Mitigating lead-induced osteoporosis: The role of butyrate in gut-bone axis restoration.

Lead (Pb) is an environmentally widespread bone toxic pollutant, contributes to the development of osteoporosis. Butyric acid, mainly produced by the fermentation of indigestible dietary fiber by gut microbiota, plays a pivotal role in the maintenance of bone homeostasis. However, the effects of butyric acids on the Pb induced osteoporosis have not yet been elucidated. In this study, our results showed that Pb exposure was negatively related to the abundance of butyric acid, in the Pb-exposed population and Pb-exposed mice. Pb exposure caused gut microbiota disorders, resulting in the decline of butyric acid-producing bacteria, such as Butyrivibrio_crossotus, Clostridium_sp._JN9, and the butyrate-producing enzymes through the acetyl-CoA pathway. Moreover, results from the NHANES data suggested that dietary intake of butyrate was associated with a reduced risk of osteoporosis in lead-burdened populations, particularly among men or participants aged 18-60 years. In addition, butyrate supplementation in mice with chronic Pb exposure improved the bone microarchitectures, repaired intestinal damage, upregulated the proportion of Treg cells. Taken together, these results demonstrated that chronic Pb exposure disturbs the gut-bone axis, which can be restored by butyric acid supplement. Our results suggest that butyrate supplementation is a possible therapeutic strategy for lead-induced bone toxicity.

Genetic variants in N6-methyladenosine are associated with bladder cancer risk in the Chinese population.

Recently N6-Methyladenosine (m6A) has been identified to guide the interaction of RNA-binding protein hnRNP C and their target RNAs, which is termed as m6A-switches. We systematically investigated the association between genetic variants in m6A-switches and bladder cancer risk. A two-stage case-control study was performed to systematically calculate the association of single nucleotide polymorphisms (SNPs) in 2798 m6A-switches with bladder cancer risk in 3,997 subjects. A logistic regression model was used to assess the effects of SNPs on bladder cancer risk. A series of experiments were adopted to explore the role of genetic variants of m6A-switches. We identified that rs5746136 (G > A) of SOD2 in m6A-switches was significantly associated with the reduced risk of bladder cancer (additive model in discovery stage: OR = 0.80, 95% CI 0.69-0.93, P = 3.6 × 10-3; validation stage: adjusted OR = 0.88, 95% CI 0.79-0.99, P = 3.0 × 10-2; combined analysis: adjusted OR = 0.85, 95% CI 0.78-0.93, P = 4.0 × 10-4). The mRNA level of SOD2 was remarkably lower in bladder cancer tissues than the paired adjacent samples. SNP rs5746136 may affect m6A modification and regulate SOD2 expression by guiding the binding of hnRNP C to SOD2, which played a critical tumor suppressor role in bladder cancer cells by promoting cell apoptosis and inhibiting proliferation, migration and invasion. In conclusion, our findings suggest the important role of genetic variants in m6A modification. SOD2 polymorphisms may influence the expression of SOD2 via an m6A-hnRNP C-dependent mechanism and be promising predictors of bladder cancer risk.

Combinations of single nucleotide polymorphisms identified in genome-wide association studies determine risk for colorectal cancer.

Genome-wide association studies (GWASs) have identified single nucleotide polymorphisms (SNPs) associated with colorectal cancer (CRC) risk, but whether these SNPs have additive effects on the risk of CRC remains unclear. We performed a systematic analysis of GWAS-identified SNPs using GWAS datasets from China (2,248 patients and 3,173 controls) and Europe (4,461 patients and 4,140 controls). We analyzed 58 independent variants from DNA samples from Chinese populations and found 19 SNPs that were significantly associated with CRC risk. We identified two genetic risk scores (GRSs) based on 58 and 19 SNPs, which were significantly associated with an increased risk of CRC. A decision curve analysis showed higher predictive power for the 58 SNPs. Using all the 58 SNPs to assess 5-year absolute risk (AR), we found that, at a cutoff of 0.4% (two times the median AR) and 0.6% (three times the median AR), approximately 32.76 and 16.45% of Chinese individuals were grouped as high risk for developing CRC, respectively. Risk stratification analysis further indicated that the population in the top 30% risk group accounted for 46.71% of the CRC cases. In addition, the 58 SNPs could explain approximately 1.13% of the phenotypic variance in Chinese populations. Similar findings were found in European populations. Combinations of SNPs identified in GWASs may therefore be useful for identifying individuals at high risk for CRC.

