal: New England Journal of Medicine (2022)

Two thirds of children with tuberculosis have nonsevere disease, which may be treatable with a shorter regimen than the current 6-month regimen.We conducted an open-label, treatment-shortening, noninferiority trial involving children with nonsevere, symptomatic, presumably drug-susceptible, smear-negative tuberculosis in Uganda, Zambia, South Africa, and India. Children younger than 16 years of age were randomly assigned to 4 months (16 weeks) or 6 months (24 weeks) of standard first-line antituberculosis treatment with pediatric fixed-dose combinations as recommended by the World Health Organization. The primary efficacy outcome was unfavorable status (composite of treatment failure [extension, change, or restart of treatment or tuberculosis recurrence], loss to follow-up during treatment, or death) by 72 weeks, with the exclusion of participants who did not complete 4 months of treatment (modified intention-to-treat population). A noninferiority margin of 6 percentage points was used. The primary safety outcome was an adverse event of grade 3 or higher during treatment and up to 30 days after treatment.From July 2016 through July 2018, a total of 1204 children underwent randomization (602 in each group). The median age of the participants was 3.5 years (range, 2 months to 15 years), 52% were male, 11% had human immunodeficiency virus infection, and 14% had bacteriologically confirmed tuberculosis. Retention by 72 weeks was 95%, and adherence to the assigned treatment was 94%. A total of 16 participants (3%) in the 4-month group had a primary-outcome event, as compared with 18 (3%) in the 6-month group (adjusted difference, -0.4 percentage points; 95% confidence interval, -2.2 to 1.5). The noninferiority of 4 months of treatment was consistent across the intention-to-treat, per-protocol, and key secondary analyses, including when the analysis was restricted to the 958 participants (80%) independently adjudicated to have tuberculosis at baseline. A total of 95 participants (8%) had an adverse event of grade 3 or higher, including 15 adverse drug reactions (11 hepatic events, all but 2 of which occurred within the first 8 weeks, when the treatments were the same in the two groups).Four months of antituberculosis treatment was noninferior to 6 months of treatment in children with drug-susceptible, nonsevere, smear-negative tuberculosis. (Funded by the U.K. Medical Research Council and others; SHINE ISRCTN number, ISRCTN63579542.).
LARGE VENTRICULAR SEPTAL DEFECT AS COMPLICATION OF MYOCARDIAL INFARCTION: A TALE OF LIMITED TRANSITIONS
Authors: Ali-Reza Ghergherehchi, Adesola Adenegan, Krishna Pabba, Daniel Lincoln Beckles, Ramachandra C. Reddy, Angel Eduardo Caldera, Amber Malhotra, Giuseppe Tavilla, Subbareddy Konda, Jaime Hernandez-Montfort
Journal: Journal of the American College of Cardiology (2022)
IMPACT OF EARLY USE RENIN-ANGIOTENSIN SYSTEM BLOCKERS ON IN-HOSPITAL OUTCOMES OF ACUTE MYOCARDIAL INFARCTION AMONG PATIENTS WITH SYSTOLIC BLOOD PRESSURE UNDER 100 MMHG AND UNDERGOING PERCUTANEOUS CORONARY INTERVENTION: FINDINGS FROM CCC-ACS PROJECT
Authors: Guanqi Zhao, Ge Wang, Changsheng Ma, Junbo Ge, Yong Huo, Yongchen Hao, Jun Liu, Jing Liu, Dong Zhao, Yaling Han, Shaoping Nie
Journal: Journal of the American College of Cardiology (2022)
USE OF THE OPTIMAL MEDICAL THERAPY SCORE FOR HEART FAILURE WITH REDUCED EJECTION FRACTION AFTER HOSPITALIZATIONS IN A LOW-INCOME NATION
Authors: Edisson Apolinar Feliz Perez, Jenniffer Mateo, Samuel Gabino Guzman, Pedro De Jesus Pallero, Angelica Rumardo, Larissa Romero, Cesar J. Herrera
Journal: Journal of the American College of Cardiology (2022)
CLINICAL OUTCOMES OF REVASCULARIZATION STRATEGY WITH PERCUTANEOUS CORONARY INTERVENTION (PCI) PRIOR TO TRANSCATHETER AORTIC VALVE REPLACEMENT (TAVR): A COMPREHENSIVE META-ANALYSIS
Authors: Ahmed Altibi, Fares H. Ghanem, Faris Hammad, Vijay K. Ramu, Gurion Lantz, Howard K. Song, Harsh Golwala, Firas E. Zahr, Hind Rahmouni
Journal: Journal of the American College of Cardiology (2022)