Single-cell sequencing reveals the heterogeneity of B cells and tertiary lymphoid structures in muscle-invasive bladder cancer.

BACKGROUND: Muscle-invasive bladder cancer (MIBC) is a highly aggressive disease with a poor prognosis. B cells are crucial factors in tumor suppression, and tertiary lymphoid structures (TLSs) facilitate immune cell recruitment to the tumor microenvironment (TME). However, the function and mechanisms of tumor-infiltrating B cells and TLSs in MIBC need to be explored further. METHODS: We performed single-cell RNA sequencing analysis of 11,612 B cells and 55,392 T cells from 12 bladder cancer patients and found naïve B cells, proliferating B cells, plasma cells, interferon-stimulated B cells and germinal center-associated B cells, and described the phenotype, gene enrichment, cell-cell communication, biological processes. We utilized immunohistochemistry (IHC) and immunofluorescence (IF) to describe TLSs morphology in MIBC. RESULTS: The interferon-stimulated B-cell subtype (B-ISG15) and germinal center-associated B-cell subtypes (B-LMO2, B-STMN1) were significantly enriched in MIBC. TLSs in MIBC exhibited a distinct follicular structure characterized by a central region of B cells resembling a germinal center surrounded by T cells. CellChat analysis showed that CXCL13 + T cells play a pivotal role in recruiting CXCR5 + B cells. Cell migration experiments demonstrated the chemoattraction of CXCL13 toward CXCR5 + B cells. Importantly, the infiltration of the interferon-stimulated B-cell subtype and the presence of TLSs correlated with a more favorable prognosis in MIBC. CONCLUSIONS: The study revealed the heterogeneity of B-cell subtypes in MIBC and suggests a pivotal role of TLSs in MIBC outcomes. Our study provides novel insights that contribute to the precision treatment of MIBC.

Urinary exosomal prostate-specific antigen is a noninvasive biomarker to detect prostate cancer: Not only old wine in new bottles.

The study aimed at evaluating the performance of urinary exosomal prostate-specific antigen (UE-PSA) to predict the results of initial prostate biopsies and discriminate clinically significant prostate cancer (Gleason score ≥ 7, csPCa) from nonsignificant PCa (Gleason score < 7, nsPCa) plus benign patients. Two hundred seventy-two consecutive participants were admitted who underwent a prostate biopsy. The UE-PSA expression was detected by enzyme-linked immunosorbent assay (ELISA). The predictive power and clinical value of UE-PSA was assessed by receiver operating characteristic (ROC), decision curve analysis (DCA) and waterfall plots. UE-PSA was upregulated in PCa compared to benign patients (P < .001) and csPCa compared to nsPCa plus benign patients (P < .001). UE-PSA achieved an AUC of 0.953 (0.905-0.989) in distinguishing PCa from benign patients and an AUC of 0.879 (0.808-0.941) in predicting csPCa from nsPCa plus benign patients. These results were validated in an additional multicenter cohort. In addition, DCA showed that UE-PSA achieved the highest net benefit at almost any threshold probability compared to tPSA and %fPSA. As the waterfall plot showed, the UE-PSA assay could avoid 57.6% (155 cases) and 34.6% (93 cases) unnecessary biopsies while only missing 2.6% (7 cases) and 1.5% (4 cases) of the cases of csPCa at the cutoff value of 90% and 95% sensitivity, respectively. We validated that UE-PSA presented great diagnostic power and clinical utility to diagnose PCa and csPCa. UE-PSA could be a promising noninvasive biomarker to improve PCa detection.

The optimal intravesical maintenance chemotherapy scheme for the intermediate-risk group non-muscle-invasive bladder cancer.

