tbuckley/cabot-search huggingface dataset:
Topical mupirocin treatment reduces interferon and myeloid signatures in cutaneous lupus erythematous lesions through targeting of <i>Staphylococcus</i> species
Authors: Lisa Abernathy‐Close, Joseph Mears, Allison C. Billi, Sirisha Sirobhushanam, Celine Berthier, Annie Lu, Zeran Zhang, Amy Hurst, Johann E. Gudjonsson, J. Michelle Kahlenberg
Journal: Arthritis & Rheumatology (2024)

Objective Cutaneous lupus erythematosus (CLE) is an inflammatory skin manifestation of systemic lupus erythematosus (SLE). Type I interferons (IFNs) promote inflammatory responses and are elevated in CLE lesions. We recently reported that CLE lesions are frequently colonized with Staphylococcus aureus ( S. aureus ). Here, we follow up in a proof‐of‐concept study to investigate whether type I IFN and inflammatory gene signatures in CLE lesions can be modulated with mupirocin, a topical antibiotic treatment against S. aureus ‐mediated skin infections. Methods Participants with active CLE lesions (n=12) were recruited and randomized into a week of topical treatment with either 2% mupirocin or petroleum jelly vehicle. Paired samples were collected before and after 7 days of treatment to assess microbial lesional skin responses. Microbial samples from nares and lesional skin were used to determine baseline and post‐treatment Staphylococcus abundance and microbial community profiles by 16S rRNA gene sequencing. Inflammatory responses were evaluated by bulk RNA sequencing of lesional skin biopsies. Results We identified 173 differentially expressed genes in CLE lesions after topical mupirocin treatment. Decreased lesional Staphylococcus burden correlated with decreased IFN pathway signaling and inflammatory gene expression and barrier dysfunction. Interestingly, mupirocin treatment lowered skin monocyte levels, and this mupirocin‐associated depletion of monocytes correlated with decreased inflammatory gene expression. Conclusion Mupirocin treatment decreased lesional Staphylococcus , and this correlated with decreased IFN signaling and inflammatory gene expression. This study suggests a topical antibiotic could be employed to decrease lupus skin inflammation and type I IFN responses by reducing Staphylococcus colonization. image
Development and Evaluation of a Comprehensive Prediction Model for Incident Coronary Heart Disease Using Genetic, Social, and Lifestyle–Psychological Factors: A Prospective Analysis of the UK Biobank
Authors: Mohammadreza Naderian, Kristjan Norland, Daniel J. Schaid, Iftikhar J. Kullo
Journal: Annals of Internal Medicine (2024)

Clinical risk calculators for coronary heart disease (CHD) do not include genetic, social, and lifestyle-psychological risk factors.
How Would You Manage This Patient With Gastroesophageal Reflux Symptoms? Grand Rounds Discussion From Beth Israel Deaconess Medical Center
Authors: Howard Libman, Timothy S. Anderson, Vikram V. Rangan, Eileen E. Reynolds
Journal: Annals of Internal Medicine (2024)

Gastroesophageal reflux disease (GERD) is a common medical condition presenting with heartburn, regurgitation, cough, hoarseness, and/or wheezing. Patients with classic GERD symptoms often do not require diagnostic studies before empirical treatment is initiated. However, if atypical features are present, including alarm symptoms for malignancy, or if symptoms do not respond to conventional treatment, upper endoscopy may be necessary. The optimal management of GERD, which is the subject of debate, depends on the frequency and severity of symptoms. In 2021, the American College of Gastroenterology published updated recommendations for diagnosis and management of GERD. In addition to histamine-2 receptor antagonist or proton-pump inhibitor therapy, which may be prescribed as needed or continuously, lifestyle and dietary modification are often advised. Here, 2 physicians, a primary care practitioner and a gastroenterologist, debate how to manage a patient with GERD symptoms. They discuss the diagnosis of this condition, its initial management, indications for upper endoscopy, and how to care for the patient whose condition does not respond to empirical therapy.
Management of Hyperglycemia in Hospitalized Patients
Authors: Roma Gianchandani, Margaret Wei, Andrew Demidowich
Journal: Annals of Internal Medicine (2024)

