The Genetic Variants of Long Noncoding RNA MEG3 and Its Association to the Clinical Features of Diabetic Retinopathy.

PURPOSE: This study aimed to investigate the potential correlation between the single-nucleotide polymorphism (SNP) of maternally expressed gene 3 (MEG3) and the clinical manifestations of diabetic retinopathy (DR). METHODS: Five loci of MEG3 SNPs including rs4081134 (G/A), rs10144253 (T/C), rs7158663 (G/A), rs3087918 (T/G) and rs11160608 (A/C) were genotyped by TaqMan allelic discrimination in 457 non-DR patients and 280 DR individuals. RESULTS: The distribution frequency of MEG3 SNP rs7158663 GA (AOR: 0.683, 95% CI: 0.478-0.975, p = 0.036) and MEG3 SNP rs7158663 GA + AA (AOR: 0.686, 95% CI: 0.487-0.968, p = 0.032) were significantly lower in the DR group. And the MEG3 SNP rs7158663 GA + AA (AOR: 0.610, 95% CI: 0.377-0.985, p = 0.043) demonstrated a significantly lower distribution frequency in the male DR group. Besides, the DR patients with MEG3 SNP rs7158663 GA + AA genotype showed a significantly lower HbA1c level than the DR patients with MEG3 SNP rs7158663 GG genotype (7.29 ± 1.23 versus 7.74 ± 1.49, p = 0.013). Moreover, in the analysis using data from gene expression data series database, a higher MEG3 level was significantly correlated to a lower miR-182 level in the database (p = 0.0114). CONCLUSIONS: In this study, the distribution frequency of MEG3 SNP rs7158663 GA + AA genotype was lower in DR, while the DR would develop under lower HbA1c level in DM patients with this MEG3 SNP variant.

Low-Intensity Extracorporeal Shock Wave Therapy Ameliorates Detrusor Hyperactivity with Impaired Contractility via Transient Potential Vanilloid Channels: A Rat Model for Ovarian Hormone Deficiency.

This study explores low-intensity extracorporeal shock wave therapy (LiESWT)'s efficacy in alleviating detrusor hyperactivity with impaired contractility (DHIC) induced by ovarian hormone deficiency (OHD) in ovariectomized rats. The rats were categorized into the following four groups: sham group; OVX group, subjected to bilateral ovariectomy (OVX) for 12 months to induce OHD; OVX + SW4 group, underwent OHD for 12 months followed by 4 weeks of weekly LiESWT; and OVX + SW8 group, underwent OHD for 12 months followed by 8 weeks of weekly LiESWT. Cystometrogram studies and voiding behavior tracing were used to identify the symptoms of DHIC. Muscle strip contractility was evaluated through electrical-field, carbachol, ATP, and KCl stimulations. Western blot and immunofluorescence analyses were performed to assess the expressions of various markers related to bladder dysfunction. The OVX rats exhibited significant bladder deterioration and overactivity, alleviated by LiESWT. LiESWT modified transient receptor potential vanilloid (TRPV) channel expression, regulating calcium concentration and enhancing bladder capacity. It also elevated endoplasmic reticulum (ER) stress proteins, influencing ER-related Ca2+ channels and receptors to modulate detrusor muscle contractility. OHD after 12 months led to neuronal degeneration and reduced TRPV1 and TRPV4 channel activation. LiESWT demonstrated potential in enhancing angiogenic remodeling, neurogenesis, and receptor response, ameliorating DHIC via TRPV channels and cellular signaling in the OHD-induced DHIC rat model.

Taurine Rescues Cancer-induced Atrophy in Human Skeletal Muscle Cells via Ameliorating the Inflammatory Tumor Microenvironment.