OBJECTIVE: Although the current European Association of Urology(EAU) guideline recommends that patients with intermediate-risk non-muscle-invasive bladder cancer (NMIBC) should accept intravesical chemotherapy or Calmette-Guerin (BCG) for no more than one year after transurethral resection of bladder tumor(TURBT), there is no consensus on the optimal duration of chemotherapy. Hence, we explored the optimal duration of maintenance intravesical chemotherapy in patients with intermediate-risk NMIBC. SUBJECTS AND METHODS: This was a real-world single-center retrospective cohort study. In total 158 patients with pathologically confirmed intermediate-risk NMIBC were included, who were divided into 4 subgroups based on the number of instillations given. We used Cox regression analysis and survival analysis chart to explore the 3-yr recurrence outcomes of tumor.The optimal duration was determined by receive operating characteristic curve (ROC). RESULTS: The median follow-up was 5.2 years. Compared with instillation for 1-2 months, the Hazard Ratios(HR) values of instillation for less than 1 month, maintenance instillation for 3-6 months and > 6 months were 3.57、1.57 and 0.22(95% CI 1.27-12.41;0.26-9.28;0.07-0.80, P = 0.03;0.62;0.02, respectively). We found a significant improvement in 3-yr relapse-free survival in intermediate-risk NMIBC patients who maintained intravesical instillation chemotherapy for longer than 6 months, and the best benefit was achieved with 10.5 months of maintenance chemotherapy by ROC. CONCLUSIONS: In our scheme, the optimal duration of intravesical instillation with pirrubicin is 10.5 months. This new understanding provides valuable experience for the precise medical treatment model of intermediate-risk NMIBC.

Long noncoding RNA as a potential diagnostic tool for prostate cancer: a systematic review and meta-analysis.

PURPOSE: To identify consistently expressed lncRNAs and suitable lncRNAs with high sensitivity and specificity from multiple independent studies as potential biomarkers for PCa diagnostics. METHODS: We searched multiple electronic databases including PubMed, Web of Science, EMBASE, Cochrane Library, CNKI, CQVIP, Wanfang, and CBMdisc for studies published up to July 2022. The quality of the included studies was assessed by two independent reviewers based on the QUADAS-2 tool using Review Manager 5.3. A vote-counting method was used based on the ranking of potential molecular biomarkers. The top-ranked lncRNAs were further assessed for diagnostic value using Meta-disc version 1.4 software. RESULTS: Among the 26 included studies, 2 circulating lncRNAs (PCA3 and MALAT-1) were reported 3 or more times in PCa patients versus non-PCa patients. In further analysis, the areas under the curve of the summary receiver operating characteristic curves for PCA3 and MALAT-1 distinguishing PCa patients were 0.775 and 0.771, respectively. CONCLUSIONS: Based on the current evidence, PCA3 and MALAT-1 are reliable lncRNAs for the diagnosis of PCa.

2.5D MFFAU-Net: a convolutional neural network for kidney segmentation.

BACKGROUND: Kidney tumors have become increasingly prevalent among adults and are now considered one of the most common types of tumors. Accurate segmentation of kidney tumors can help physicians assess tumor complexity and aggressiveness before surgery. However, segmenting kidney tumors manually can be difficult because of their heterogeneity. METHODS: This paper proposes a 2.5D MFFAU-Net (multi-level Feature Fusion Attention U-Net) to segment kidneys, tumors and cysts. First, we propose a 2.5D model for learning to combine and represent a given slice in 2D slices, thereby introducing 3D information to balance memory consumption and model complexity. Then, we propose a ResConv architecture in MFFAU-Net and use the high-level and low-level feature in the model. Finally, we use multi-level information to analyze the spatial features between slices to segment kidneys and tumors. RESULTS: The 2.5D MFFAU-Net was evaluated on KiTS19 and KiTS21 kidney datasets and demonstrated an average dice score of 0.924 and 0.875, respectively, and an average Surface dice (SD) score of 0.794 in KiTS21. CONCLUSION: The 2.5D MFFAU-Net model can effectively segment kidney tumors, and the results are comparable to those obtained with high-performance 3D CNN models, and have the potential to serve as a point of reference in clinical practice.

Gut microbiota mediate melatonin signalling in association with type 2 diabetes.

