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Life Science Alliance Aug 2024Calcium signaling is integral for neuronal activity and synaptic plasticity. We demonstrate that the calcium response generated by different sources modulates neuronal...
Calcium signaling is integral for neuronal activity and synaptic plasticity. We demonstrate that the calcium response generated by different sources modulates neuronal activity-mediated protein synthesis, another process essential for synaptic plasticity. Stimulation of NMDARs generates a protein synthesis response involving three phases-increased translation inhibition, followed by a decrease in translation inhibition, and increased translation activation. We show that these phases are linked to NMDAR-mediated calcium response. Calcium influx through NMDARs elicits increased translation inhibition, which is necessary for the successive phases. Calcium through L-VGCCs acts as a switch from translation inhibition to the activation phase. NMDAR-mediated translation activation requires the contribution of L-VGCCs, RyRs, and SOCE. Furthermore, we show that IP3-mediated calcium release and SOCE are essential for mGluR-mediated translation up-regulation. Finally, we signify the relevance of our findings in the context of Alzheimer's disease. Using neurons derived from human fAD iPSCs and transgenic AD mice, we demonstrate the dysregulation of NMDAR-mediated calcium and translation response. Our study highlights the complex interplay between calcium signaling and protein synthesis, and its implications in neurodegeneration.
Topics: Animals; Protein Biosynthesis; Receptors, N-Methyl-D-Aspartate; Mice; Calcium; Receptors, Metabotropic Glutamate; Calcium Signaling; Humans; Neurons; Mice, Transgenic; Alzheimer Disease; Neuronal Plasticity; Induced Pluripotent Stem Cells
PubMed: 38749544
DOI: 10.26508/lsa.202402594 -
Life Science Alliance Aug 2024Phosphatidylcholine (PC) is the major membrane phospholipid in most eukaryotic cells. Bi-allelic loss of function variants in , encoding the first step in the synthesis...
Phosphatidylcholine (PC) is the major membrane phospholipid in most eukaryotic cells. Bi-allelic loss of function variants in , encoding the first step in the synthesis of PC, is the cause of a rostrocaudal muscular dystrophy in both humans and mice. Loss of sarcolemma integrity is a hallmark of muscular dystrophies; however, how this occurs in the absence of choline kinase function is not known. We determine that in mice there is a failure of the α7β1 integrin complex that is specific to affected muscle. We observed that in hindlimb muscles there is a decrease in sarcolemma association/abundance of the PI(4,5)P binding integrin complex proteins vinculin, and α-actinin, and a decrease in actin association with the sarcolemma. In cells, pharmacological inhibition of choline kinase activity results in internalization of a fluorescent PI(4,5)P reporter from discrete plasma membrane clusters at the cell surface membrane to cytosol, this corresponds with a decreased vinculin localization at plasma membrane focal adhesions that was rescued by overexpression of .
Topics: Animals; Mice; Vinculin; Mice, Knockout; Muscular Dystrophies; Integrins; Choline Kinase; Sarcolemma; Humans; Focal Adhesions; Cell Membrane; Actinin; Muscle, Skeletal; Phosphatidylinositol 4,5-Diphosphate; Actins; Disease Models, Animal
PubMed: 38749543
DOI: 10.26508/lsa.202301956 -
Journal For Immunotherapy of Cancer May 2024Cancer-intrinsic type I interferon (IFN-I) production triggered by radiotherapy (RT) is mainly dependent on cytosolic double-stranded DNA (dsDNA)-mediated cGAS/STING...
BACKGROUND
Cancer-intrinsic type I interferon (IFN-I) production triggered by radiotherapy (RT) is mainly dependent on cytosolic double-stranded DNA (dsDNA)-mediated cGAS/STING signaling and increases cancer immunogenicity and enhances the antitumor immune response to increase therapeutic efficacy. However, cGAS/STING deficiency in colorectal cancer (CRC) may suppress the RT-induced antitumor immunity. Therefore, we aimed to evaluate the importance of the dsRNA-mediated antitumor immune response induced by RT in patients with CRC.
