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Characterization of gastric cancer-stimulated signaling pathways and function of CTGF in cancer-associated fibroblasts
Get PDFBackground: Cancer-associated fibroblasts (CAFs) are key components of the tumor microenvironment (TME) that play an important role in cancer progression. Although the mechanism by which CAFs promote tumorigenesis has been well investigated, the underlying mechanism of CAFs activation by neighboring cancer cells remains elusive. In this study, we aim to investigate the signaling pathways involved in CAFs activation by gastric cancer cells (GC) and to provide insights into the therapeutic targeting of CAFs for overcoming GC. Methods: Alteration of receptor tyrosine kinase (RTK) activity in CAFs was analyzed using phospho-RTK array. The expression of CAFs effector genes was determined by RT-qPCR or ELISA. The migration and invasion of GC cells co-cultured with CAFs were examined by transwell migration/invasion assay. Results: We found that conditioned media (CM) from GC cells could activate multiple receptor tyrosine kinase signaling pathways, including ERK, AKT, and STAT3. Phospho-RTK array analysis showed that CM from GC cells activated PDGFR tyrosine phosphorylation, but only AKT activation was PDGFR-dependent. Furthermore, we found that connective tissue growth factor (CTGF), a member of the CCN family, was the most pronouncedly induced CAFs effector gene by GC cells. Knockdown of CTGF impaired the ability of CAFs to promote GC cell migration and invasion. Although the PDGFR-AKT pathway was pronouncedly activated in CAFs stimulated by GC cells, its pharmacological inhibition affected neither CTGF induction nor CAFs-induced GC cell migration. Unexpectedly, the knockdown of SRC and SRC-family kinase inhibitors, dasatinib and saracatinib, significantly impaired CTGF induction in activated CAFs and the migration of GC cells co-cultured with CAFs. SRC inhibitors restored the reduced expression of epithelial markers, E-cadherin and Zonula Occludens-1 (ZO-1), in GC cells co-cultured with CAFs, as well as CAFs-induced aggregate formation in a 3D tumor spheroid model. Conclusions: This study provides a characterization of the signaling pathways and effector genes involved in CAFs activation, and strategies that could effectively inhibit it in the context of GC
Guarea microcarpa C. DC. extract inhibits NLRP3 inflammasome by suppressing its ATPase activity
Get PDFEthnopharmacological relevance: Guarea genus comprises tropical and subtropical terrestrial herbs inhabiting Central and South America. These plants, including Guarea guidonia (L.) Sleumer, have anti-inflammatory, analgesic, antibacterial, antiviral, and immune-enhancing properties. Aim of the study: Although various species of the Guarea genus are known for their medicinal properties, comprehensive data on their anti-inflammatory effects remain limited. Therefore, we investigated the NLRP3 inflammasome-inhibiting effects of the Guarea genus in this study. Materials and methods: To evaluate the anti-inflammatory activities of 18 members of the Guarea genus, we treated NLRP3 inflammasome activators with their extracts in LPS-primed J774A.1 and THP-1 cells. Cell viability was determined by water soluble tetrazolium salt (WST) and cytokine production, protein expression, and nuclear fractionation were determined by western blotting. Reactive oxygen species (ROS) production and apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) oligomerization were measured using confocal microscopic analysis. Inflammation-induced zebrafish was used in the in vivo experiments. Results: Among the 18 Guarea members tested, Guarea microcarpa C. DC. extract (GM) exhibited no cytotoxicity and specifically suppressed the activation of the NLRP3 inflammasome, but not of the AIM2 or NLRC4 inflammasomes, by inhibiting the ATPase activity of NLRP3. This was achieved without affecting NF-κB signaling, potassium efflux, or intracellular ROS production, all of which are involved in NLRP3 activation. The reduced ATPase activity of NLRP3 led to decreased ASC oligomerization. Furthermore, GM exhibited anti-inflammatory effects in vivo. Additionally, GM treatment alleviated inflammation at the organismal level in an LPS-induced inflammation model using zebrafish embryos. Conclusion: Our results demonstrate the anti-inflammatory effects of GM via suppressing the NLRP3 inflammasome. Therefore, GM can be a potential therapeutic candidate for various inflammatory diseases caused by aberrant NLRP3 inflammasome activation
Complex interplay of oral health, muscle and bone metabolism, and frailty in older individuals
