tbuckley/cabot-search huggingface dataset:
Pharmacological Approaches to Hearing Loss
Authors: Christopher R Cederroth, Jonas Dyhrfjeld-Johnsen, Barbara Canlon
Journal: Pharmacological Reviews (2024)

Hearing disorders pose significant challenges to individuals experiencing them and their overall quality of life, emphasizing the critical need for advanced pharmacological approaches to address these conditions. Current treatment options often focus on amplification devices, cochlear implants, or other rehabilitative therapies, leaving a substantial gap regarding effective pharmacological interventions. Advancements in our understanding of the molecular and cellular mechanisms involved in hearing disorders induced by noise, aging, and ototoxicity have opened new avenues for drug development, some of which have led to numerous clinical trials, with promising results. The development of optimal drug delivery solutions in animals and humans can also enhance the targeted delivery of medications to the ear. Moreover, large genome studies contributing to a genetic understanding of hearing loss in humans combined with advanced molecular technologies in animal studies have shown a great potential to increase our understanding of the etiologies of hearing loss. The auditory system exhibits circadian rhythms and temporal variations in its physiology, its vulnerability to auditory insults, and its responsiveness to drug treatments. The cochlear clock rhythms are under the control of the glucocorticoid system, and preclinical evidence suggests that the risk/benefit profile of hearing disorder treatments using chronopharmacological approaches would be beneficial. If translatable to the bedside, such approaches may improve the outcome of clinical trials. Ongoing research into the molecular and genetic basis of auditory disorders, coupled with advancements in drug formulation and delivery as well as optimized timing of drug administration, holds great promise of more effective treatments. SIGNIFICANCE STATEMENT: Hearing disorders pose significant challenges to individuals and their overall quality of life, emphasizing the critical need for advanced pharmacological approaches to address these conditions. Ongoing research into the molecular and genetic basis of auditory disorders, coupled with advancements in drug delivery procedures and optimized timing of drug administration, holds the promise of more effective treatments.
Exosomal miRNAs: the tumor's trojan horse in selective metastasis
Authors: Mobina Bayat, Javid Sadri Nahand
Journal: Molecular Cancer (2024)

Organs of future metastasis are not passive receivers of circulating tumor cells, but are instead selectively and actively modified by the primary tumor before metastatic spread has even occurred. Tumors orchestrate a pre-metastatic program by conditioning distant organs to create microenvironments that foster the survival and proliferation of tumor cells before their arrival, thereby establishing pre-metastatic niches. Primary tumor-derived exosomes modulate these pre-metastatic niches, generating a permissive environment that facilitates the homing and expansion of tumor cells. Moreover, microRNAs have emerged as a key component of exosomal cargo, serving not only to induce the formation of pre-metastatic niches but also to prime these sites for the arrival and colonization of specific secondary tumor populations. Against this backdrop, this review endeavors to elucidate the impact of tumor-derived exosomal microRNAs on the genesis of their individualized pre-metastatic niches, with a view towards identifying novel means of specifying cancer metastasis and exploiting this phenomenon for cancer immunotherapy.
Closing the gap: addressing telehealth disparities across specialties in the sustained pandemic era
Authors: Saki Amagai, Edward Vonesh, James Adams, Yuan Luo
Journal: npj Digital Medicine (2024)

Missed appointments, or no-shows, disrupt healthcare delivery, exacerbating chronic disease management and leading to worse health outcomes. Telehealth has surged as a viable solution to reduce no-shows and improve healthcare accessibility, especially during the COVID-19 pandemic. However, telehealth disparities and its long-term efficacy across various medical specialties remain understudied. To address this, we performed a retrospective analysis of electronic health records from a heterogenous network of hospitals in Illinois, examining telehealth use and no-shows across among 444,752 adult patients with 1,973,098 outpatient encounters across nine specialties during the sustained pandemic phase (i.e., January 1, 2021 to July 1, 2022). Among them, 84,290 (4.27%) were no-shows, and telehealth constituted 202,933 (10.3%) of the total encounters. Telehealth use during the sustained phase varied significantly by specialty type. Overall, telehealth encounters were associated with reduced no-show odds compared to in-person encounters (OR, 0.28; 95% CI, 0.26-0.29). Black and Hispanic patients, as well as those with Medicaid, had higher no-show odds relative to their counterparts, even when using telehealth. Mental health specialty had the highest telehealth usage rate and the highest no-show odds (OR, 2.99; 95% CI, 2.84-3.14) relative to other specialties included in the study. Moreover, specialty type had differential effects on no-shows for telehealth. These results underscore the variability in telehealth use by specialty type and pervasive disparities telehealth use and no-shows. As we move beyond the pandemic, our findings can inform policymakers to tailor policies and incentives to reach different patient groups as well as specialties, with varying needs, to promote equitable telehealth utilization.
Dietary fiber for the prevention of childhood obesity: a focus on the involvement of the gut microbiota
Authors: Zhongmin Yang, Mingyue Yang, Edward C. Deehan, Chenxi Cai, Karen L. Madsen, Eytan Wine, Guiling Li, Jian Li, Jingwen Liu, Zhengxiao Zhang
Journal: Gut Microbes (2024)

