tbuckley/cabot-search huggingface dataset:
Reply: How does bile acid–induced IRF3 phosphorylation mediate cholestatic liver and kidney injury?—More needs to be known
Authors: Yuan Zhuang, Gyongyi Szabo
Journal: Hepatology (2024)

We have read with great interest the Letter to the Editor from Yang and colleagues and appreciate their comments. In our publication, we showed that interferon regulatory factor 3 (IRF3) phosphorylation occurs in various cell types following in vitro bile acids treatment. Specifically, we observed that IRF3 deficiency in primary hepatocytes and bone marrow-derived macrophages leads to reduced cell death after bile acids treatment. However, to develop more precise therapeutic strategies for cholestatic liver diseases, we agree that it will be desirable to specify the cell type in which IRF3 deficiency alleviates cholestasis-induced liver and kidney injury. We believe this could be elucidated further by using conditional knockout mice in future studies. Our group previously demonstrated that IRF3 regulates apoptosis in hepatocytes via interacting with Bax following ethanol administration.1 Additionally, IRF3 mediates mitochondria-associated apoptosis depending on its ubiquitination status.2 However, we found no evidence for increased IRF3 ubiquitination in the cholestatic liver disease model at least 14 days after bile duct ligation. In the context of cholestasis, it is possible that multiple cell death pathways are activated. Furthermore, we did not rule out the possibility of interaction between IRF3-Bax. We observed apoptosis, necroptosis, and pyroptosis in the liver of cholestatic mice and human patients. Therefore, we believe IRF3-Z-DNA binding protein 1 (ZBP1) axis is the novel mechanism to explain the critical role of IRF3 in cholestasis. We acknowledge that the role of ZBP1 needs further investigation at the molecular level, particularly a cell-specific role in regulating cell death and inflammation. Our observations indicate that IRF3-ZBP1 axis exists in hepatocytes and bone marrow-derived macrophages. Recent studies have highlighted the vital role of ZBP1 in regulating cell death and inflammation under various pathological conditions, such as heatstroke inflammatory and infectious diseases.3,4 Moreover, ZBP1-mediated PANoptosis contributes to the elimination of infected cells and tumor cells as well as induces a strong inflammatory response that leads to immunopathology.4 Hence, we believe future studies could use conditional knockout mice to understand ZBP1's cell-specific role in cholestasis. We agree that the cell-specific role of IRF3-ZBP1 in contribution to cholestasis-induced liver and kidney injury remains to be further investigated. Our study provides an initial understanding of the IRF3-ZBP1 axis in hepatocytes and bone marrow-derived macrophages, and future studies can build on this knowledge to further explore knowledge toward developing therapeutic targets.
Continuous home terlipressin infusion increases handgrip strength and reduces ascites—A prospective randomized crossover study
Authors: Ryma Terbah, Adam G. Testro, Rudolf Hoermann, Avik Majumdar, Brooke Chapman, Paul J. Gow, Marie Sinclair
Journal: Hepatology (2024)

Observational studies suggest a beneficial effect of continuous terlipressin infusion (CTI) on ascites and sarcopenia in decompensated cirrhosis with portal hypertension.
Letter to the Editor: How does bile acid–induced IRF3 phosphorylation mediate cholestatic liver and kidney injury?—More needs to be known
Authors: Lingzhen Jiang, Zaixing Yang
Journal: Hepatology (2024)