BACKGROUND/AIM: Cancer cachexia is a wasting syndrome that has a devastating impact on the prognosis of patients with cancer. It is well-documented that pro-inflammatory cytokines are involved in the progression of this disorder. Therefore, this study was conducted to investigate the protective effect of taurine, an essential nonprotein amino acid with great anti-inflammatory properties, in attenuating muscle atrophy induced by cancer. MATERIALS AND METHODS: Conditioned media (CM) derived from T24 human bladder carcinoma cells with or without 5 mM taurine were incubated with human skeletal muscle cells (HSkMCs) and their differentiation was examined. The intracellular reactive oxygen species (ROS), morphology, and the catabolic pathway were monitored. RESULTS: T24-derived CM with high levels of TNF-α and IL-6 caused aberrant ROS accumulation and formation of atrophic myotubes by HSkMCs. In T24 cancer cells, taurine significantly inhibited the production of TNF-α and IL-6. In HSkMCs, taurine increased ROS clearance during differentiation and preserved the myotube differentiation ability impaired by the inflammatory tumor microenvironment. In addition, taurine ameliorated myotube atrophy by regulating the Akt/FoxO1/MuRF1 and MAFbx signaling pathways. CONCLUSION: Taurine rescues cancer-induced atrophy in human skeletal muscle cells by ameliorating the inflammatory tumor microenvironment. Taurine supplementation may be a promising approach for intervening with the progression of cancer cachexia.

Mitochondrial calcium uniporter as biomarker and therapeutic target for breast cancer: Prognostication, immune microenvironment, epigenetic regulation and precision medicine.

INTRODUCTION: Mitochondrial calcium uniporter (MCU) is a central subunit of MCU complex that regulate the levels of calcium ions within mitochondria. A comprehensive understanding the implications of MCU in clinical prognostication, biological understandings and therapeutic opportunity of breast cancer (BC) is yet to be determined. OBJECTIVES: This study aims to investigate the role of MCU in predictive performance, tumor progression, epigenetic regulation, shaping of tumor immune microenvironment, and pharmacogenetics and the development of anti-tumor therapy for BC. METHODS: The downloaded TCGA datasets were used to identify predictive ability of MCU expressions via supervised learning principle. Functional enrichment, mutation landscape, immunological profile, drug sensitivity were examined using bioinformatics analysis and confirmed by experiments exploiting human specimens, in vitro and in vivo models. RESULTS: MCU copy numbers increase with MCU gene expression. MCU expression, but not MCU genetic alterations, had a positive correlation with known BC prognostic markers. Higher MCU levels in BC showed modest efficacy in predicting overall survival. In addition, high MCU expression was associated with known BC prognostic markers and with malignancy. In BC tumor and sgRNA-treated cell lines, enrichment pathways identified the involvement of cell cycle and immunity. miR-29a was recognized as a negative epigenetic regulator of MCU. High MCU levels were associated with increased mutation levels in oncogene TP53 and tumor suppression gene CDH1, as well as with an immunosuppressive microenvironment. Sigle-cell sequencing indicated that MCU mostly mapped on to tumor cell and CD8 T-cells. Inter-databases verification further confirmed the aforementioned observation. miR-29a-mediated knockdown of MCU resulted in tumor suppression and mitochondrial dysfunction, as well as diminished metastasis. Furthermore, MCU present pharmacogenetic significance in cellular docetaxel sensitivity and in prediction of patients' response to chemotherapeutic regimen. CONCLUSION: MCU shows significant implication in prognosis, outcome prediction, microenvironmental shaping and precision medicine for BC. miR-29a-mediated MCU inhibition exerts therapeutic effect in tumor growth and metastasis.

Assessing risk of recurrent small bowel obstruction after non-operative management in patients with history of intra-abdominal surgery: a population-based comprehensive analysis in Taiwan.

BACKGROUND: Despite a significant 30% ten-year readmission rate for SBO patients, investigations into recurrent risk factors after non-operative management are scarce. The study aims to generate a risk factor scoring system, the 'Small Bowel Obstruction Recurrence Score' (SBORS), predicting 6-month recurrence of small bowel obstruction (SBO) after successful non-surgical management in patients who have history of intra-abdominal surgery. METHODS: We analyzed data from patients aged ≥ 18 with a history of intra-abdominal surgery and diagnosed with SBO (ICD-9 code: 560, 568) and were successful treated non-surgically between 2004 and 2008. Participants were divided into model-derivation (80%) and validation (20%) group. RESULTS: We analyzed 23,901 patients and developed the SBORS based on factors including the length of hospital stay > 4 days, previous operations > once, hemiplegia, extra-abdominal and intra-abdominal malignancy, esophagogastric surgery and intestino-colonic surgery. Scores > 2 indicated higher rates and risks of recurrence within 6 months (12.96% vs. 7.27%, OR 1.898, p < 0.001 in model-derivation group, 12.60% vs. 7.05%, OR 1.901, p < 0.001 in validation group) with a significantly increased risk of mortality and operative events for recurrent episodes. The SBORS model demonstrated good calibration and acceptable discrimination, with an area under curve values of 0.607 and 0.599 for the score generation and validation group, respectively. CONCLUSIONS: We established the effective 'SBORS' to predict 6-month SBO recurrence risk in patients who have history of intra-abdominal surgery and have been successfully managed non-surgically for the initial obstruction event. Those with scores > 2 face higher recurrence rates and operative risks after successful non-surgical management.