Given the worldwide epidemic of overweight and obesity among children, evidence-based dietary recommendations are fundamentally important for obesity prevention. Although the significance of the human gut microbiome in shaping the physiological effects of diet and obesity has been widely recognized, nutritional therapeutics for the mitigation of pediatric obesity globally are only just starting to leverage advancements in the nutritional microbiology field. In this review, we extracted data from PubMed, EMBASE, Scopus, Web of Science, Google Scholar, CNKI, Cochrane Library and Wiley online library that focuses on the characterization of gut microbiota (including bacteria, fungi, viruses, and archaea) in children with obesity. We further review host-microbe interactions as mechanisms mediating the physiological effects of dietary fibers and how fibers alter the gut microbiota in children with obesity. Contemporary nutritional recommendations for the prevention of pediatric obesity are also discussed from a gut microbiological perspective. Finally, we propose an experimental framework for integrating gut microbiota into nutritional interventions for children with obesity and provide recommendations for the design of future studies on precision nutrition for pediatric obesity.
Positive feedback loop PU.1-IL9 in Th9 promotes rheumatoid arthritis development
Authors: Jiajie Tu, Weile Chen, Wei Huang, Xinming Wang, Yilong Fang, Xuming Wu, Huiru Zhang, Chong Liu, Xuewen Tan, Xiangling Zhu, Huihui Wang, Dafei Han, Yizhao Chen, Anqi Wang, Yuanyuan Zhou, Zimeng Xue, Hui Xue, Shangxue Yan, Lingling Zhang, Zhenbao Li, Chunlan Yang, Yujie Deng, Shihao Zhang, Chen Zhu, Wei Wei
Journal: Annals of the Rheumatic Diseases (2024)

T helper 9 (Th9) cells are recognised for their characteristic expression of the transcription factor PU.1 and production of interleukin-9 (IL-9), which has been implicated in various autoimmune diseases. However, its precise relationship with rheumatoid arthritis (RA) pathogenesis needs to be further clarified.
Evaluation of dupilumab on the disease burden in children and adolescents with atopic dermatitis: A population‐based cohort study
Authors: Serena Yun‐Chen Tsai, Jonathan M. Gaffin, Elena B. Hawryluk, Hana B. Ruran, Lisa M. Bartnikas, Michiko K. Oyoshi, Lynda C. Schneider, Wanda Phipatanakul, Kevin Sheng‐Kai Ma
Journal: Allergy (2024)

Abstract Background Dupilumab is the first and only biologic agent approved for the treatment of atopic dermatitis (AD) in pediatric patients aged from 6 months to 17 years. The study aimed to evaluate the impact of dupilumab on the occurrence of comorbidities in pediatric patients with AD. Methods In this population‐based cohort study, we utilized electronic health records from multiple healthcare organizations across the United States. Pediatric patients (&lt;18 years of age) with a diagnosis of AD initiating dupilumab were propensity‐score matched 1:1 to those initiating other systemic agents (azathioprine, cyclosporine, methotrexate, mycophenolate mofetil, or systemic corticosteroids). The primary outcomes were new‐onset comorbidities emerging during the study period measured by the risk ratio (RR) and its confidence interval (CI). Subgroup analyses were stratified by age (0–5 years, 6–11 years, and 12–17 years), sex, and race. Results A total of 3575 pediatric patients with AD treated with dupilumab were matched to 3575 patients treated with other systemic agents. The dupilumab cohort was associated with a lowered risk of new‐onset atopic comorbidities (including asthma [RR, 0.72; 95% CI, 0.59–0.89] and allergic rhinitis [RR, 0.62; 95% CI, 0.52–0.74]), infections (e.g., skin and soft tissue infection [RR, 0.70; 95% CI, 0.63–0.76] and respiratory tract infection [RR = 0.56; 95% CI, 0.51–0.61]), psychiatric disorders (e.g., mood disorder [RR, 0.52; 95% CI, 0.39–0.70] and anxiety [RR, 0.57; 95% CI, 0.46–0.70], sleep disturbance [RR, 0.60; 95% CI, 0.47–0.77]), neurologic and developmental disorders (e.g., attention deficit hyperactivity disorder [RR, 0.54; 95% CI, 0.38–0.75]). Furthermore, the positive effects are found to be more pronounced in younger children (aged 0–5 years) with AD. Conclusions Treatment with dupilumab compared to systemic agents resulted in reductions in AD‐related comorbidities in pediatric patients.
Intravenous infusions of mesenchymal stromal cells have cumulative beneficial effects in a porcine model of chronic ischemic cardiomyopathy
Authors: Xian-Liang Tang, Marcin Wysoczynski, Anna M Gumpert, Mitesh Solanki, Yan Li, Wen-Jian Wu, Shirong Zheng, Halina Ruble, Hong Li, Heather Stowers, Shengnan Zheng, Qinghui Ou, Nida Tanveer, Jan Slezak, Dinesh K Kalra, Roberto Bolli
Journal: Cardiovascular Research (2024)

