20260 research outputs found
Sort by
TIMP-1 associates with myelin membrane and preserves myelin in injured peripheral nerve
No full textMyelin enables rapid impulse propagation in axons across long distances. Following peripheral nerve injury, Schwann cells provide trophic, metabolic, and immune support to damaged neurons. To facilitate myelin repair, Schwann cells activate a robust transcriptional program, including the tissue inhibitor of metalloproteinase (TIMP)-1 gene. TIMP-1 is a potent protease inhibitor and neurotrophic factor, traditionally known as a secreted protein. This study presents the first evidence of a myelin/membrane-associated (mm)TIMP-1 protein fraction in the nervous system. Specifically, we identified mmTIMP-1 in the rat sciatic nerve after chronic constriction injury (CCI) using multiple complementary approaches. Dual-immunofluorescence revealed TIMP-1 co-localization with myelin protein in the myelin sheath of CCI nerve. Immunoblotting and mass-spectrometry of sucrose gradient-fractionated nerves further confirmed presence of TIMP-1 in myelin/membrane lipid rafts. Both TIMP-1 and (mm)TIMP-1 levels increased in the nerves during the early phase (day 1) and declined in the late phase (day 28) of CCI. Recombinant (r)TIMP-1 replacement therapy during the late phase CCI, administered by intraneural injection, led to improved myelin neuropathology and accumulation of myelin protein. This study identifies a novel subcellular TIMP-1 fraction associated with the myelin sheath and highlights TIMP-1's reparative activity in peripheral nerve myelin in vivo, opening new avenues for exploring functional activities of TIMP-1 isoforms in the nervous system
Prospective Multicenter Observational Study on Postoperative Quality of Life According to Type of Gastrectomy for Gastric Cancer
No full textPURPOSE: This study evaluated the postoperative quality of life (QoL) after various types of gastrectomy for gastric cancer. MATERIALS AND METHODS: A multicenter prospective observational study was conducted in Korea using the Korean Quality of Life in Stomach Cancer Patients Study (KOQUSS)-40, a new QoL assessment tool focusing on postgastrectomy syndrome. Overall, 496 patients with gastric cancer were enrolled, and QoL was assessed at 5 time points: preoperatively and at 1, 3, 6, and 12 months after surgery. RESULTS: Distal gastrectomy (DG) and pylorus-preserving gastrectomy (PPG) showed significantly better outcomes than total gastrectomy (TG) and proximal gastrectomy (PG) with regard to total score, indigestion, and dysphagia. DG, PPG, and TG also showed significantly better outcomes than PG in terms of dumping syndrome and worry about cancer. Postoperative QoL did not differ significantly according to anastomosis type in DG, except for Billroth I anastomosis, which achieved better bowel habit change scores than the others. No domains differed significantly when comparing double tract reconstruction and esophagogastrostomy after PG. The total QoL score correlated significantly with postoperative body weight loss (more than 10%) and extent of resection (P<0.05 for both). Reflux as assessed by KOQUSS-40 did not correlate significantly with reflux observed on gastroscopy 1 year postoperatively (P=0.064). CONCLUSIONS: Our prospective observation using KOQUSS-40 revealed that DG and PPG lead to better QoL than TG and PG. Further study is needed to compare postoperative QoL according to anastomosis type in DG and PG
Hoping Against Hope: Ethical Considerations when Trying Unproven Treatments for Seriously Ill Children
No full textModern medicine is continually evolving, yet developing and validating new treatments for paediatric patients presents significant challenges. Ethical dilemmas often arise when parents consider nonstandard treatments for their children, driven by desperation and the hope of finding effective interventions. Therefore, there is an urgent need for robust ethical frameworks to guide thier decision-making processes. Such frameworks must include the necessity for informed consent, ensuring that parents understand the potential risks and benefits of unproven treatments. Additionally, clear and open communication between parents and healthcare providers throughout the treatment journey is crucial. This ensures that decisions are made in the best interest of paediatric patients, considering their unique needs and vulnerabilities. By addressing the ethical considerations of trying unproven treatment for seriously ill children, healthcare professionals can better navigate these complexities, and ultimately foster a more compassionate and ethically sound healthcare environment