Association of sodium-glucose cotransporter 2 inhibitors with the incidence of corneal diseases in type 2 diabetes mellitus.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors revealed the protective function on various systemic diseases. This study aimed to determine whether the usage of SGLT2 inhibitors associates with incidences of superficial keratopathy and infectious keratitis in type 2 diabetes mellitus (T2DM) patients. A retrospective cohort study with the usage of National Health Insurance Research Database of Taiwan was conducted. The T2DM patients were divided into the SGLT2 inhibitors and control groups according to the usage of SGLT2 inhibitors or not. The major outcomes were defined as the occurrence of superficial keratopathy and infectious keratitis. There were 766 and 1037 episodes of superficial keratopathy in the SGLT2 inhibitors and control groups and SGLT2 inhibitors group showed a significantly lower incidence of superficial keratopathy than the control group (aHR: 0.721, 95% CI: 0.656-0.791, P < 0.0001). Also, there were 166 and 251 infectious keratitis events in the SGLT2 inhibitors and control groups and patients in the SGLT2 inhibitors group revealed a significantly lower infectious keratitis incidence than those in the control group (aHR: 0.654, 95% CI: 0.537-0.796, P < 0.0001). In addition, the patients that received SGLT2 inhibitors demonstrated lower cumulative incidences of both superficial keratopathy and infectious keratitis compared to the non-SGLT2 inhibitors users (both P < 0.0001). In conclusion, the usage of SGLT2 inhibitors correlates to lower incidence of superficial keratopathy and infectious keratitis in T2DM individuals, which is more significant in patients with persistent SGLT2 inhibitors application.

Association between Mastery Motivation, Executive Function, and Daily Participation of Young Children with and without Global Developmental Delays.

This study aimed to examine the group differences in participation level between children with and without global delays and to explore the associations between mastery motivation, executive function, and participation in young children with and without global developmental delays (GDD). Methods: we recruited 26 children with GDD aged 2 to 5 years and 26 children with sex- and mental age-matched developing typically (TD). The participants were assessed child development using the standardized developmental test, and their mothers were asked to fill in questionnaires, including the revised Dimension of Mastery Questionnaire (DMQ 18) with preschool version to assess mastery motivation, the Behavior Rating Inventory of Executive Function with preschool version (BRIEF-P) to assess executive function, and the Young Children's Participation and Environment Measure (YC-PEM) used to obtain participation levels. Results and conclusions: young children with GDD showed significantly lower participation levels at home, daycare, and community than TD group. We found that for young children, child mastery pleasure, health condition, and total persistence were significant predictors of child participation. Therefore, coaching parents to observe and facilitate their children's motivation and executive function, as well as child developmental abilities, is important in order to enhance children's participation in daily activities.

Test-Retest Reliability, Criterion-Related Validity, and Ecological Validity of the Test of Visual-Motor Skills, Third Edition, in Kindergarten Children With Developmental Coordination Disorder.