No full textObjectives: To investigate molecular and clinical background of associations among oral health, muscle and bone metabolism, and frailty incidence in patients with fall and fracture history. Materials and methods: In total, 88 elderly participants (mean age 71.9 ± 5.8 years) with the distal radius fractures were included. Participants were divided into three groups based on an Oral Health Assessment Tool score. Fried criteria and Mini-nutritional assessments were adopted to diagnose frailty and malnutrition, respectively. Blood samples were collected and analyzed for serum levels of bone turnover markers, proteins, insulin-like growth factor-1, 25-hydroxyvitamin D, and inflammatory cytokines. The mRNA levels of markers of inflammation, muscle synthesis and wasting, and muscle homeostasis regulator in the pronator quadratus muscle were analyzed. Results: Patients with deteriorated oral health demonstrated a higher prevalence of frailty and malnutrition. Significantly lower serum levels of total protein and higher concentrations of tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) were detected in patients with poor oral health. Significant interaction effects between oral health and frailty level in gait speed, serum TNF-α, IL-1β, and total protein levels were exhibited. Significantly different mRNA expression levels in the pronator quadratus muscle of TNF-α, IL-1β, NF kB, MYOG, and FOXO1 following the oral health were detected. Conclusion: This study highlights relationship between oral health, nutritional uptake, systemic inflammation, and their combined impact on muscle and bone metabolism, ultimately affecting frailty development in the aging populations. Clinical relevance: A comprehensive understanding of mutual interactions among oral health, nutrition, and inflammation is essential for managing frailty
Perspectives and gaps in the management of food allergy and anaphylaxis in the Asia-Pacific Region
Get PDFBackground: Food allergy (FA), which is a condition that has no effective cure and can result in severe life-threatening allergic reactions, remains a global public health concern; however, little is known about how FAs are currently managed in the Asia-Pacific region. Objective: The main objective of this survey was to evaluate the epidemiology of FA, as well as the availability of resources and practices for management of FA and anaphylaxis by health care providers across Asia. Methods: From June 2022 to September 2022, a questionnaire-based survey comprising 66 questions was electronically sent to member societies of the Asia Pacific Association of Allergy Asthma and Clinical Immunology by using Survey Monkey. Results: A total of 20 responses were received from 15 member countries and territories. Compared with the pediatric data, there was a lack of prevalence data for FA in adults. Except for Australia and Japan, most regions had between 0.1 and 0.5 allergists per 100,000 population and some had fewer than 0.1 allergists per 100,000 population. The perceived rate of FA in regions with a short supply of allergists was high. Although specific IgE tests and oral food challenges were available in all regions, the median wait time for oral food challenges at government facilities was 37 days (interquartile range = 10.5-60 days). Seven regions still relied on prescriptions of ampules and syringes of injectable adrenaline, and adrenaline autoinjectors were not accessible in 4 regions. Oral immunotherapy as FA treatment was available in half of the surveyed countries and territories. Conclusions: Our study offers a cross-sectional evaluation of the management practices for FA in each Asia Pacific Association of Allergy Asthma and Clinical Immunology member country or territory. Urgent actions are required to enhance allergy services, improve the accessibility and affordability of adrenaline autoinjectors, and conduct robust epidemiologic studies
Efficacy and safety of once weekly semaglutide 2·4 mg for weight management in a predominantly east Asian population with overweight or obesity (STEP 7): a double-blind, multicentre, randomised controlled trial
No full textBackground: Data on the benefits of the once weekly GLP-1 receptor agonist semaglutide 2·4 mg for weight management in people from east Asia are insufficient. The objective of this study was to determine the efficacy and safety of once weekly semaglutide 2·4 mg versus placebo for weight management in a predominantly east Asian adult population. Methods: This randomised phase 3a, double-blind multicentre controlled trial (STEP 7) recruited participants from 23 hospitals and trial centres in China, Hong Kong, Brazil, and South Korea. Adults with overweight or obesity, with or without type 2 diabetes, were randomly assigned (2:1) to receive a subcutaneous injection of either semaglutide 2·4 mg or placebo once a week for 44 weeks, plus