People with diabetes account for 25% of hospitalizations, or 8 million admissions annually. Poor glycemic control in the hospital is associated with increased morbidity, mortality, length of stay, and readmissions. Key considerations of inpatient diabetes management include initiation of appropriate insulin or medication regimens and frequent dose adjustments based on patient-specific factors. Inpatient diabetes management teams and new technologies are increasingly prevalent and can assist in achieving glycemic targets in the hospital. At discharge, standardized checklists should be used to ensure successful transitions of care.
Enhancing non-viral DNA delivery systems: Recent advances in improving efficiency and target specificity
Authors: Mahboubeh Hosseini-Kharat, Kristen Bremmell, Branka Grubor-Bauk, Clive A Prestidge
Journal: Journal of Controlled Release (2024)

DNA-based therapies are often limited by challenges such as stability, long-term integration, low transfection efficiency, and insufficient targeted DNA delivery. This review focuses on recent progress in the design of non-viral delivery systems for enhancing targeted DNA delivery and modulation of therapeutic efficiency. Cellular uptake and intracellular trafficking mechanisms play a crucial role in optimizing gene delivery efficiency. There are two main strategies employed to improve the efficiency of gene delivery vectors: (i) explore different administration routes (e.g., mucosal, intravenous, intramuscular, subcutaneous, intradermal, intratumoural, and intraocular) that best facilitates optimal uptake into the targeted cells and organs and (ii) modify the delivery vectors with cell-specific ligands (e.g., natural ligands, antibodies, peptides, carbohydrates, or aptamers) that enable targeted uptake to specific cells with higher specificity and improved biodistribution. We describe how recent progress in employing these DNA delivery strategies is advancing the field and increasing the clinical translation and ultimate clinical application of DNA therapies.
Dietary inulin ameliorates obesity-induced severe acute pancreatitis via gut-pancreas axis
Authors: Xin Li, Pan Zheng, Yaoyu Zou, Langyi Guan, Nianshuang Li, Jianping Liu, Nonghua Lu, Yin Zhu, Cong He
Journal: Gut Microbes (2024)

Obesity is a definitive factor of severity and mortality of acute pancreatitis (AP), and gut microbiota dysbiosis is involved in its pathogenesis. However, the effect of gut microbiota modulation by dietary components on high fat diet (HFD)-induced severe AP remains unclear. Here, we found that the inulin, a soluble dietary fiber, mitigated pancreatic injury and systematic inflammation in mice fed HFD, which was dependent on gut microbiota as this protective effect was attenuated in germ-free mice. Inulin treatment suppressed the overgrowth of pathogenic bacteria Escherichia Shigella, Enterococcus, Klebsiella, while increased the abundance of probiotics Akkermansia. Fecal microbiota transplantation from inulin-treated mice to recipient mice reduced pancreatic damage and remodeled intestinal homeostasis. Additionally, inulin increased fecal short chain fatty acids (SCFAs), strengthened gut barrier and restored Paneth cells. The beneficial effect of inulin on improving pancreatic damage and leaky gut was diminished after the suppression of SCFAs. Notably, SCFAs administration, especially butyrate, to HFD mice blocked pancreatic and intestinal injury with the inhibition of histone deacetylase 3 (HDAC3), and pharmacological HDAC3 inhibition mimicked the ameliorative effect of SCFAs. Mechanically, butyrate modulated macrophage M1/M2 polarization balance by suppressing HDAC3 and subsequent acetylation of histone H3K27. Collectively, our data offer new insights into the gut microbiota-pancreas axis that may be leveraged to augment the potential supplementation of prebiotic inulin in the management of obesity associated severe AP.
Endothelial FUNDC1 Deficiency Drives Pulmonary Hypertension
Authors: Yandong Pei, Dongfeng Ren, Yuanhao Yin, Jiajia Shi, Qianyuan Ai, Wenxin Hao, Xiaofan Luo, Chenyue Zhang, Yanping Zhao, Chenyu Bai, Lin Zhu, Qiong Wang, Shuangling Li, Yuwei Zhang, Jiangtao Lu, Lin Liu, Lin Zhou, Yuli Wu, Yiqi Weng, Yongle Jing, Chengzhi Lu, Yujie Cui, Hao Zheng, Yanjun Li, Guo Chen, Gang Hu, Quan Chen, Xudong Liao
Journal: Circulation Research (2024)

