tbuckley/cabot-search huggingface dataset:
Repurposing an epithelial sodium channel inhibitor as a therapy for murine and human skin inflammation
Authors: Mårten C. G. Winge, Mazen Nasrallah, Leandra V. Jackrazi, Konnie Q. Guo, Jessica M. Fuhriman, Rebecca Szafran, Muthukumar Ramanathan, Irina Gurevich, Ngon T. Nguyen, Zurab Siprashvili, Mohammed Inayathullah, Jayakumar Rajadas, Douglas F. Porter, Paul A. Khavari, Atul J. Butte, M. Peter Marinkovich
Journal: Science Translational Medicine (2024)

Inflammatory skin disease is characterized by a pathologic interplay between skin cells and immunocytes and can result in disfiguring cutaneous lesions and systemic inflammation. Immunosuppression is commonly used to target the inflammatory component; however, these drugs are often expensive and associated with side effects. To identify previously unidentified targets, we carried out a nonbiased informatics screen to identify drug compounds with an inverse transcriptional signature to keratinocyte inflammatory signals. Using psoriasis, a prototypic inflammatory skin disease, as a model, we used pharmacologic, transcriptomic, and proteomic characterization to find that benzamil, the benzyl derivative of the US Food and Drug Administration–approved diuretic amiloride, effectively reversed keratinocyte-driven inflammatory signaling. Through three independent mouse models of skin inflammation (Rac1 G12V transgenic mice, topical imiquimod, and human skin xenografts from patients with psoriasis), we found that benzamil disrupted pathogenic interactions between the small GTPase Rac1 and its adaptor NCK1. This reduced STAT3 and NF-κB signaling and downstream cytokine production in keratinocytes. Genetic knockdown of sodium channels or pharmacological inhibition by benzamil prevented excess Rac1-NCK1 binding and limited proinflammatory signaling pathway activation in patient-derived keratinocytes without systemic immunosuppression. Both systemic and topical applications of benzamil were efficacious, suggesting that it may be a potential therapeutic avenue for treating skin inflammation.
ATP citrate lyase drives vascular remodeling in systemic and pulmonary vascular diseases through metabolic and epigenetic changes
Authors: Yann Grobs, Charlotte Romanet, Sarah-Eve Lemay, Alice Bourgeois, Pierre Voisine, Charlie Theberge, Melanie Sauvaget, Sandra Breuils-Bonnet, Sandra Martineau, Reem El Kabbout, Chanil Valasarajan, Prakash Chelladurai, Andreanne Pelletier, Manon Mougin, Elizabeth Dumais, Jean Perron, Nicolas Flamand, François Potus, Steeve Provencher, Soni Savai Pullamsetti, Olivier Boucherat, Sebastien Bonnet
Journal: Science Translational Medicine (2024)

ATP citrate lyase (ACLY), a crucial enzyme in de novo lipid synthesis and histone acetylation, plays a key role in regulating vascular smooth muscle cell (VSMC) proliferation and survival. We found that human coronary and pulmonary artery tissues had up-regulated ACLY expression during vascular remodeling in coronary artery disease and pulmonary arterial hypertension. Pharmacological and genetic inhibition of ACLY in human primary cultured VSMCs isolated from the coronary arteries of patients with coronary artery diseases and from the distal pulmonary arteries of patients with pulmonary arterial hypertension resulted in reduced cellular proliferation and migration and increased susceptibility to apoptosis. These cellular changes were linked to diminished glycolysis, reduced lipid synthesis, impairment in general control nonrepressed protein 5 (GCN5)-dependent histone acetylation and suppression of the transcription factor FOXM1. In vivo studies using a pharmacological inhibitor and VSMC-specific
Increased keratinocyte activity and PIEZO1 signaling contribute to paclitaxel-induced mechanical hypersensitivity
Authors: Alexander R. Mikesell, Elena Isaeva, Marie L. Schulte, Anthony D. Menzel, Anvitha Sriram, Megan M. Prahl, Seung Min Shin, Katelyn E. Sadler, Hongwei Yu, Cheryl L. Stucky
Journal: Science Translational Medicine (2024)