A genetic variation in the CpG island of pseudogene GBAP1 promoter is associated with gastric cancer susceptibility.

BACKGROUND: Previous genome-wide association studies (GWASs) have identified that several single nucleotide polymorphisms (SNPs) are implicated in gastric cancer (GC) risk. However, the multiple statistical comparisons of GWASs may reject some true biological positives with subthreshold P values. METHODS: This study annotated the genomic locations of all CpG islands in the genome using the Encyclopedia of DNA Elements (ENCODE). The SNPs in the regions were then genotyped using the Illumina 660W Quad chip. The effects of the prominent variations on GC risk were further confirmed in the other independent cohorts. RESULTS: SNP rs2990245, which is located in the promoter of pseudogene GBAP1, was associated with GC risk using GWASs data. An additional cohort of 1275 GC patients and 1424 controls validated that individuals with the CC genotype had a 62% decreased risk of GC compared with those who carried the TT genotype (P = 2.01E-04) in the codominant model. The significant association was observed in the additive, dominant, and recessive models. A meta-analysis combining the results from the GWASs and replication studies revealed that rs2990245 was significantly associated with decreased GC risk (P = 5.59E-12). Importantly, rs2990245 can regulate the expression of GBAP1 by influencing the methylation status of the GBAP1 promoter. GBAP1 can act as a competing endogenous RNA by binding competitively with micro-RNA-212-3p and then promoting GBA expression. CONCLUSION: rs2990245 is significantly associated with a decreased risk of GC. Pseudogene GBAP1 contributes to the development and progression of GC by sequestering the miR-212-3p from binding to GBA.

Selection of three miRNA signatures with prognostic value in non-M3 acute myeloid leukemia.

BACKGROUND: MiRNAs that are potential biomarkers for predicting prognosis for acute myeloid leukemia (AML) have been identified. However, comprehensive analyses investigating the association between miRNA expression profiles and AML survival remain relatively deficient. METHOD: In the present study, we performed multivariate Cox's analysis and principal component analysis (PCA) using data from The Cancer Genome Atlas (TCGA) to identify potential molecular signatures for predicting non-M3 AML prognosis. RESULT: We found that patients who were still living were significantly younger at diagnosis than those who had died (P = 0.001). In addition, there was a marked difference in living status among different risk category groups (P = 0.022). A multivariate Cox model suggested that three miRNAs were potential biomarkers of non-M3 AML prognosis, including miR-181a-2, miR-25 and miR-362. Subsequently, PCA analyses were conducted to comprehensively represent the expression levels of these three miRNAs in each patient with a PCA value. According to the log-rank test, AML outcome for patients with lower PCA values was significantly different from those with higher PCA values (P < 0.001). Further bioinformatic analysis revealed the biological functions of the selected miRNAs. CONCLUSION: We conducted a comprehensive analysis of TCGA non-M3 AML data, identifying three miRNAs that are significantly correlated with AML survival. PCA values for the identified miRNAs are valuable for predicting AML prognosis.

Hypermethylation of EIF4E promoter is associated with early onset of gastric cancer.