AIMS/HYPOTHESIS: It has been shown that melatonin plays a general beneficial role in type 2 diabetes in rodents but its role in humans is controversial. In the present study, we investigated the association between serum melatonin and type 2 diabetes risk in a southern Chinese population in a case-control study. We also examined the role of gut microbiota in this relationship. METHODS: Individuals with type 2 diabetes (cases) and healthy individuals (controls) (n=2034) were recruited from a cross-sectional study and were matched for age and sex in a case-control study. The levels of serum melatonin were measured and the association between serum melatonin and type 2 diabetes risk was examined using a multivariable logistic regression model. We further conducted a rigorously matched case-control study (n=120) in which gut microbial 16S rRNA was sequenced and metabolites were profiled using an untargeted LC-MS/MS approach. RESULTS: Higher levels of serum melatonin were significantly associated with a lower risk of type 2 diabetes (OR 0.82 [95% CI 0.74, 0.92]) and with lower levels of fasting glucose after adjustment for covariates (ß -0.25 [95% CI -0.38, -0.12]). Gut microbiota exhibited alteration in the individuals with type 2 diabetes, in whom lower levels of serum melatonin, lower α- and ß-diversity of gut microbiota (p<0.05), greater abundance of Bifidobacterium and lower abundance of Coprococcus (linear discriminant analysis [LDA] >2.0) were found. Seven genera were correlated with melatonin and type 2 diabetes-related traits; among them Bifidobacterium was positively correlated with serum lipopolysaccharide (LPS) and IL-10, whereas Coprococcus was negatively correlated with serum IL-1ß, IL-6, IL-10, IL-17, TNF-α and LPS (Benjamini-Hochberg-adjusted p value [false discovery rate (FDR)] <0.05). Moreover, altered metabolites were detected in the participants with type 2 diabetes and there was a significant correlation between tryptophan (Trp) metabolites and the melatonin-correlated genera including Bifidobacterium and Coprococcus (FDR<0.05). Similarly, a significant correlation was found between Trp metabolites and inflammation factors, such as IL-1ß, IL-6, IL-10, IL-17, TNF-α and LPS (FDR<0.05). Further, we showed that Trp metabolites may serve as a biomarker to predict type 2 diabetes status (AUC=0.804). CONCLUSIONS/INTERPRETATION: A higher level of serum melatonin was associated with a lower risk of type 2 diabetes. Gut microbiota-mediated melatonin signalling was involved in this association; especially, Bifidobacterium- and Coprococcus-mediated Trp metabolites may be involved in the process. These findings uncover the importance of melatonin and melatonin-related bacteria and metabolites as potential therapeutic targets for type 2 diabetes.

Association of both prenatal and early childhood multiple metals exposure with neurodevelopment in infant: A prospective cohort study.

BACKGROUND: Impaired neurodevelopment of children has become a growing public concern; however, the associations between metals exposure and neurocognitive function have remained largely unknown. OBJECTIVES: We systematically evaluated the associations of multiple metals exposure during pregnancy and childhood on the neurodevelopment of children aged 2-3 years. METHODS: We measured 22 metals in the serum and urine among703 mother-child pairs from the Guangxi Birth Cohort Study. The neurocognitive development of children was assessed by the Gesell Development Diagnosis Scale (GDDS; Chinese version). Multiple linear regression models were used to evaluate the relationship between the metals (selected by elastic net regression) and the outcomes. The Bayesian kernel machine regression (BKMR) was used to evaluate the possible joint effect between the multiple metal mixture and the outcomes. RESULTS: Prenatal aluminum (Al) exposure was negatively associated with the fine motor developmental quotient (DQ) (ß = -1.545, 95%CI: 2.231, -0.859), adaption DQ (ß = -1.182, 95%CI: 1.632, -0.732), language DQ (ß = -1.284, 95% CI: 1.758, -0.809), and social DQ (ß = -1.729, 95% CI: 2.406, -1.052) in the multi-metal model. Prenatal cadmium (Cd) exposure was negatively associated with gross motor DQ (ß = -2.524, 95% CI: 4.060, -0.988), while postpartum Cd exposure was negatively associated with language DQ (ß = -1.678, 95% CI: 3.227, -0.129). In stratified analyses, infants of different sexes had different sensitivities to metal exposure, and neurobehavioral development was more significantly affected by metal exposure in the first and second trimester. BKMR analysis revealed a negative joint effect of the Al, Cd, and selenium (Se) on the language DQ score; postpartum Cd exposure played a major role in this relationship. CONCLUSION: Prenatal exposure to Al, Ba, Cd, molybdenum (Mo), lead (Pb), antimony (Sb), and strontium (Sr), and postpartum exposure to cobalt (Co), Cd, stannum (Sn), iron (Fe), nickel (Ni), and Se are associated with neurological development of infants. The first and second trimester might be the most sensitive period when metal exposure affects neurodevelopment.

