tbuckley/cabot-search huggingface dataset:
Succinate dehydrogenase/complex II is critical for metabolic and epigenetic regulation of T cell proliferation and inflammation
Authors: Xuyong Chen, Benjamin Sunkel, Meng Wang, Siwen Kang, Tingting Wang, J. N. Rashida Gnanaprakasam, Lingling Liu, Teresa A. Cassel, David A. Scott, Ana M. Muñoz-Cabello, Jose Lopez-Barneo, Jun Yang, Andrew N. Lane, Gang Xin, Benjamin Z. Stanton, Teresa W.-M. Fan, Ruoning Wang
Journal: Science Immunology (2022)

Effective T cell-mediated immune responses require the proper allocation of metabolic resources to sustain growth, proliferation, and cytokine production. Epigenetic control of the genome also governs T cell transcriptome and T cell lineage commitment and maintenance. Cellular metabolic programs interact with epigenetic regulation by providing substrates for covalent modifications of chromatin. By using complementary genetic, epigenetic, and metabolic approaches, we revealed that tricarboxylic acid (TCA) cycle flux fueled biosynthetic processes while controlling the ratio of succinate/α-ketoglutarate (α-KG) to modulate the activities of dioxygenases that are critical for driving T cell inflammation. In contrast to cancer cells, where succinate dehydrogenase (SDH)/complex II inactivation drives cell transformation and growth, SDH/complex II deficiency in T cells caused proliferation and survival defects when the TCA cycle was truncated, blocking carbon flux to support nucleoside biosynthesis. Replenishing the intracellular nucleoside pool partially relieved the dependence of T cells on SDH/complex II for proliferation and survival. SDH deficiency induced a proinflammatory gene signature in T cells and promoted T helper 1 and T helper 17 lineage differentiation. An increasing succinate/α-KG ratio in SDH-deficient T cells promoted inflammation by changing the pattern of the transcriptional and chromatin accessibility signatures and consequentially increasing the expression of the transcription factor, PR domain zinc finger protein 1. Collectively, our studies revealed a role of SDH/complex II in allocating carbon resources for anabolic processes and epigenetic regulation in T cell proliferation and inflammation.
Optimal reperfusion strategy in acute high-risk pulmonary embolism requiring extracorporeal membrane oxygenation support: a systematic review and meta-analysis
Authors: Romain Chopard, Peter Nielsen, Fabio Ius, Serghei Cebotari, Fiona Ecarnot, Hugo Pilichowski, Matthieu Schmidt, Benedict Kjaergaard, Iago Sousa-Casasnovas, Mehrdad Ghoreishi, Rajeev L. Narayan, Su Nam Lee, Gregory Piazza, Nicolas Meneveau
Journal: European Respiratory Journal (2022)

Background The optimal pulmonary revascularisation strategy in high-risk pulmonary embolism (PE) requiring implantation of extracorporeal membrane oxygenation (ECMO) remains controversial. Methods We conducted a systematic review and meta-analysis of evidence comparing mechanical embolectomy and other strategies, including systemic thrombolysis, catheter-directed thrombolysis or ECMO as stand-alone therapy, with regard to mortality and bleeding outcomes. Results We identified 835 studies, 17 of which were included, comprising 327 PE patients. Overall, 32.4% were treated with mechanical pulmonary reperfusion (of whom 85.9% had surgical embolectomy), while 67.6% received other strategies. The mortality rate was 22.6% in the mechanical reperfusion group and 42.8% in the “other strategies” group. The pooled odds ratio for mortality with mechanical reperfusion was 0.439 (95% CI 0.237–0.816) (p=0.009; I 2 =35.2%) versus other reperfusion strategies and 0.368 (95% CI 0.185–0.733) (p=0.004; I 2 =32.9%) for surgical embolectomy versus thrombolysis. The rate of bleeding in patients under ECMO was 22.2% in the mechanical reperfusion group and 19.1% in the “other strategies” group (OR 1.27, 95% CI 0.54–2.96; I 2 =7.7%). The meta-regression model did not identify any relationship between the covariates “more than one pulmonary reperfusion therapy”, “ECMO implantation before pulmonary reperfusion therapy”, “clinical presentation of PE” or “cancer-associated PE” and the associated outcomes. Conclusions The results of the present meta-analysis and meta-regression suggest that mechanical reperfusion, notably by surgical embolectomy, may yield favourable results regardless of the timing of ECMO implantation in the reperfusion timeline, independent of thrombolysis administration or cardiac arrest presentation.
Bronchiolitis Obliterans Syndrome after Hematopoietic Stem Cell Transplant Diagnosed Using Ultrathin Bronchoscopy
Authors: Masayuki Sato, Yuko Waseda, Tomoaki Sonoda, Akihiko Tanizawa, Harumi Itoh, Motohiro Kobayashi, Tamiko Takemura, Tamotsu Ishizuka
Journal: American Journal of Respiratory and Critical Care Medicine (2022)
A nuclear function for an oncogenic microRNA as a modulator of snRNA and splicing
Authors: Rachid El Fatimy, Yanhong Zhang, Evgeny Deforzh, Mahalakshmi Ramadas, Harini Saravanan, Zhiyun Wei, Rosalia Rabinovsky, Nadiya M. Teplyuk, Erik J. Uhlmann, Anna M. Krichevsky
Journal: Molecular Cancer (2022)

