HSF5 Deficiency Causes Male Infertility Involving Spermatogenic Arrest at Meiotic Prophase I in Humans and Mice.

Meiosis is a specialized cell division process that generates gametes for sexual reproduction. However, the factors and underlying mechanisms involving meiotic progression remain largely unknown, especially in humans. Here, it is first showed that HSF5 is associated with human spermatogenesis. Patients with a pathogenic variant of HSF5 are completely infertile. Testicular histologic findings in the patients reveal rare postmeiotic germ cells resulting from meiotic prophase I arrest. Hsf5 knockout (KO) mice confirms that the loss of HSF5 causes defects in meiotic recombination, crossover formation, sex chromosome synapsis, and sex chromosome inactivation (MSCI), which may contribute to spermatocyte arrest at the late pachytene stage. Importantly, spermatogenic arrest can be rescued by compensatory HSF5 adeno-associated virus injection into KO mouse testes. Mechanistically, integrated analysis of RNA sequencing and chromatin immunoprecipitation sequencing data revealed that HSF5 predominantly binds to promoters of key genes involved in crossover formation (e.g., HFM1, MSH5 and MLH3), synapsis (e.g., SYCP1, SYCP2 and SYCE3), recombination (TEX15), and MSCI (MDC1) and further regulates their transcription during meiotic progression. Taken together, the study demonstrates that HSF5 modulates the transcriptome to ensure meiotic progression in humans and mice. These findings will aid in genetic diagnosis of and potential treatments for male infertility.

The tRNA Gm18 methyltransferase TARBP1 promotes hepatocellular carcinoma progression via metabolic reprogramming of glutamine.

Cancer cells rely on metabolic reprogramming to sustain the prodigious energetic requirements for rapid growth and proliferation. Glutamine metabolism is frequently dysregulated in cancers and is being exploited as a potential therapeutic target. Using CRISPR/Cas9 interference (CRISPRi) screening, we identified TARBP1 (TAR (HIV-1) RNA Binding Protein 1) as a critical regulator involved in glutamine reliance of cancer cell. Consistent with this discovery, TARBP1 amplification and overexpression are frequently observed in various cancers. Knockout of TARBP1 significantly suppresses cell proliferation, colony formation and xenograft tumor growth. Mechanistically, TARBP1 selectively methylates and stabilizes a small subset of tRNAs, which promotes efficient protein synthesis of glutamine transporter-ASCT2 (also known as SLC1A5) and glutamine import to fuel the growth of cancer cell. Moreover, we found that the gene expression of TARBP1 and ASCT2 are upregulated in combination in clinical cohorts and their upregulation is associated with unfavorable prognosis of HCC (hepatocellular carcinoma). Taken together, this study reveals the unexpected role of TARBP1 in coordinating the tRNA availability and glutamine uptake during HCC progression and provides a potential target for tumor therapy.

Primate-Specific DAZ Regulates Translation of Cell Proliferation-Related mRNAs and is Essential for Maintenance of Spermatogonia.

Primate-specific DAZ (deleted in azoospermia) has evolved in the azoospermia factor c (AZFc) locus on the Y chromosome. Loss of DAZ is associated with azoospermia in patients with deletion of the AZFc region (AZFc_del). However, the molecular mechanisms of DAZ in spermatogenesis remain uncertain. In this study, the molecular mechanism of DAZ is identified, which is unknown since it is identified 40 years ago because of the lack of a suitable model. Using clinical samples and cell models, it is shown that DAZ plays an important role in spermatogenesis and that loss of DAZ is associated with defective proliferation of c-KIT-positive spermatogonia in patients with AZFc_del. Mechanistically, it is shown that knockdown of DAZ significantly downregulated global translation and subsequently decreased cell proliferation. Furthermore, DAZ interacted with PABPC1 via the DAZ repeat domain to regulate global translation. DAZ targeted mRNAs that are involved in cell proliferation and cell cycle phase transition. These findings indicate that DAZ is a master translational regulator and essential for the maintenance of spermatogonia. Loss of DAZ may result in defective proliferation of c-KIT-positive spermatogonia and spermatogenic failure.

scRNA-seq reveals that origin recognition complex subunit 6 regulates mouse spermatogonial cell proliferation and apoptosis via activation of Wnt/ß-catenin signaling.

