Comprehensive metabolomic analysis identifies key biomarkers and modulators of immunotherapy response in NSCLC patients.

Although immune checkpoint inhibitors (ICIs) have revolutionized immuno-oncology with effective clinical responses, only 30 to 40 % of patients respond to ICIs, highlighting the need for reliable biomarkers to predict and enhance therapeutic outcomes. This study investigated how amino acid, glycolysis, and bile acid metabolism affect ICI efficacy in non-small cell lung cancer (NSCLC) patients. Through targeted metabolomic profiling and machine learning analysis, we identified amino acid metabolism as a key factor, with histidine (His) linked to favorable outcomes and homocysteine (HCys), phenylalanine (Phe), and sarcosine (Sar) linked to poor outcomes. Importantly, the His/HCys+Phe+Sar ratio emerges as a robust biomarker. Furthermore, we emphasize the role of glycolysis-related metabolites, particularly lactate. Elevated lactate levels post-immunotherapy treatment correlate with poorer outcomes, underscoring lactate as a potential indicator of treatment efficacy. Moreover, specific bile acids, glycochenodeoxycholic acid (GCDCA) and taurolithocholic acid (TLCA), are associated with better survival and therapeutic response. Particularly, TLCA enhances T cell activation and anti-tumor immunity, suggesting its utility as a predictive biomarker and therapeutic agent. We also suggest a connection between gut microbiota and TLCA levels, with the Eubacterium genus modulating this relationship. Therefore, modulating specific metabolic pathways-particularly amino acid, glycolysis, and bile acid metabolism-could predict and enhance the efficacy of ICI therapy in NSCLC patients, with potential implications for personalized treatment strategies in immuno-oncology. ONE SENTENCE SUMMARY: Our study identifies metabolic biomarkers and pathways that could predict and enhance the outcomes of immune checkpoint inhibitor therapy in NSCLC patients.

Association between circulating bile acid alterations and nonalcoholic steatohepatitis independent of obesity and diabetes mellitus.

BACKGROUND AND AIMS: Bile acid (BA) dysregulation is related to not only metabolic diseases but also nonalcoholic fatty liver disease (NAFLD). We investigated whether circulating BA levels are altered according to the histological severity of NAFLD independent of metabolic derangements. METHODS: Global metabolic profiling and targeted BA analysis using sera collected from biopsy-proven no-NAFLD (n = 67), nonalcoholic fatty liver (NAFL) (n = 99), and nonalcoholic steatohepatitis (NASH, n = 75) subjects were performed sequentially. Circulating metabolome analysis integrated with the hepatic transcriptome was performed to elucidate the mechanistic basis of altered circulating BA profiles after stratification by obesity (body mass index ≤ 25 kg/m2 ). Circulating BA alterations were also validated in an independent validation cohort (29 no-NAFLD, 70 NAFL and 37 NASH). RESULTS: Global profiling analysis showed that BA was the metabolite significantly altered in NASH compared to NAFL. Targeted BA analysis demonstrated that glyco-/tauro-conjugated primary BAs were commonly increased in nonobese and obese NASH, while unconjugated primary BAs increased only in nonobese NASH. These characteristic primary BA level changes were maintained even after stratification according to diabetes status and were replicated in the independent validation cohort. Compared to nonobese NAFL patients, nonobese NASH patients exhibited upregulated hepatic expression of CYP8B1. CONCLUSIONS: BA metabolism is dysregulated as the histological severity of NAFLD worsens, independent of obesity and diabetes status; dysregulation is more prominent in nonobese NAFLD patients. Metabolome-driven omics approach provides new insight into our understanding of altered BA metabolism associated with individual phenotypes of NAFLD.

GS Hip Nail versus Affixus Hip Fracture Nail for the Intramedullary Nailing of Intertrochanteric Fractures.

BACKGROUND: Intertrochanteric fractures are a global health concern, especially in aging populations like the Republic of Korea. Surgical treatments like intramedullary nailing are preferred for their benefit. Various hip nails are used worldwide, each with unique features and challenges. This study aims to compare the GS hip nail with the Affixus hip fracture nail for the treatment of intertrochanteric fractures. MATERIAL AND METHODS: This retrospective study, conducted at a single center, included 179 patients who underwent intramedullary nailing for intertrochanteric fractures using the GS hip nail or the Affixus hip fracture nail. Excluding specific cases, 43 patients in the GS group and 46 in the Affixus group met the minimum 6-month follow-up criteria. RESULT: The GS group exhibited a significantly shorter mean operation time (43.26 min) compared to the Affixus group (51.11 min). Radiographically, both groups showed no significant differences in their reduction quality, tip, and apex distance (TAD), or Cleveland index in the immediate postoperative window. However, the GS group achieved a greater valgus reduction based on the contralateral femoral neck shaft angle (NSA). At 6 months post-operation, there were no significant differences in TAD or advancement and sliding distances. Complication rates were similar between the two groups, with no implant breakages. Clinical outcomes, as measured via mHHS and EQ-5D-5L, showed no significant differences. Despite a slightly higher implant cost, the GS group had a lower total hospital cost than the Affixus group, but this was not statistically significant. CONCLUSIONS: This study highlights the efficiency of the GS hip nail in reducing the operation time compared to the Affixus hip fracture nail with comparable radiologic and clinical outcomes. Further research with long-term follow-up and larger patient studies are needed to fully assess its effectiveness in improving patient outcomes in hip fracture treatment.

