tbuckley/cabot-search huggingface dataset:
Antioxidant Hydrogels: Antioxidant Mechanisms, Design Strategies, and Applications in the Treatment of Oxidative Stress‐Related Diseases
Authors: Bin Hu, Yongliang Ouyang, Tong Zhao, Zhengyue Wang, Qiling Yan, Qinyuan Qian, Wenyi Wang, Shige Wang
Journal: Advanced Healthcare Materials (2024)

Oxidative stress is a biochemical process that disrupts the redox balance due to an excess of oxidized substances within the cell. Oxidative stress is closely associated with a multitude of diseases and health issues, including cancer, diabetes, cardiovascular diseases, neurodegenerative disorders, inflammatory conditions, and aging. Therefore, the developing of antioxidant treatment strategies has emerged as a pivotal area of medical research. Hydrogels have garnered considerable attention due to their exceptional biocompatibility, adjustable physicochemical properties, and capabilities for drug delivery. Numerous antioxidant hydrogels have been developed and proven effective in alleviating oxidative stress. In the pursuit of more effective treatments for oxidative stress-related diseases, there is an urgent need for advanced strategies for the fabrication of multifunctional antioxidant hydrogels. Consequently, the authors' focus will be on hydrogels that possess exceptional reactive oxygen species and reactive nitrogen species scavenging capabilities, and their role in oxidative stress therapy will be evaluated. Herein, the antioxidant mechanisms and the design strategies of antioxidant hydrogels and their applications in oxidative stress-related diseases are discussed systematically in order to provide critical insights for further advancements in the field.
Mavacamten Treatment for Symptomatic Obstructive Hypertrophic Cardiomyopathy
Authors: Florian Rader, Artur Oręziak, Lubna Choudhury, Sara Saberi, David Fermin, Matthew T. Wheeler, Theodore P. Abraham, Pablo Garcia-Pavia, Donna R. Zwas, Ahmad Masri, Anjali Owens, Sheila M. Hegde, Tim Seidler, Shawna Fox, Ganesh Balaratnam, Amy J. Sehnert, Iacopo Olivotto
Journal: JACC Heart Failure (2024)

Data assessing the long-term safety and efficacy of mavacamten treatment for symptomatic obstructive hypertrophic cardiomyopathy are needed. The authors sought to evaluate interim results from the EXPLORER-Long Term Extension (LTE) cohort of MAVA-LTE (A Long-Term Safety Extension Study of Mavacamten in Adults Who Have Completed EXPLORER-HCM; NCT03723655). After mavacamten or placebo withdrawal at the end of the parent EXPLORER-HCM (Clinical Study to Evaluate Mavacamten [MYK-461] in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy; NCT03470545), patients could enroll in MAVA-LTE. Patients received mavacamten 5 mg once daily; adjustments were made based on site-read echocardiograms. Between April 9, 2019, and March 5, 2021, 231 of 244 eligible patients (94.7%) enrolled in MAVA-LTE (mean age: 60 years; 39% female). At data cutoff (August 31, 2021) 217 (93.9%) remained on treatment (median time in study: 62.3 weeks; range: 0.3-123.9 weeks). At 48 weeks, patients showed improvements in left ventricular outflow tract (LVOT) gradients (mean change ± SD from baseline: resting: −35.6 ± 32.6 mm Hg; Valsalva: −45.3 ± 35.9 mm Hg), N-terminal pro–B-type natriuretic peptide (NT-proBNP) levels (median: −480 ng/L; Q1-Q3: −1,104 to −179 ng/L), and NYHA functional class (67.5% improved by ≥1 class). LVOT gradients and NT-proBNP reductions were sustained through 84 weeks in patients who reached this timepoint. Over 315 patient-years of exposure, 8 patients experienced an adverse event of cardiac failure, and 21 patients had an adverse event of atrial fibrillation, including 11 with no prior history of atrial fibrillation. Twelve patients (5.2%) developed transient reductions in site-read echocardiogram left ventricular ejection fraction of <50%, resulting in temporary treatment interruption; all recovered. Ten patients discontinued treatment due to treatment-emergent adverse events. Mavacamten treatment showed clinically important and durable improvements in LVOT gradients, NT-proBNP levels, and NYHA functional class, consistent with EXPLORER-HCM. Mavacamten treatment was well tolerated over a median 62-week follow-up.
Construction and characterization of a humanized SLCO1B1 rat model with its application in evaluating the uptake of different statins
Authors: Yuanjin Zhang, Junze Huang, Shengbo Huang, Jie Liu, Luyao Deng, Chenmeizi Liang, Yuanqing Guo, Bingyi Yao, Xin Wang
Journal: Acta Pharmaceutica Sinica B (2024)