Although gastric cancer (GC) in young adults (≤ 45 years) accounts for fewer than 10% of newly diagnosed cases, the young patients are more likely to have advanced disease at presentation compared with elderly patients. Previous studies have identified that the DNA methylation of genomes are different during aging. Our study aimed to explore the association between DNA methylation and the onset of GC. We applied Illumina HumanMethylation450 BeadChip to examine methylation expression profiles and compared methylation expression patterns in five early onset GC patients and seven elderly patients. Additionally, we evaluated the associations of methylation expression with different clinicopathological characteristics of GC. Our results showed that the pattern of genome-wide methylation expression was significantly different between early onset and elderly GC. The top 10 hypomethylation and hypermethylation CpG sites were selected for further analyses in The Cancer Genome Atlas (TCGA) database. We found that the hypermethylation of cg11037477, located at the promoter of EIF4E, was significantly associated with age at diagnosis and the expression of EIF4E. Besides, GC patients with high level of cg11037477 were more likely to have advance disease with T3/T4 invasion and III/IV stage. The cg11037477 hypermethylation and EIF4E down-expression were significantly related to poor survival of GC patients. Our study provides new insights into the molecular mechanism of early onset patients with GC and suggests that methylation of cg11037477 and expression of EIF4E may act as prognostic markers in GC.

LncRNA MT1JP functions as a ceRNA in regulating FBXW7 through competitively binding to miR-92a-3p in gastric cancer.

BACKGROUND: Emerging evidence has shown that dysregulation function of long non-coding RNAs (lncRNAs) implicated in gastric cancer (GC). However, the role of the differentially expressed lncRNAs in GC has not fully explained. METHODS: LncRNA expression profiles were determined by lncRNA microarray in five pairs of normal and GC tissues, further validated in another 75 paired tissues by quantitative real-time PCR (qRT-PCR). Overexpression of lncRNA MT1JP was conducted to assess the effect of MT1JP in vitro and in vivo. The biological functions were demonstrated by luciferase reporter assay, western blotting and rescue experiments. RESULTS: LncRNA MT1JP was significantly lower in GC tissues than adjacent normal tissues, and higher MT1JP was remarkably related to lymph node metastasis and advance stage. Besides, GC patients with higher MT1JP expression had a well survival. Functionally, overexpression of lncRNA MT1JP inhibited cell proliferation, migration, invasion and promoted cell apoptosis in vitro, and inhibited tumor growth and metastasis in vivo. Functional analysis showed that lncRNA MT1JP regulated FBXW7 expression by competitively binding to miR-92a-3p. MiR-92a-3p and down-regulated FBXW7 reversed cell phenotypes caused by lncRNA MT1JP by rescue analysis. CONCLUSION: MT1JP, a down-regulated lncRNA in GC, was associated with malignant tumor phenotypes and survival of GC. MT1JP regulated the progression of GC by functioning as a competing endogenous RNA (ceRNA) to competitively bind to miR-92a-3p and regulate FBXW7 expression. Our study provided new insight into the post-transcriptional regulation mechanism of lncRNA MT1JP, and suggested that MT1JP may act as a potential therapeutic target and prognosis biomarker for GC.

Polymorphisms of nucleotide factor of activated T cells cytoplasmic 2 and 4 and the risk of acute rejection following kidney transplantation.

BACKGROUND: Acute rejection (AR) is a common complication of kidney transplantation. Nuclear factors of activated T cells (NFATs) are transcription factors involved in the activation of T lymphocytes, but their association with AR is unclear. METHODS: This retrospective, case-control study included 200 renal transplant recipients who were divided into the AR group (n = 69) and stable group (n = 131). Their blood samples were collected, and DNA was extracted from the whole blood. High-throughput next-generation sequencing was used to identify single nucleotide polymorphisms (SNPs) of the NFATC2 and NFATC4 genes. The correlation of these SNPs with AR was determined by logistic analysis. RESULTS: Seventy-one SNPs of the NFATC2 and NFATC4 genes were identified by the sequencing and Hardy-Weinberg equilibrium analyses. After adjusting for age, gender and immunosuppressive protocols, 27 SNPs were correlated with AR, of which the SNP rs2426295 of the NFATC2 gene showed a significant correlation with AR in the HET model (AA vs. AC: OR = 0.43, 95% CI = 0.19-0.98, P = 0.045), but no significant NFATC4 SNPs were identified. CONCLUSIONS: Our study shows that the rs2426295 variant of the NFATC2 gene is significantly associated with the occurrence of AR following kidney transplantation. And patients with AA genotypes in rs2426295 are inclined to suffer from AR pathogenesis.