Korean Brain Rehabilitation Registry for rehabilitation of persons with brain disorders: annual report in 2009.

This first annual report provides a description of patients discharged from rehabilitation facilities in Korea based on secondary data analysis of Korean Brain Rehabilitation Registry V1.0 subscribed in 2009. The analysis included 1,697 records of patients with brain disorders including stroke, traumatic brain injury, brain tumor and other disorders from 24 rehabilitation facilities across Korea. The data comprised 1,380 cases of stroke, 104 cases of brain injury, 55 cases of brain tumor, and 58 cases of other brain diseases. The functional status of each patient was measured using the Korean version of the Modified Barthel Index (KMBI). The average change in the KMBI score was 15.9 for all patients in the inpatient rehabilitation facility. The average length of stay for inpatient rehabilitation was 36.9 days. The transfer rates to other hospitals were high, being 62.4% when all patients were considered. Patients with brain disorders of Korea in 2009 and measurable functional improvement was observed in patients. However, relatively high percentages of patients were not discharged to the community after inpatient rehabilitation. Based on the results of this study, consecutive reports of the status of rehabilitation need to be conducted in order to provide useful information to many practitioners.

Lipidomic profiling analysis of human plasma from subjects with hypercholesterolemia to evaluate the intake of yellow yeast rice fermented by Aspergillus terreus DSMK01.

Yellow yeast rice (YYR) is a Korean functional food fermented with Aspergillus terreus and contains monacolin K, a cholesterol-lowering ingredient. However, the effects of YYR on lipid metabolism alterations have not been reported until now. In this study, we performed a mass spectrometry-based lipidomic analysis of plasma samples from subjects (31 from the YYR group and 27 from the placebo group) with LDL-C higher than 130 mg dL-1 to investigate the effects of the intake of YYR. Lipidomic profiling showed that the levels of sphingomyelin (SM) were significantly decreased in the YYR intake group compared with the placebo group. The SM level in the YYR intake group showed a significant association with the ApoB/ApoA1 ratio (p = 0.004, r = 0.503), an indicator of the effect of lipid-lowering therapy. This study suggests that global lipidomic profiling could be used to identify changes in lipid metabolism induced by YYR intake and provide information that these lipid changes are associated with improved hypercholesterolemia.

Yellow Yeast Rice Prepared Using Aspergillus terreus DSMK01 Lowers Cholesterol Levels by Stimulating Bile Salt Export Pump in Subjects with Mild-to-Moderate Hypercholesterolemia: A Randomized Controlled Trial.

SCOPE: Aspergillus terreus is an industrial microorganism used in the brewing and sauce industries. It produces monacolin K, a natural statin. The study conducted an 8-week randomized controlled trial with hypercholesterolemic subjects to examine the hypocholesterolemic effects and mechanisms of supplementation with yellow yeast rice (YYR) prepared by growing Aspergillus fungi on steamed rice. METHODS AND RESULTS: YYR supplementation markedly reduced total cholesterol, LDL, and apolipoprotein B100 levels in plasma compared with the placebo. In addition, YYR induced a significantly increased ATP binding cassette subfamily B member 11 (ABCB11) gene expression compared with the placebo, indicating the role of YYR in lowering intrahepatic cholesterol availability by stimulating the bile salt export pump. Upregulation of LDL receptor (LDLR) and 3-methylglutaryl-CoA reductase (HMGCR) gene expressions provided additional evidence to support the role of YYR in reducing hepatic cholesterol availability. Plasma metabolomic profiling revealed the possibility of diminishing bile acid absorption. Finally, Spearman rank analysis showed correlations of plasma cholesterol profiles with HMGCR and LDLR gene expressions (negative) and plasma bile acids (positive). Plasma bile acids also correlated with ABCB11 (negative) and LDLR (positive) gene expressions. CONCLUSION: These findings suggest that daily YYR supplementation exerted hypocholesterolemic effects in mild-to-moderate hypercholesterolemic subjects by reducing intrahepatic cholesterol availability through stimulating bile salt export pumps and inhibiting cholesterol biosynthesis.

Identification of Potential Biomarkers in the Cervicovaginal Fluid by Metabolic Profiling for Preterm Birth.