ABSTRACT: The regulation of spermatogonial proliferation and apoptosis is of great significance for maintaining spermatogenesis. The single-cell RNA sequencing (scRNA-seq) analysis of the testis was performed to identify genes upregulated in spermatogonia. Using scRNA-seq analysis, we identified the spermatogonia upregulated gene origin recognition complex subunit 6 (Orc6), which is involved in DNA replication and cell cycle regulation; its protein expression in the human and mouse testis was detected by western blot and immunofluorescence. To explore the potential function of Orc6 in spermatogonia, the C18-4 cell line was transfected with control or Orc6 siRNA. Subsequently, 5-ethynyl-2-deoxyuridine (EdU) and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assays, flow cytometry, and western blot were used to evaluate its effects on proliferation and apoptosis. It was revealed that ORC6 could promote proliferation and inhibit apoptosis of C18-4 cells. Bulk RNA sequencing and bioinformatics analysis indicated that Orc6 was involved in the activation of wingless/integrated (Wnt)/ ß-catenin signaling. Western blot revealed that the expression of ß-catenin protein and its phosphorylation (Ser675) were significantly decreased when silencing the expression of ORC6. Our findings indicated that Orc6 was upregulated in spermatogonia, whereby it regulated proliferation and apoptosis by activating Wnt/ß-catenin signaling.

Identification of a missense variant of MND1 in meiotic arrest and non-obstructive azoospermia.

Meiotic arrest is a common pathologic phenotype of non-obstructive azoospermia (NOA), yet its genetic causes require further investigation. Meiotic nuclear divisions 1 (MND1) has been proved to be indispensable for meiotic recombination in many species. To date, only one variant of MND1 has been reported associated with primary ovarian insufficiency (POI), yet there has been no report of variants in MND1 associated with NOA. Herein, we identified a rare homozygous missense variant (NM_032117:c.G507C:p.W169C) of MND1 in two NOA-affected patients from one Chinese family. Histological analysis and immunohistochemistry demonstrated meiotic arrest at zygotene-like stage in prophase I and lack of spermatozoa in the proband's seminiferous tubules. In silico modeling demonstrated that this variant might cause possible conformational change in the leucine zippers 3 with capping helices (LZ3wCH) domain of MND1-HOP2 complex. Altogether, our study demonstrated that the MND1 variant (c.G507C) is likely responsible for human meiotic arrest and NOA. And our study provides new insights into the genetic etiology of NOA and mechanisms of homologous recombination repair in male meiosis.

A homozygous frameshift variant in SYCP2 caused meiotic arrest and non-obstructive azoospermia.

Genetic causation for the majority of non-obstructive azoospermia (NOA) remains unclear. Mutations in synaptonemal complex (SC)-associated genes could cause meiotic arrest and NOA. Previous studies showed that heterozygous truncating variants in SYCP2 encoding a protein essential for SC formation, are associated with non-obstructive azoospermia and severe oligozoospermia. Herein, we showed a homozygous loss-of-function variant in SYCP2 (c.2689_2690insT) in an NOA-affected patient. And this variant was inherited from heterozygous parental carriers by natural reproduction. HE, IF, and meiotic chromosomal spread analyses demonstrated that spermatogenesis was arrested at the zygotene stage in the proband with NOA. Thus, this study revealed that SYCP2 associated with NOA segregates in an autosomal recessive inheritance pattern, rather than an autosomal dominant pattern. Furthermore, our study expanded the knowledge of variants in SYCP2 and provided new insight into understanding the genetic etiology of NOA.

Bi-allelic MEI1 variants cause meiosis arrest and non-obstructive azoospermia.