Organic anion-transporting polypeptides 1B1 (OATP1B1) plays a crucial role in the transport of statins. However, there are too few animal models related to OATP1B1, especially humanized animal models. In this study, the human SLCO1B1 cDNA was inserted into the second exon of the rat Slco1b2 gene using CRISPR/Cas9 technology. Pharmacokinetic characteristics of statins were conducted in wild-type (WT), humanized OATP1B1 (hOATP1B1), and OATP1B2 knockout (OATP1B2 KO) rats, respectively. The results showed that human OATP1B1 was successfully expressed in rat liver and exhibited transport function. Furthermore, the pharmacokinetic results revealed that OATP1B1 exhibited varying uptake levels of pivastatin, rosuvastatin, and fluvastatin, leading to different levels of exposure within the body. These results were consistent with those obtained from in vitro experiments using overexpressed cell lines. In conclusion, we established a novel humanized SLCO1B1 transgenic rat model to assess the role of human OATP1B1 in the uptake of different statins. The different uptake mediated by OATP1B1 may be an important reason for the different efficacy of statins. The hOATP1B1 rat is a promising model for improving the prediction of human drug transport.
Newly identified roles for <scp>PIEZO1</scp> mechanosensor in controlling normal megakaryocyte development and in primary myelofibrosis
Authors: Vittorio Abbonante, Anastasia Iris Karkempetzaki, Catherine Leon, Anandi Krishnan, Nasi Huang, Christian A. Di Buduo, Daniele Cattaneo, Christina Marie Ward, Shinobu Matsuura, Ines Guinard, Josiane Weber, Aurora De Acutis, Giovanni Vozzi, Alessandra Iurlo, Katya Ravid, Alessandra Balduini
Journal: American Journal of Hematology (2024)

Abstract Mechanisms through which mature megakaryocytes (Mks) and their progenitors sense the bone marrow extracellular matrix to promote lineage differentiation in health and disease are still partially understood. We found PIEZO1, a mechanosensitive cation channel, to be expressed in mouse and human Mks. Human mutations in PIEZO1 have been described to be associated with blood cell disorders. Yet, a role for PIEZO1 in megakaryopoiesis and proplatelet formation has never been investigated. Here, we show that activation of PIEZO1 increases the number of immature Mks in mice, while the number of mature Mks and Mk ploidy level are reduced. Piezo1/2 knockout mice show an increase in Mk size and platelet count, both at basal state and upon marrow regeneration. Similarly, in human samples, PIEZO1 is expressed during megakaryopoiesis. Its activation reduces Mk size, ploidy, maturation, and proplatelet extension. Resulting effects of PIEZO1 activation on Mks resemble the profile in Primary Myelofibrosis (PMF). Intriguingly, Mks derived from Jak2 V617F PMF mice show significantly elevated PIEZO1 expression, compared to wild‐type controls. Accordingly, Mks isolated from bone marrow aspirates of JAK2 V617F PMF patients show increased PIEZO1 expression compared to Essential Thrombocythemia. Most importantly, PIEZO1 expression in bone marrow Mks is inversely correlated with patient platelet count. The ploidy, maturation, and proplatelet formation of Mks from JAK2 V617F PMF patients are rescued upon PIEZO1 inhibition. Together, our data suggest that PIEZO1 places a brake on Mk maturation and platelet formation in physiology, and its upregulation in PMF Mks might contribute to aggravating some hallmarks of the disease.
Response to Commentary: Accounting for diverse transposable element landscapes is key to developing and evaluating accurate de novo annotation strategies
Authors: Shujun Ou, Ning Jiang, Candice N. Hirsch, Matthew B. Hufford
Journal: Genome biology (2024)