Evaluation of genome-wide genotyping concordance between tumor tissues and peripheral blood.

Tumor tissues were potential resources in cancer susceptibility studies. To assess the genotyping concordance between tumor tissues and peripheral blood, we conducted this study in a large sample size and genome-wide scale. Genome-wide genotypes of human colon adenocarcinoma (COAD) retrieved from The Cancer Genome Atlas (TCGA) was analyzed. A total of 387 pairs of matched fresh frozen tumor tissues and peripheral blood samples passed the quality control processes. High concordant rate (94.85% with no-calls and 97.89% without no-calls) was found between tumor tissues and peripheral blood. The discordant rate raised with the increase of heterozygote rate, and the tendency was statistically significant. The total missing rate was 3.10%. We also verified 14 susceptibility SNPs and the average genotyping concordant rate was 97.42%. These findings suggest that majority of SNPs could be accurately genotyped using DNA isolated from tumor tissues.

KCNMA1 cooperating with PTK2 is a novel tumor suppressor in gastric cancer and is associated with disease outcome.

BACKGROUND: Inactivation of tumor suppressor genes by promoter hypermethylation plays a key role in the tumorgenesis. It is necessary to uncover the detailed pattern of whole genome-wide abnormal DNA methylation during the development of gastric cancer (GC). METHOD: We performed a genome-wide methylation detection using 12 paired of GC tissues and their corresponding normal tissues. Methylation-specific PCR (MSP) and bisulphite sequencing (BSP) were used to measure methylation status of specific CpG site. Based on the bioinformatic analysis, the cell phenotypes and mouse model experiments were constructed to detect effect of the target gene. Using the Kaplan-Meier survival curve, the clinical value of KCNMA1 was assessed in GC patients. RESULTS: The CpG site cg24113782 located at the promoter of KCNMA1 showed the most significant difference, contributing to the commonly silenced KCNMA1in gastric cancer cells and primary GC tissues. The promoter methylation of KCNMA1 was detected in 68.7% (77/112) of tumor tissues, compared with 16.2% (18/112) of normal tissues (P < 0.001). The survival curve indicated that KCNMA1 hypermethylation was significantly associated with the shortened survival in GC patients (P = 0.036). KCNMA1 significantly inhibited biological malignant behavior of gastric cancer cell by inducing cell apoptosis in vitro, and suppressed xenograft tumor growth in subcutaneous mouse models (both P < 0.001). Furthermore, the anti-tumor effect of KCNMA1was mediated through suppressing the expression of PTK2. CONCLUSION: KCNMA1 is a critical tumor suppressor in gastric carcinogenesis and its hypermethylation is an independent prognostic factor in patients with gastric cancer.

MLXIPL associated with tumor-infiltrating CD8+ T cells is involved in poor prostate cancer prognosis.

Introduction: Within tumor microenvironment, the presence of preexisting antitumor CD8+ T Q7 cells have been shown to be associated with a favorable prognosis in most solid cancers. However, in the case of prostate cancer (PCa), they have been linked to a negative impact on prognosis. Methods: To gain a deeper understanding of the contribution of infiltrating CD8+ T cells to poor prognosis in PCa, the infiltration levelsof CD8+ T cells were estimated using the TCGA PRAD (The Cancer Genome Atlas Prostate Adenocarcinoma dataset) and MSKCC (Memorial Sloan Kettering Cancer Center) cohorts. Results: Bioinformatic analyses revealed that CD8+ T cells likely influence PCa prognosis through increased expression of immune checkpoint molecules and enhanced recruitment of regulatory T cells. The MLXIPL was identified as the gene expressed in response to CD8+ T cell infiltration and was found to be associated with PCa prognosis. The prognostic role of MLXIPL was examined in two cohorts: TCGA PRAD (p = 2.3E-02) and the MSKCC cohort (p = 1.6E-02). Subsequently, MLXIPL was confirmed to be associated with an unfavorable prognosis in PCa, as evidenced by an independent cohort study (hazard ratio [HR] = 2.57, 95% CI: 1.42- 4.65, p = 1.76E-03). Discussion: In summary, the findings suggested that MLXIPL related to tumor-infiltrating CD8+ T cells facilitated a poor prognosis in PCa.