Single-cell transcriptomes reveal characteristic features of cell types within the human adrenal microenvironment.

Various cells within the adrenal microenvironment are important in maintaining the body homeostasis. However, our understanding of adrenal disease pathogenesis is limited by an incomplete molecular characterization of the cell types responsible for the organ's multiple homeostatic functions. We report a cellular landscape of the human adrenal gland using single-cell RNA sequencing. We reveal characteristic features of cell types within the human adrenal microenvironment and found immune activation of nonimmune cells in the adrenal endothelial cells. We also reveal that abundant immune cells occupied a lot of space in adrenal gland. Additionally, Sex-related diversity in the adrenocortical cells and different gene expression profiles between the left and right adrenal gland are also observed at single-cell resolution. Together, at single-cell resolution, the transcriptomic map presents a comprehensive view of the human adrenal gland, which serves as a fundamental baseline description of this organ and paves a way for the further studies of adrenal diseases.

Carcinogenic effect of adenylosuccinate lyase (ADSL) in prostate cancer development and progression through the cell cycle pathway.

BACKGROUND: Prostate cancer (PCa) is still a serious male malignant disease across the world. However, no exact pathogenesis had been explained. Although adenylosuccinate lyase (ADSL) gene was identified to be important in PCa early in 1987, its comprehensive functions for PCa have not been presented. METHODS: The cBioPortal for Cancer Genomics, Oncomine and GEO database were retrieved to investigate the associations between of the ADSL gene and PCa. Then, the PC-3, DU145 and C4-2B cell lines were applied in vitro experiments. RNA sequencing and further western blot (WB) were applied to explore the potential mechanisms of ADSL gene in PCa. RESULTS: Based on PCa clinical datasets, we firstly found ADSL gene highly expressed in PCa tissues. Moreover, its transcript level increased in the metastatic PCa further. Elevated ADSL gene expression indicated a poor prognosis of PCa. While inhibiting the expression of ADSL with siRNA, the ability of cell proliferation and migration all declined markedly, with increased cell apoptosis inversely. Most of cells were blocked in the G0/G1 phase. Additionally, RNA sequencing also discovered the inactivity of cell cycle pathway after ADSL knockdown, which had also confirmed on the proteins levels. CONCLUSIONS: Our study identified the ADSL as an oncogene of PCa through regulating the cell cycle pathway firstly, with explicit cell and clinical phenotypes. Further mechanisms were needed to confirm its carcinogenic effect.

Waist-to-height ratio, an optimal anthropometric indicator for metabolic dysfunction associated fatty liver disease in the Western Chinese male population.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) has been entitled as metabolic-dysfunction associated fatty liver disease (MAFLD). Therefore anthropometric indicators of adiposity may provide a non-invasive predictive and diagnostic tool for this disease. This study intended to validate and compare the MAFLD predictive and diagnostic capability of eight anthropometric indicators. METHODS: The study involved a population-based retrospective cross-sectional design. The Fangchenggang area male health and examination survey (FAMHES) was used to collect data of eight anthropometric indicators, involving body mass index (BMI), waist-to-height ratio (WHtR), waist-hip ratio (WHR), body adiposity index (BAI), cardiometabolic index (CMI), lipid accumulation product (LAP), visceral adiposity index (VAI), and abdominal volume index (AVI). Receiver operating characteristics (ROC) curves and the respective areas under the curves (AUCs) were utilized to compare the diagnostic capacity of each indicator for MAFLD and to determine the optimal cutoff points. Binary logistic regression analysis was applied to identify the odds ratios (OR) with 95% confidence intervals (95% CI) for all anthropometric indicators and MAFLD. The Spearman rank correlation coefficients of anthropometric indicators, sex hormones, and MAFLD were also calculated. RESULTS: All selected anthropometric indicators were significantly associated with MAFLD (P < 0.001), with an AUC above 0.79. LAP had the highest AUC [0.868 (95% CI, 0.853-0.883)], followed by WHtR [0.863 (95% CI, 0.848-0.879)] and AVI [0.859 (95% CI, 0.843-0.874)]. The cutoff values for WHtR, LAP and AVI were 0.49, 24.29, and 13.61, respectively. WHtR [OR 22.181 (95% CI, 16.216-30.340)] had the strongest association with MAFLD, regardless of potential confounders. Among all the anthropometric indicators, the strongest association was seen between LAP and sex hormones. CONCLUSION: All anthropometric indicators were associated with MAFLD. WHtR was identified as the strongest predictor of MAFLD in young Chinese males, followed by LAP and AVI. The strongest association was found between LAP and sex hormones.