IMPORTANCE: Establishing empirical evidence on the psychometric properties of the Test of Visual-Motor Skills (3rd ed.; TVMS-3) is helpful for guiding its use as an assessment of visual-motor integration (VMI) skills in kindergarten children with developmental coordination disorder (DCD). OBJECTIVE: To investigate the test-retest reliability, criterion-related validity, and ecological validity of the TVMS-3 in Taiwanese kindergarten children with DCD. DESIGN: A nonexperimental, descriptive, correlational design. SETTING: A hospital in Central Taiwan. PARTICIPANTS: Fifty-seven kindergarten children with DCD were recruited in the study. OUTCOMES AND MEASURES: Intraclass correlation coefficient, percentage of minimal detectable change, and paired t test (Wilcoxon signed rank test) were used to investigate the test-retest reliability of the TVMS-3. The correlations (Pearson's r) between the TVMS-3 accuracy score and the scores of each of the four domains and the adaptive behavior composite score of the Vineland Adaptive Behavior Scales (3rd ed.; Vineland-3) were calculated, respectively, to examine criterion-related validity and ecological validity. RESULTS: The accuracy score of the TVMS-3 had excellent test-retest reliability and acceptable random measurement error. Moreover, it showed good criterion-related validity and sufficient ecological validity with the Vineland-3 in Taiwanese kindergarten children with DCD. CONCLUSIONS AND RELEVANCE: The accuracy score of the TVMS-3 is applicable to Taiwanese kindergarten children with DCD in clinical and research settings. Plain-Language Summary: The accuracy score of the Test of Visual-Motor Skills (3rd ed.; TVMS-3) is a useful assessment tool to detect deficits in visual-motor integration for Taiwanese kindergarten children with developmental coordination disorder. The TVMS-3 has excellent test-retest reliability, good criterion-related validity, and sufficient ecological validity.

Heteronemin promotes iron-dependent cell death in pancreatic cancer.

The marine environment has been recognized as a prolific source of potent bioactive compounds with significant anticancer properties. Among these, heteronemin, a sesterterpenoid-type natural product, has shown promise. This study delves into the potential of heteronemin as a ferroptotic agent against pancreatic cancer, using the Panc-1 cell line as a model. The cytotoxic potential of heteronemin was assessed using cell viability assays. Furthermore, its effect on lipid peroxidation was determined spectrophotometrically, while the changes it induced in autophagy- and ferritin-related protein expressions were evaluated using immunoblotting techniques. Various cell-based tests were employed to scrutinize its anticancer efficacy. Heteronemin displayed a notable cytotoxic effect, reducing cell viability by 50% at a concentration of 55 nM. This cytotoxicity was discernibly linked to ferroptosis, as evidenced by the reversal of cell death upon treatment with the ferroptosis inhibitor, ferrostatin-1. Heteronemin treatment led to a marked increase in ferroptosis markers and malondialdehyde (MDA) levels. Conversely, the expression of glutathione peroxidase-4 (GPX4), a key anti-ferroptotic protein, was suppressed. Furthermore, significant modulations in the expression of ferritinophagy- and iron-related proteins such as Atg5, Atg7, FTL, STEAP3, and DMT-1 were evident post-treatment (p < 0.05). This study underscores the potential of heteronemin as a ferroptosis inducer in pancreatic cancer cells. Given its robust cytotoxicity, heteronemin emerges as a promising lead compound for further exploration in cancer therapeutics.

Unveiling the multifaceted nexus of subjective aging, biological aging, and chronological age: Findings from a nationally representative cohort study.

OBJECTIVES: This study aims to investigate how subjective aging influences the psychological and behavioral responses of older individuals, specifically focusing on the associations between subjective aging and longitudinal changes in biological age. METHODS: This is a retrospective cohort study retrieving data from the Taiwan Longitudinal Study on Aging (TLSA), over a 4-year follow-up period. Subjective aging is assessed by asking participants if they perceive themselves as old, while frailty is measured using a frailty index comprising 34 deficits from various domains. Participants are categorized into three groups based on their chronological age. The association between subjective aging and transition of biological age (as indicated by an increased frailty index) from 2011 to 2015 is examined using logistic regression models. RESULTS: The study consisted of 2412 participants, who were categorized into middle-age (n = 1,082), young-old (n = 779), and old-old (n = 551) groups. Among them, individuals exhibiting subjective aging at baseline were more likely to be older in chronological age, female, illiterate, and unemployed, compared to those without subjective aging. The adjusted odds ratios (aORs) for the association between subjective aging and an increased biological age were 1.72 [95% CI: 0.88-3.34], 1.61 [0.77-3.37], and 1.08 [0.65-1.80], in the middle-age, young-old, and old-old groups, respectively. DISCUSSIONS: No significant associations were found between changes in biological age and subjective aging across various chronological age groups. Notably, within the younger age group, a discernible trend towards an association was observed, indicating the potential age-related nuances in the complex interrelation between subjective age, biological aging, and chronological aging.