HCMMD: systematic evaluation of metabolites in body fluids as liquid biopsy biomarker for human cancers.

Metabolomics is a rapidly expanding field in systems biology used to measure alterations of metabolites and identify metabolic biomarkers in response to disease processes. The discovery of metabolic biomarkers can improve early diagnosis, prognostic prediction, and therapeutic intervention for cancers. However, there are currently no databases that provide a comprehensive evaluation of the relationship between metabolites and cancer processes. In this review, we summarize reported metabolites in body fluids across pan-cancers and characterize their clinical applications in liquid biopsy. We conducted a search for metabolic biomarkers using the keywords ("metabolomics" OR "metabolite") AND "cancer" in PubMed. Of the 22,254 articles retrieved, 792 were deemed potentially relevant for further review. Ultimately, we included data from 573,300 samples and 17,083 metabolic biomarkers. We collected information on cancer types, sample size, the human metabolome database (HMDB) ID, metabolic pathway, area under the curve (AUC), sensitivity and specificity of metabolites, sample source, detection method, and clinical features were collected. Finally, we developed a user-friendly online database, the Human Cancer Metabolic Markers Database (HCMMD), which allows users to query, browse, and download metabolite information. In conclusion, HCMMD provides an important resource to assist researchers in reviewing metabolic biomarkers for diagnosis and progression of cancers.

Diagnostic role of plasma ORM2 in differentiating prostate cancer from benign prostatic hyperplasia.

PURPOSE: Markers are needed to increase the diagnostic accuracy of prostate-specific antigen (PSA) in prostate cancer (PCa) screening. Mounting evidence has shown that plasma proteins can be hopeful biomarkers for cancer diagnosis. METHODS: Tandem mass tag (TMT)-based proteomics and parallel reaction monitoring (PRM) analysis were used to screen the differential proteins and further validated in other independent studies (n = 539). Receiver-operating characteristic (ROC), decision curves and nomograms were applied to assess the diagnostic accuracy of biomarkers. RESULTS: Three candidate proteins (DBP, LCAT and ORM2) were preliminarily screened. Subsequent validation studies revealed significant upregulation of ORM2 in PCa patients across other independent cohorts. ORM2 yielded excellent discriminative power for PCa from benign prostatic hyperplasia (BPH) patients (AUC = 0.861 and 0.814 in validation phases 2a and 2b, respectively). Importantly, the combination of ORM2 and PSA gave better predictive accuracy than PSA alone. We incorporated age, PSA and ORM2 into a nomogram, which yielded C-index of 0.883 in validation phase 2a. A similar C-index of 0.879 was obtained in external validation phase 2b. CONCLUSIONS: In summary, our study suggests that ORM2 could be treated as a complementary biomarker for PSA in distinguishing PCa from BPH.

Variability of body mass index and risks of prostate, lung, colon, and ovarian cancers.

Objective: We investigated the association between cancer incidence and body mass index (BMI) variability calculated from the recall of weight at decades of age by participants in the USA Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. Methods: A total of 89,822 individuals' BMI were recorded as recalled the participant's aged 30, 40, 50, 60, 70 years, and baseline. BMI variability was assessed using four indices: SD, coefficient of variation (CV), variability independent of the mean (VIM), and average real variability (ARV). The multivariate Cox regression analysis was performed to calculate hazard ratios (HRs) of these measures for incident cancers and corresponding 95% CIs. Results: During the median follow-up of 11.8 years, there were newly diagnosed 5,012 cases of prostate cancer, 792 cases of lung cancer, 994 cases of colon cancer, and 132 cases of ovarian cancer. Compared with the lowest quartile (Q1) group, the highest quartile (Q4) group of BMI variability indices was associated with increased lung cancer risk, including BMI_SD (HR, 1.58; 95% CI, 1.17-2.12), BMI_CV (HR, 1.46; 95% CI, 1.10-1.94), BMI_VIM (HR, 1.73; 95% CI, 1.33-2.25), and BMI_ARV (HR, 2.17; 95% CI, 1.62-2.91). Associations between BMI variability and prostate, colon, and ovarian cancer incidences were of limited significance. Conclusion: The findings imply that maintaining a stable weight across adulthood is associated with a decreased incidence of lung cancer.