EDTA is an evolving tool for transposable element (TE) annotation that is under continual development.We are a group of plant biologists; hence, EDTA 1.0 was developed and benchmarked for use primarily in plant genomes, in which non-long terminal repeat (LTR) retrotransposons contribute only a small fraction of TE content.A major limitation that was discussed in the original paper describing EDTA for broad application was the lack of reliable tools at that time (May 2019) for structural annotation of non-LTR retrotransposons, including long interspersed nuclear elements (LINEs) and short interspersed nuclear element (SINEs), and the over inclusiveness of the search engine for Helitrons [1].Since its original release, we have continued to make improvements that address concerns raised by users.Below, we detail new benchmarking that was done in response to the specific concerns raised in the commentary by Gozashti and Hoekstra [2], ongoing improvements to EDTA, and best practices for using the software when applying to species with variable TE landscapes.EDTA first begins with structural annotation of intact transposable elements using specialized annotation programs (e.g., TIR-Learner to annotate terminal inverted repeat (TIR) elements and LTR_retriever to annotate LTR retrotransposons).EDTA then builds a filtered, non-redundant library of intact TE sequences from structurally annotated elements to perform homology-based annotation of non-intact TE sequences in the genome.At this stage, a user is able to provide a reference library to augment the library generated from the EDTA-identified, structurally intact elements.If a user is annotating a species with a TE landscape that is not reflected in the structural annotation tools currently included in EDTA (e.g., LINEs and SINEs), EDTA will not perform optimally
Lifetime Gained With Cancer Screening
Authors: Hermann Brenner, Michael Hoffmeister
Journal: JAMA Internal Medicine (2024)

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 Internal Medicine HomeNew OnlineCurrent IssueFor Authors Podcast Journals 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) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2024 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 Internal Medicine journal
Automated External Defibrillator Use After Out-of-Hospital Cardiac Arrest at Recreational Facilities
Authors: Ahmed A. Kolkailah, Paul S. Chan, Qiang Li, Anezi Uzendu, Mirza S. Khan, Saket Girotra
Journal: JAMA Internal Medicine (2024)

This cohort study examines bystander automated external defibrillator (AED) application and survival outcomes for out-of-hospital cardiac arrest at recreational facilities in US states with and without AED legislation.
Lifetime Gained With Cancer Screening—Reply
Authors: Michael Bretthauer, Michal F. Kaminski, Mette Kalager
Journal: JAMA Internal Medicine (2024)

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 Internal Medicine HomeNew OnlineCurrent IssueFor Authors Podcast Journals 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) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2024 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 Internal Medicine journal
Enhanced Electrochemical Characterization of the Immune Checkpoint Protein PD‐L1 using Aptamer‐Functionalized Magnetic Metal‐Organic Frameworks
Authors: Ying Ma, Maoqiang Wu, Fayin Mo, Zuanguang Chen, Jing Lu, Duanping Sun
Journal: Advanced Healthcare Materials (2024)

Abstract Programmed death ligand 1 (PD‐L1) is highly expressed in cancer cells and participates in the immune escape process of tumor cells. However, as one of the most promising biomarkers for cancer immunotherapy monitoring, the key problem ahead of practical usage is how to effectively improve the detection sensitivity of PD‐L1. Herein, an electrochemical aptasensor for the evaluation of tumor immunotherapy is developed based on the immune checkpoint protein PD‐L1. The fundamental principle of this method involves the utilization of DNA nanotetrahedron (NTH)‐based capture probes and aptamer‐modified magnetic metal‐organic framework nanocomposites as signaling probes. A synergistic enhancement is observed in the electrocatalytic effect between Fe 3 O 4 and UiO‐66 porous shells in Fe 3 O 4 @UiO‐66 nanocomposites. Therefore, the integration of aptamer‐modified Fe 3 O 4 @UiO‐66@Au with NTH‐assisted target immobilization as an electrochemical sensing platform can significantly enhance sensitivity and specificity for target detection. This method enables the detection of targets at concentrations as low as 7.76 pg mL −1 over a wide linear range (0.01 to 1000 ng mL −1 ). The authors have successfully employed this sensor for in situ characterization of PD‐L1 on the cell surface and for monitoring changes in PD‐L1 expression during drug therapy, providing a cost‐effective yet robust alternative to highly expensive and expertise‐dependent flow cytometry.
<scp>D</scp>‐dimer and sinusoidal obstructive syndrome‐novel poor prognostic features of thrombotic microangiopathy in children after hematopoietic cellular therapy in a single institution prospective cohort study
Authors: Michelle L. Schoettler, Kaley French, Anora Harris, Elyse Bryson, Laura Deeb, Zuri Hudson, Jeremy Obordo, Shanmuganathan Chandrakasan, Suhag Parikh, Benjamin Watkins, Elizabeth Stenger, Muna Qayed, Satheesh Chonat, Adrianna Westbrook, Jeffrey Switchenko, Kirsten M. Williams
Journal: American Journal of Hematology (2024)

