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Schizophrenia is a chronic and complex severe psychiatric disorder. Male and female are different in their risks for schizophrenia for the biologic and sociocultural reasons. Homocysteine (Hcy), Cysteine (Cys), and methionine (Met) play important roles in metabolism, and the three amino acids may also be involved in pathogenesis of schizophrenia. This study aimed to test the associations between sulfur-containing amino acid blood levels and risk of schizophrenia, evaluating the different risk in male and female. We organized a case-control study on 876 individuals with schizophrenia and 913 age- and sex-matched healthy subjects as control group. The concentrations of Hcy, Cys and Met were measured by liquid chromatography-tandem mass spectrometry technology. Subsequently, restricted cubic spline was applied to explore full-range associations of these amino acids with schizophrenia. Interactions between levels of the three amino acids and sex on additive scale were also tested. Hcy levels at ≤29 μmol/L were associated with sharply increased risk of schizophrenia, inversely, Met was associated with sharply decreased risk of schizophrenia at levels ≤22 μmol/L. Increased Cys levels were associated with decreased risk of schizophrenia. Almost inverse associations were observed between Cys/Hcy and Met/Hcy ratios and schizophrenia. Significant synergistic interactions between levels of all the three amino acids and sex were discovered on an additive scale. Our study suggests a close association between sulfur-containing amino acids and schizophrenia with different risk in male and female. Future studies are demanded to clarify the pathogenic role of Hcy, Cys and Met in schizophrenia. [ABSTRACT FROM AUTHOR]

Background: Gout is the most common inflammatory arthritis and closely related to metabolic syndrome, leading to excruciating pain and the decline in quality of patients' life. However, the pathogenesis of gout is still unclear, and novel biomarkers are demanded for the early prediction and diagnosis of gout. Objective: This study aimed at profiling the dysregulated metabolic pathways in asymptomatic hyperuricemia (AHU) and gout and elucidating the associations between AHU, gout and metabolomics, which may aid in performing gout screening. Methods: A total of 300 participants, including 114 healthy controls, 92 patients with AHU, and 94 patients with gout, were analyzed by using a combination of dried blood spot (DBS) sampling and mass spectrometry (MS) technology. Multiple algorithms were applied to characterize altered metabolic profiles in AHU and gout. The mainly altered metabolites were identified by random forest analysis. Results: There were significant differences in AHU and gout compared with control group. The altered metabolites were involved in oxidation of fatty acids, carnitine synthesis, urea cycle, and amino acid metabolism in AHU and gout. Random forest classification of 16 metabolites yielded 3 important features to distinguish gout from AHU. Conclusions: Distinct metabolomic signatures were observed in AHU and gout. The selected metabolites may have the potential to improve the early detection of gout. [ABSTRACT FROM AUTHOR]

Background: Locoregional recurrence is of high risk and is associated with a poor prognosis in terms of OS for non‐small cell lung cancer (NSCLC). Local control is essential for radical cure of NSCLC. Previous studies have investigated the clinicopathological risk factors for locoregional recurrence, but the genomic biomarkers associated with locoregional recurrence have been inadequately studied. Methods: A total of 118 patients who underwent tumor resection with mutation‐detected tumor specimens were included. Tumor samples at surgery and pretreatment/postoperative blood samples were collected for mutational profiling. Results: Among 48 patients with disease recurrence, 46% developed locoregional recurrence (LR) and 75% developed distant metastasis (DM). The 3‐year actuarial risk of LR and DM was 25% and 43%, respectively. The first sites of failure were locoregional only (29%), locoregional and distant (10%), and distant only (61%). Patients with LR showed significantly higher ctDNA level than those with only DM at the time of initial recurrence. On multivariate analysis of baseline risk factors, the presence of allele frequency heterogeneity and baseline ctDNA shedding were found to be independently associated with a higher risk of LR. Patients with disruptive TP53 mutations had significantly lower LR‐free survival as compared to patients with wild‐type TP53 or nondisruptive mutations. EGFR mutations showed a favorable prognostic value for LR and is not induced by EGFR tyrosine kinase inhibitor therapy. Both disruptive TP53 mutation and EGFR mutation remained the significant prognostic factor after adjustment for histological type, pathologic nodal stage and adjuvant therapy. Conclusions: Nearly half of disease recurrences after surgery for NSCC involved locoregional sites. We identified genomic biomarkers from baseline tumor and ctDNA samples which showed promising prognostic value for LR only. This can help identify patients who had a higher risk of locoregional recurrence regardless of the risk of distant metastasis. [ABSTRACT FROM AUTHOR]