a diet and physical activity intervention. Randomisation was done in blocks of six with an interactive web response system and was stratified by diagnosis of type 2 diabetes. Participants, investigators, and the trial sponsor were masked to treatment allocation until after database lock. Primary endpoints were percentage change in mean bodyweight and proportion of participants having reached a weight reduction of at least 5% of bodyweight from baseline to week 44. Safety was assessed in all participants who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, NCT04251156, and is now complete. Findings: From Dec 8, 2020, to Aug 23, 2022, 448 participants were screened, of whom 375 were randomly assigned to either the semaglutide 2·4 mg group (n=249) or the placebo group (n=126). Estimated mean percentage change in bodyweight from baseline to week 44 was −12·1% (SE 0·5) with semaglutide 2·4 mg versus −3·6% (0·7) with placebo (estimated treatment difference –8·5 percentage points [95% CI –10·2 to –6·8]; p<0·0001). At week 44, the proportion of participants who lost 5% or more of their bodyweight was higher in the semaglutide 2·4 mg group than in the placebo group (203/238 [85%] vs 36/116 [31%]); odds ratio 13·1 (95% CI 7·4–23·1; p<0·0001). Adverse events were reported by 231 (93%) of 249 participants in the semaglutide 2·4 mg group and 108 (86%) of 126 participants in the placebo group, the most common of which were gastrointestinal disorders (168/249, 67% vs 45/126, 36%). Interpretation: The results of this study support the use of semaglutide 2·4 mg for weight management in people of east Asian ethnicity with overweight or obesity and with or without type 2 diabetes. Funding: Novo Nordisk. Translations: For the Mandarin, Portuguese and South Korean translations of the abstract see Supplementary Materials section
Precise individual muscle segmentation in whole thigh CT scans for sarcopenia assessment using U-net transformer
Get PDFThe study aims to develop a deep learning based automatic segmentation approach using the UNETR(U-net Transformer) architecture to quantify the volume of individual thigh muscles(27 muscles in 5 groups) for Sarcopenia assessment. By automating the segmentation process, this approach improves the efficiency and accuracy of muscle volume calculation, facilitating a comprehensive understanding of muscle composition and its relationship to Sarcopenia. The study utilized a dataset of 72 whole thigh CT scans from hip fracture patients, annotated by two radiologists. The UNETR model was trained to perform precise voxel-level segmentation and various metrics such as dice score, average symmetric surface distance, volume correlation, relative absolute volume difference and Hausdorff distance were employed to evaluate the model's performance. Additionally, the correlation between Sarcopenia and individual thigh muscle volumes was examined. The proposed model demonstrated superior segmentation performance compared to the baseline model, achieving higher dice scores (DC = 0.84) and lower average symmetric surface distances (ASSD = 1.4191 ± 0.91). The volume correlation between Sarcopenia and individual thigh muscles in the male group. Furthermore, the correlation analysis of grouped thigh muscles also showed negative associations with Sarcopenia in the male participants. This thesis presents a deep learning based automatic segmentation approach for quantifying individual thigh muscle volume in sarcopenia assessment. The results highlights the associations between Sarcopenia and specific individual muscles as well as grouped thigh muscle regions, particularly in males. The proposed method improves the efficiency and accuracy of muscle volume calculation, contributing to a comprehensive evaluation of Sarcopenia. This research enhances our understanding of muscle composition and performance, providing valuable insights for effective interventions in Sarcopenia management
국내 사람면역결핍바이러스 감염 및 후천면역결핍증후군의 현황과 전망
No full textBackground: Over the past decade, approximately 1,100 newly diagnosed cases of human immunodeficiency virus (HIV) infection have been reported annually in South Korea, with 1,066 newly diagnosed cases reported in 2022. A decrease in HIV infection rate can be achieved only through coordinated prevention, diagnosis, and treatment. South Korea is lagging in the worldwide decreasing trend of HIV infection, and a brief review of this situation may suggest improvements necessary for progress. Current Concepts: In South Korea, the proportion of patients with CD4 cell count below 200 cells/mm3 at initial diagnosis of HIV infection remains high, suggesting that a significant population is diagnosed at the late stage of the disease. Since 2019, the Korean National Health Insurance Service