Non-obstructive azoospermia (NOA) is characterized by the failure of sperm production due to testicular disorders and represents the most severe form of male infertility. Growing evidences have indicated that gene defects could be the potential cause of NOA via genome-wide sequencing approaches. Here, bi-allelic deleterious variants in meiosis inhibitor protein 1 (MEI1) were identified by whole-exome sequencing in four Chinese patients with NOA. Testicular pathologic analysis and immunohistochemical staining revealed that spermatogenesis is arrested at spermatocyte stage, with defective programmed DNA double-strand breaks (DSBs) homoeostasis and meiotic chromosome synapsis in patients carrying the variants. In addition, our results showed that one missense variant (c.G186C) reduced the expression of MEI1 and one frameshift variant (c.251delT) led to truncated proteins of MEI1 in in vitro. Furthermore, the missense variant (c.T1585A) was assumed to affect the interaction between MEI1 and its partners via bioinformatic analysis. Collectively, our findings provide direct genetic and functional evidences that bi-allelic variants in MEI1 could cause defective DSBs homoeostasis and meiotic chromosome synapsis, which subsequently lead to meiosis arrest and male infertility. Thus, our study deepens our knowledge of the role of MEI1 in male fertility and provides a novel insight to understand the genetic aetiology of NOA.

Bi-allelic SPATA22 variants cause premature ovarian insufficiency and nonobstructive azoospermia due to meiotic arrest.

The genetic causes of idiopathic premature ovarian insufficiency (POI) and nonobstructive azoospermia (NOA) remain unclear. We performed whole-exome sequencing (WES) in members of a consanguineous family with two POI and two NOA patients to screen for potential pathogenic variants for familial POI and NOA. And a homozygous variant in SPATA22 (c.400C>T:p.R134X) was identified. Histological analysis and spermatocyte spreading assay demonstrated that the spermatogenesis was arrested at a zygotene-like stage in the proband with NOA. The candidate gene was further screened in the in-house WES database of idiopathic POI-affected patients. One additional compound heterozygous variant in SPATA22 (c.900+1G>A and c.31C>T:p.R11X) was found in one patient with sporadic POI and validated by minigene assay. Thus, this is the first report identifying SPATA22 as the causative gene for human POI. Combined with the observations in the familial patient with NOA, our findings highlighted the essential role of meiotic HR genes in gametogenesis and gonadal function maintenance.

Identification of new biomarkers in immune microenvironment of testicular germ cell tumour.

To seek novel prognostic biomarkers for testicular germ cell tumour (TGCT) and investigate the tumour immune microenvironment, we identified critical differentially expressed genes (DEGs) by overlapping GSE1818 dataset from Gene Expression Omnibus (GEO). Protein-protein interaction (PPI) network was used to investigate key modules and hub genes. Functional enrichment analysis was performed to investigate the underlying molecular functions of the DEGs in TGCT development and progression. The following survival analysis based on The Cancer Genome Atlas (TCGA) TGCT dataset indicated that AKAP4, SPA17 and TNP1 are correlated with TGCT prognosis. Immunohistochemistry and quantitative real-time polymerase chain reaction verified the down-regulation of the 3 hub genes in TGCT. Gene set enrichment analysis was conducted to further explore the role of the 3 hub genes in TGCT respectively. In addition, TGCT samples had high infiltration of CD8+ T cells, M0 and M1 macrophage cells, and resting myeloid dendritic cells in immune microenvironment. We also constructed the microRNA-gene regulatory networks to identify the key upstream microRNAs in TGCT. In conclusion, our findings indicated that AKAP4, SPA17 and TNP1 are promising biomarkers of TGCT. AKAP4 and TNP1 might regulate immune cells infiltration in immune microenvironment.

Novel Bi-Allelic Variants of FANCM Cause Sertoli Cell-Only Syndrome and Non-Obstructive Azoospermia.

Non-obstructive azoospermia (NOA) is the most severe disease in male infertility, but the genetic causes for the majority of NOA remain unknown. FANCM is a member of Fanconi Anemia (FA) core complex, whose defects are associated with cell hypersensitivity to DNA interstrand crosslink (ICL)-inducing agents. It was reported that variants in FANCM (MIM: 609644) might cause azoospermia or oligospermia. However, there is still a lack of evidence to explain the association between different FANCM variants and male infertility phenotypes. Herein, we identified compound heterozygous variants in FANCM in two NOA-affected brothers (c. 1778delG:p. R593Qfs*76 and c. 1663G > T:p. V555F), and a homozygous variant in FANCM (c. 1972C > T:p. R658X) in a sporadic case with NOA, respectively. H&E staining and immunohistochemistry showed Sertoli cell-only Syndrome (SCOS) in the three patients with NOA. Collectively, our study expands the knowledge of variants in FANCM, and provides a new insight to understand the genetic etiology of NOA.