Abstract Transplant‐associated thrombotic microangiopathy (TA‐TMA) is a common, severe complication of allogeneic hematopoietic cellular therapy (HCT). Even when treated in many studies, morbidity and mortality rates are high. This prospective single‐institution cohort study serially enrolled all allogeneic HCT recipients from August 2019–August 2022. Patients were universally screened for TA‐TMA and intermediate and high‐risk patients were immediately treated with eculizumab. Sub‐distribution cox‐proportional hazards models were used to identify sub‐distribution hazard ratios (sHR) for multi‐organ dysfunction (MOD) and non‐relapse‐related mortality (NRM). Of 136 patients, 36 (26%) were diagnosed with TA‐TMA and 21/36 (58%) developed MOD, significantly more than those without TA‐TMA, ( p &lt; .0001). Of those with TA‐TMA, 18 (50%) had high‐risk TA‐TMA (HR‐TA‐TMA), 11 (31%) had intermediate‐risk TA‐TMA (IR‐TA‐TMA), and 8 (22%) had standard risk (SR‐TA‐TMA). Twenty‐six were treated with eculizumab (1/8 SR, 7/11 IR, and 18/18 HR). Elevated D‐dimer predicted the development of MOD (sHR 7.6, 95% confidence interval [CI] 1.8–32.3). Children with concurrent sinusoidal obstructive syndrome (SOS) and TA‐TMA had an excess risk of MOD of 34% and data supported a biologic interaction. The adjusted NRM risk was significantly higher in the TA‐TMA patients (sHR 10.54, 95% CI 3.8–29.2, p &lt; .0001), despite prompt treatment with eculizumab. Significant RF for NRM in TA‐TMA patients included SOS (HR 2.89, 95% 1.07–7.80) and elevated D‐dimer (HR 3.82, 95% CI 1.14–12.84). An unrelated donor source and random urine protein to creatine ratio ≥2 mg/mg were significantly associated with no response to eculizumab (odds ratio 15, 95% CI 2.0–113.6 and OR 6.5, 95% CI 1.1–38.6 respectively). TA‐TMA was independently associated with NRM despite early diagnosis and treatment with eculizumab in this large pediatric transplant cohort. Prognostic implications of D‐dimer in TA‐TMA merit further investigation as this is a readily accessible biomarker. Concurrent SOS is an exclusion criterion of many ongoing clinical trials, but these data highlight these patients could benefit from novel therapeutic approaches. Multi‐institutional clinical trials are needed to understand the impact of TA‐TMA‐targeted therapies.
IKKβ stabilizes Mitofusin 2 and suppresses doxorubicin cardiomyopathy
Authors: Matthew Guberman, Rimpy Dhingra, Jenna Cross, Victoria Margulets, Hongying Gang, Inna Rabinovich-Nikitin, Lorrie A Kirshenbaum
Journal: Cardiovascular Research (2024)

Abstract Aims The mitochondrial dynamics protein Mitofusin 2 (MFN2) coordinates critical cellular processes including mitochondrial bioenergetics, quality control, and cell viability. The NF-κB kinase IKKβ suppresses mitochondrial injury in doxorubicin cardiomyopathy, but the underlying mechanism is undefined. Methods and results Herein, we identify a novel signalling axis that functionally connects IKKβ and doxorubicin cardiomyopathy to a mechanism that impinges upon the proteasomal stabilization of MFN2. In contrast to vehicle-treated cells, MFN2 was highly ubiquitinated and rapidly degraded by the proteasomal-regulated pathway in cardiac myocytes treated with doxorubicin. The loss of MFN2 activity resulted in mitochondrial perturbations, including increased reactive oxygen species (ROS) production, impaired respiration, and necrotic cell death. Interestingly, doxorubicin-induced degradation of MFN2 and mitochondrial-regulated cell death were contingent upon IKKβ kinase activity. Notably, immunoprecipitation and proximity ligation assays revealed that IKKβ interacted with MFN2 suggesting that MFN2 may be a phosphorylation target of IKKβ. To explore this possibility, mass spectrometry analysis identified a novel MFN2 phospho-acceptor site at serine 53 that was phosphorylated by wild-type IKKβ but not by a kinase-inactive mutant IKKβK–M. Based on these findings, we reasoned that IKKβ-mediated phosphorylation of serine 53 may influence MFN2 protein stability. Consistent with this view, an IKKβ-phosphomimetic MFN2 (MFN2S53D) was resistant to proteasomal degradation induced by doxorubicin whereas wild-type MFN2 and IKKβ-phosphorylation defective MFN2 mutant (MFNS53A) were readily degraded in cardiac myocytes treated with doxorubicin. Concordantly, gain of function of IKKβ or MFN2S53D suppressed doxorubicin-induced mitochondrial injury and cell death. Conclusions The findings of this study reveal a novel survival pathway for IKKβ that is mutually dependent upon and obligatory linked to the phosphorylation and stabilization of the mitochondrial dynamics protein MFN2.
Hyperbaric oxygen augments susceptibility to <i>C. difficile</i> infection by impairing gut microbiota ability to stimulate the HIF-1α-IL-22 axis in ILC3
Authors: José L. Fachi, Laís. P. Pral, Helder C. Assis, Sarah Oliveira, Vinícius R. Rodovalho, Jefferson A. C. dos Santos, Mariane F. Fernandes, Valquíria A. Matheus, Renata Sesti-Costa, Paulo J. Basso, Marina Flóro e Silva, Niels O. S. Câmara, Selma Giorgio, Marco Colonna, Marco A. R. Vinolo
Journal: Gut Microbes (2024)