BACKGROUND: Pulmonary hypertension (PH) is associated with endothelial dysfunction. However, the cause of endothelial dysfunction and its impact on PH remain incompletely understood. We aimed to investigate whether the hypoxia-inducible FUNDC1 (FUN14 domain-containing 1)-dependent mitophagy pathway underlies PH pathogenesis and progression. METHODS: We first analyzed FUNDC1 protein levels in lung samples from patients with PH and animal models. Using rodent PH models induced by HySu (hypoxia+SU5416) or chronic hypoxia, we further investigated PH pathogenesis and development in response to global and cell-type-specific Fundc1 loss/gain-of-function. We also investigated the spontaneous PH in mice with inducible loss of endothelial Fundc1 . In addition, histological, metabolic, and transcriptomic studies were performed to delineate molecular mechanisms. Finally, findings were validated in vivo by compound deficiency of HIF2α (hypoxia-inducible factor 2α; Epas1 ) and pharmacological intervention. RESULTS: FUNDC1 protein levels were reduced in PH lung vessels from clinical subjects and animal models. Global Fundc1 deficiency exacerbated PH, while its overexpression was protective. The effect of FUNDC1 was mediated by endothelial cells rather than smooth muscle cells. Further, inducible loss of endothelial Fundc1 in postnatal mice was sufficient to cause PH spontaneously, whereas augmenting endothelial Fundc1 protected against PH before and after the onset of disease. Mechanistically, Fundc1 deficiency impaired basal mitophagy in endothelial cells, leading to the accumulation of dysfunctional mitochondria, metabolic reprogramming toward aerobic glycolysis, pseudohypoxia, and senescence, likely via a mtROS-HIF2α signaling pathway. Subsequently, Fundc1 -deficient endothelial cells increased IGFBP2 (insulin-like growth factor-binding protein 2) secretion that drove pulmonary arterial remodeling to instigate PH. Finally, proof-of-principle in vivo studies showed significant efficacy on PH amelioration by targeting endothelial mitophagy, pseudohypoxia, senescence, or IGFBP2. CONCLUSIONS: Collectively, we show that FUNDC1-mediated basal mitophagy is critical for endothelial homeostasis, and its disruption instigates PH pathogenesis. Given that similar changes in FUNDC1 and IGFBP2 were observed in PH patients, our findings are of significant clinical relevance and provide novel therapeutic strategies for PH.
Inositol 1,4,5-Trisphosphate Receptor 1 Gain-of-Function Increases the Risk for Cardiac Arrhythmias in Mice and Humans
Authors: Bo Sun, Mingke Ni, Yanhui Li, Zhenpeng Song, Hui Wang, Hai-Lei Zhu, Jinhong Wei, Darrell Belke, Shitian Cai, Wenting Guo, Jinjing Yao, Shanshan Tian, John Paul Estillore, Ruiwu Wang, Mads Toft Sondergaard, Malene Brohus, Palle Duun Rohde, Yongxin Mu, Alexander Vallmitjana, Raul Benitez, Leif Hove-Madsen, Michael Toft Overgaard, Glenn I. Fishman, Ju Chen, Shubhayan Sanatani, Arthur A.M. Wilde, Michael Fill, Josefina Ramos-Franco, Mette Nyegaard, S.R. Wayne Chen
Journal: Circulation (2024)