The Prognostic Effect of Dexamethasone on Patients With Glioblastoma: A Systematic Review and Meta-Analysis.

Background: Dexamethasone (DEX) is widely adopted to reduce tumor-associated edema in glioblastoma (GBM) patients despite its side effects. However, the benefits of using DEX in GBM patients remains elusive. Methods: In this study, we performed a comprehensive meta-analysis to address this concern. We searched the relevant studies from PubMed, Web of Science, and EMBASE databases, and then applied random or fixed-effects models to generate estimated summary hazard radios (HRs) and the 95% confidence intervals (CIs). Moreover, subgroup and sensitivity analysis were conducted and publication bias were further evaluated. Results: Ten articles with a total of 2,230 GBM patients were eligible according to the inclusion criteria. In the assessment of overall survival (OS), meta-analysis data revealed that DEX was significantly associated with the poor prognosis of GBM patients (HR=1.44, 95% CI=1.32-1.57). In the progression-free survival (PFS), the pooled results indicated that the use of DEX can increase 48% death risk for GBM patients (HR=1.48, 95% CI=1.11-1.98). Subgroup analyses revealed that DEX was associated with poorer outcome of GBM in subgroup of newly diagnosed patients and GBM patients treated with ≥ 2mg/day. Sensitivity analyses showed that no study changed the pooled results materially for both OS and PFS analyses. The funnel plot had no obvious asymmetry. Conclusion: Our findings partly confirmed that use of DEX was associated with poor treatment outcome in GBM patients. To reach a definitive conclusion, large samples from multi-centers are urgent to address this concern.

Identification of low-frequency variants of UGT1A3 associated with bladder cancer risk by next-generation sequencing.

Although genome-wide association studies (GWASs) have successfully revealed many common risk variants for bladder cancer, the heritability is still largely unexplained. We hypothesized that low-frequency variants involved in bladder cancer risk could reveal the unexplained heritability. Next-generation sequencing of 113 patients and 118 controls was conducted on 81 genes/regions of known bladder cancer GWAS loci. A two-stage validation comprising 3,350 cases and 4,005 controls was performed to evaluate the effects of low-frequency variants on bladder cancer risk. Biological experiments and techniques, including electrophoretic mobility shift assays, CRISPR/Cas9, RNA-Seq, and bioinformatics approaches, were performed to assess the potential functions of low-frequency variants. The low-frequency variant rs28898617 was located in the first exon of UGT1A3 and was significantly associated with increased bladder cancer risk (odds ratio = 1.50, P = 3.10 × 10-6). Intriguingly, rs28898617 was only observed in the Asian population, but monomorphism was observed in the European population. The risk-associated G allele of rs28898617 increased UGT1A3 expression, facilitated UGT1A3 transcriptional activity, and enhanced the binding activity. In addition, UGT1A3 deletion significantly inhibited the proliferation, invasion, and migration of bladder cancer cells and xenograft tumor growth. Mechanistically, UGT1A3 induced LAMC2 expression by binding CBP and promoting histone acetylation, which remarkably promoted the progression of bladder cancer. This is the first targeted sequencing study to reveal that the novel low-frequency variant rs28898617 and its associated gene UGT1A3 are involved in bladder cancer development, providing new insights into the genetic architecture of bladder cancer.

The association between inflammatory bowel disease and prostate cancer risk: a meta-analysis.