Abstract Background miRNAs are regulatory transcripts established as repressors of mRNA stability and translation that have been functionally implicated in carcinogenesis. miR-10b is one of the key onco-miRs associated with multiple forms of cancer. Malignant gliomas exhibit particularly striking dependence on miR-10b. However, despite the therapeutic potential of miR-10b targeting, this miRNA’s poorly investigated and largely unconventional properties hamper the clinical translation. Methods We utilized Covalent Ligation of Endogenous Argonaute-bound RNAs and their high-throughput RNA sequencing to identify miR-10b interactome and a combination of biochemical and imaging approaches for target validation. They included Crosslinking and RNA immunoprecipitation with spliceosomal proteins, a combination of miRNA FISH with protein immunofluorescence in glioma cells and patient-derived tumors, native Northern blotting, and the transcriptome-wide analysis of alternative splicing. Results We demonstrate that miR-10b binds to U6 snRNA, a core component of the spliceosomal machinery. We provide evidence of the direct binding between miR-10b and U6, in situ imaging of miR-10b and U6 co-localization in glioma cells and tumors, and biochemical co-isolation of miR-10b with the components of the spliceosome. We further demonstrate that miR-10b modulates U6 N-6-adenosine methylation and pseudouridylation, U6 binding to splicing factors SART3 and PRPF8, and regulates U6 stability, conformation, and levels. These effects on U6 result in global splicing alterations, exemplified by the altered ratio of the isoforms of a small GTPase CDC42, reduced overall CDC42 levels, and downstream CDC42 -mediated effects on cell viability. Conclusions We identified U6 snRNA, the key RNA component of the spliceosome, as the top miR-10b target in glioblastoma. We, therefore, present an unexpected intersection of the miRNA and splicing machineries and a new nuclear function for a major cancer-associated miRNA.
Vitamin K2 and D in Patients With Aortic Valve Calcification: A Randomized Double-Blinded Clinical Trial
Authors: Axel C.P. Diederichsen, Jes S. Lindholt, Sören Möller, Kristian A. Øvrehus, Søren Auscher, Jess Lambrechtsen, Susanne E. Hosbond, Dilek H. Alan, Grazina Urbonaviciene, Søren W. Becker, Maise H. Fredgart, Selma Hasific, Lars Folkestad, Oke Gerke, Lars Melholt Rasmussen, Jacob E. Møller, Hans Mickley, Jordi S. Dahl
Journal: Circulation (2022)