Recent work demonstrates that epidermal keratinocytes are critical for normal touch sensation. However, it is unknown whether keratinocytes contribute to touch-evoked pain and hypersensitivity after tissue injury. Here, we used a mouse model of paclitaxel treatment to determine the extent to which keratinocyte activity contributes to the severe neuropathic pain that accompanies chemotherapy. We found that keratinocyte inhibition by either optogenetic or chemogenetic methods largely alleviated paclitaxel-induced mechanical hypersensitivity across acute and persistent time points from 2 days through 3 weeks. Furthermore, we found that paclitaxel exposure sensitized mouse and human keratinocytes to mechanical stimulation and enhanced currents of PIEZO1, a mechanosensitive channel highly expressed in keratinocytes. Deletion of PIEZO1 from keratinocytes alleviated paclitaxel-induced mechanical hypersensitivity in mice. These findings suggest that nonneuronal cutaneous cells contribute substantially to neuropathic pain and pave the way for the development of new pain relief strategies that target epidermal keratinocytes and PIEZO1.
Engineering FRET biosensor for H3K9 acetylation imaging in single living cells
Authors: Shitian Li, Chang Sun, Reed E. S. Harrison, Leonardo Cheng, Li Gao, Longwei Liu, Yingxiao Wang, Qin Peng
Journal: Med-X (2024)

Abstract Histone acetylation is an important epigenetic modification that governs gene expression, chromatin changes in stress response, and cell fate transition. FRET biosensors have been developed for various epigenetic events to enable spatiotemporal tracking of sub-cellular signaling events. Previously reported histone H3 acetylation biosensor recognizing two acetyl residues lacked specificity. In this study, using a single bromodomain of the BRD4, we have developed a genetically encoded H3K9ac biosensor. We systematically investigated different combinations of the BET family protein as binding domains and performed site-saturated mutagenesis to optimize the biosensor, achieving a dynamic FRET change up to 30% under TSA treatment. With the application of the optimized H3K9ac biosensor, we revealed different basal active chromatin architectures in invasive tumor cells compared to benign tumor cells. Furthermore, we found that H3K9ac level increased dramatically when cancer cells passed through microchannels, which models the physical constraints and mechanical microenvironmental conditions that cancer cells encounter when passing through narrow spaces within the body. This result highlights the chromatin plasticity in response to external mechanical stresses. In summary, our H3K9ac biosensor provides a versatile tool for mechanistic investigation of cell fate transition in cancer and mechanotransduction. Graphical Abstract
The dominance of old blood, and age-related increase in protein production and noise
Authors: Alexandra Sviercovich, Xiaoyue Mei, Grace Xie, Michael J Conboy, Irina M Conboy
Journal: Ageing Research Reviews (2024)

This concise review provides new perspectives on systemic reduction of tissue aging by comparing different strategies, such as heterochronic parabiosis, injections of young blood plasma, neutral blood exchange (NBE) and therapeutic plasma exchange (TPE). Unlike previous literature that primarily discusses the need for young blood factors, we emphasize the potential of diluting age-elevated proteins as the way to re-calibrate systemic proteome to its younger state without donor blood. Furthermore, we introduce modulation of proteome noise, as an important part of understanding tissue aging and as a critical mechanism for tissue rejuvenation. We discuss studies on the dominance of aged systemic milieu in promoting progeric phenotypes in young cells, in vitro, and in multiple tissues of young animals, in vivo. We support our arguments with evidence showing a significant age-related increase in protein synthesis, in noise of newly synthesized proteomes, and in the rapid induction of these aging phenotypes in young muscle by exposure to aged tissue. We summarize the significance of these findings for future research on aging and longevity.
ELECTRICALLY CONDUCTIVE “SMART” HYDROGELS FOR ON-DEMAND DRUG DELIVERY
Authors: Soumajyoti Ghosh, Nikhil Kumar, Santanu Chattopadhyay
Journal: Asian Journal of Pharmaceutical Sciences (2024)

In the current transformative era of biomedicine, hydrogels have established their presence in biomaterials due to their superior biocompatibility, tuneability and resemblance with native tissue. However, hydrogels typically exhibit poor conductivity due to their hydrophilic polymer structure. Electrical conductivity provides an important enhancement to the properties of hydrogel-based systems in various biomedical applications such as drug delivery and tissue engineering. Consequently, researchers are developing combinatorial strategies to develop electrically responsive "SMART" systems to improve the therapeutic efficacy of biomolecules. Electrically conductive hydrogels have been explored for various drug delivery applications, enabling higher loading of therapeutic cargo with on-demand delivery. This review emphasizes the properties, mechanisms, fabrication techniques and recent advancements of electrically responsive "SMART" systems aiding on-site drug delivery applications. Additionally, it covers prospects for the successful translation of these systems into clinical research.
Care Models for Cancer Survivors
Authors: Abhay Singh, Akriti G. Jain, Betty K. Hamilton, Alex Adjei
Journal: Annual Review of Medicine (2024)