Adiponectin affects estimated glomerular filtration rate: A two-sample bidirectional Mendelian randomization study.

BACKGROUND: The causal relationship between adiponectin (ADPN) and estimated glomerular filtration rate (eGFR) is unclear. This study adopts a two-sample bidirectional Mendelian randomization (MR) study to explore the causal relationship between ADPN and eGFR. METHODS: Using eight single nucleotide polymorphisms (SNP) of ADPN and 26 SNP of eGFR as instrumental variables, the study performs a two-sample bidirectional MR study using MR inverse-variance weighted (IVW), MR-Egger and weighted median approach to evaluate the causal relationship between ADPN and eGFR. Using the genetic risk score (GRS) of ADPN and eGFR as instrumental variables, the study performs a second MR analysis to assess the association between ADPN and eGFR. RESULTS: In ADPN to eGFR MR analysis, the IVW, weighted median and GRS analysis all showed that ADPN had a causal effect on eGFR after removing potential confounders of the ADPN-eGFR relation (IVW: ß = .016, P = .002; weighted median: ß = .012, P = .022; GRS: ß = .016, P = 1.48E-05). As both ADPN and eGFR were natural log-transformed in the corresponding GWAS, eGFR increased by 0.15% for any 10% increase in ADPN. In eGFR to ADPN MR analysis, eGFR had no causal effect on ADPN after removing potential confounders of the eGFR-ADPN relation (All P values > 0.05). The heterogeneity test and sensitivity analysis indicated some heterogeneity, but no directional pleiotropy. CONCLUSION: Adiponectin has a causal effect on eGFR, while eGFR has no causal effect on ADPN. ADPN may be a clinical target for improving eGFR and treating chronic kidney disease caused by decreased eGFR.

Broad- and narrow-sense validity performance of three polygenic risk score methods for prostate cancer risk assessment.

BACKGROUND: Several polygenic risk score (PRS) methods are available for measuring the cumulative effect of multiple risk-associated single nucleotide polymorphisms (SNPs). Their performance in predicting risk at the individual level has not been well studied. METHODS: We compared the performance of three PRS methods for prostate cancer risk assessment in a clinical trial cohort, including genetic risk score (GRS), pruning and thresholding (P + T), and linkage disequilibrium prediction (LDpred). Performance was evaluated for score deciles (broad-sense validity) and score values (narrow-sense validity). RESULTS: A training process was required to identify the best P + T model (397 SNPs) and LDpred model (3 011 362 SNPs). In contrast, GRS was directly calculated based on 110 established risk-associated SNPs. For broad-sense validity in the testing population, higher deciles were significantly associated with higher observed risk; Ptrend was 7.40 × 10-11 , 7.64 × 10-13 , and 7.51 × 10-10 for GRS, P + T, and LDpred, respectively. For narrow-sense validity, the calibration slope (1 is best) was 1.03, 0.77, and 0.87, and mean bias score (0 is best) was 0.09, 0.21, and 0.10 for GRS, P + T, and LDpred, respectively. CONCLUSIONS: The performance of GRS was better than P + T and LDpred. Fewer and well-established SNPs of GRS also make it more feasible and interpretable for genetic testing at the individual level.

Analysis of Prostate-Specific Antigen-Related Indexes, Neutrophil-to-Lymphocyte Ratio in Patients with Concurrent Benign Prostatic Hyperplasia and Histologic Prostatitis.