began to cover the cost of pre-exposure prophylaxis for sexual partners of patients living with HIV, but few have started the regimen due to several barriers. Insurance criteria for a prophylaxis regimen should be modified, and accessibility to the regimen should be made available through multiple pathways. Proactive use of rapid HIV testing kits in community health centers and clinics should be expanded. Legal and administrative environments encouraging voluntary testing, early diagnosis, and treatment should be fostered. Medical personnel must be able to offer medical care without discrimination regardless of HIV infection status. Discussion and Conclusion: The HIV epidemic in South Korea has not yet decreased. To end it, efforts should be required across broad areas, including voluntary HIV testing, early diagnosis, active pre-exposure prophylaxis, a stigma- and discrimination-free social environment, and changes in legal and medical environments
Monocyte Count and Systemic Immune-Inflammation Index Score as Predictors of Delayed Cerebral Ischemia after Aneurysmal Subarachnoid Hemorrhage
Get PDFObjective: Delayed cerebral ischemia (DCI) is a major cause of disability in patients who survive aneurysmal subarachnoid hemorrhage (aSAH). Systemic inflammatory markers, such as peripheral leukocyte count and systemic immune-inflammatory index (SII) score, have been considered predictors of DCI in previous studies. This study aims to investigate which systemic biomarkers are significant predictors of DCI. Methods: We conducted a retrospective, observational, single-center study of 170 patients with SAH admitted between May 2018 and March 2022. We analyzed the patients’ clinical and laboratory parameters within 1 hour and 3–4 and 5–7 days after admission. The DCI and non-DCI groups were compared. Variables showing statistical significance in the univariate logistic analysis (p<0.05) were entered into a multivariate regression model. Results: Hunt-Hess grade “4–5” at admission, modified Fisher scale grade “3–4” at admission, hydrocephalus, intraventricular hemorrhage, and infection showed statistical significance (p<0.05) on a univariate logistic regression. Lymphocyte and monocyte count at admission, SII scores and C-reactive protein levels on days 3–4, and leukocyte and neutrophil counts on days 5–7 exhibited statistical significance on the univariate logistic regression. Multivariate logistic regression analysis revealed that monocyte count at admission (odds ratio [OR], 1.64; 95% confidence interval [CI], 1.04–2.65; p=0.036) and SII score at days 3–4 (OR, 1.55; 95% CI, 1.02–2.47; p=0.049) were independent predictors of DCI. Conclusion: Monocyte count at admission and SII score 3–4 days after rupture are independent predictors of clinical deterioration caused by DCI after aSAH. Peripheral monocytosis may be the primer for the innate immune reaction, and the SII score at days 3–4 can promptly represent the propagated systemic immune reaction toward DCI
Objective and subjective efficacy of hearing aids in patients with mild-to-moderate unilateral hearing loss: a prospective study
No full textPurpose: In patients with unilateral sensorineural hearing loss (USNHL), we explored both objective functional audiological gains and subjective satisfaction, indicating when a unilateral hearing aid is valuable. Methods: Thirty-seven patients with mild-to-moderate USNHL (mean pure-tone thresholds between 25 and 70 dB) were prescribed unilateral hearing aids. Functional gain, the aided speech discrimination score (SDS), the Hearing in Noise Test (HINT) score, and the sound localization test score were collected, and a questionnaire (the Hearing Handicap Inventory for the Elderly, HHIE) completed after 1, 2, and 3 months of hearing aid use. We classified the participants as having ‘no handicap’ (HHIE < 17), ‘mild-to-moderate handicap’ (17–42), and ‘significant handicap’ (> 42). Results: The decrease in handicap afforded by unilateral hearing aids was largest in the ‘significant handicap’ group (the HHIE total score fell from 59.1 to 37.2; P = 0.007). There were no between-group differences in either functional gain or the aided SDS. Only the ‘significant handicap’ group evidenced an improved HINT score; the composite signal-to-noise ratio (SNR) fell from – 1.5 to – 2.2 dB [S/N] (P = 0.023). The HHIE usefully indicated when a hearing aid alleviated the discomfort of USNHL; patients with unaided HHIE scores ≥ 20 evidenced significant decreases in the composite SNR (– 1.7 to – 2.0 dB [S/N]; P = 0.045). Conclusions: When considering whether to prescribe a unilateral hearing aid for patients with mild-to-moderate USNHL, it is helpful to use the HHIE to evaluate discomfort. If the total score is ≥ 20, a hearing aid is appropriate