To the editor, We read with great interest the article by Zhuang et al1, presenting a novel finding that bile acid (BA) can induce interferon regulatory factor 3 (IRF3) phosphorylation in hepatocytes, liver nonparenchymal cells, bone marrow-derived macrophages and HEK293T cells. Furthermore, they used comprehensive data to demonstrate that increased IRF3 phosphorylation can mediate cell death, inflammatory responses, and fibrosis of the liver and kidney in cholestatic diseases. We appreciate their huge amount of work, but we also would like to highlight 2 confusing issues that require clarification. Firstly, the cell types involved in IRF3 phosphorylation were not specified, nor were the cell types where deletion of IRF3 contributes to protecting cell PANoptosis, inflammatory responses, and fibrosis of liver and kidney in bile duct ligation mice. As far as we know, the function of IRF3 (induces apoptosis or promotes proliferation) depends on the type of cells.2,3 Accordingly, specifying the cell type where irf3 knockout alleviates cholestasis-induced liver and kidney injury is critical for choosing a more precise therapeutic strategy in cholestatic liver diseases. Secondly, data from this study are insufficient to support the conclusion that BA-induced IRF3 phosphorylation mediated cell death, inflammation, and fibrosis through the IRF3-Z–conformation nucleic acid binding protein 1 (ZBP1) axis. Firstly, although authors observed that Bax expression was not affected by the absence of IRF3, this result could not exclude the possibility of cell death mediated by Bax in that activated IRF3 induces mitochondria-associated apoptosis through interaction with Bax instead of regulating Bax expression.2 Secondly, authors found that IRF3 can regulate the expression of ZBP1, NOD-like receptor protein 3, receptor-interacting protein kinase (RIPK) 1 and RIPK3, and that ZBP1 can interact with NOD-like receptor protein 3, RIPK1 and RIPK3. However, they failed to verify whether ZBP1 can regulate the expression of NOD-like receptor protein 3, RIPK1, and RIPK3 and whether ZBP1 plays an important role in IRF3-mediated cell death, inflammation, and fibrosis. A recent study suggested that ZBP1 can promote myeloma cell proliferation by direct and functional interaction with IRF3.3 As such, the detailed role of up-regulated ZBP1 in cholestasis-induced liver and kidney injury deserves further investigation.
Letter to the Editor: Provider preparedness for functional cure of chronic hepatitis B
Authors: Robert P. Perrillo, Harry L.A. Janssen
Journal: Hepatology (2024)

To the editor, A search for treatments that promote sustained HBsAg clearance (functional cure of chronic hepatitis B) has gained considerable momentum in the past decade. Multiple classes of new treatments have entered phase 2 trials, and 1 in a phase 3 trial.1,2 The development of safe and effective therapy for HBsAg clearance would be a milestone achievement and help meet 2030 WHO mortality targets. However, as recently described in the review by Howell et al, several considerations for HBV cure preparedness are needed.3 The authors underscore the cost of delivery in low/middle-income countries where the greatest burden of HBV disease lies. They also describe a need for point-of-care testing and better monitoring tools. As the therapeutic landscape will change substantially, we feel that attention must also be given to provider preparedness. Unlike nucleoside analog (NA) therapy, which targets HBV reverse transcriptase activity, compounds in the functional cure pipeline target various phases of the HBV life cycle (viral translation, HBsAg secretion, and HBV nucleocapsid assembly). One or more of these agents combined with shorter-term NA therapy are likely to become a dominant strategy. Understanding the HBV life cycle will become a critical asset in planning the most effective combinations to achieve a functional cure. In ongoing trials, functional cure regimens often include an arm with peginterferon alfa due to its known effect on HBsAg decline and immunomodulatory property. Many hepatologists in the United States and Europe have little, if any, experience with peginterferon for chronic hepatitis B and will need to be trained in its use. Also, cure regimens are likely to result in expanded treatment recommendations. Inactive HBsAg carriers currently undergo observational care but could become a targeted group for siRNA inhibitors to prevent future HCC especially since these individuals tend to have low baseline HBsAg levels. Several immunotherapies are currently under development, and immune-tolerant disease (HBV DNA ≥ 7 log IU, normal alanine aminotransferase, and high-level HBsAg) might become treatable by immunotherapy in combination with an NA and siRNA inhibitor. The relative complexity of care with functional cure regimens is very likely to limit the use of these agents by primary care providers, infectious disease specialists, and even gastroenterologists. Such providers may either keep patients on indefinite NA therapy or refer them to hepatologists with established experience in hepatitis B treatment. In the authors' opinion, the hepatology community should begin to contemplate and plan for the new realities likely to be required for successful functional cure programs.
Antagonistic effects of the cytotoxic molecules granzyme B and TRAIL in the immunopathogenesis of sclerosing cholangitis
Authors: Mareike Kellerer, Sana Javed, Christian Casar, Nico Will, Laura K. Berkhout, Dorothee Schwinge, Christian F. Krebs, Christoph Schramm, Katrin Neumann, Gisa Tiegs
Journal: Hepatology (2024)