Effects of declines in personal mastery on self-perceived mobility, physical function, cognitive function, and depressive symptoms: a 6-year follow-up study from the Social Environment and Biomarkers of Aging Study.

OBJECTIVES: As the psychosocial competence, personal mastery helps individuals to cope with stressful life events, and this study aims to examine impacts of declines in personal mastery on healthy aging among community-dwelling middle-aged and older adults using a nationally representative cohort. METHODS: Data from 648 study participants in the Social Environment and Biomarkers of Aging Study (SEBAS) were retrieved for analysis. All participants were divided into four groups based on their baseline and changes of personal mastery (measured by the Pearlin mastery score) during the 6-year follow-up. Multivariate logistic regression models were adopted to examine associations between declines in personal mastery and indicators for healthy aging (declines in self-perceived mobility, physical function (activities of daily living (ADLs) and instrumental activities of daily living (IADLs)), cognitive function and depressive symptoms). RESULTS: After adjustments for demographics and comorbidities, those with declines in personal mastery were associated with greater risks of declines in self-perceived mobility (adjusted odds ratio (aOR) 1.50 [95% confidence interval 1.01-2.22], p < 0.05). Although the point estimate in the unadjusted models indicated similar associations between declines in personal mastery and declines in ADLs, IADLs, cognitive function or depressive symptoms, these outcomes did not reach statistical significance in the adjusted model. CONCLUSIONS: Declines in personal mastery were negatively associated with indicators related to healthy aging (particularly locomotion) in a 6-year follow-up. Further investigations are needed to explore the effects of preventing declines in personal mastery in promoting healthy aging over time.

Utilization of sodium-glucose cotransporter 2 inhibitors on dry eye disease severity in patients with type 2 diabetes mellitus.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors have protective effects against various systemic diseases and neoplasms. This retrospective cohort study evaluated the severity of dry eye disease (DED) in patients with type 2 diabetes mellitus (T2DM) who were treated with SGLT2 inhibitors. Data were obtained from the National Health Insurance Research Database of Taiwan. Patients with T2DM who were treated with SGLT2 inhibitors were assigned to the SGLT2 group. Each patient in the SGLT2 group was matched to two individuals with T2DM who had not used SGLT2 inhibitors, constituting the control group. The primary outcomes were the development of DED and severe DED. A diagnosis of severe DED was indicated by the usage of cyclosporine. Cox proportional hazard regression was applied to yield adjusted hazard ratios (aHR) and 95% confidence intervals (CIs). In the SGLT2 group, 1864 new DED events and 147 severe DED events were recorded. Conversely, 4367 new DED events and 392 severe DED events were recorded in the control group. The incidence (aHR: 0.858, 95% CI: 0.811-0.908, p = 0.0010) and severity (aHR: 0.652, 95% CI: 0.481-0.777, p = 0.0006) of DED were significantly lower in the SGLT2 group than the control group after adjusting for multiple covariates. In subgroup analyses, the incidence and severity of DED were significantly lower in patients younger than 60 years old who were treated with SGLT2 inhibitors than in their older counterparts (p = 0.0008 and 0.0011, respectively). In conclusion, utilization of SGLT2 inhibitors in the T2DM population could reduce both the incidence and severity of DED.

Application of remodeled glove puppetry for children with developmental disabilities: a randomized controlled trial.

This study aimed to improve hand performance and play behavior in children with developmental disabilities (DD) using a remodeled glove puppetry approach. Overall, 62 children with DD were randomly assigned to experimental and control groups (n = 31 each). The experimental group underwent a 12-week rehabilitation program by playing with the remodeled glove puppetry, while the children in the control group played with non-remodeled glove puppetry. The Chinese puppet was remodeled using a Lego EV3® robot. Hand kinematics were analyzed through the Siliconcoach® Pro 7 software, which measured the force produced by the baseline ® hydraulic pinch gauge. Play behavior was measured using the Knox Preschool Play Scale-revised (KPPS-r). The experimental group exhibited significant improvements compared to the control group in hand kinematics (wrist range of motion [ROM], p < .05; metacarpophalangeal ROM, p < .05; proximal interphalangeal ROM, p < .05) and KPPS-r scores (space management, p < .05; material management, p < .05; pretense-symbolic, p < .05; participation, p < .05). After the 12-week rehabilitation with the remodeled glove puppetry, the experimental group exhibited significant improvement in kinematics and KPPS-r scores.