BACKGROUND: This study was performed to explore the total prostate-specific antigen (tPSA) concentration, free PSA (fPSA) concentration, free-to-total PSA ratio (% fPSA), tPSA density (tPSAD), and neutrophil-to-lymphocyte ratio (NLR) in blood in patients with concurrent benign prostatic hyperplasia (BPH) and histologic prostatitis, and to provide new ideas for the diagnosis of prostatitis. METHODS: Patients who underwent transurethral bipolar plasmakinetic prostatectomy from June 2017 to June 2018 were retrospectively divided into two groups according to the degree of pathological inflammation of the resected prostate tissue: group A (BPH with histologic acute and chronic inflammation), group B (BPH with histologic chronic inflammation). The preoperative PSA-related indexes and NLR in blood were respectively compared between two groups. RESULTS: Groups A and B comprised 59 and 41 cases, respectively. The values of tPSA, tPSAD, and NLR were all significantly higher in group A than B, and the value of % fPSA was significantly lower in group A than B (p < 0.05). There was no significant difference for the value of fPSA between the two groups (p > 0.05). CONCLUSIONS: Histologic acute prostatitis can cause changes of PSA-related indexes and NLR in blood, which has important clinical significance in diagnosis of prostatitis.

Elevated C-reactive protein and complement C3 levels are associated with preterm birth: a nested case-control study in Chinese women.

BACKGROUND: Currently, there are many studies researched the associations between maternal serum inflammatory indicators (i.e. ferritin, C-reactive protein [CRP], C3 and C4) and preterm birth (PTB). The results, however, are inconsistent. Therefore, the aim of this study was to estimate the relationship between maternal serum inflammatory indicators and PTB in a nested case-control (NCC)study. METHODS: A NCC study was conducted by Guangxi Birth Cohort Study which enrolled a total of 6203 pregnant women between 50/7 and 346/7 weeks of gestational age (wGA) from six cities in China between 2015 and 2016. There were 206women who delivered preterm (< 370/7 wGA), and 412 women who delivered term birth, those women were matched by maternal age, birth place, gender of infants, and wGA at blood collection. The inflammatory indicators were quantified by immunoturbidimetric methods. RESULTS: Highest quartile concentrations of all inflammatory indicators were determined versus median. After adjusting for maternal age, high levels of CRP (CRP > 16.60 mg/L) are related to the risk of PTB (OR = 2.16, 95% CI: 1.02-4.56, p = 0.044) in the first trimester. The association of C3 was extremely related to those who delivered PTB (OR = 2.53, 95% CI: 1.14-5.64, p = 0.023) in the first trimester. Moreover, no significant associations were found in C4 (p = 0.079) and ferritin (p = 0.067) between PTB. CONCLUSIONS: Elevated concentrations of CRP and C3 in the first trimester were associated with increased risk of PTB. Inflammatory indicators may act a pivotal part in early diagnosis and prognosis of PTB.

Single-Cell Transcriptomic Map of the Human and Mouse Bladders.

BACKGROUND: Having a comprehensive map of the cellular anatomy of the normal human bladder is vital to understanding the cellular origins of benign bladder disease and bladder cancer. METHODS: We used single-cell RNA sequencing (scRNA-seq) of 12,423 cells from healthy human bladder tissue samples taken from patients with bladder cancer and 12,884 cells from mouse bladders to classify bladder cell types and their underlying functions. RESULTS: We created a single-cell transcriptomic map of human and mouse bladders, including 16 clusters of human bladder cells and 15 clusters of mouse bladder cells. The homology and heterogeneity of human and mouse bladder cell types were compared and both conservative and heterogeneous aspects of human and mouse bladder evolution were identified. We also discovered two novel types of human bladder cells. One type is ADRA2A+ and HRH2+ interstitial cells which may be associated with nerve conduction and allergic reactions. The other type is TNNT1+ epithelial cells that may be involved with bladder emptying. We verify these TNNT1+ epithelial cells also occur in rat and mouse bladders. CONCLUSIONS: This transcriptomic map provides a resource for studying bladder cell types, specific cell markers, signaling receptors, and genes that will help us to learn more about the relationship between bladder cell types and diseases.

A phenomics-based approach for the detection and interpretation of shared genetic influences on 29 biochemical indices in southern Chinese men.