Simple Summary: In this study, we found 299 circadian genes that were differentially expressed in pancreatic cancer (PACA). The expression levels of MBOAT2, CDA, LPCAT2 and B4GALT5, which were enriched in metabolic pathways, were not only highly connected with overall survival and other clinical parameters in PACA patients, but were also closely correlated with the level of immune cell infiltration. In conclusion, there was a close link between circadian genes, cancer marker pathways and immune infiltration. These findings could lay the foundation for the use of personalized chronotherapy and immune checkpoint inhibitors in the treatment of pancreatic cancer. Pancreatic cancer (PACA) is a highly malignant tumor with a poor prognosis. Recent studies have discovered substantial differences in the expression levels of several circadian genes in PACA samples compared to normal samples. The goal of this research was to find differentially expressed rhythm genes (DERGs) in PACA samples and determine their role in the development of PACA. A total of 299 DERGs were identified in PACA, including 134 downregulated genes and 165 upregulated genes. DERGs were significantly abundant in the metabolic pathway and immune response pathways, according to GO and KEGG analyses. Survival analyses showed that PACA patients who had higher expression levels of MBOAT2/CDA/LPCAT2/B4GALT5 had shorter overall survival times. Using cell assay verification, the mRNA levels of MBOAT2/CDA/LPCAT2/B4GALT5 in Patu-8988 and PNAC-1 cells were found to be significantly higher than those in HPDE6-C7 cells, which was in line with previous studies on PACA patient data. Through conducting univariate Cox analysis, it was determined that MBOAT2/CDA/LPCAT2/B4GALT5 expression, age and grade were all high-risk factors. The MBOAT2/CDA/LPCAT2/B4GALT5 genes were independently correlated with overall survival, according to the multivariate Cox analysis. The proportion of immune cells in PACA and normal samples significantly changed, according to the immune infiltration analysis. Furthermore, MBOAT2/CDA/LPCAT2/B4GALT5 expression levels were significantly related to the level of immune cell infiltration. The protein–protein interaction network of the MBOAT2/CDA/LPCAT2/B4GALT5 genes included 54 biological nodes and 368 interacting genes. In conclusion, the finding of these DERGs adds to the investigation of the molecular processes underlying the onset and progression of PACA. In the future, DERGs may serve as prognostic and diagnostic biomarkers as well as drug targets for chronotherapy in PACA patients. [ABSTRACT FROM AUTHOR]

PURPOSE: To evaluate early circulating tumor DNA (ctDNA) kinetics using a tumor-naïve assay and correlate it with clinical outcomes in early phase immunotherapy (IO) trials. METHODS: Plasma samples were analyzed using a 425-gene next-generation sequencing panel at baseline and before cycle 2 (3-4 weeks) in patients with advanced solid tumors treated with investigational IO agents. Variant allele frequency (VAF) for mutations in each gene, mean VAF (mVAF) from all mutations, and change in mVAF between both time points were calculated. Hyperprogression (HyperPD) was measured using Matos and Caramella criteria. RESULTS: A total of 162 plasma samples were collected from 81 patients with 27 different tumor types. Patients were treated in 37 different IO phase I/II trials, 72% of which involved a PD-1/PD-L1 inhibitor. ctDNA was detected in 122 plasma samples (75.3%). A decrease in mVAF from baseline to precycle 2 was observed in 24 patients (37.5%) and was associated with longer progression-free survival (hazard ratio [HR], 0.43; 95% CI, 0.24 to 0.77; P <.01) and overall survival (HR, 0.54; 95% CI, 0.3 to 0.96; P =.03) compared with an increase. These differences were more marked if there was a >50% decrease in mVAF for both progression-free survival (HR, 0.29; 95% CI, 0.13 to 0.62; P <.001) and overall survival (HR, 0.23; 95% CI, 0.09 to 0.6; P =.001). No differences in mVAF changes were observed between the HyperPD and progressive disease patients. CONCLUSION: A decrease in ctDNA within 4 weeks of treatment was associated with treatment outcomes in patients in early phase IO trials. Tumor-naïve ctDNA assays may be useful for identifying early treatment benefits in phase I/II IO trials. Circulating tumor DNA kinetics during the first 3 weeks of immunotherapy can predict treatment outcomes in early-phase clinical trials. [ABSTRACT FROM AUTHOR]