Background and Aims: Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterized by biliary inflammation and fibrosis. We showed an elevated interferon γ response in patients with primary sclerosing cholangitis and in multidrug resistance protein 2-deficient ( Mdr2 −/− ) mice developing sclerosing cholangitis. Interferon γ induced expression of the cytotoxic molecules granzyme B (GzmB) and TRAIL in hepatic lymphocytes and mediated liver fibrosis in sclerosing cholangitis. Approach and Results: In patient samples and Mdr2 −/− mice, we identified lymphocyte clusters with a cytotoxic gene expression profile using single-cell RNA-seq and cellular indexing of transcriptomes and epitopes by sequencing analyses combined with multi-parameter flow cytometry. CD8 + T cells and NK cells showed increased expression of GzmB and TRAIL in sclerosing cholangitis. Depletion of CD8 + T cells ameliorated disease severity in Mdr2 −/− mice. By using Mdr2 −/− × Gzmb −/− and Mdr2 −/− × Tnfsf10 −/− mice, we investigated the significance of GzmB and TRAIL for disease progression in sclerosing cholangitis. Interestingly, the lack of GzmB resulted in reduced cholangiocyte apoptosis, liver injury, and fibrosis. In contrast, sclerosing cholangitis was aggravated in the absence of TRAIL. This correlated with elevated GzmB and interferon γ expression by CD8 + T cells and NK cells enhanced T-cell survival, and increased apoptosis and expansion of cholangiocytes. Conclusions: GzmB induces apoptosis and fibrosis in sclerosing cholangitis, whereas TRAIL regulates inflammatory and cytotoxic immune responses, subsequently leading to reduced liver injury and fibrosis.
Autoimmune diseases in primary sclerosing cholangitis and their first-degree relatives
Authors: Aiva Lundberg Båve, Erik von Seth, Michael Ingre, Caroline Nordenvall, Annika Bergquist
Journal: Hepatology (2024)

Primary sclerosing cholangitis (PSC) is linked to inflammatory bowel disease (IBD). However, there is limited overlap between IBD and PSC risk genes, but a stronger association between PSC and other autoimmune conditions. We aimed to assess the coexistence and familial association of autoimmune disorders in PSC, and the influence of autoimmune comorbidity on severe outcomes.
Engineering an extracellular matrix-functionalized, load-bearing tendon substitute for effective repair of large-to-massive tendon defects
Authors: Shuting Huang, Ying Rao, Meng Zhou, Anna M. Blocki, Xiao Chen, Chunyi Wen, Dai Fei Elmer Ker, Rocky S. Tuan, Dan Michelle Wang
Journal: Bioactive Materials (2024)

A significant clinical challenge in large-to-massive rotator cuff tendon injuries is the need for sustaining high mechanical demands despite limited tissue regeneration, which often results in clinical repair failure with high retear rates and long-term functional deficiencies. To address this, an innovative tendon substitute named "BioTenoForce" is engineered, which uses (i) tendon extracellular matrix (tECM)'s rich biocomplexity for tendon-specific regeneration and (ii) a mechanically robust, slow degradation polyurethane elastomer to mimic native tendon's physical attributes for sustaining long-term shoulder movement. Comprehensive assessments revealed outstanding performance of BioTenoForce, characterized by robust core-shell interfacial bonding, human rotator cuff tendon-like mechanical properties, excellent suture retention, biocompatibility, and tendon differentiation of human adipose-derived stem cells. Importantly, BioTenoForce, when used as an interpositional tendon substitute, demonstrated successful integration with regenerative tissue, exhibiting remarkable efficacy in repairing large-to-massive tendon injuries in two animal models. Noteworthy outcomes include durable repair and sustained functionality with no observed breakage/rupture, accelerated recovery of rat gait performance, and >1 cm rabbit tendon regeneration with native tendon-like biomechanical attributes. The regenerated tissues showed tendon-like, wavy, aligned matrix structure, which starkly contrasts with the typical disorganized scar tissue observed after tendon injury, and was strongly correlated with tissue stiffness. Our simple yet versatile approach offers a dual-pronged, broadly applicable strategy that overcomes the limitations of poor regeneration and stringent biomechanical requirements, particularly essential for substantial defects in tendon and other load-bearing tissues.
Endocarditis prevention: time for a review of NICE guidance
Authors: Martin Thornhill, Bernard Prendergast, Mark Dayer, Ash Frisby, Larry M. Baddour
Journal: The Lancet Regional Health - Europe (2024)