The population of cancer survivors is on the rise due to an increase in cancer incidence and a decline in cancer mortality. This growing survivor population creates a number of challenges. Although there have been improvements in care planning for cancer survivors, our healthcare system still lacks the delivery of coordinated care between primary care physicians and specialists. Understanding the needs of cancer survivors can help improve the current care models. In this review we describe existing survivorship care models. We also describe emerging models using some programs at the Cleveland Clinic to highlight various potential approaches.
Climate Change and Mental Health
Authors: Susan Clayton, Tara Crandon
Journal: Annual Review of Clinical Psychology (2024)

Climate change negatively threatens mental health through acute, chronic, indirect, and vicarious pathways. Though these psychological consequences will be felt globally, specific populations are at increased risk. This article describes the complex and diverse ways in which climate change can affect mental health and the resulting challenges that health care services will inevitably face. In responding to these threats, both prevention and intervention are urgently needed. Although mitigating the extent of climate change is crucial, we can also foster resilience to climate change-the ability to manage, respond to, and prepare for climate-related adversity-at the systemic, community, and individual levels. The mental health field must prepare for the significant burden that climate change will place on population health and well-being in the long term. In this review, we aim to inform and provide examples of how decision makers, the mental health discipline, and mental health professionals can respond.
Modified human mesenchymal stromal/stem cells restore cortical excitability after focal ischemic stroke in rats
Authors: Barbara Klein, Agnieszka Ciesielska, Patricia Morán Losada, Anna Sato, Sajita Shah-Morales, Jeremy B Ford, Bryan Higashikubo, Dale Tager, Alexander Urry, Juliane Bombosch, Wei-Cheng Chang, Yaisa Andrews-Zwilling, Bijan Nejadnik, Zuha Warraich, Jeanne T Paz
Journal: Molecular Therapy (2024)

Allogeneic modified bone marrow-derived mesenchymal stromal/stem cells (hMSC-SB623 cells) are in clinical development for the treatment of chronic motor deficits after traumatic brain injury and cerebral ischemic stroke. However, their exact mechanisms of action remain unclear. Here, we investigated the effects of this cell therapy on cortical network excitability, brain tissue and peripheral blood at a chronic stage after ischemic stroke in a rat model. One month after focal cortical ischemic stroke, hMSC-SB623 cells or the vehicle solution were injected into the peri-stroke cortex. Starting one-week post-treatment, cortical excitability was assessed ex vivo. hMSC-SB623 cell transplants reduced stroke-induced cortical hyperexcitability, restoring cortical excitability to control levels. Histology of brain tissue revealed an increase of factors relevant to neuroregeneration and synaptic and cellular plasticity. Whole-blood RNA sequencing and serum protein analyses showed that intracortical hMSC-SB623 cell transplantation reversed effects of stroke on peripheral blood factors known to be involved in stroke pathophysiology. Our findings demonstrate that intra-cortical transplants of hMSC-SB623 cells correct stroke-induced circuit disruptions even at the chronic stage, suggesting broad utility as a therapeutic for neurological conditions with network hyperexcitability. Additionally, the transplanted cells exert far-reaching immunomodulatory effects whose therapeutic impact remains to be explored.
Predicting Herpes Zoster Incidence Using a Combined Seasonal Autoregressive Integrated Moving Average and Back propagation Neural Network Model: A Time Series Analysis
Authors: Chenlu Fan, Kangjun Xu, Zhexin Xu, Chuanxi Fu
Journal: Journal of Infection (2024)

Highlights•Herpes zoster cases exhibited both seasonal and periodic patterns;•The SARIMA (0,0,2) (1,1,1) ₁₂ - BP (1-2-1) model demonstrated best performance;•This study offering an effective tool for epidemiological forecasting.
Left atrial myxoma associated with multivessel coronary embolism confirmed by cardiac magnetic resonance imaging: a case of myocardial infarction with non-obstructive coronary arteries
Authors: Annalisa Pasquini, Andrea Caffè, Monica Filice, Rosa Lillo, Rocco Antonio Montone, Giovanni Alfonso Chiariello, Natalia Pavone, Marialisa Nesta, Maria Grandinetti, Piergiorgio Bruno, Francesco Burzotta, Massimo Massetti
Journal:  (2024)