Identification and verification of hub microRNAs in varicocele rats through high-throughput sequencing and bioinformatics analysis.

Varicocele (VC) is the most common treatable cause of infertility, but it is difficult to distinguish fertile from infertile VC populations because the pathogenesis is unclear. In order to study the related mechanism of VC causing male sterility, we made VC rats model by surgery, analyzed the rat epididymal sperm, and use the transcriptome sequencing compared all the miRNA expression differences in testicular tissue between VC rats, surgical treatment rats and control rats. The differentially expressed miRNAs (DEMs) of testicular tissue were also screened by the edgeR package in R software. We found that rno-miR-210-3p, rno-miR-6316, rno-miR-190a-5p and rno-miR-135b-5p were key miRNAs for VC and they were all up-regulated in VC samples and they are enriched in regulation of immune system process (GO:0002683), innate immune system (R-RNO-168,249) and apoptotic signaling pathway (GO:0097190). We hypothesize that negative regulation of immune system and apoptosis play an important role in the occurrence and development of VC, and it is induced the abnormal expression of target genes (such as Kitlg, Cxcl12) may involve in the development of VC associated infertility. Four key miRNAs, rno-miR-210-3p, rno-miR-6316, rno-miR-190a-5p and rno-miR-135b-5p, as well as their target genes are critical in VC, which could have attractive applications to provide new biomarkers for VC.

Development and Validation of a Nomogram to Predict Lymph Node Metastasis in Patients With T1 High-Grade Urothelial Carcinoma of the Bladder.

PURPOSE: This study aims to develop and validate a nomogram to predict lymph node (LN) metastasis preoperatively in patients with T1 high-grade urothelial carcinoma. METHODS: We retrospectively evaluated the data of 2,689 patients with urothelial carcinoma of the bladder (UCB) treated with radical cystectomy (RC) and bilateral lymphadenectomy in two medical centers. Eventually, 412 patients with T1 high-grade urothelial carcinoma were enrolled in the primary cohort to develop a prognostic nomogram designed to predict LN status. An independent validation cohort (containing 783 consecutive patients during the same period) was subjected to validate the predicting model. Binary regression analysis was used to develop the predicting nomogram. We assessed the performance of the nomogram concerning its clinical usefulness, calibration, and discrimination. RESULTS: Overall, 69 (16.75%), and 135 (17.24%) patients had LN metastasis in the primary cohort and external validation cohort, respectively. The final nomogram included information on tumor number, tumor size, lymphovascular invasion (LVI), fibrinogen, and monocyte-to-lymphocyte ratio (MLR). The nomogram showed good predictive accuracy and calibration with a concordance index in the primary cohort of 0.853. The application of the nomogram in the external validation cohort still gave good discrimination (C-index, 0.845) and good calibration. The analysis of the decision curve shows that the nomogram has clinical application value. CONCLUSION: The nomogram that incorporated the tumor number, tumor size, LVI, fibrinogen, and MLR showed favorable predictive accuracy for LN metastasis. It may be conveniently used to predict LN metastasis in patients with T1 high-grade urothelial carcinoma and be helpful in guiding treatment decisions.

Relationship between aryl hydrocarbon receptor and spermatogenic dysfunction in male patients with varicocele.

The main purpose of this project is to verify whether there is a difference in the expression of aryl hydrocarbon receptor (AhR) between varicocele (VC) and normal male semen, and determine whether there is a connection with the parameters of semen analysis. The risk factors of infertility in patients with VC were also studied. Semen samples were collected for semen analysis and Western blot. Logistic regression was used to investigate the risk factors associated with infertility in patients with VC. Men with VC had lower AhR expression compared to healthy men; correlation analysis results showed that: AhR expression in patients with VC group was significantly positively correlated with sperm concentration and sperm motility; significantly negatively correlated with the diameter of spermatic veins during Valsalva and the percentage of abnormal sperm morphology; the research results of related risk factors show that the risk of infertility of patients with grade III is 1.67 times that of patients with grades I and II. For each unit of abnormal sperm morphology, the risk of infertility increases 1.04 times. Sperm concentration, total sperm viability and each unit the expression of AhR protein decreases the risk of infertility by 3%, 9% and 11% respectively.