As one of the most common malignancies, gastric cancer (GC) is the third leading cause of cancer-related deaths in China. GC is asymptomatic in early stages, and the majority of GC mortality is due to delayed symptoms. It is an urgent task to find reliable biomarkers for the identification of GC in order to improve outcomes. A combination of dried blood spot sampling and direct infusion mass spectrometry (MS) technology was used to measure blood metabolic profiles for 166 patients with GC and 183 healthy individuals, and 93 metabolites including amino acids, carnitine/acylcarnitines and their derivatives, and related ratios were quantified. Multiple algorithms were used to characterize the changes of metabolic profiles in patients with GC compared to healthy individuals. A biomarker panel was identified in training set, and assessed by tenfold cross-validation and external test data set. After systematic selection of 93 metabolites, a biomarker panel consisting of Ala, Arg, Gly, Orn, Tyr/Cit, Val/Phe, C4-OH, C5/C3, C10:2 shows the potential to distinguish patients with GC from healthy individuals in tenfold cross-validation model (sensitivity: 0.8750, specificity: 0.9006) and test set (sensitivity: 0.9545, specificity: 0.8636). This metabolomic analysis makes contribution to the identification of disease-associated biomarkers and to the development of new diagnostic tools for patients with GC. [ABSTRACT FROM AUTHOR]

Background: Plasma biomarkers showed a promising value in the disease diagnosis and management of Alzheimer's disease (AD). However, profiles of the biomarkers and the associations with cognition across a spectrum of cognitive stages have seldom been reported. Methods: We recruited 320 individuals with cognitive impairment and 131 cognitively normal participants from a memory clinic and a community cohort. Participants were classified into 6 groups based on their Clinical Dementia Rating (CDR) scores and clinical diagnosis, including AD, amnestic mild cognitive impairment (aMCI), and normal cognition (NC). A battery of neuropsychological tests was used to assess the global and domain-specific cognition. Plasma Aβ1-40, Aβ1-42, Aβ1-42/Aβ1-40, total tau (t-tau), neurofilament protein light chain (NfL), and phosphorylated tau at threonine 181 (p-tau181) were quantified using the single-molecule array (Simoa) platform. Results: All the plasma markers (Aβ1-40, Aβ1-42, Aβ1-42/Aβ1-40, t-tau, NfL, p-tau181) showed certain discrepancies among NC, aMCI, and AD groups. The p-tau181 level showed a continuous escalating trend as the CDR scores increased from 0 (NC group) to 3 (severe AD). Compared with other biomarkers, p-tau181 had correlations with broader cognitive domains, covering global cognition (r = −0.536, P < 0.0001), memory (r = −0.481, P < 0.0001), attention (r = −0.437, P < 0.0001), visuospatial function (r = −0.385, P < 0.0001), and language (r = −0.177, P = 0.0003). Among participants with CDR ≥ 1, higher p-tau181 was correlated with worse global cognition (r = −0.301, P < 0.001). Conclusions: Plasma p-tau181 had correlations with broader cognitive domains, suggesting its potential as a promising clinical-relevant blood-based biomarker. [ABSTRACT FROM AUTHOR]

Purpose: Although definitive chemoradiation therapy (dCRT) remains the most effective treatment modality in limited stage small cell lung cancer (SCLC), some patients progress quickly or develop serious radiation-induced thoracic toxicity (RITT). Molecular correlates of response to dCRT remain to be explored.Methods and Materials: Genomic profiling was performed retrospectively on 231 patients with limited-stage SCLC treated with dCRT between 2015 and 2019 using a customized panel covering cancer and radiation therapy response-related genes. Exploratory associations of progression-free survival, overall survival, and RITT with clinical features, tumor genetics, genomic and molecular pathway alterations, and single nucleotide polymorphisms were conducted.Results: In addition to the common SCLC genes, such as TP53, RB1, and NOTCH1/2, potentially actionable mutations in EGFR, KRAS, and BRCA1/2 were among the top alterations in the cohort. At the single-gene level, CDK4 and GATA6 alterations were independent predictors of poor survival by multivariate analysis. At the genomic level, high tumor mutational burden was strongly associated with favorable survival outcome. Pathway-level analysis showed that activating mutations in the MAPK/ERK pathway genes, particularly those in EGFR/ERBB2, correlated with poor survival. Combined analysis enabled optimized risk stratification of post-dCRT survival. On the other hand, our study also confirmed that single nucleotide polymorphisms in MTHFR, CYP2B6, NQO1, and LIG4 were risk alleles of high-grade RITT. Remarkably, somatic loss-of-function mutations in the DNA damage repair pathway genes were associated with increased risk of high-grade RITT, particularly pneumonitis, which likely reflect a complex interplay between the tumor and its immune microenvironment.Conclusions: Taken together, by examining the mutational landscape of a large cohort of limited-stage SCLC, we identified novel molecular predictors of survival and RITT. Our findings also implicate several key molecular pathways, including the MAPK/ERK and DNA damage repair pathways, in the regulation of dCRT response. [ABSTRACT FROM AUTHOR]