Abstract Aims Explore the diagnostic value of multimodal imaging in identifying considerably rare causes of myocardial infarction. Methods and results We report a case of myocardial infarction with non-obstructive coronary arteries (MINOCA) probably due to coronary embolism associated with a left atrial myxoma. A 56-year-old male presented with non-ST-elevation myocardial infarction, with coronary angiography showing mild coronary atherosclerosis without significant epicardial stenosis. Transthoracic echocardiography and cardiac magnetic resonance imaging (CMR) revealed a large left atrial mass, suspected to be an atrial myxoma. CMR also showed an ischaemic pattern involving multiple coronary territories, suggesting coronary embolism as the cause of the MINOCA. The patient underwent successful surgical excision of the left atrial mass, and histopathology confirmed the diagnosis of cardiac myxoma. Conclusions This case highlights the relevance of CMR in detecting ischaemic patterns in patients with a working diagnosis of MINOCA and underlines the diagnostic value of multimodal imaging in identifying considerably rare causes of myocardial infarction, such as myxoma-associated coronary embolism.
Hypoxia-Induced Senescent Fibroblasts Secrete IGF1 to Promote Cancer Stemness in Esophageal Squamous Cell Carcinoma
Authors: Zhengjie Ou, Liang Zhu, Xinjie Chen, Tianyuan Liu, Guoyu Cheng, Rucheng Liu, Shaosen Zhang, Wen Tan, Dongxin Lin, Chen Wu
Journal: Cancer Research (2024)

Cancer-associated fibroblasts (CAFs) contribute to cancer initiation and progression and play a pivotal role in therapeutic response and patient prognosis. CAFs exhibit functional and phenotypic heterogeneity, highlighting the need to clarify the specific subtypes of CAFs to facilitate the development of targeted therapies against pro-tumorigenic CAFs. Here, using single-cell RNA sequencing on patient samples of esophageal squamous cell carcinoma (ESCC), we identified a CAF subcluster associated with tumor stemness that was enriched in genes associated with hypoxia and senescence. The CAF subpopulation, termed as hypoxia-induced senescent fibroblasts (hsCAFs), displayed high secretion of insulin-like growth factor 1 (IGF1). The hsCAFs inhibited AMP-activated protein kinase (AMPK) activity in cancer cells via IGF1 to promote tumor stemness. The formation of hsCAFs was induced by the synergetic effect of hypoxia and cancer cells. Activation of nuclear factor erythroid 2-related factor 2 (NRF2) in cancer cells under hypoxia drove interleukin-1 alpha (IL-1α) production to trigger CAF senescence and IGF1 secretion via nuclear factor I A (NFIA). Knockout of IGF1 in CAFs or NRF2 in ESCC cells suppressed the tumor growth and chemotherapy resistance induced by CAFs in vivo. Importantly, patients with high proportions of hsCAFs showed poor survival and a worse response to chemotherapy. In summary, these findings identify a hsCAF subpopulation generated by interplay between cancer cells and CAFs under hypoxic conditions that promotes ESCC stemness and reveal targeting hsCAFs as an effective therapeutic strategy against chemotherapy-resistant ESCC.
When I use a word . . . Academic felonies and misdemeanours—adverse effects
Authors: Jeffrey K Aronson
Journal: BMJ (2024)

Estimates of the frequencies of the different types of academic felonies (research misconduct), fabrication, falsification, and plagiarism, are in single figures, at between 2% and 5% of all publications. Misdemeanours are more common. However, these figures are probably underestimates of the true frequencies, and even if the numbers seem relatively low, felonies are likely to have marked effects on research results. There is, for example, some evidence that they may contribute to the problem of poor reproducibility of research results. Furthermore, the quality of the data included in meta-analyses of published studies can certainly affect the conclusions of the analyses, as the example of ivermectin in the treatment of covid-19 shows.
Multiple gene therapy as a tool for regulating the expression of molecules involved in neovascular age-related macular degeneration
Authors: Thomas J Corydon, Toke Bek
Journal: Progress in Retinal and Eye Research (2024)