The development of cell therapy as a widely available clinical option for ischaemic cardiomyopathy is hindered by the invasive nature of current cell delivery methods. Furthermore, the rapid disappearance of cells after transplantation provides a cogent rationale for using repeated cell doses, which, however, has not been done thus far in clinical trials because it is not feasible with invasive approaches. The goal of this translational study was to test the therapeutic utility of the intravenous route for cell delivery.
Targeting the I <sub>Ks</sub> Channel PKA Phosphorylation Axis to Restore Its Function in High-Risk LQT1 Variants
Authors: Ling Zhong, Zhenzhen Yan, Dexiang Jiang, Kuo-Chan Weng, Yue Ouyang, Hangyu Zhang, Xiaoqing Lin, Chenxin Xiao, Huaiyu Yang, Jing Yao, Xinjiang Kang, Changhe Wang, Chen Huang, Bing Shen, Sookja Kim Chung, Zhi-Hong Jiang, Wandi Zhu, Erwin Neher, Jonathan R. Silva, Panpan Hou
Journal: Circulation Research (2024)

BACKGROUND: The KCNQ1+KCNE1 (I Ks ) potassium channel plays a crucial role in cardiac adaptation to stress, in which β-adrenergic stimulation phosphorylates the I Ks channel through the cyclic adenosine monophosphate (cAMP)/PKA (protein kinase A) pathway. Phosphorylation increases the channel current and accelerates repolarization to adapt to an increased heart rate. Variants in KCNQ1 can cause long-QT syndrome type 1 (LQT1), and those with defective cAMP effects predispose patients to the highest risk of cardiac arrest and sudden death. However, the molecular connection between I Ks channel phosphorylation and channel function, as well as why high-risk LQT1 mutations lose cAMP sensitivity, remain unclear. METHODS: Regular patch clamp and voltage clamp fluorometry techniques were utilized to record pore opening and voltage sensor movement of wild-type and mutant KCNQ1/I Ks channels. The clinical phenotypic penetrance of each LQT1 mutation was analyzed as a metric for assessing their clinical risk. The patient-specific–induced pluripotent stem-cell model was used to test mechanistic findings in physiological conditions. RESULTS: By systematically elucidating mechanisms of a series of LQT1 variants that lack cAMP sensitivity, we identified molecular determinants of I Ks channel regulation by phosphorylation. These key residues are distributed across the N-terminus of KCNQ1 extending to the central pore region of I Ks . We refer to this pattern as the I Ks channel PKA phosphorylation axis. Next, by examining LQT1 variants from clinical databases containing 10 579 LQT1 carriers, we found that the distribution of the most high-penetrance LQT1 variants extends across the I Ks channel PKA phosphorylation axis, demonstrating its clinical relevance. Furthermore, we found that a small molecule, ML277, which binds at the center of the phosphorylation axis, rescues the defective cAMP effects of multiple high-risk LQT1 variants. This finding was then tested in high-risk patient-specific induced pluripotent stem cell–derived cardiomyocytes, where ML277 remarkably alleviates the beating abnormalities. CONCLUSIONS: Our findings not only elucidate the molecular mechanism of PKA-dependent I Ks channel phosphorylation but also provide an effective antiarrhythmic strategy for patients with high-risk LQT1 variants.
The relationship between ultrasound and physical examination in the assessment of enthesitis in <scp>SpA</scp> patients: results from the <scp>DEUS</scp> multicentre study
Authors: Andrea Di Matteo, Stefano Di Donato, Gianluca Smerilli, Andrea Becciolini, Federica Camarda, Alberto Cauli, Tomás Cazenave, Edoardo Cipolletta, Davide Corradini, Juan Jose de Agustin, Giulia M Destro Castaniti, Eleonora Di Donato, Emine Duran, Bayram Farisogullari, Marco Fornaro, Francesca Francioso, Pamela Giorgis, Raquel Granados, Amelia Granel, Cristina Hernandez Diaz, Rudolf Horvath, Jana Hurnakova, Diogo Jesus, Omer Karadag, Ling Li, Yang Li, Maria G Lommano, Josefina Marin, María Victoria Martire, Xabier Michelena, Laura Muntean, Matteo Piga, Marcos Rosemffet, João Rovisco, Fausto Salaffi, Liliana Saraiva, Crescenzio Scioscia, Maria‐Magdalena Tamas, Shun Tanimura, Aliki Venetsanopoulou, Lucio Ventura Rios, Orlando Villota, Catalina Villota‐Eraso, Paraskevi V Voulgari, Gentiana Vukatana, Johana Zacariaz Hereter, Walter Grassi, Emilio Filippucci
Journal: Arthritis & Rheumatology (2024)