Can the combination of biparametric magnetic resonance imaging and PSA-related indicators predict the prostate biopsy outcome?

To assess the value of biparametric magnetic resonance imaging (bpMRI) for detecting and ruling out prostate cancer in patients with elevated prostate-specific antigen (PSA). The basic information and bpMRI images of enrolled patients who took transperineal template saturate biopsy were retrospectively collected for analysis. Based on our results, we found that free/total PSA, and PI-RADS score were independent risk factors of PCa (p < .05), the PSA density, PI-RADS score were the independent risk factors of csPCa (p < .05). PI-RADS score threshold of 3 could achieve the highest Yonder index for predicting PCa, and PI-RADS score threshold of 4 could achieve the highest Yonder index for predicting csPCa. Therefore, we draw a conclusion that PI-RADSv2 score-based bpMRI could diminish the unnecessary prostate biopsies in patients with elevated PSA when combined with other PSA-related indicators.

The prevalence and prognostic and clinicopathological value of PD-L1 and PD-L2 in renal cell carcinoma patients: a systematic review and meta-analysis involving 3,389 patients.

BACKGROUND: The research of the prognostic and clinicopathologic values of programmed cell death ligand 1/2 (PD-L1/2) in renal cell carcinoma (RCC) patients has been mired by a dearth of studies and considerable controversy. We thus conducted a systematic review and meta-analysis to report the prevalence and prognostic and clinicopathological value of programmed cell death ligand 1 (PD-L1) and programmed cell death-legend 2 (PD-L2) in RCC patients. METHODS: The PubMed, Cochrane Library, EMBASE databases were searched to find human studies limited to English language literature published through October 1, 2019. Using random or fixed effects models, hazard ratios (HRs) and 95% confidence intervals (CIs) were evaluated to explore the prognostic value of PD-Ls expression, while odds ratios (ORs) and 95% CIs were evaluated to investigate clinicopathological parameters. The protocol of the study was registered in PROSPERO (CRD42019135199). RESULTS: After pooling all 16 eligible studies comprising 3,389 patients, we found that the overall prevalence of PD-L1 and PD-L2 in RCC patients was 27% and 39%, respectively. Furthermore, PD-L1 over-expression was a strong negative predictor for overall survival (OS), disease-free survival/progression-free survival (DFS/PFS), and cancer-specific survival (CSS) in renal cell carcinoma patients (HR =2.86, 95% CI: 1.83-4.47, P<0.001; HR =2.64, 95% CI: 1.99-3.52, P<0.001; HR =2.78, 95% CI: 2.17-3.56, P<0.001). Meanwhile, PD-L2 over-expression was only a weak negative predictor for CSS (HR =1.66, 95% CI: 1.05-2.65, P<0.05). Subgroup analysis showed that Caucasians had worse OS (HR =3.60, 95% CI: 1.77-7.33, P<0.001), PFS (HR =3.56, 95% CI: 2.44-5.18, P<0.001), and CSS (HR =3.13, 95% CI: 2.37-4.14, P<0.001) than Asians. PD-L1 was a strong indicator for worse prognosis (P<0.05 for all), while PD-L2 over-expression was only associated with sarcomatoid features (presence vs. absence, OR =1.80, 95% CI: 1.13-2.86, P=0.014). Notably, PD-L1 overexpression was more prevalent in women (male vs. female, OR =0.68, 95% CI: 0.51-0.90, P=0.006). CONCLUSIONS: Higher PD-L1 expression is more closely associated with poor prognosis and more advanced clinicopathological features in RCC patients than PD-L2, especially in women and Caucasian patients. PD-L2 was a weak negative predictor of poor CSS of RCC and was not a prompt for the metastasis of RCC.

Do testosterone supplements enhance response to phosphodiesterase 5 inhibitors in men with erectile dysfunction and hypogonadism: a systematic review and meta-analysis.