Anti-vascular endothelial growth factor (VEGF) therapies have revolutionized the treatment of neovascular age-related macular degeneration (nAMD) and other retinal diseases. However, the necessity for repeated intravitreal injections and the observation of variable treatment responses calls for new treatment modalities where fewer and more effective interventions can result in a clinical effect. Gene therapy might be such an alternative, and therefore the development and clinical application of gene therapy aimed at modifying gene expression has received considerable attention. The article reviews current knowledge of the background, pathophysiological mechanisms, technologies, limitations, and future directions for gene therapy aimed at modifying the synthesis of compounds involved in acquired and senescent retinal disease. The authors have contributed to the field by developing gene therapy to reduce the expression of vascular endothelial growth factor (VEGF), as well as multiple gene therapy for simultaneous downregulation of the synthesis of VEGF and upregulation of pigment epithelium-derived factor (PEDF) using adeno-associated virus (AAV) vectors. It is suggested that such multi-target gene therapy might be included in future treatments of retinal diseases where the underlying mechanisms are complex and cannot be attributed to one specific mediator. Such diseases might include dry AMD (dAMD) with geographic atrophy, but also diabetic macular edema (DME) and retinal vein occlusion (RVO). Gene therapy can be expected to be most beneficial for the patients in need of multiple intra-vitreal injections and in whom the therapeutic response is insufficient. It is concluded, that in parallel with basic research, there is a need for clinical studies aimed at identifying factors that can be used to identify patients who will benefit from gene therapy already at the time of diagnosis of the retinal disease.
Performance of molecular tests for diagnosis of bloodstream infections in the clinical setting: a systematic literature review and meta-analysis
Authors: Yu Wang, Kristina Lindsley, Tammy C Bleak, Sarah Jiudice, Jennifer Uyei, Yifan Gu, Yi Wang, Tristan T Timbrook, Joan-Miquel Balada-Llasat
Journal: Clinical Microbiology and Infection (2024)

Rapid identification of bloodstream pathogens and associated antimicrobial resistance (AMR) profiles by molecular tests from positive blood cultures (PBCs) have the potential to improve patient management and clinical outcomes. A systematic review and meta-analysis were conducted to evaluate diagnostic test accuracy (DTA) of molecular tests from PBCs for detecting pathogens and AMR in the clinical setting. . Medline, Embase, Cochrane, conference proceedings, and study bibliographies were searched. Studies evaluating DTA of commercially available molecular tests vs. traditional phenotypic identification and susceptibility testing methods in patients with PBCs were eligible. Patients with PBCs. Commercially available molecular tests. Traditional phenotypic identification and susceptibility testing methods (standard of care, SOC). Study quality was assessed using Quality Assessment of Diagnostic Accuracy Studies-2. Summary DTA outcomes were estimated using bivariate random-effects models for gram-negative bacteria (GNB), gram-positive bacteria (GPB), yeast, GNB-AMR, GPB-AMR, and specific targets when reported by ≥ 2 studies (PROSPERO CRD42023488057). Seventy-four studies including 24 590 samples were analysed, most of which had a low risk of bias. When compared with SOC, molecular tests showed 92-99% sensitivity, 99-100% specificity, 99-100% positive predictive value, and 97-100% negative predictive value for identifying total GNB (43 studies), GPB (38 studies), yeast (24 studies), GNB-AMR (35 studies), and GPB-AMR (39 studies). For individual pathogen targets, 93-100% sensitivity, 98-100% specificity, 86-100% positive predictive value, and 99-100% negative predictive value were estimated. Five of seven AMR genes had 91-99% sensitivity and 99-100% specificity. Sensitivity was lower for IMP (four studies; 62%; 95% CI, 34-83%) and VIM (four studies; 70%; 95% CI, 38-90%) carbapenemases, where genes were not detected or were not harboured in Pseudomonas aeruginosa (i.e. low prevalence). Performance of molecular tests in detecting AMR was generally comparable when grouped by geographical region (Europe, North America, and East Asia). High DTA support the use of molecular tests in identifying a broad panel of pathogens and detecting AMR in GNB and GPB.
Integration of Multiple Climate Change Mitigation Actions and Health Co-Benefits: A Framework Using the Global Calculator
Authors: Paolo Vineis, Lorenzo Mangone, Kristine Belesova, Cathryn Tonne, Rossella Alfano, Alexandre Strapasson, Christopher Millett, Neil Jennings, Jem Woods, Onesmus Mwabonje
Journal: Environmental Health Perspectives (2024)

The Global Calculator is an open-source model of the world's energy, land, and food systems. It is a pioneering online calculator to project the impact of interventions to mitigate climate change on global temperature. A few studies have been conducted to evaluate the health co-benefits of climate change mitigation, though they are still fragmentary.