In 2023, the European Society of Cardiology (ESC) updated its infective endocarditis (IE) guidelines strongly endorsing antibiotic prophylaxis (AP) before invasive dental procedures (IDPs) for high-risk patients, elevating their recommendation to Class I. The American Heart Association (AHA) is aligned with this view and reaffirmed the need for AP to prevent IE in those at high-risk in its 2021 guidelines. In contrast, the UK's National Institute for Health and Care Excellence (NICE) recommends against routine AP use. Despite considerable new evidence, NICE has not reviewed this recommendation since 2015. In this Personal View, we review the new evidence that has arisen since 2015. Our analysis establishes the association between IDPs and IE and shows that AP is both safe and effective in reducing the IE-risk following IDPs in those at high-risk. Data also show that AP is cost-effective and would result in significant cost savings and health benefits if re-introduced into the UK's National Health Service for high-risk patients. Given these insights, we argue it is time NICE reviewed its guidance so that high-risk patients in the UK receive the same protection against IE that is afforded to patients in the rest of the world.
Clinical features-based machine learning models to separate sexually transmitted infections from other skin diagnoses
Authors: Nyi Nyi Soe, Phyu Mon Latt, Zhen Yu, David Lee, Cham-Mill Kim, Daniel Tran, Jason J. Ong, Zongyuan Ge, Christopher K. Fairley, Lei Zhang
Journal: Journal of Infection (2024)

Many sexual health services are overwhelmed and cannot cater for all the individuals who present with sexually transmitted infections (STIs). Digital health software that separates STIs from non-STIs could improve the efficiency of clinical services. We developed and evaluated a machine learning model that predicts whether patients have an STI based on their clinical features.
Power Doppler signal at the enthesis and bone erosions are the most discriminative OMERACT ultrasound lesions for SpA: results from the DEUS (Defining Enthesitis on Ultrasound in Spondyloarthritis) multicentre study
Authors: Andrea Di Matteo, Gianluca Smerilli, Stefano Di Donato, An Ran Liu, Andrea Becciolini, Federica Camarda, Tomas Cazenave, Edoardo Cipolletta, Davide Corradini, Juan José de Agustín, Giulia Maria Destro Castaniti, Eleonora Di Donato, Luca Di Geso, Emine Duran, Bayram Farisogullari, Marco Fornaro, Francesca Francioso, Pamela Giorgis, Amelia Granel, Cristina Hernández-Díaz, Rudolf Horvath, Jana Hurnakova, Diogo Jesus, Omer Karadag, Ling Li, Josefina Marin, María Victoria Martire, Xabier Michelena, Erica Moscioni, Laura Muntean, Matteo Piga, Marcos Rosemffet, João Rovisco, Didem Sahin, Fausto Salaffi, Liliana Saraiva, Crescenzio Scioscia, Maria-Magdalena Tamas, Shun Tanimura, Aliki Venetsanopoulou, Lucio Ventura-Rios, Orlando Villota, Catalina Villota-Eraso, Paraskevi V Voulgari, Gentiana Vukatana, Johana Zacariaz Hereter, Helena Marzo-Ortega, Walter Grassi, Emilio Filippucci
Journal: Annals of the Rheumatic Diseases (2024)

To assess, in spondyloarthritis (SpA), the discriminative value of the Outcome Measures in Rheumatology (OMERACT) ultrasound lesions of enthesitis and their associations with clinical features in this population.
Psoriasis and non-Hodgkin’s lymphoma in a diverse sample of U.S. adults: a propensity matched case-control study
Authors: Michael J. Diaz, Zaim Haq, Jasmine T. Tran, Parsa Abdi, Kiran Motaparthi, Jane M. Grant-Kels, Marjorie E. Montanez-Wiscovich
Journal: Journal of the American Academy of Dermatology (2024)
Reply: Is right heart assessment vital for evaluating terlipressin-related outcomes in hepatorenal syndrome-acute kidney injury?
Authors: Akash Roy, Kamal Kajal, Manhal Izzy, Bhupendra K. Sihag, Madhumita Premkumar
Journal: Hepatology (2024)