Menaquinone-7 (MK-7), also known as vitamin K2, is a cofactor for the carboxylation of proteins involved in the inhibition of arterial calcification and has been suggested to reduce the progression rate of aortic valve calcification (AVC) in patients with aortic stenosis.In a randomized, double-blind, multicenter trial, men from the community with an AVC score >300 arbitrary units (AU) on cardiac noncontrast computer tomography were randomized to daily treatment with tablet 720 µg MK-7 plus 25 µg vitamin D or matching placebo for 24 months. The primary outcome was the change in AVC score. Selected secondary outcomes included change in aortic valve area and peak aortic jet velocity on echocardiography, heart valve surgery, change in aortic and coronary artery calcification, and change in dp-ucMGP (dephosphorylated-undercarboxylated matrix Gla-protein). Safety outcomes included all-cause death and cardiovascular events.From February 1, 2018, to March 21, 2019, 365 men were randomized. Mean age was 71.0 (±4.4) years. The mean (95% CI) increase in AVC score was 275 AU (95% CI, 225-326 AU) and 292 AU (95% CI, 246-338 AU) in the intervention and placebo groups, respectively. The mean difference on AVC progression was 17 AU (95% CI, -86 to 53 AU; P=0.64). The mean change in aortic valve area was 0.02 cm2 (95% CI, -0.09 to 0.12 cm2; P=0.78) and in peak aortic jet velocity was 0.04 m/s (95% CI, -0.11 to 0.02 m/s; P=0.21). The progression in aortic and coronary artery calcification score was not significantly different between patients treated with MK-7 plus vitamin D and patients receiving placebo. There was no difference in the rate of heart valve surgery (1 versus 2 patients; P=0.99), all-cause death (1 versus 4 patients; P=0.37), or cardiovascular events (10 versus 10 patients; P=0.99). Compared with patients in the placebo arm, a significant reduction in dp-ucMGP was observed with MK-7 plus vitamin D (-212 pmol/L versus 45 pmol/L; P<0.001).In elderly men with an AVC score >300 AU, 2 years MK-7 plus vitamin D supplementation did not influence AVC progression.URL: https://www.gov; Unique identifier: NCT03243890.
Projecting prevalence of frailty and dementia and the economic cost of care in Japan from 2016 to 2043: a microsimulation modelling study
Authors: Megumi Kasajima, Karen Eggleston, Shoki Kusaka, Hiroki Matsui, Tomoki Tanaka, Bo-Kyung Son, Katsuya Iijima, Kazuo Goda, Masaru Kitsuregawa, Jay Bhattacharya, Hideki Hashimoto
Journal: The Lancet Public Health (2022)

Dementia and frailty often accompany one another in older age, requiring complex care and resources. Available projections provide little information on their joint impact on future health-care need from different segments of society and the associated costs. Using a newly developed microsimulation model, we forecast this situation in Japan as its population ages and decreases in size.In this microsimulation modelling study, we built a model that simulates an individual's status transition across 11 chronic diseases (including diabetes, coronary heart disease, and stroke) as well as depression, functional status, and self-reported health, by age, sex, and educational strata (less than high school, high school, and college and higher), on the basis of nationally representative health surveys and existing cohort studies. Using the simulation results, we projected the prevalence of dementia and frailty, life expectancy with these conditions, and the economic cost for formal and informal care over the period 2016-43 in the population of Japan aged 60 years and older.Between 2016 and 2043, life expectancy at age 65 years will increase from 23·7 years to 24·9 years in women and from 18·7 years to 19·9 years in men. Years spent with dementia will decrease from 4·7 to 3·9 years in women and 2·2 to 1·4 years in men. By contrast, years spent with frailty will increase from 3·7 to 4·0 years for women and 1·9 to 2·1 for men, and across all educational groups. By 2043, approximately 29% of women aged 75 years and older with a less than high school education are estimated to have both dementia and frailty, and so will require complex care. The expected need for health care and formal long-term care is anticipated to reach costs of US$125 billion for dementia and $97 billion for frailty per annum in 2043 for the country.Japan's Government and policy makers should consider the potential social challenges in caring for a sizable population of older people with frailty and dementia, and a widening disparity in the burden of those conditions by sex and by educational status. The future burden of dementia and frailty should be countered not only by curative and preventive technology innovation, but also by social policies to mitigate the health gap.Japan Society for the Promotion of Science, Hitachi - the University of Tokyo Laboratory for a sustainable society, and the National Institute of Ageing.
Through the layers: how macrophages drive atherosclerosis across the vessel wall
Authors: Leah I. Susser, Katey J. Rayner
Journal: Journal of Clinical Investigation (2022)

Cardiovascular disease (CVD) accounts for almost half of all deaths related to non-communicable disease worldwide, making it the single largest global cause of mortality. Although the risk factors for coronary artery disease - the most common cause of CVD - are well known and include hypertension, high cholesterol, age, and genetics, CVDs are now recognized as chronic inflammatory conditions. Arterial blockages, known as atherosclerosis, develop due to excess cholesterol accumulating within the arterial wall, creating a perpetually inflammatory state. The normally quiescent intimal layer of the vessel wall becomes laden with inflammatory cells, which alters the surrounding endothelial, smooth muscle, and extracellular matrix components to propagate disease. Macrophages, which can be either tissue resident or monocyte derived, are a key player in atherosclerotic disease progression and regression, and the understanding of their functions and origins continues to evolve with the use of deep phenotyping methodologies. This Review outlines how macrophages interact with each layer of the developing atherosclerotic plaque and discusses new concepts that are challenging our previous views on how macrophages function and our evolving understanding of the contribution of macrophages to disease.
Chimeric Fusion between Clostridium Ramosum IgA Protease and IgG Fc Provides Long-Lasting Clearance of IgA Deposits in Mouse Models of IgA Nephropathy
Authors: Xinfang Xie, Jingyi Li, Pan Liu, Manliu Wang, Li Gao, Feng Wan, Jicheng Lv, Hong Zhang, Jing Jin
Journal: Journal of the American Society of Nephrology (2022)