BACKGROUND: Ca 2+ mishandling in cardiac Purkinje cells is a well-known cause of cardiac arrhythmias. The Purkinje cell resident inositol 1,4,5-trisphosphate receptor 1 (ITPR1) is believed to play an important role in Ca 2+ handling, and ITPR1 gain-of-function (GOF) has been implicated in cardiac arrhythmias. However, nearly all known disease-associated ITPR1 variants are loss-of-function and are primarily linked to neurological disorders. Whether ITPR1 GOF has pathological consequences, such as cardiac arrhythmias, is unclear. This study aimed to identify human ITPR1 GOF variants and determine the impact of ITPR1 GOF on Ca 2+ handling and arrhythmia susceptibility. METHODS: There are a large number of rare ITPR1 missense variants reported in open data repositories. Based on their locations in the ITPR1 channel structure, we selected and characterized 33 human ITPR1 missense variants from open databases and identified 21 human ITPR1 GOF variants. We generated a mouse model carrying a human ITPR1 GOF variant, ITPR1-W1457G (W1447G in mice). RESULTS: We showed that the ITPR1-W1447G ± and recently reported ITPR1-D2594K ± GOF mutant mice were susceptible to stress-induced ventricular arrhythmias. Confocal Ca 2+ and voltage imaging in situ in heart slices and Ca 2+ imaging and patch-clamp recordings of isolated Purkinje cells showed that ITPR1-W1447G ± and ITPR1-D2594K ± variants increased the occurrence of stress-induced spontaneous Ca 2+ release, delayed afterdepolarization, and triggered activity in Purkinje cells. To assess the potential role of ITPR1 variants in arrhythmia susceptibility in humans, we looked up a gene-based association study in the UK Biobank data set and identified 7 rare ITPR1 missense variants showing potential association with cardiac arrhythmias. Remarkably, in vitro functional characterization revealed that all these 7 ITPR1 variants resulted in GOF. CONCLUSIONS: Our studies in mice and humans reveal that enhanced function of ITPR1, a well-known movement disorder gene, increases the risk for cardiac arrhythmias.
Machine learning approach to identify phenotypes in patients with ischaemic heart failure with reduced ejection fraction
Authors: Luca Monzo, Emmanuel Bresso, Kenneth Dickstein, Bertram Pitt, John G.F. Cleland, Stefan D. Anker, Carolyn S.P. Lam, Mandeep R. Mehra, Dirk J. van Veldhuisen, Barry Greenberg, Faiez Zannad, Nicolas Girerd
Journal: European Journal of Heart Failure (2024)

Aims Patients experiencing ischaemic heart failure with reduced ejection fraction (HFrEF) represent a diverse group. We hypothesize that machine learning clustering can help separate distinctive patient phenotypes, paving the way for personalized management. Methods and results A total of 8591 ischaemic HFrEF patients pooled from the EPHESUS and CAPRICORN trials (64 ± 12 years; 28% women) were included in this analysis. Clusters were identified using both clinical and biological variables. Association between clusters and the composite of (i) heart failure hospitalization or all‐cause death, (ii) cardiovascular (CV) hospitalization or all‐cause death, and (iii) major adverse CV events was assessed. The derived algorithm was applied in the COMMANDER‐HF trial ( n = 5022) for external validation. Five clinical distinctive clusters were identified: Cluster 1 ( n = 2161) with the older patients, higher prevalence of atrial fibrillation and previous CV events; Cluster 2 ( n = 1376) with the higher prevalence of older hypertensive women and smoking habit; Cluster 3 ( n = 1157) with the higher prevalence of diabetes and peripheral artery disease; Cluster 4 ( n = 2073) with relatively younger patients, mostly men and with the higher left ventricular ejection fraction; Cluster 5 ( n = 1824) with the younger patients and lower CV events burden. Cluster membership was efficiently predicted by a random forest algorithm. Clusters were significantly associated with outcomes in derivation and validation datasets, with Cluster 1 having the highest risk, and Cluster 4 the lowest. Mineralocorticoid receptor antagonist benefit on CV hospitalization or all‐cause death was magnified in clusters with the lowest risk of events (Clusters 2 and 4). Conclusion Clustering reveals distinct risk subgroups in the heterogeneous array of ischaemic HFrEF patients. This classification, accessible online, could enhance future outcome predictions for ischaemic HFrEF cases.
Radiotherapy-immunomodulated nanoplatform triggers both hypoxic and normoxic tumor associated antigens generation for robust abscopal effect and sustained immune memory
Authors: Jie Li, Chenfeng Tan, Jin Yang, Zhongzheng Xiang, Yan Wang, Meiling Shen, Shunyao Zhu, Tao He, Xiuqi Liang, Bianfei Shao, Haijun Li, Zhike Li, Lei Liu, Changyang Gong
Journal: Biomaterials (2024)
Serotonin neurons integrate GABA and dopamine inputs to regulate meal initiation
Authors: Kristine M Conde, HueyZhong Wong, Shuzheng Fang, Yongxiang Li, Meng Yu, Yue Deng, Qingzhuo Liu, Xing Fang, Mengjie Wang, Yuhan Shi, Olivia Z Ginnard, Yuxue Yang, Longlong Tu, Hesong Liu, Hailan Liu, Na Yin, Jonathan C Bean, Junying Han, Megan E Burt, Sanika V Jossy, Yongjie Yang, Qingchun Tong, Benjamin R Arenkiel, Chunmei Wang, Yang He, Yong Xu
Journal: Metabolism (2024)
Lipidomic analysis of plant-derived extracellular vesicles for guidance of potential anti-cancer therapy
Authors: Fei Wang, Lanya Li, Junyao Deng, Jiacong Ai, Shushan Mo, Dandan Ding, Yingxian Xiao, Shiqi Hu, Dashuai Zhu, Qishan Li, Yan Zeng, Zhitong Chen, Ke Cheng, Zhenhua Li
Journal: Bioactive Materials (2024)
Macrophages boosting human skin morphogenesis
Authors: Martin E. Baumdick, Madeleine J. Bunders
Journal: Trends in Immunology (2024)