METHODS
Cytosolic dsRNA level and its sensors were evaluated via cell-based assays (co-culture assay, confocal microscopy, pharmacological inhibition and immunofluorescent staining) and in vivo experiments. Biopsies and surgical tissues from patients with CRC who received preoperative chemoradiotherapy (neoCRT) were collected for multiplex cytokine assays, immunohistochemical analysis and SNP genotyping. We also generated a cancer-specific adenovirus-associated virus (AAV)-IFNβ1 construct to evaluate its therapeutic efficacy in combination with RT, and the immune profiles were analyzed by flow cytometry and RNA-seq.
RESULTS
Our studies revealed that RT stimulates the autonomous release of dsRNA from cancer cells to activate TLR3-mediated IFN-I signatures to facilitate antitumor immune responses. Patients harboring a dysfunctional TLR3 variant had reduced serum levels of IFN-I-related cytokines and intratumoral CD8 immune cells and shorter disease-free survival following neoCRT treatment. The engineered cancer-targeted construct AAV-IFNβ1 significantly improved the response to RT, leading to systematic eradication of distant tumors and prolonged survival in defective TLR3 preclinical models.
CONCLUSION
Our results support that increasing cancer-intrinsic IFNβ1 expression is an immunotherapeutic strategy that enhances the RT-induced antitumor immune response in locally patients with advanced CRC with dysfunctional TLR3.
Topics: Humans; Colorectal Neoplasms; RNA, Double-Stranded; Interferon-beta; Mice; Animals; Interferon Type I; Signal Transduction; Female; Male
PubMed: 38749537
DOI: 10.1136/jitc-2023-008515 -
Stroke and Vascular Neurology May 2024This study aims to investigate the prevalence of familial cerebral cavernous malformations (FCCMs) in first-degree relatives (FDRs) using familial screening, to describe...
OBJECTIVE
This study aims to investigate the prevalence of familial cerebral cavernous malformations (FCCMs) in first-degree relatives (FDRs) using familial screening, to describe the distribution of initial symptoms, lesion count on cranial MRI and pathogenic gene in patients.
METHODS
Patients with multiple CCMs who enrolled from the Treatments and Outcomes of Untreated Cerebral Cavernous Malformations in China database were considered as probands and FDRs were recruited. Cranial MRI was performed to screen the CCMs lesions, and whole-exome sequencing was performed to identify CCM mutations. MRI and genetic screening were combined to diagnose FCCM in FDRs, and the results were presented as prevalence and 95% CIs. The Kaplan-Meier (KM) method was used to calculate the cumulative incidence of FCCM.
RESULTS
33 (76.74%) of the 43 families (110 FDRs) were identified as FCCM (85 FDRs). Receiver operating characteristic analysis revealed three lesions on T2-weighted imaging (T2WI) were the strong indicator for distinguishing probands with FCCM (sensitivity, 87.10%; specificity, 87.50%). Of the 85 FDRs, 31 were diagnosed with FCCM, resulting in a prevalence of 36.5% (26.2%-46.7%). In families with FCCMs, the mutation rates for , and were 45.45%, 21.21% and 9.09%, respectively. Furthermore, 53.13% of patients were asymptomatic, 17.19% were intracranial haemorrhage and 9.38% were epilepsy. The mean age of symptom onset analysed by KM was 46.67 (40.56-52.78) years.
CONCLUSION
Based on MRI and genetic analysis, the prevalence of CCMs in the FDRs of families with FCCMs in China was 36.5%. Genetic counselling and MRI screening are recommended for FDRs in patients with more than three CCM lesions on T2WI.
PubMed: 38749536
DOI: 10.1136/svn-2023-003004 -
BMJ Open Respiratory Research May 2024Self-management, as the most common method of chronic obstructive pulmonary disease (COPD) management, is not an isolated behaviour, but a set of physical, social,...
INTRODUCTION
Self-management, as the most common method of chronic obstructive pulmonary disease (COPD) management, is not an isolated behaviour, but a set of physical, social, cultural, psychological and existential factors affecting it.