Longitudinal impact of distinct infection trajectories on all-cause mortality of older people in Taiwan: a retrospective, nationwide, population-based study.

BACKGROUND: Infectious diseases are the leading cause of deaths in adults aged 65 years or older. Studies of adverse infection outcomes have been limited to specific infections and acute episodes and have not investigated longitudinal trends of cumulative infections. We aimed to identify distinct trajectories of longitudinal infection episodes in older adults and to assess their corresponding risk of all-cause mortality. METHODS: In this retrospective cohort study, we included people aged 65 years or older who were admitted to hospital between Jan 1 and Dec 31, 2011, with one of the following infections: urinary tract, pneumonia, sepsis, cellulitis, cholecystitis, peritonitis, endocarditis, and meningitis. Participants were identified from Taiwan's National Health Insurance Research Database. We analysed infection episodes on a quarterly basis during a 5-year period (2011-15) and used group-based trajectory modelling to identify distinct trajectories. We examined the associations between infection trajectories and all-cause mortality using Kaplan-Meier curves and the Cox proportional hazard model. FINDINGS: Among 79 666 eligible older adults, we identified four distinct infection trajectories over the 5-year follow-up: infrequent (58 619 [73·6%]), increasing (9746 [12·2%]), decreasing (9069 [11·4%]), and frequent (2232 [2·8%]). Compared with people with infrequent infections, the adjusted hazard ratios for all-cause mortality were 2·96 (95% CI 2·82-3·11) in participants with frequent infections, 2·15 (2·09-2·22) in those with increasing infections, and 1·85 (1·80-1·91) in those with decreasing infections. INTERPRETATION: Older adults with multiple infection episodes, irrespective of type, pathogens, and distinct infection pattern, had greater risk of all-cause mortality compared with those with infrequent infections. Further research to define the overall infection burden in older adults is needed for risk stratification and to inform prevention strategies. FUNDING: The Interdisciplinary Research Center for Healthy Longevity of National Yang Ming Chiao Tung University from The Featured Areas Research Center Program within the framework of the Higher Education Sprout Project by the Ministry of Education, the National Science and Technology Council, and the Ministry of Science and Technology in Taiwan.

Docosahexaenoic Acid Alleviates Trimethylamine-N-oxide-mediated Impairment of Neovascularization in Human Endothelial Progenitor Cells.

BACKGROUND: Human endothelial progenitor cells (hEPCs), originating from hemangioblasts in bone marrow (BM), migrate into the blood circulation, differentiate into endothelial cells, and could act as an alternative tool for tissue regeneration. In addition, trimethylamine-N-oxide (TMAO), one of the gut microbiota metabolites, has been identified as an atherosclerosis risk factor. However, the deleterious effects of TMAO on the neovascularization of hEPCs have not been studied yet. RESULTS: Our results demonstrated that TMAO dose-dependently impaired human stem cell factor (SCF)-mediated neovascularization in hEPCs. The action of TMAO was through the inactivation of Akt/endothelial nitric oxide synthase (eNOS), MAPK/ERK signaling pathways, and an upregulation of microRNA (miR)-221. Docosahexaenoic acid (DHA) could effectively inhibit the cellular miR-221 level and induce the phosphorylation level of Akt/eNOS, MAPK/ERK signaling molecules, and neovascularization in hEPCs. DHA enhanced cellular amounts of reduced form glutathione (GSH) through an increased expression of the gamma-glutamylcysteine synthetase (γ-GCS) protein. CONCLUSIONS: TMAO could significantly inhibit SCF-mediated neovascularization, in part in association with an upregulation of miR-221 level, inactivation of Akt/eNOS and MAPK/ERK cascades, suppression of γ-GCS protein, and decreased levels of GSH and GSH/GSSG ratio. Furthermore, the DHA could alleviate the detrimental effects of TMAO and induce neovasculogenesis through suppression of miR-221 level, activation of Akt/eNOS and MAPK/ERK signaling cascades, increased expression of γ-GCS protein, and increment of cellular GSH level and GSH/GSSG ratio in hEPCs.