Hyperbaric oxygen (HBO) therapy is a well-established method for improving tissue oxygenation and is typically used for the treatment of various inflammatory conditions, including infectious diseases. However, its effect on the intestinal mucosa, a microenvironment known to be physiologically hypoxic, remains unclear. Here, we demonstrated that daily treatment with hyperbaric oxygen affects gut microbiome composition, worsening antibiotic-induced dysbiosis. Accordingly, HBO-treated mice were more susceptible to Clostridioides difficile infection (CDI), an enteric pathogen highly associated with antibiotic-induced colitis. These observations were closely linked with a decline in the level of microbiota-derived short-chain fatty acids (SCFAs). Butyrate, a SCFA produced primarily by anaerobic microbial species, mitigated HBO-induced susceptibility to CDI and increased epithelial barrier integrity by improving group 3 innate lymphoid cell (ILC3) responses. Mice displaying tissue-specific deletion of HIF-1 in RORγt-positive cells exhibited no protective effect of butyrate during CDI. In contrast, the reinforcement of HIF-1 signaling in RORγt-positive cells through the conditional deletion of VHL mitigated disease outcome, even after HBO therapy. Taken together, we conclude that HBO induces intestinal dysbiosis and impairs the production of SCFAs affecting the HIF-1α-IL-22 axis in ILC3 and worsening the response of mice to subsequent C. difficile infection.
DSS treatment does not affect murine colonic microbiota in absence of the host
Authors: Jannike Lea Krause, Beatrice Engelmann, Stephanie Serena Schaepe, Ulrike Rolle-Kampczyk, Nico Jehmlich, Hyun-Dong Chang, Ulla Slanina, Maximillian Hoffman, Jörg Lehmann, Ana Claudia Zenclussen, Gunda Herberth, Martin von Bergen, Sven-Bastiaan Haange
Journal: Gut Microbes (2024)

The prevalence of inflammatory bowel disease (IBD) is rising globally; however, its etiology is still not fully understood. Patient genetics, immune system, and intestinal microbiota are considered critical factors contributing to IBD. Preclinical animal models are crucial to better understand the importance of individual contributing factors. Among these, the dextran sodium sulfate (DSS) colitis model is the most widely used. DSS treatment induces gut inflammation and dysbiosis. However, its exact mode of action remains unclear. To determine whether DSS treatment induces pathogenic changes in the microbiota, we investigated the microbiota-modulating effects of DSS on murine microbiota in vitro. For this purpose, we cultured murine microbiota from the colon in six replicate continuous bioreactors. Three bioreactors were supplemented with 1% DSS and compared with the remaining PBS-treated control bioreactors by means of microbiota taxonomy and functionality. Using metaproteomics, we did not identify significant changes in microbial taxonomy, either at the phylum or genus levels. No differences in the metabolic pathways were observed. Furthermore, the global metabolome and targeted short-chain fatty acid (SCFA) quantification did not reveal any DSS-related changes. DSS had negligible effects on microbial functionality and taxonomy in vitro in the absence of the host environment. Our results underline that the DSS colitis mouse model is a suitable model to study host–microbiota interactions, which may help to understand how intestinal inflammation modulates the microbiota at the taxonomic and functional levels.