AIM
This study aimed to explore the facilitators and barriers to self-management in men with COPD in the unique social, cultural, political and economic context of Iran.
METHODS
This paper reports part of the findings of a qualitative grounded theory study aimed at exploring the process of self-management in Iranian men with COPD, which was conducted in Iran from January 2019 to July 2023. Participants included men with COPD, their family members and pulmonologists. The selection of participants in this research began with the purposeful sampling method. Data was collected using semistructured interviews. Data collection continued until the data saturation was achieved. A total of 15 interviews were conducted with nine patients, three family members of patients and three pulmonologists. The data was analysed using the constant comparative analysis method.
RESULTS
The findings of this study showed that knowledge, education, experience, family involvement and financial support are the factors that facilitate self-management. Factors related to deficits include lack of education, lack of treatment support, family cooperation deficit, financial problems, medication obtaining problems and factors related to disease impacts include specific nature of the disease, residual effect, comorbidity and factors related to negative patients characteristics include false beliefs, poor self-efficacy, feeling shame and non-adherence are barriers to self-management in men with COPD.
CONCLUSION
Based on results of this study, healthcare providers and health planners can strengthen the factors that facilitate self-management and weaken or remove the barriers to self-management, so that these patients use self-management strategies with maximum capacity to control the disease.
Topics: Humans; Pulmonary Disease, Chronic Obstructive; Male; Iran; Qualitative Research; Self-Management; Middle Aged; Aged; Health Knowledge, Attitudes, Practice; Adult; Grounded Theory
PubMed: 38749535
DOI: 10.1136/bmjresp-2023-002245 -
BMJ Open Respiratory Research May 2024The prevalence, Medicaid use and mortality risk associated with low forced expiratory volume in 1 s (FEV) among young adults aged 20-35 years are not well understood,...
BACKGROUND
The prevalence, Medicaid use and mortality risk associated with low forced expiratory volume in 1 s (FEV) among young adults aged 20-35 years are not well understood, despite its potential implications for the development of chronic pulmonary disease and overall prognosis.
METHODS
A retrospective cohort study was conducted among young adults aged 20-35 years old, using data from the National Health and Nutrition Examination Survey, National Death Index and Centers for Medicare & Medicaid Services. Participants were categorised into a low FEV group (pre-bronchodilator FEV%pred <80%) and a normal FEV group (FEV%pred ≥80%). Weighted logistic regression analysis was employed to identify the risk factors associated with low FEV, while Cox proportional hazard models were used to calculate the hazard ratio (HR) for Medicaid use and the all-cause mortality between the two groups.
RESULTS
A total of 5346 participants aged 20-35 were included in the study, with 329 in the low FEV group and 5017 in the normal group. The weighted prevalence of low FEV among young adults was 7.1% (95% CI 6.0 to 8.2). Low body mass index (OR=3.06, 95% CI 1.79 to 5.24), doctor-diagnosed asthma (OR=2.25, 1.28 to 3.93), and wheezing or whistling (OR=1.57, 1.06 to 2.33) were identified as independent risk factors for low FEV. Over a 15-year follow-up, individuals in the low FEV group exhibited a higher likelihood of Medicaid use compared with those in the normal group (HR=1.73, 1.07 to 2.79). However, there was no statistically significant increase in the risk of all-cause mortality over a 30-year follow-up period (HR=1.48, 1.00 to 2.19).
CONCLUSIONS
A considerable portion of young adults demonstrated low FEV levels, a characteristic that was associated with a higher risk of Medicaid use over a long-term follow-up, yet not linked to an augmented risk of all-cause mortality.
Topics: Humans; Adult; United States; Retrospective Studies; Male; Young Adult; Female; Medicaid; Prevalence; Forced Expiratory Volume; Risk Factors; Nutrition Surveys; Lung Diseases
PubMed: 38749533
DOI: 10.1136/bmjresp-2023-001918 -
BMJ Health & Care Informatics May 2024The objective of this paper is to provide a comprehensive overview of the development and features of the Taipei Medical University Clinical Research Database (TMUCRD),...