The study objectives were (i) to explore the agreement between the Outcome Measures in Rheumatology (OMERACT) ultrasound lesions of enthesitis and physical examination in assessing enthesitis in patients with spondyloarthritis (SpA) and (ii) to investigate the prevalence and clinical relevance of subclinical enthesitis in this population.
A single-cell and spatially resolved atlas of human osteosarcomas
Authors: Xuejing Zheng, Xu Liu, Xinxin Zhang, Zhenguo Zhao, Wence Wu, Shengji Yu
Journal: Journal of Hematology & Oncology (2024)

Osteosarcomas are intricate cellular ecosystems, where heterotypic interactions significantly influence disease progression and therapeutic outcomes. Despite their importance, a detailed understanding of their cellular composition and organizational structure remains elusive. In this study, we provide a comprehensive single-cell and spatially resolved transcriptomics analysis of human osteosarcomas. We construct a cellular meta-map to dissect spatial transcriptomic data, unveiling a detailed atlas of osteosarcoma compositional subgroups. We meticulously characterize the unique gene signatures and functional states of each subgroup and investigate the impact of chemotherapy on these cellular subpopulations. Additionally, our spatial transcriptomics analysis identifies a distinct spatial niche, located at the forefront of tumor necrotic zones, potentially associated with chemotherapy resistance. We also delve into the crosstalk between different cellular subgroups. This study furnishes a comprehensive transcriptional atlas of osteosarcoma's cellular architecture, enriching our comprehension of its complexity and laying the groundwork for more targeted therapeutic approaches.
Posttranslational Modifications of<b>α</b>-Synuclein, Their Therapeutic Potential, and Crosstalk in Health and Neurodegenerative Diseases
Authors: Kambiz Hassanzadeh, Jun Liu, Santhosh Maddila, M Maral Mouradian
Journal: Pharmacological Reviews (2024)

α-Synuclein (α-Syn) aggregation in Lewy bodies and Lewy neurites has emerged as a key pathogenetic feature in Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. Various factors, including posttranslational modifications (PTMs), can influence the propensity of α-Syn to misfold and aggregate. PTMs are biochemical modifications of a protein that occur during or after translation and are typically mediated by enzymes. PTMs modulate several characteristics of proteins including their structure, activity, localization, and stability. α-Syn undergoes various posttranslational modifications, including phosphorylation, ubiquitination, SUMOylation, acetylation, glycation, O-GlcNAcylation, nitration, oxidation, polyamination, arginylation, and truncation. Different PTMs of a protein can physically interact with one another or work together to influence a particular physiological or pathological feature in a process known as PTMs crosstalk. The development of detection techniques for the cooccurrence of PTMs in recent years has uncovered previously unappreciated mechanisms of their crosstalk. This has led to the emergence of evidence supporting an association between α-Syn PTMs crosstalk and synucleinopathies. In this review, we provide a comprehensive evaluation of α-Syn PTMs, their impact on misfolding and pathogenicity, the pharmacological means of targeting them, and their potential as biomarkers of disease. We also highlight the importance of the crosstalk between these PTMs in α-Syn function and aggregation. Insight into these PTMS and the complexities of their crosstalk can improve our understanding of the pathogenesis of synucleinopathies and identify novel targets of therapeutic potential. SIGNIFICANCE STATEMENT: α-Synuclein is a key pathogenic protein in Parkinson's disease and other synucleinopathies, making it a leading therapeutic target for disease modification. Multiple posttranslational modifications occur at various sites in α-Synuclein and alter its biophysical and pathological properties, some interacting with one another to add to the complexity of the pathogenicity of this protein. This review details these modifications, their implications in disease, and potential therapeutic opportunities.
Hypoxia Stimulates PYGB Enzymatic Activity to Promote Glycogen Metabolism and Cholangiocarcinoma Progression
Authors: Yani Pan, Yue Zhou, Yonghua Shen, Lei Xu, Hongwen Liu, Nannan Zhang, Tianlu Huang, Kui Meng, Yu Liu, Lishan Wang, Ge Bai, Qi Chen, Yun Zhu, Xiaoping Zou, Siliang Wang, Zhangding Wang, Lei Wang
Journal: Cancer Research (2024)