Supervised Learning and Multi-Omics Integration Reveals Clinical Significance of Inner Membrane Mitochondrial Protein (IMMT) in Prognostic Prediction, Tumor Immune Microenvironment and Precision Medicine for Kidney Renal Clear Cell Carcinoma.

Kidney renal clear cell carcinoma (KIRC) accounts for approximately 75% of all renal cancers. The prognosis for patients with metastatic KIRC is poor, with less than 10% surviving five years after diagnosis. Inner membrane mitochondrial protein (IMMT) plays a crucial role in shaping the inner mitochondrial membrane (IMM), regulation of metabolism and innate immunity. However, the clinical relevance of IMMT in KIRC is not yet fully understood, and its role in shaping the tumor immune microenvironment (TIME) remains unclear. This study aimed to investigate the clinical significance of IMMT in KIRC using a combination of supervised learning and multi-omics integration. The supervised learning principle was applied to analyze a TCGA dataset, which was downloaded and split into training and test datasets. The training dataset was used to train the prediction model, while the test and the entire TCGA dataset were used to evaluate its performance. Based on the risk score, the cutoff between the low and high IMMT group was set at median value. A Kaplan-Meier curve, receiver operating characteristic (ROC) curve, principal component analysis (PCA) and Spearman's correlation were conducted to evaluate the prediction ability of the model. Gene Set Enrichment Analysis (GSEA) was used to investigate the critical biological pathways. Immunogenicity, immunological landscape and single-cell analysis were performed to examine the TIME. Databases including Gene Expression Omnibus (GEO), Human Protein Atlas (HPA) and Clinical Proteomic Tumor Analysis Consortium (CPTAC) were employed for inter-database verification. Pharmacogenetic prediction was analyzed via single-guide RNA (sgRNA)-based drug sensitivity screening using Q-omics v.1.30. Low expressions of IMMT in tumor predicted dismal prognosis in KIRC patients and correlated with KIRC progression. GSEA revealed that low expressions of IMMT were implicated in mitochondrial inhibition and angiogenetic activation. In addition, low IMMT expressions had associations with reduced immunogenicity and an immunosuppressive TIME. Inter-database verification corroborated the correlation between low IMMT expressions, KIRC tumors and the immunosuppressive TIME. Pharmacogenetic prediction identified lestaurtinib as a potent drug for KIRC in the context of low IMMT expressions. This study highlights the potential of IMMT as a novel biomarker, prognostic predictor and pharmacogenetic predictor to inform the development of more personalized and effective cancer treatments. Additionally, it provides important insights into the role of IMMT in the mechanism underlying mitochondrial activity and angiogenesis development in KIRC, which suggests IMMT as a promising target for the development of new therapies.

Association of the nasopharyngeal carcinoma and the subsequent open glaucoma development: a nationwide cohort study.

This study aimed to investigate the possible association between nasopharyngeal carcinoma (NPC) and following open angle glaucoma (OAG). A retrospective research applying the National Health Insurance Research Database (NHIRD) of Taiwan was conducted with a follow up period from January 1, 2000 to December 31, 2016. There were 4184 and 16736 participants that selected and categorized into the NPC and non-NPC groups after exclusion. The major outcome of our study was the development of OAG according to diagnostic codes, exam and managements. The Cox proportional hazard regression was employed to estimate the adjusted hazard ratio (aHR) and 95% confidence interval (CI) of OAG between the two groups. In this study, a numbers of 151 and 513 OAG episodes occurred in the NPC and non-NPC groups and the NPC population showed a significantly higher incidence of OAG compared to the non-NPC population in multivariable analysis (aHR: 1.293, 95% CI: 1.077-1.551, p = 0.0057). Besides, the cumulative probability of OAG was significantly higher in the NPC group than that in the non-NPC population (p = 0.0041). About other risk factor for OAG, age older than 40 years old, diabetes mellitus and persistent steroid usage were related to OAG occurrence (all p < 0.05). In conclusion, the NPC may be an independent risk factor of following OAG development.