During pregnancy, dysbiosis in the vaginal microbiota directly affects the metabolic profiles, which might impact preterm birth (PTB). In this study, we performed cervicovaginal fluid (CVF) metabolic profiling using nuclear magnetic resonance (NMR) spectroscopy and identified the metabolic markers for predicting PTB. In this nested case-control study, 43 South Korean pregnant women with PTB (n = 22), and term birth (TB; n = 21) were enrolled with their demographic profiles, and CVF samples were collected by vaginal swabs. The PTB group had two subgroups based on post-CVF sampling birth: PTB less than (PTB < 7 d) and more than 7 days (PTB ≥ 7 d). We observed significant differences in the gestational age at birth (GAB), cervical length (CL), and neonatal birth weight among the groups. The principal component analysis (PCA), and partial least square discriminant analysis (PLS-DA) scatter plot showed the separation between the PTB < 7 d group, and the TB group. Out of 28 identified metabolites, acetone, ethanol, ethylene glycol, formate, glycolate, isopropanol, methanol, and trimethylamine N-oxide (TMAO) were significantly increased in the PTB group compared with the TB group. The ROC curve analysis revealed that the acetone, ethylene glycol, formate, glycolate, isopropanol, methanol, and TMAO had the best predictive values for PTB. Additionally, the correlation analysis of these metabolites showed a strong negative correlation with GAB and CL. These metabolites could be beneficial markers for the clinical application of PTB prediction.

Cytotoxicity and apoptosis induction of sodium fluoride in human promyelocytic leukemia (HL-60) cells.

The role of sodium fluoride (NaF) in cytotoxicity and induction of apoptosis was investigated by treating human promyelocytic leukemia (HL-60) cells with varying concentrations of NaF, from 0 to 250 ppm for different periods (0-72 h). At lower concentrations (0-50 ppm), no significant cytotoxicity was observed in response to NaF treatment. However, at higher concentrations (100-250 ppm), NaF reduced cell viability, and decreased DNA and protein biosynthesis capability in cultured HL-60 cells. The growth inhibitory and antiproliferative effects of NaF appear to be attributable to its induction of apoptotic cell death, as NaF induced morphological changes, internucleosomal DNA fragmentation, and increased the proportion of hypodiploid cells. NaF treatment also gradually decreased the expression of the anti-apoptotic protein Bcl-2, and increased activation of caspase-3 and cleavage of poly (ADP-ribose) polymerase. These results provides important information towards understanding the mechanism by which NaF mediates cytotoxicity and apoptosis.

Age specificity in general and rehabilitation medical services in children with cerebral palsy.

OBJECTIVE: To review the medical utilization in children with cerebral palsy according to age and discern particularities. METHODS: From January 2007 to December 2007, 10,659 children and adolescents between 1 and 18 years of age who had filed national insurance claims for a diagnosis of cerebral palsy were selected. Age was chosen as an independent variable, and the population was categorized into specific age groups to verify any differences in medical service utilization. Admission duration to rehabilitation, number of visits to rehabilitation outpatient clinics, numbers of admission dates and outpatient clinic visits for general medical services, number of rehabilitation utilizations, and type of rehabilitations treatment were selected as dependent variables. One-way ANOVA was used for statistical evaluation, and analysis was done with SAS software. RESULTS: In general medical use, adolescences diagnosed with cerebral palsy had the highest mean admission duration (p<0.001). The mean visit day to outpatient clinics for general medical services was highest for infants (p<0.001). In rehabilitation treatment, infants diagnosed with cerebral palsy had the highest mean admission duration (p<0.001). The mean visit day to outpatient clinics for rehabilitation treatment was highest for infants (p<0.001). CONCLUSION: Significant differences in use of general and rehabilitation medical services among pediatric age groups with cerebral palsy were evident. This implies that particular attention is necessary when setting up a national medical care policy for patient with cerebral palsy.

Total, direct, and indirect serum bilirubin concentrations and metabolic syndrome among the Korean population.

Total bilirubin, not direct or indirect bilirubin, has been reported to associate inversely with metabolic syndrome. Therefore, we aimed to evaluate the association between bilirubin subtypes and metabolic syndrome among the Korean population. This study included 5,231 Koreans (3,008 men, 2,223 women) aged 30-87 years, who visited the Health promotion centers in Seoul from April, 2006 to June, 2007. The associations of direct, indirect, and total bilirubin classified in quartiles with metabolic syndrome were measured by logistic regression analyses in men and women. Odds ratios (95% confidence intervals) of the lowest, 2nd and 3rd quartiles of direct serum bilirubin compared with the highest quartile (reference) were 2.3 (1.6-3.2), 1.8 (1.3-2.4), and 1.8 (1.4-2.4) among men, and 5.5 (2.6-11.5), 3.1 (1.5-6.7), and 1.9 (0.9-4.3) among women, respectively. In a multivariable adjusted model, however, the significance of inverse associations with total and indirect bilirubin became attenuated. The relation was consistent particularly with direct bilirubin in subgroups of metabolic syndrome components such as central obesity, hypertriglyceridemia, hyperglycemia, and low HDL-cholesterol in both men and women. Of the three subtypes of serum bilirubin, the inverse association of metabolic syndrome was significantly apparent and consistent with direct bilirubin.