Significance Statement IgA nephropathy is the most common glomerulonephritis worldwide and a leading cause of kidney failure. The disease often progresses through episodes of flare-ups that require effective treatments to tame inflammation. We followed a rational design strategy to construct a recombinant fusion IgA protease derived from commensal gut microbiota Clostridium ramosum . The fusion protease, referred to as Fc-AK183, showed week-long activity in mice to completely obliterate IgA in circulation and clear pathologic deposits in the kidney. Therefore, the recombinant enzyme is a promising drug candidate for future treatment of IgA nephropathy. Background IgA nephropathy is a common primary glomerulonephritis caused by mesangial deposition of poly-IgA complexes. The disease follows a variable course of clinical progression, with a high risk of kidney failure. Although no specific therapy is available, enzymatic strategies to clear IgA deposits are being considered for the treatment of rapidly progressive IgA nephropathy. Methods We chose an IgA protease of commensal bacterium Clostridium ramosum , termed AK183, as the template for constructing a recombinant biologic. To extend the t 1/2 in blood, we fused AK183 to the Fc segment of human IgG1. Activities of this Fc-AK183 fusion protein toward the cleavage and subsequent clearance of IgA were tested in mouse models. Results First, we discovered an autocleavage activity of AK183 that separates the N-terminal protease from its C-terminal autotransporter β domain. Therefore, we grafted Fc to the N terminus of AK183 and demonstrated its week-long enzymatic activity in mice. In addition, the proteolytic fragments of IgA generated in the reaction with Fc-AK183 were effectively removed from circulation via kidney filtration. The combined actions of Fc-AK183-mediated cleavage and subsequent renal clearance of IgA resulted in a lasting obliteration of blood IgA, as demonstrated in a human IgA-injection model and in a humanized α1KI transgenic model. Fc-AK183 was also able to remove chronic IgA and associated complement C3 deposits in the glomerulus. Conclusion We constructed a chimeric fusion of IgA protease with Fc and demonstrated its long-lasting efficacy as a promising targeted therapy for IgA nephropathy in mouse models.
C‐X‐C motif chemokine ligand 1 induced by Hedgehog signaling promotes mouse extrahepatic bile duct repair after acute injury
Authors: Nureen H. Mohamad Zaki, Junya Shiota, Ashley N. Calder, Theresa M. Keeley, Benjamin L. Allen, Kazuhiko Nakao, Linda C. Samuelson, Nataliya Razumilava
Journal: Hepatology (2022)