BACKGROUND: Patients with inflammatory bowel disease (IBD) are at increased risk of gastrointestinal and extraintestinal malignancies. However, the associations between IBD and prostate cancer (PCa) risk remain conflicting. METHODS: We conducted a systematic literature search in PubMed, EMBASE, and Web of Science databases. According to the inclusion and exclusion criteria, a total of nine studies were included in the meta-analysis. The pooled standardized incidence ratios (SIRs) or relative risks (RRs) and corresponding 95% confidence intervals (CIs) were calculated to determine the relationship of IBD and PCa risk. RESULTS: For cohort studies, the pooled SIR was 1.33 (95% CI = 1.03-1.71). The further subgroup analysis showed that the PCa risk was higher in patients with ulcerative colitis (UC) (pooled SIR = 1.58, 95% CI = 1.08-2.30), but not in patients with Crohn's disease (CD) (pooled SIR = 1.12, 95% CI = 0.97-1.31). Besides, for the three case-control studies, the results indicated that compared with normal group, the pooled RR of PCa was 1.81 for the patients with IBD (95% CI = 1.43-2.29). In addition, sensitivity analysis indicated that the results were robust and no significant publication bias were observed. CONCLUSIONS: Our findings based on the large and multicenter samples strongly indicated that men with IBD especial UC have significantly elevated PCa risk. Future efforts are needed to define the mechanism underlying the link between IBD and PCa or clinically significant PCa risk.

Circulating let-7f-5p improve risk prediction of prostate cancer in patients with benign prostatic hyperplasia.

Background: Although the prostate-specific antigen (PSA) testing was widely used for early detection of prostate cancer (PCa), it is difficult for PSA to distinguish the PCa from benign prostatic hyperplasia (BPH) patients. Emerging evidence has shown that microRNA (miRNA) was a promising biomarker for PCa screening. Methods: We applied miRNA profiling from microarray or high-throughput sequencing in Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases to identify the differentially expressed miRNAs in PCa patients (n = 1,017) and controls (n = 413). Then, qRT-PCR analysis was used to validate the expression of candidate miRNAs in our independent cohort, include 66 PCa cases and 63 BPH patients diagnosed by biopsy. The area under the receiver operating characteristic curve (AUC) was conducted to evaluate the diagnostic efficacy of miRNAs and PSA. Results: In the microarray analysis, we identified two consistently differently expressed miRNAs (miR-103a-3p and let-7f-5p) between PCa patients and controls. In the subsequent qRT-PCR analysis, the let-7f-5p was upregulated in PCa compared with BPH patients (P=2.17E-07), but no statistically difference of miR-103a-3p expression was observed (P=0.456). The AUC was 0.904 for combination of lef-7f-5p and PSA, which was significantly higher than that of let-7f-5p (0.782) or PSA (0.795) alone (P=7.55E-04 and P=2.09E-03, respectively). Besides, the results of decision curve analysis and nomogram prediction indicated that combination of let-7f-5p and PSA had superior predictive accuracy of PCa. Conclusions: Our study suggests that plasma let-7f-5p combining PSA could serve as potentially diagnostic biomarkers for PCa.

Advanced paternal age and risk of cancer in offspring.

Many risk factors of cancer have been established, but the contribution of paternal age in this regard remains largely unexplored. To further understand the etiology of cancer, we investigated the relationship between paternal age and cancer incidence using PLCO cohort. Cox proportional hazards models were performed to assess the association between paternal age and the risk of cancers. During follow-up time (median 11.5 years), 18,753 primary cancers occurred. Paternal age was associated with reduced risk of cancers of the female genitalia (HR, 0.79; 95%CI, 0.66-0.94; P = 0.008) as well as cancers of the respiratory and intrathoracic organs (HR, 0.78; 95%CI, 0.63-0.97; P = 0.026). The association was stronger for lung cancer (HR, 0.67; 95%CI, 0.52-0.86; P = 0.002). The subgroup analysis suggested that age, gender, smoking and BMI were related to the decreased cancer incidence of the respiratory and intrathoracic organs, lung and the female genitalia. Positive linear associations were observed between paternal age and cancer incidence of the female genitalia, respiratory and intrathoracic organs and the lungs. These findings indicate that advanced paternal age is an independent protective factor against various cancers in offspring.