OBJECTIVE
The objective of this paper is to provide a comprehensive overview of the development and features of the Taipei Medical University Clinical Research Database (TMUCRD), a repository of real-world data (RWD) derived from electronic health records (EHRs) and other sources.
METHODS
TMUCRD was developed by integrating EHRs from three affiliated hospitals, including Taipei Medical University Hospital, Wan-Fang Hospital and Shuang-Ho Hospital. The data cover over 15 years and include diverse patient care information. The database was converted to the Observational Medical Outcomes Partnership Common Data Model (OMOP CDM) for standardisation.
RESULTS
TMUCRD comprises 89 tables (eg, 29 tables for each hospital and 2 linked tables), including demographics, diagnoses, medications, procedures and measurements, among others. It encompasses data from more than 4.15 million patients with various medical records, spanning from the year 2004 to 2021. The dataset offers insights into disease prevalence, medication usage, laboratory tests and patient characteristics.
DISCUSSION
TMUCRD stands out due to its unique advantages, including diverse data types, comprehensive patient information, linked mortality and cancer registry data, regular updates and a swift application process. Its compatibility with the OMOP CDM enhances its usability and interoperability.
CONCLUSION
TMUCRD serves as a valuable resource for researchers and scholars interested in leveraging RWD for clinical research. Its availability and integration of diverse healthcare data contribute to a collaborative and data-driven approach to advancing medical knowledge and practice.
Topics: Electronic Health Records; Humans; Taiwan; Databases, Factual; Hospitals, University
PubMed: 38749529
DOI: 10.1136/bmjhci-2023-100890 -
BMJ Global Health May 2024There are no published data on the long-term impact of invasive group B disease (iGBS) on economic costs or health-related quality of life (HRQoL) in low-income and...
INTRODUCTION
There are no published data on the long-term impact of invasive group B disease (iGBS) on economic costs or health-related quality of life (HRQoL) in low-income and middle-income countries. We assessed the impact of iGBS on healthcare utilisation, costs and HRQoL in Argentina, India, Kenya, Mozambique and South Africa.
METHODS
Inpatient and outpatient visits, out-of-pocket (OOP) healthcare payments in the 12 months before study enrolment, and health-state utility of children and caregivers (using the EuroQol 5-Dimensions-3-Level) were collected from iGBS survivors and an unexposed cohort matched on site, age at recruitment and sex. We used logistic or Poisson regression for analysing healthcare utilisation and zero-inflated gamma regression models for family and health system costs. For HRQoL, we used a zero-inflated beta model of disutility pooled data.
RESULTS
161 iGBS-exposed and 439 unexposed children and young adults (age 1-20) were included in the analysis. Compared with unexposed participants, iGBS was associated with increased odds of any healthcare utilisation in India (adjusted OR 11.2, 95% CI 2.9 to 43.1) and Mozambique (6.8, 95% CI 2.2 to 21.1) and more frequent healthcare visits (adjusted incidence rate ratio (IRR) for India 1.7 (95% CI 1.4 to 2.2) and for Mozambique 6.0 (95% CI 3.2 to 11.2)). iGBS was also associated with more frequent days in inpatient care in India (adjusted IRR 4.0 (95% CI 2.3 to 6.8) and Kenya 6.4 (95% CI 2.9 to 14.3)). OOP payments were higher in the iGBS cohort in India (adjusted mean: Int$682.22 (95% CI Int$364.28 to Int$1000.16) vs Int$133.95 (95% CI Int$72.83 to Int$195.06)) and Argentina (Int$244.86 (95% CI Int$47.38 to Int$442.33) vs Int$52.38 (95% CI Int$-1.39 to Int$106.1)). For all remaining sites, differences were in the same direction but not statistically significant for almost all outcomes. Health-state disutility was higher in iGBS survivors (0.08, 0.04-0.13 vs 0.06, 0.02-0.10).
CONCLUSION
The iGBS health and economic burden may persist for years after acute disease. Larger studies are needed for more robust estimates to inform the cost-effectiveness of iGBS prevention.