Abstract Background and Aims In extrahepatic bile duct (EHBD) cholangiopathies, including primary sclerosing cholangitis, a reactive cholangiocyte phenotype is associated with inflammation and epithelial hyperproliferation. The signaling pathways involved in EHBD injury response are poorly understood. In this study, we investigated the role of Hedgehog (HH) signaling and its downstream effectors in controlling biliary proliferation and inflammation after EHBD injury. Approach and Results Using mouse bile duct ligation as an acute EHBD injury model, we used inhibitory paradigms to uncover mechanisms promoting the proliferative response. HH signaling was inhibited genetically in Gli1−/− mice or by treating wild‐type mice with LDE225. The role of neutrophils was tested using chemical (SB225002) and biological (lymphocyte antigen 6 complex locus G6D [Ly6G] antibodies) inhibitors of neutrophil recruitment. The cellular response was defined through morphometric quantification of proliferating cells and CD45+ and Ly6G+ immune cell populations. Key signaling component expression was measured and localized to specific EHBD cellular compartments by in situ hybridization, reporter strain analysis, and immunohistochemistry. Epithelial cell proliferation peaked 24 h after EHBD injury, preceded stromal cell proliferation, and was associated with neutrophil influx. Indian HH ligand expression in the biliary epithelium rapidly increased after injury. HH‐responding cells and neutrophil chemoattractant C‐X‐C motif chemokine ligand 1 (CXCL1) expression mapped to EHBD stromal cells. Inhibition of HH signaling blocked CXCL1 induction, diminishing neutrophil recruitment and the biliary proliferative response to injury. Directly targeting neutrophils by inhibition of the CXCL1/C‐X‐C motif chemokine receptor 2/Ly6G signaling axis also decreased biliary proliferation. Conclusions HH‐regulated CXCL1 orchestrates the early inflammatory response and biliary proliferation after EHBD injury through complex cellular crosstalk.
The effect of cardiac resynchronization without a defibrillator on morbidity and mortality: an <scp>individual patient data meta‐analysis</scp> of <scp>COMPANION</scp> and <scp>CARE‐HF</scp>
Authors: John G.F. Cleland, Michael R. Bristow, Nicholas Freemantle, Brian Olshansky, Daniel Gras, Leslie Saxon, Luigi Tavazzi, John Boehmer, Stefano Ghio, Arthur M. Feldman, Jean‐Claude Daubert, David de Mets
Journal: European Journal of Heart Failure (2022)
Activated SUMOylation restricts MHC class I antigen presentation to confer immune evasion in cancer
Authors: Uta M. Demel, Marlitt Böger, Schayan Yousefian, Corinna Grunert, Le Zhang, Paul W. Hotz, Adrian Gottschlich, Hazal Köse, Konstandina Isaakidis, Dominik Vonficht, Florian Grünschläger, Elena Rohleder, Kristina Wagner, Judith Dönig, Veronika Igl, Bernadette Brzezicha, Francis Baumgartner, Stefan Habringer, Jens Löber, Björn Chapuy, Carl Weidinger, Sebastian Kobold, Simon Haas, Antonia B. Busse, Stefan Müller, Matthias Wirth, Markus Schick, Ulrich Keller
Journal: Journal of Clinical Investigation (2022)

Activated SUMOylation is a hallmark of cancer. Starting from a targeted screening for SUMO-regulated immune evasion mechanisms, we identified an evolutionarily conserved function of activated SUMOylation, which attenuated the immunogenicity of tumor cells. Activated SUMOylation allowed cancer cells to evade CD8+ T cell-mediated immunosurveillance by suppressing the MHC class I (MHC-I) antigen-processing and presentation machinery (APM). Loss of the MHC-I APM is a frequent cause of resistance to cancer immunotherapies, and the pharmacological inhibition of SUMOylation (SUMOi) resulted in reduced activity of the transcriptional repressor scaffold attachment factor B (SAFB) and induction of the MHC-I APM. Consequently, SUMOi enhanced the presentation of antigens and the susceptibility of tumor cells to CD8+ T cell-mediated killing. Importantly, SUMOi also triggered the activation of CD8+ T cells and thereby drove a feed-forward loop amplifying the specific antitumor immune response. In summary, we showed that activated SUMOylation allowed tumor cells to evade antitumor immunosurveillance, and we have expanded the understanding of SUMOi as a rational therapeutic strategy for enhancing the efficacy of cancer immunotherapies.
Authors’ Reply: More Research is Still Needed to Support the Real-World Generalizability of the Benefits of Lifestyle Interventions for Chronic Kidney Disease
Authors: Kassia S. Beetham, Jeff S. Coombes, Erin J. Howden
Journal: Journal of the American Society of Nephrology (2022)

We thank the authors for their interest in our recent publication1 and agree in premise that further research is required to aid the generalizability of our findings, especially among populations that were not the focus of the study.2 We agree with the authors that evaluating the effects of lifestyle interventions on hard endpoints, such as cardiovascular and all-cause mortality, are important to move the field forward. However, this was not within the scope of this study and would require larger sample sizes and longer follow-up. There is robust evidence that demonstrates the strength of cardiorespiratory fitness as a surrogate endpoint for cardiovascular and all-cause mortality.3 But we agree this is an important area for further investigation in people with kidney disease, as are studies that include the objective evaluation of physical activity levels. As noted by the authors, there is indeed potential bias in the use of recall to measure physical activity, yet this approach is still commonly used.4 Future studies should incorporate objective measures of habitual physical activity, which is more feasible given the contemporary widespread use of trackers5 and access to accelerometers to determine the effects of intervention and relationship between this behavior and outcomes in patients with CKD. Disclosures All authors have nothing to disclose. Funding None.