In vivo composition of the mitochondrial nucleoid in mice
No full textMitochondrial DNA (mtDNA) is compacted into dynamic structures called mitochondrial nucleoids (mt-nucleoids), with the mitochondrial transcription factor A (TFAM) as the core packaging protein. We generated bacterial artificial chromosome (BAC) transgenic mice expressing FLAG-tagged TFAM protein (Tfam-FLAG(BAC) mice) to investigate the mt-nucleoid composition in vivo. Importantly, we show that the TFAM-FLAG protein is functional and complements the absence of the wild-type TFAM protein in homozygous Tfam knockout mice. We performed immunoprecipitation experiments from different mouse tissues and identified 12 proteins as core mt-nucleoid components by proteomics analysis. Among these, eight proteins correspond to mtDNA replication and transcription factors, while the other four are involved in the mitoribosome assembly. In addition, we used the Tfam-FLAG(BAC) mice to identify ten proteins that may stabilize TFAM-FLAG upon depletion of the mitochondrial RNA polymerase despite the absence of mtDNA and induction of the LONP1 protease. Finally, we evaluated the changes in mt-nucleoids caused by very high levels of TFAM unraveling nine interactors that could counteract the high TFAM levels to maintain active mtDNA transcription. Altogether, we demonstrate that the Tfam-FLAG(BAC) mice are a valuable tool for investigating the mt-nucleoid composition in vivo
Correction: Predicting Nottingham grade in breast cancer digital pathology using a foundation model
No full textA randomized controlled trial of a digital lifestyle intervention involving postoperative patients with colorectal cancer
No full textFew studies have investigated quality of life (QoL) improvements in patients with colorectal cancer or the benefits of digital healthcare interventions. This randomized controlled trial assessed the impact of mobile applications on postoperative QoL in patients scheduled for curative surgery for colorectal cancer. Patients were randomized into three intervention groups (each using a different mobile application for postoperative lifestyle management) and a control group. QoL was evaluated using the European Quality of Life-5 Dimensions (EQ-5D), with physical and metabolic parameters and fat/muscle areas measured preoperatively, and every six months postoperatively. At six months, no significant differences in the EQ-5D scores from baseline were observed across groups. Intervention Group C showed a significant increase in skeletal muscle area compared to the control group (P = 0.046). Overall, mobile application use had a minimal effect on postoperative health-related QoL, warranting further research on their efficacy and compliance rates. Trial registration: CRIS.nih.go.kr: KCT0005447. Registration date: June 23, 2020
Difficult-to-treat rheumatoid arthritis among elderly patients from the KOBIO registry
No full textBACKGROUND: 'Difficult-to-treat (D2T)' rheumatoid arthritis (RA) refers to patients who fail to achieve low disease activity or remission despite multiple biologic or targeted synthetic disease modifying anti-rheumatic drugs (b/tsDMARD) cycles. Elderly RA patients often have higher disease activity and more comorbidities. This study aimed to determine the prevalence of D2T-RA in elderly RA patients treated with b/tsDMARDs and examine their characteristics and treatment outcomes. METHODS: Data were extracted from the Korean College of Rheumatology Biologics registry for RA patients receiving b/tsDMARDs. RESULTS: Among 516 elderly RA patients (>/=65 years) on b/tsDMARDs, 54 (10.5 %) had D2T-RA. Younger age (OR = 0.905, p = 0.012), higher RAPID3 scores (OR = 1.082, p = 0.044), lack of prior leflunomide use (OR = 0.446, p = 0.009), and lack of prior use of two or more conventional synthetic DMARDs (csDMARDs) (OR = 0.114, p < 0.001) were associated with D2T-RA. Drug survival rates were similar between D2T-RA and non-D2T-RA groups (p = 0.53). Discontinuation and switching rates did not differ, but inefficacy was a more frequent withdrawal reason in D2T-RA (63 % vs. 29.7 %, p = 0.001). Disease activity scores remained higher in D2T-RA patients at 1- and 2-year follow-ups. CONCLUSIONS: Among elderly RA patients on b/tsDMARDs, 10.5 % had D2T-RA. Younger age, higher RAPID3, absence of prior leflunomide use, and absence of prior use of two or more csDMARDs were associated with D2T-RA. Despite comparable drug survival, persistent disease activity underscores the need for ongoing efficacy evaluation and tailored treatment strategies for better disease control
Cardiorenal outcomes and safety of SGLT2 inhibitors in patients with diabetes secondary to disorders of the exocrine pancreas: a nationwide population-based study