BACKGROUND: Combining testosterone and phosphodiesterase 5 inhibitors (PDE5-Is) has become increasingly common in the treatment of men with erectile dysfunction (ED) and low testosterone levels, but combination therapy involving PDE5-Is and testosterone is highly debated, with strong reasons for and against argued by the various opinion leaders. PDE5-Is can be given prior to, alongside or after the commencement of any testosterone replacement therapy. Meanwhile, combination of PDE5-Is and testosterone is reported to better increase testosterone levels and thus improve International Index of Erectile Function (IIEF) score in hypogonadal men. The objective of this meta-analysis was to assess whether testosterone therapy (TTh) can possibly enhance the reaction to PDE5-Is in men with ED and hypogonadism. METHODS: Relevant studies and available data were extensively collected form Medline, Embase, and Cochrane Library databases until June 2019. We calculated standard mean differences (SMDs) with their 95% confidence intervals (CIs) for IIEF including IIEF-5 and IIEF-EFD. Trial sequential analysis (TSA) was performed to explore whether the sample size of the accumulated evidence is sufficient. RESULTS: There were 8 studies including 913 patients. The pooled SMD of erectile function (EF) component change was 0.663 [(0.299 to 1.027); P<0.0001], which concluded that combination therapy (TTh plus PDE5-Is) is superior to PDE5-Is monotherapy group. We also conducted a subgroup analysis according to trial follow-up, baseline serum total testosterone, baseline EF score and PDE5-Is type, which may explain for the underlying source of heterogeneity in part. The frequency of adverse events and change in PSA levels did not differ between the 2 groups. None of the patients experienced an increase in the prostate specific antigen (PSA) level above 4 ng/mL. Hematocrit increased significantly more in the testosterone group than in the placebo group but not greater than 0.54. CONCLUSIONS: In summary, the present results confirm that combination therapy is effective and safe. TTh can enhance the reaction to PDE5-Is in men with ED and hypogonadism, but this effect also depends on the specific diagnosis and initial response to PDE5-Is. Most patients with adverse events during treatment are mild, and have a stable overall safety of combination therapy.

Identification and verification of key genes in varicocele rats through high-throughput sequencing and bioinformatics analysis.

Varicocele (VC) is the most common treatable cause of infertility, but it is difficult to distinguish fertile from infertile VC populations because the pathogenesis is unclear. In order to study the related mechanism of VC causing male sterility, we made VC rat model by surgery, analysed the rat epididymal spermatozoa and used the transcriptome sequencing to compare all the mRNA expression differences in testicular tissue between VC rats and control rats. The differentially expressed genes (DEGs) of testicular tissue were also screened by the limma package in R software (version 3.6.1). The 273 DEGs were identified from the four profile data sets including 124 up-regulated genes and 149 down-regulated genes in the VC group compared to control group. We found that Sod1, Casp9, Atg7, Casp3 and Sirt1 in module 1 had higher degrees of connectivity in the first 10 hub genes. Gene ontology (GO) functional enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis demonstrated that Sod1, Casp9, Atg7, Casp3 and Sirt1 are enriched in regulation of oxidative stress-induced cell death (GO:1,903,201) and Amyotrophic lateral sclerosis (KEGG:05,014). From the above evidence, we speculate that hypoxia plays an important role in the occurrence and development of VC, and it induced the abnormal expression of autophagy and apoptosis-related proteins may involve in the development of VC-associated infertility. Sod1, Casp9, Atg7, Casp3 and Sirt1 as well as their module are hub genes for VC, which will have attractive applications to provide new treatment targets for VC.

Gene Expression Profiles Identified Novel Urine Biomarkers for Diagnosis and Prognosis of High-Grade Bladder Urothelial Carcinoma.