Topics: Humans; Quality of Life; Male; Female; Child; Mozambique; Streptococcal Infections; Child, Preschool; Infant; Adolescent; Developing Countries; Kenya; Young Adult; India; Cohort Studies; Streptococcus agalactiae; Patient Acceptance of Health Care; South Africa; Argentina; Health Care Costs
PubMed: 38749511
DOI: 10.1136/bmjgh-2023-014367 -
International Journal of Hyperthermia :... 2024Incomplete thermal ablation (ITA) fosters the malignancy of residual cells in Hepatocellular carcinoma (HCC) with unclear mechanisms now. This study aims to investigate...
Exploring the impact of insufficient thermal ablation on hepatocellular carcinoma: NDST2 overexpression mechanism and its role in facilitating growth and invasion of residual cancer cells.
OBJECTIVE
Incomplete thermal ablation (ITA) fosters the malignancy of residual cells in Hepatocellular carcinoma (HCC) with unclear mechanisms now. This study aims to investigate the expression changes of NDST2 following ITA of HCC and its impact on residual cancer cells.
METHODS
An model of heat stress-induced liver cancer was constructed to measure the expression of NDST2 using Quantitative Real-Time PCR and Western blotting experiments. The sequencing data from nude mice were used for validation. The clinical significance of NDST2 in HCC was evaluated by integrating datasets. Gene ontology and pathway analysis were conducted to explore the potential signaling pathways regulated by NDST2. Additionally, NDST2 was knocked down in heat stress-induced HCC cells, and the effects of NDST2 on these cells were verified using Cell Counting Kit-8 assays, scratch assays, and Transwell assays.
RESULTS
NDST2 expression levels are elevated in HCC, leading to a decrease in overall survival rates of HCC patients. Upregulation of immune checkpoint levels in high NDST2-expressing HCC may contribute to immune evasion by liver cancer cells. Additionally, the low mutation rate of NDST2 in HCC suggests a relatively stable expression of NDST2 in this disease. Importantly, animal and cell models treated with ITA demonstrate upregulated expression of NDST2. Knockdown of NDST2 in heat stress-induced liver cancer cells results in growth inhibition associated with gene downregulation.
CONCLUSION
The upregulation of NDST2 can accelerate the progression of residual HCC after ITA, suggesting a potential role for NDST2 in the therapeutic efficacy and prognosis of residual HCC.
Topics: Carcinoma, Hepatocellular; Liver Neoplasms; Humans; Mice; Animals; Mice, Nude; Cell Line, Tumor
PubMed: 38749506
DOI: 10.1080/02656736.2024.2353309 -
ESC Heart Failure May 2024The efficacy and safety of new-generation devices (NGDs) for severe aortic regurgitation (AR) have mostly been based on single-arm studies with limited sample sizes. Our... (Review)
Review
The efficacy and safety of new-generation devices (NGDs) for severe aortic regurgitation (AR) have mostly been based on single-arm studies with limited sample sizes. Our goal was to summarize the current evidence on NGDs and compare the safety and efficacy of 'off-label' and 'on-label' devices in NGDs. We searched MEDLINE, Embase, Cochrane Library, and Scopus for articles on transcatheter aortic valve replacement in patients with AR. A total of 31 studies that included 1851 patients were identified through April 2023. Among these, 1067 (57.6%) patients received treatment with 'on-label' devices (JenaValve and J-Valve). For NGDs, the total device success rate at 30 days was 94.5% (on-label: 97.8%, off-label: 89.9%; P < 0.001), the all-cause mortality was 4.2% (on-label: 2.6%, off-label: 5.1%; P = 0.006), permanent pacemaker implantation (PPI) was 8.8% (on-label: 6.9%, off-label: 18.4%; P < 0.001), and the rate of greater-than-mild paravalvular leak (PVL) was 1.2% (on-label: 0.9%, off-label: 3.8%; P = 0.003). On-label devices showed significantly better safety and efficacy in terms of the success rate, PPI, greater-than-mild PVL, and 30 day mortality than off-label devices.
PubMed: 38749505
DOI: 10.1002/ehf2.14832