Cholangiocarcinoma (CCA) displays enhanced glycolysis, pivotal for fulfilling the heightened energy demands intrinsic to its malignant progression. Recent research has indicated that endogenous glycogen rather than exogenous glucose acts as the major carbon source for glycolysis, highlighting the need to better understand the regulation of glycogen homeostasis in CCA. Here, through comprehensive integrative analysis, we identified that glycogen phosphorylase brain form (PYGB), the main enzyme involved in glycogen homeostasis, was markedly upregulated in CCA tissues, serving as an independent prognostic indicator for human patients with CCA. Moreover, elevated PYGB expression potentiated cholangiocarcinogenesis and augmented CCA cell proliferation in both organoid and xenograft models. Hypoxia stimulated PYGB activity in a phosphoglycerate kinase 1-dependent manner, leading to glycogenolysis and the subsequent release of glucose-6-phosphate (G6P) and thereby facilitating aerobic glycolysis. Notably, a virtual screening pinpointed the β-blocker carvedilol as a potent pharmacologic inhibitor of PYGB that could attenuate CCA progression. Collectively, these findings position PYGB as a promising prognostic biomarker and therapeutic target for CCA. Significance: Cholangiocarcinoma cells exhibit high glycogen phosphorylase activity under hypoxic conditions that mediates metabolic reprograming to promote glycolysis and support tumor development.
Relationship of Subendocardial Perfusion to Myocardial Injury, Cardiac Structure, and Clinical Outcomes Among Patients With Hypertension
Authors: Xiaolei Xu, Sanjay Divakaran, Brittany N. Weber, Jon Hainer, Shelby S. Laychak, Benjamin Auer, Marie Foley Kijewski, Ron Blankstein, Sharmila Dorbala, Ludovic Trinquart, Piotr J. Slomka, Li Zhang, Jenifer M. Brown, Marcelo F. Di Carli
Journal: Circulation (2024)

BACKGROUND: Coronary microvascular dysfunction has been implicated in the development of hypertensive heart disease and heart failure, with subendocardial ischemia identified as a driver of sustained myocardial injury and fibrosis. We aimed to evaluate the relationships of subendocardial perfusion with cardiac injury, structure, and a composite of major adverse cardiac and cerebrovascular events consisting of death, heart failure hospitalization, myocardial infarction, and stroke. METHODS: Layer-specific blood flow and myocardial flow reserve (MFR; stress/rest myocardial blood flow) were assessed by 13 N-ammonia perfusion positron emission tomography in consecutive patients with hypertension without flow-limiting coronary artery disease (summed stress score &lt;3) imaged at Brigham and Women’s Hospital (Boston, MA) from 2015 to 2021. In this post hoc observational study, biomarkers, echocardiographic parameters, and longitudinal clinical outcomes were compared by tertiles of subendocardial MFR (MFR subendo ). RESULTS: Among 358 patients, the mean age was 70.6±12.0 years, and 53.4% were male. The median MFR subendo was 2.57 (interquartile range, 2.08–3.10), and lower MFR subendo was associated with older age, diabetes, lower renal function, greater coronary calcium burden, and higher systolic blood pressure ( P &lt;0.05 for all). In cross-sectional multivariable regression analyses, the lowest tertile of MFR subendo was associated with myocardial injury and with greater left ventricular wall thickness and volumes compared with the highest tertile. Relative to the highest tertile, low MFR subendo was independently associated with an increased rate of major adverse cardiac and cerebrovascular events (adjusted hazard ratio, 2.99 [95% CI, 1.39–6.44]; P =0.005) and heart failure hospitalization (adjusted hazard ratio, 2.76 [95% CI, 1.04–7.32; P =0.042) over 1.1 (interquartile range, 0.6–2.8) years median follow-up. CONCLUSIONS: Among patients with hypertension without flow-limiting coronary artery disease, impaired MFR subendo was associated with cardiovascular risk factors, elevated cardiac biomarkers, cardiac structure, and clinical events.