Gopee and colleagues' recent analyses of diverse high-dimensional datasets of prenatal and adult skin, together with data from complex skin organoids, uncover the important contributions of macrophages in modulating prenatal skin development, scarless wound healing, and angiogenesis. These findings identify a role for skin immune cells in tissue development.
Liberal or Restrictive Transfusion Strategy in Aneurysmal Subarachnoid Hemorrhage
Authors: Shane W English, Anthony Delaney, Dean A Fergusson, Michaël Chassé, Alexis F Turgeon, François Lauzier, Angie Tuttle, Ofer Sadan, Donald E Griesdale, Gary Redekop, Martin Chapman, Mathew Hannouche, Andreas Kramer, Ian Seppelt, Andrew Udy, Demetrios J Kutsogiannis, Ryan Zarychanski, Frédérick D'Aragon, J Gordon Boyd, Gavin Salt, Judith Bellapart, Gordon Wood, Luis Cava, Gwynedd Pickett, Lauren Koffman, Irene Watpool, Frances Bass, Naomi Hammond, Tim Ramsay, Ranjeeta Mallick, Damon C Scales, Christopher R Andersen, Emily Fitzgerald, Phil Talbot, Dar Dowlatshahi, John Sinclair, Jason Acker, Shawn C Marshall, Lauralyn McIntyre
Journal: New England Journal of Medicine (2024)

BackgroundThe effect of a liberal red-cell transfusion strategy as compared with a restrictive strategy in patients during the critical care period after an aneurysmal subarachnoid hemorrhage is unclear.MethodsWe randomly assigned critically ill adults with acute aneurysmal subarachnoid hemorrhage and anemia to a liberal strategy (mandatory transfusion at a hemoglobin level of ≤10 g per deciliter) or a restrictive strategy (optional transfusion at a hemoglobin level of ≤8 g per deciliter). The primary outcome was an unfavorable neurologic outcome, defined as a score of 4 or higher on the modified Rankin scale (range, 0 to 6, with higher scores indicating greater disability) at 12 months. Secondary outcomes included 12-month functional independence as assessed with the Functional Independence Measure (FIM; scores range from 18 to 126) and quality of life as assessed with the EuroQol five-dimension, five-level (EQ-5D-5L) utility index (scores range from −0.1 to 0.95) and a visual analogue scale (VAS; scores range from 0 to 100); on each assessment, higher scores indicate better health status or quality of life.ResultsA total of 742 patients underwent randomization at 23 centers. The analysis of the primary outcome at 12 months included 725 patients (97.7%). An unfavorable neurologic outcome occurred in 122 of 364 patients (33.5%) in the liberal-strategy group and in 136 of 361 patients (37.7%) in the restrictive-strategy group (risk ratio, 0.88; 95% confidence interval [CI], 0.72 to 1.09; P=0.22). The mean (±SD) FIM score was 82.8±54.6 in the liberal-strategy group and 79.8±54.5 in the restrictive-strategy group (mean difference, 3.01; 95% CI, −5.49 to 11.51). The mean EQ-5D-5L utility index score was 0.5±0.4 in both groups (mean difference, 0.02; 95% CI, −0.04 to 0.09). The mean VAS score was 52.1±37.5 in the liberal-strategy group and 50±37.1 in the restrictive-strategy group (mean difference, 2.08; 95% CI, −3.76 to 7.93). The incidence of adverse events was similar in the two groups.ConclusionsIn patients with aneurysmal subarachnoid hemorrhage and anemia, a liberal transfusion strategy did not result in a lower risk of an unfavorable neurologic outcome at 12 months than a restrictive strategy. (Funded by the Canadian Institutes of Health Research and others; SAHARA ClinicalTrials.gov number, NCT03309579.)
Immunogenicity of cell death and cancer immunotherapy with immune checkpoint inhibitors
Authors: Elena Catanzaro, Manuel Beltrán-Visiedo, Lorenzo Galluzzi, Dmitri V Krysko
Journal: Cellular and Molecular Immunology (2024)