No full textAIMS: Limited data are available on the effectiveness of pharmacological treatments for diabetes secondary to disorders of the exocrine pancreas (DEP). This study evaluated the real-world effectiveness and safety of sodium-glucose cotransporter 2 (SGLT2) inhibitors in individuals with DEP. METHODS: A retrospective cohort study was conducted using data from the Korean National Health Insurance Service database. Data on 66,120 individuals with DEP who initiated glucose-lowering drugs (GLDs) between September 2014 and December 2022 were analyzed. Patients initiating SGLT2 inhibitors were matched 1:1 with patients initiating other GLDs using propensity-score matching. The effectiveness outcomes included major adverse cardiovascular events (MACEs), heart failure, end-stage kidney disease (ESKD), and all-cause mortality. The safety outcomes included hypoglycemia, diabetic ketoacidosis, genital infections, urinary tract infections, fractures, pancreatitis, and pancreatic cancer. RESULTS: After matching, 4,128 SGLT2 inhibitor-other GLD user pairs were included in the analysis, with a mean follow-up of 2.3 years. Compared with use of other GLDs, use of SGLT2 inhibitors was associated with a significantly lower risk of MACE (hazard ratio [HR]: 0.69; 95% confidence interval [CI]: 0.51-0.93), hospitalization for heart failure (HR: 0.70; 95% CI: 0.51-0.95), ESKD (HR: 0.19; 95% CI: 0.06-0.61), and all-cause mortality (HR: 0.38; 95% CI: 0.27-0.53). SGLT2 inhibitor use was associated with a reduced risk of urinary tract infections (HR: 0.87; 95% CI: 0.78-0.96) and pancreatitis (HR 0.71; 95% CI 0.58-0.87). CONCLUSIONS: SGLT2 inhibitors were associated with a reduced risk of adverse cardiorenal outcomes and all-cause mortality and were safely used in patients with DEP
The machine learning prediction model of non-alcoholic fatty liver; the role of hydrogen and methane breath tests
No full textNonalcoholic fatty liver disease (NAFLD) is now the leading cause of global chronic liver disease, affecting approximately 32.4% of the population in various regions and imposing healthcare and economic burdens. The gold standard for the diagnosis of NAFLD, such as liver biopsy, has numerous limitations in large-scale screening. Recent studies have explored the use of machine learning to diagnose NAFLD. In this study, we investigated the effect of the lactulose breath test (LBT) on a machine-learning model for predicting NAFLD. The input variables for machine learning included three combination sets to assess the effect of the LBT results: anthropometric characteristics and blood test results; anthropometric characteristics and LBT results; and anthropometric characteristics, blood test results, and LBT results. The machine learning models developed in this study included linear regression, support vector machine, K-nearest neighbour, Random forest, and extreme gradient boosting (XGBoost) with 536 participants. The model performance was evaluated using six metrics: Accuracy, Area Under the Receiver Operating Characteristic curve (AUROC), specificity, sensitivity, precision, and F1 score. Among the six models, XGBoost had the highest AUROC at 0.88. The AUROC results from the three combination variable sets indicate that the LBT results significantly improve the model performance. LBT results improve the NAFLD prediction model and provide an opportunity for additional NAFLD screening in patients receiving LBT
The role of 7-dehydrocholesterol in inducing ER stress and apoptosis of head and neck squamous cell carcinoma
No full textAlterations of metabolic pathways that sustain cancer cell survival often offer promising therapeutic avenues. Here, we show that enhanced de novo cholesterol biosynthesis is crucial for the survival of head and neck squamous cell carcinoma (HNSCC). Transcriptomic analysis of HNSCC tissues identified profound dysregulation in steroid and cholesterol metabolism compared to normal tissues. Inhibition of two key enzymes, DHCR7 and DHCR24, which mediate cholesterol biosynthesis, induced apoptosis in HNSCC cells, even when cholesterol levels were restored. Metabolomic profiling revealed the accumulation of 7-dehydrocholesterol (7-DHC) upon DHCR7 or DHCR24 inhibition, triggering endoplasmic reticulum (ER) stress and promoting further cell death. These findings suggest that HNSCC cells adapt to ER stress by modulating 7-DHC levels through enhancing DHCR7 and DHCR24 levels, highlighting a metabolic vulnerability in HNSCC and demonstrating a direct link between cholesterol metabolism and ER stress in cancer cell viability