BACKGROUND: Phenomics provides new technologies and platforms as a systematic phenome-genome approach. However, few studies have reported on the systematic mining of shared genetics among clinical biochemical indices based on phenomics methods, especially in China. This study aimed to apply phenomics to systematically explore shared genetics among 29 biochemical indices based on the Fangchenggang Area Male Health and Examination Survey cohort. RESULT: A total of 1999 subjects with 29 biochemical indices and 709,211 single nucleotide polymorphisms (SNPs) were subjected to phenomics analysis. Three bioinformatics methods, namely, Pearson's test, Jaccard's index, and linkage disequilibrium score regression, were used. The results showed that 29 biochemical indices were from a network. IgA, IgG, IgE, IgM, HCY, AFP and B12 were in the central community of 29 biochemical indices. Key genes and loci associated with metabolism traits were further identified, and shared genetics analysis showed that 29 SNPs (P < 10- 4) were associated with three or more traits. After integrating the SNPs related to two or more traits with the GWAS catalogue, 31 SNPs were found to be associated with several diseases (P < 10- 8). Using ALDH2 as an example to preliminarily explore its biological function, we also confirmed that the rs671 (ALDH2) polymorphism affected multiple traits of osteogenesis and adipogenesis differentiation in 3 T3-L1 preadipocytes. CONCLUSION: All these findings indicated a network of shared genetics and 29 biochemical indices, which will help fully understand the genetics participating in biochemical metabolism.

Two novel genetic variants in the STK38L and RAB27A genes are associated with glioma susceptibility.

Glioma is the most common malignant primary brain tumors with poor prognosis. Genome wide association studies (GWAS) of glioma in populations with Western European ancestry were completed in the US and UK. However, our previous results strongly suggest the genetic heterogeneity could be important in glioma risk. To systematically investigate glioma risk-associated variants in Chinese population, we performed a multistage GWAS of glioma in the Han Chinese population, with a total of 3,097 glioma cases and 4,362 controls. In addition to confirming two associations reported in other ancestry groups, this study identified one new risk-associated locus for glioma on chromosome 12p11.23 (rs10842893, pmeta = 2.33x10-12, STK38L) as well as a promising association at 15q15-21.1 (rs4774756, pmeta = 6.12x10-8, RAB27A) in 3,097 glioma cases and 4,362 controls. Our findings demonstrate two novel association between the glioma risk region marked by variant rs10842893 and rs4774756) and glioma risk. These findings may advance the understanding of genetic susceptibility to glioma.

Concept and benchmarks for assessing narrow-sense validity of genetic risk score values.

BACKGROUND: While higher genetic risk score (GRS) has been statistically associated with increased disease risk (broad-sense validity), the concept and tools for assessing the validity of reported GRS values from tests (narrow-sense validity) are underdeveloped. METHODS: We propose two benchmarks for assessing the narrow-sense validity of GRS. The baseline benchmark requires that the mean GRS value in a general population approximates 1.0. The calibration benchmark assesses the agreement between observed risks and estimated risks (GRS values). We assessed benchmark performance for three prostate cancer (PCa) GRS tests, derived from three SNP panels with increasing stringency of selection criteria, in a PCa chemoprevention trial where 714 of 3225 men were diagnosed with PCa during the 4-year follow-up. RESULTS: GRS from Panels 1, 2, and 3 were all statistically associated with PCa risk; P = 5.58 × 10-3 , P = 1 × 10-3 , and P = 1.5 × 10-13 , respectively (broad-sense validity). For narrow-sense validity, the mean GRS value among men without PCa was 1.33, 1.09, and 0.98 for Panels 1, 2, and 3, respectively (baseline benchmark). For assessing the calibration benchmark, observed risks were calculated for seven groups of men with GRS values <0.3, 0.3-0.79, 0.8-1.19, 1.2-1.49, 1.5-1.99, 2-2.99, and ≥3. The calibration slope (higher is better) was 0.15, 0.12, and 0.60, and the bias score (lower is better) between the observed risks and GRS values was 0.08, 0.08, and 0.02 for Panels 1, 2, and 3, respectively. CONCLUSION: Performance differed considerably among GRS tests. We recommend that all GRS tests be evaluated using the two benchmarks before clinical implementation for individual risk assessment.

Germline Duplication of SNORA18L5 Increases Risk for HBV-related Hepatocellular Carcinoma by Altering Localization of Ribosomal Proteins and Decreasing Levels of p53.