Effects of Therapeutic Platelet-Rich Plasma on Overactive Bladder via Modulating Hyaluronan Synthesis in Ovariectomized Rat.

Postmenopausal women who have ovary hormone deficiency (OHD) may experience urological dysfunctions, such as overactive bladder (OAB) symptoms. This study used a female Sprague Dawley rat model that underwent bilateral ovariectomy (OVX) to simulate post-menopause in humans. The rats were treated with platelet-rich plasma (PRP) or platelet-poor plasma (PPP) after 12 months of OVX to investigate the therapeutic effects of PRP on OHD-induced OAB. The OVX-treated rats exhibited a decrease in the expression of urothelial barrier-associated proteins, altered hyaluronic acid (hyaluronan; HA) production, and exacerbated bladder pathological damage and interstitial fibrosis through NFƘB/COX-2 signaling pathways, which may contribute to OAB. In contrast, PRP instillation for four weeks regulated the inflammatory fibrotic biosynthesis, promoted cell proliferation and matrix synthesis of stroma, enhanced mucosal regeneration, and improved urothelial mucosa to alleviate OHD-induced bladder hyperactivity. PRP could release growth factors to promote angiogenic potential for bladder repair through laminin/integrin-α6 and VEGF/VEGF receptor signaling pathways in the pathogenesis of OHD-induced OAB. Furthermore, PRP enhanced the expression of HA receptors and hyaluronan synthases (HAS), reduced hyaluronidases (HYALs), modulated the fibroblast-myofibroblast transition, and increased angiogenesis and matrix synthesis via the PI3K/AKT/m-TOR pathway, resulting in bladder remodeling and regeneration.

Multi-omics and experimental analysis unveil theragnostic value and immunological roles of inner membrane mitochondrial protein (IMMT) in breast cancer.

BACKGROUND: The inner membrane mitochondrial protein (IMMT) is a central unit of the mitochondrial contact site and cristae organizing system (MICOS). While researchers continue to demonstrate the physiological function of IMMT in regulating mitochondrial dynamics and preserving mitochondrial structural integrity, the roles of IMMT in clinicopathology, the tumor immune microenvironment (TIME), and precision oncology in breast cancer (BC) remain unclear. METHODS: Multi-omics analysis was used here to evaluate the diagnostic and prognostic value of IMMT. Web applications aimed at analyzing the whole tumor tissue, single cells, and spatial transcriptomics were used to examine the relationship of IMMT with TIME. Gene set enrichment analysis (GSEA) was employed to determine the primary biological impact of IMMT. Experimental verification using siRNA knockdown and clinical specimens of BC patients confirmed the mechanisms behind IMMT on BC cells and the clinical significance, respectively. Potent drugs were identified by accessing the data repositories of CRISPR-based drug screenings. RESULTS: High IMMT expression served as an independent diagnostic biomarker, correlated with advanced clinical status, and indicated a poor relapse-free survival (RFS) rate for patients with BC. Although, the contents of Th1, Th2, MSC, macrophages, basophil, CD4 + T cell and B cell, and TMB levels counteracted the prognostic significance. Single-cell level and whole-tissue level analyses revealed that high IMMT was associated with an immunosuppressive TIME. GSEA identified IMMT perturbation as involved in cell cycle progression and mitochondrial antioxidant defenses. Experimental knockdown of IMMT impeded the migration and viability of BC cells, arrested the cell cycle, disturbed mitochondrial function, and increased the ROS level and lipid peroxidation. The clinical values of IMMT were amenable to ethnic Chinese BC patients, and can be extrapolated to some other cancer types. Furthermore, we discovered that pyridostatin acted as a potent drug candidate in BC cells harboring an elevated IMMT expression. CONCLUSION: This study combined a multi-omics survey with experimental verification to reveal the novel clinical significance of IMMT in BC, demonstrating its role in TIME, cancer cell growth and mitochondrial fitness, and identified pyridostatin as a promising drug candidate for the development of precision medicine.