Bladder urothelial carcinoma (BC) has been identified as one of the most common malignant neoplasm worldwide. High-grade bladder urothelial carcinoma (HGBC) is aggressive with a high risk of recurrence, progression, metastasis, and poor prognosis. Therefore, HGBC clinical management is still a challenge. We performed the present study to seek new urine biomarkers for HGBC and investigate how they promote HGBC progression and thus affect the prognosis based on large-scale sequencing data. We identified the overlapped differentially expressed genes (DEGs) by combining GSE68020 and The Cancer Genome Atlas (TCGA) datasets. Subsequent receiver operating characteristic (ROC) curves, Kaplan-Meier (KM) curves, and Cox regression were conducted to test the diagnostic and prognostic role of the hub genes. Chi-square test and logistic regression were carried out to analyze the associations between clinicopathologic characteristics and the hub genes. Ultimately, we performed gene set enrichment analysis (GSEA), protein-protein interaction (PPI) networks, and Bayesian networks (BNs) to explore the underlying mechanisms by which ECM1, CRYAB, CGNL1, and GPX3 are involved in tumor progression. Immunohistochemistry based on The Human Protein Atlas and quantitative real-time polymerase chain reaction based on urine samples confirmed the downregulation and diagnostic values of the hub genes in HGBC. In conclusion, our study indicated that CRYAB, CGNL1, ECM1, and GPX3 are potential urine biomarkers of HGBC. These four novel urine biomarkers will have attractive applications to provide new diagnostic methods, prognostic predictors and treatment targets for HGBC, which could improve the prognosis of HGBC patients, if validated by further experiments and larger prospective clinical trials.

Relationship Between the ApaI (rs7975232), BsmI (rs1544410), FokI (rs2228570), and TaqI (rs731236) Variants in the Vitamin D Receptor Gene and Urolithiasis Susceptibility: An Updated Meta-Analysis and Trial Sequential Analysis.

The relationship between urolithiasis and vitamin D receptor (VDR) gene variants is still under debate according to the available published literature. To assess correlations between VDR gene variants ApaI (rs7975232), BsmI (rs1544410), FokI (rs2228570), and TaqI (rs731236) and urolithiasis susceptibility, we performed the present study through meta-analysis. The PubMed, Cochrane Library, China National Knowledge Infrastructure, EMBASE, Web of Science, and Wanfang databases were searched to retrieve qualified case-control studies. Finally, 31 reports were selected for the present meta-analysis. The results demonstrated that the VDR gene TaqI TT genotype was related to decreased risk of urolithiasis in the overall population (TT vs. Tt+tt: P = 0.011, OR = 0.824, 95% CI = 0.709-0.957). In ethnicity subgroup analysis, we found that the TaqI variant was obviously correlated to urolithiasis risk among Asians and Caucasians (P < 0.05). Additionally, significant urolithiasis risk was identified in adults. However, the FokI, BsmI, and ApaI variants did not have an increased risk of developing urolithiasis. Trial sequential analysis results were on a sufficiently large number of participants and did not require more research to confirm associations. Our research suggested that the VDR gene variant TaqI was correlated with urolithiasis susceptibility and that the t-allele might be the risk gene and T-allele the protective gene in VDR TaqI variant.

Predictive value of haematologic parameters in diagnosis of testicular torsion: Evidence from a systematic review and meta-analysis.

To compare the difference of mean platelet volume (MPV), platelet lymphocyte ratio (PLR), neutrophil-lymphocyte ratio (NLR), platelet (PLT) and leucocyte between testicular torsion (TT), epididymo-orchitis and healthy controls and further evaluate predictive values of these haematologic parameters in diagnosis and the differential diagnosis of TT. Databases were systematically retrieved, and reference search was also conducted manually. We applied Stata software 12.0 to perform a systematic review and meta-analysis. Ultimately, five case-control studies with 672 participants were recruited for analyses. Pooled analyses indicated that TT patients had lower NLR (WMD = -1.66, 95% CI = -3.25 to -0.06) and PLT (WMD = -27.39, 95% CI = -48.03 to -6.75) compared to epididymo-orchitis patients. In the meantime, TT patients had higher NLR and leucocyte than healthy controls (p < .05). That is to say, when a man develops TT, his NLR and leucocyte will rise up but his NLR will not reach the level of epididymo-orchitis. To sum up, NLR, PLT and leucocyte were vital factors for TT diagnosis. Leucocyte is an useful parameter for diagnosing both TT and epididymo-orchitis, but it cannot be used in differentiating the two diseases. NLR is beneficial parameter for differential diagnosis between TT and epididymo-orchitis. PLT can also be utilised in differential diagnosis among young patients.