BACKGROUND & AIMS: Single nucleotide polymorphisms could affect risk for hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). We performed a germline copy number variation (CNV)-based genome-wide association study (GWAS) in populations of Chinese ancestry to search for germline CNVs that increase risk of HCC. METHODS: We conducted a CNV-based GWAS of 1583 HCC cases (persons with chronic HBV infection and HCC) and 1540 controls (persons with chronic HBV infection without HCC) in Chinese populations. Identified candidates were expressed in L-02, HepG2, or TP53-/- or wild-type HCT116 cells, and knocked down with short hairpin RNAs in HepG2, Bel-7402, and SMMC-7721 cells; proliferation, colony formation, and apoptosis were measured. Formation of xenograft tumors from cell lines was monitored in nude mice. Subcellular localization of ribosome proteins and levels or activity of p53 were investigated by co-immunoprecipitation, immunofluorescence, and immunoblot analyses. Levels of small nucleolar RNA H/ACA box 18-like 5 (SNORA18L5) were quantified by quantitative reverse transcription polymerase chain reaction. RESULTS: We identified a low-frequency duplication at chromosome 15q13.3 strongly associated with risk of HBV-related HCC (overall P = 3.17 × 10-8; odds ratio, 12.02). Copy numbers of the 15q13.3 duplication correlated with the expression of SNORA18L5 in liver tissues. Overexpression of SNORA18L5 increased HCC cell proliferation and growth of xenograft tumors in mice; knockdown reduced HCC proliferation and tumor growth. SNORA18L5 overexpression in HepG2 and SMMC-7721 cells inhibited p53-dependent cell cycle arrest and apoptosis. Overexpression of SNORA18L5 led to hyperactive ribosome biogenesis, increasing levels of mature 18S and 28S ribosomal RNAs and causing the ribosomal proteins RPL5 and RPL11 to stay in the nucleolus, which kept them from binding to MDM2. This resulted in increased MDM2-mediated ubiquitination and degradation of p53. Levels of SNORA18L5 were increased in HCC tissues compared with nontumor liver tissues and associated with shorter survival times of patients. CONCLUSIONS: In a CNV-based GWAS, we associated duplication at 15q13.3 with increased risk of HBV-related HCC. We found SNORA18L5 at this location to promote HCC cell proliferation and tumor growth in mice. SNORA18L5 increases ribosome biogenesis, facilitates ribosomal RNA maturation, and alters localization of RPL5 and RPL11, allowing for increased MDM2-mediated proteolysis of p53 and cell cycle arrest.

Serum multiple cytokines for the prediction of spontaneous preterm birth in asymptomatic women: A nested case-control study.

BACKGROUND: Current biomarkers such as fetal fibronectin and cervical length are accurate predictors of spontaneous preterm birth (sPTB) in women with clinically suspected preterm risk; however, these are not effective for predicting the risk of sPTB in asymptomatic women. Therefore, we performed this study with the objective of determining whether the combinations of specific serum cytokines could accurately predict the sPTB risk in asymptomatic women. METHODS: We conducted a nested case-control study with 129 incident sPTB cases and 258 individually matched controls who participated in an ongoing birth cohort study. The maternal serum levels of the selected 35 cytokines were measured. We evaluated the relationship between the multiple cytokines and sPTB risk using conditional logistic regression and elastic net model. RESULTS: A panel of cytokines was significantly associated with an increased risk of sPTB. The odds ratio (OR) of sPTB per standard deviation (SD) increase of the predictive model score was 1.57 (95% CI 1.25-1.97) for the cytokines model. The combination of the selected serum cytokines was substantially more effective in predicting the risk for sPTB, as the receiver-operator characteristic curve (AUC) values were 0.546 and 0.559 in the single cytokine model and it improved to 0.642 in the multiple cytokines model (PAUC difference = 0.02 for TNF-α vs. multiple cytokines; PAUC difference = 0.05 for TRAIL vs. multiple cytokines). Moreover, the prediction was more accurate in overweight pregnant women, with an AUC = 0.879. CONCLUSIONS: The current study suggested that the combination of selected serum cytokines can more effectively predict the risk of sPTB in asymptomatic women compared with the use of single cytokine.