While immunotherapy with immune checkpoint inhibitors (ICIs) has revolutionized the clinical management of various malignancies, a large fraction of patients are refractory to ICIs employed as standalone therapeutics, necessitating the development of combinatorial treatment strategies. Immunogenic cell death (ICD) inducers have attracted considerable interest as combinatorial partners for ICIs, at least in part owing to their ability to initiate a tumor-targeting adaptive immune response. However, compared with either approach alone, combinatorial regimens involving ICD inducers and ICIs have not always shown superior clinical activity. Here, we discuss accumulating evidence on the therapeutic interactions between ICD inducers and immunotherapy with ICIs in oncological settings, identify key factors that may explain discrepancies between preclinical and clinical findings, and propose strategies that address existing challenges to increase the efficacy of these combinations in patients with cancer.
Alterations of gut virome with close interaction in the progression of estrogen deficiency-induced osteoporosis
Authors: Yueqi Chen, Chuan Yang, Zihan Deng, Tingwen Xiang, Jiulin Tan, Jianzhong Xu, Dong Sun, Fei Luo
Journal: Gut Microbes (2024)

Previous research has established a link between gut microbiota and osteoporosis (OP) advancement. However, there remains a limited understanding of the crucial contribution of the gut virome in the onset and progression of OP. We employed metagenomic shotgun sequencing and gut virome sequencing to process the ovariectomy (OVX)-induced OP murine model, which revealed significant disparities in bacteriome and virome compositions between subjects with OP and healthy controls. One hundred and seventy-four altered viral strains were identified to participate in the multifaceted regulation of bone loss, involving immune modulation, microbial metabolic activity, and intricate host-virus dynamics. Our findings suggested that the gut virome may influence bone metabolism, potentially altering the balance of bone-modulating compounds like short-chain fatty acids. This comprehensive analysis of the gut virome in OP highlighted the diagnostic potential of combined gut viral and bacterial biomarkers for OP.
The novel DNA cross-linking agent KL-50 is active against patient-derived models of new and recurrent post-temozolomide mismatch repair-deficient glioblastoma
Authors: Matthew McCord, Thomas Sears, Wenxia Wang, Rahul Chaliparambil, Shejuan An, Jann Sarkaria, C David James, Bruce Ruggeri, Susan Gueble, Ranjit Bindra, Craig Horbinski
Journal: Neuro-Oncology (2024)

Acquired resistance to temozolomide (TMZ) chemotherapy due to DNA mismatch repair (MMR) enzyme deficiency is a barrier to improving outcomes for IDH wild-type glioblastoma (GBM) patients. KL-50 is a new imidazotetrazine-based therapeutic designed to induce DNA interstrand cross links, and subsequent double-stranded breaks, in an MMR-independent manner in cells with O-6-Methylguanine-DNA Methyltransferase (MGMT) deficiency. Previous research showed its efficacy against LN229 glioma cells with MMR and MGMT knockdown. Its activity against patient-derived GBM that model post-TMZ recurrent tumors is unclear.