To the editor, We read with interest the letter by Guo and colleagues and appreciate their insights.1 Assessment of right ventricular (RV) function is often overlooked in bedside cardiac assessment and right heart catheterization is infrequent in critically ill patients with cirrhosis. The contemporary definition of cirrhotic cardiomyopathy includes abnormally high tricuspid regurgitant velocity, exclusive to the absence of pulmonary hypertension. We did analyze RV systolic pressure, tricuspid annular plane systolic excursion, and right atrial pressure (refer Tables 2 and 3 in Premkumar et al1). While tricuspid annular plane systolic excursion and right atrial pressure were similar between responders and nonresponders (20.7±5.8 vs. 20.6±5.8, p=0.7, 11.5±3.5 vs. 11.8±4.9, p=0.07), we noted significant differences in RV systolic pressure (23.5±4.7 vs. 28.0±7.3, p=0.003) in predicting terlipressin response. However, this difference is not clinically significant since it falls below the cutoff of 38 mm Hg suggestive of pulmonary hypertension.2 Furthermore, when RV systolic pressure was included in the Cox Proportional Hazards model, it did not predict terlipressin response (adjusted hazard ratio: 0.97, 0.9–0.1, p=0.9). Also, clinically significant tricuspid regurgitation jet velocity (ie, >2.8 m/s) (N=21/140, 15%) was not associated with terlipressin nonresponse (6/21 [28.6%]) or mortality (3/21 [14.3%]) (p=0.5, 0.7, respectively). We also reported the analysis for individual components of cirrhotic cardiomyopathy criteria in predicting terlipressin nonresponse, which suggests left heart diastolic dysfunction, reflective of cirrhotic cardiomyopathy, rather than right heart function being predictive of nonresponse. As Guo and colleagues point out, primary RV enlargement does compromise LV filling, leading to decreased cardiac output. However, in our data, the RV dimensions, with median diameters of 2.7, 2.9, and 2.9 cm at 0, 48, and 72 hours, respectively, did not predict terlipressin response. While data about RV dimensions and terlipressin response interplay are limited, Kalambokis et al showed a decrease in pulmonary vascular resistance (158.8±8.9 vs. 186.5±13.9 dyne), whereas Narahara et al have reported an increase in pulmonary artery pressure, pulmonary capillary wedge pressure, and right atrial pressure.3,4 Guo and colleagues raised a reasonable concern about the use of nonselective beta-blockers in a subset (33%). However, as mentioned, nonselective beta-blockers were withheld at the time of diagnosis of acute kidney injury, and given their short half-life it is unlikely to affect terlipressin response. In conclusion, we share the thoughts of Guo and colleagues that comprehensive left- and right-sided cardiac assessment is needed. We hope that our work provides a stepping stone in understanding the complex cardiac pathophysiology in this patient population.
Fiber and whole grain intakes in relation to liver cancer risk: An analysis in 2 prospective cohorts and systematic review and meta-analysis of prospective studies
Authors: Cody Z. Watling, Aika Wojt, Andrea A. Florio, Gisela Butera, Demetrius Albanes, Stephanie J. Weinstein, Wen-Yi Huang, Dominick Parisi, Xuehong Zhang, Barry I. Graubard, Jessica L. Petrick, Katherine A. McGlynn
Journal: Hepatology (2024)

The association between fiber or whole grain intakes and the risk of liver cancer remains unclear. We assessed the associations between fiber or whole grain intakes and liver cancer risk among 2 prospective studies, and systematically reviewed and meta-analyzed these results with published prospective studies.
CD8+ T cells sustain antitumor response by mediating crosstalk between adenosine A2A receptor and glutathione/GPX4
Authors: Siqi Chen, Jie Fan, Ping Xie, Jihae Ahn, Michelle Fernandez, Leah K. Billingham, Jason Miska, Jennifer D. Wu, Derek A. Wainwright, Deyu Fang, Jeffrey A. Sosman, Yong Wan, Yi Zhang, Navdeep S. Chandel, Bin Zhang
Journal: Journal of Clinical Investigation (2024)

Antitumor responses of CD8+ T cells are tightly regulated by distinct metabolic fitness. High levels of glutathione (GSH) are observed in the majority of tumors contributing to cancer progression and treatment resistance in part by preventing glutathione peroxidase 4 (GPX4) dependent ferroptosis. Here, we show the necessity of the adenosine A2A receptor (A2AR) signaling and the glutathione (GSH)-GPX4 axis in orchestrating metabolic fitness and survival of functionally competent CD8+ T cells. Activated CD8+ T cells treated ex vivo with simultaneous inhibition of A2AR and lipid peroxidation acquire a superior capacity to proliferate and persist in vivo, demonstrating a translatable means to prevent ferroptosis in adoptive cell therapy (ACT). Additionally, we identify a particular cluster of intratumoral CD8+ T cells expressing a putative gene signature of GSH metabolism (GMGS) in association with clinical response and survival across several human cancers. Our study addresses a key role of GSH-GPX4 and adenosinergic pathways in fine-tuning the metabolic fitness of antitumor CD8+ T cells.