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Polo‐like kinase 4 (PLK4) has been reported to contribute to tumor growth, invasion, and metastasis. However, the role of PLK4 in human bladder cancer (BC) remains unclear. Here, we demonstrate the regulatory function of PLK4 in human BC progression. PLK4 is overexpressed in BC cell lines and tissues, and its overexpression correlated with poor prognosis. Our transcriptome analysis combined with subsequent functional assays indicated that PLK4 inhibition can suppress BC cell growth and induce cell cycle arrest at G1 phase via activation of the p38/p53/p21 pathway in vitro and in vivo. Overall, our data suggest that PLK4 is a critical regulator of BC cell proliferation, and thus, it may have potential as a novel molecular target for BC treatment., We demonstrate that Polo‐like kinase 4 (PLK4) is overexpressed in human bladder cancer (BC) cell lines and tissues, and its overexpression correlates with poor prognosis. PLK4 inhibition suppresses BC cell growth and induces G1 phase arrest via activating the p38/p53/p21 pathway in vitro and in vivo. The data suggest that PLK4 might serve as a novel molecular target for BC treatment.

The formation of natural bone tissue is the result of the joint regulation of multiple template molecules. Although its complex hierarchical structure has been studied for many years, the mechanism of biomineralization of hard bone tissue has not been fully clarified. In this paper, the nanocomposites obtained by mineralization were characterized and analyzed, and the effect of the template on the crystal formation of hydroxyapatite was studied. The characterization results show that the main phase of the inorganic mineral obtained by template mineralization is the hydroxyapatite phase. The nano-apatite composite particles with an inorganic component content of 90.2% have the highest loading efficiency, reaching 67.9 mg/g. By statistical analysis of the pain scores at 5 days, 10 days, and 15 days after ankle injury, it was found that the average pain score of the treatment group was smaller than that of the control group. Two weeks later, the clinical efficacy judgment standard statistics show that the treatment group has a 22.5% improvement in healing rate, a significant increase in 3.18%, and a total effective rate of 8.71%, which is significantly better than the control group.

Deep vein thrombosis (DVT) is the blood clot formed in a vein deep in body, mostly occurred in the lower leg or thigh. Early studies indicate that DVT is a complex disorder affected by both environmental and genetic factors. Previous biological evidence have indicated that KEAP1 gene may play an important role in the pathogenesis of DVT. In the present study, we aimed to investigate the genetic association between genetic polymorphisms of KEAP1 gene and the risk of DVT in Han Chinese population. A total of 2558 study subjects comprised of 660 DVT following orthopedics surgery cases and 1898 controls were recruited as discovery sample. In addition, we have also recruited another independent sample sets including 704 DVT following orthopedics surgery cases and 1056 controls for replication. Ten tag SNPs located on KEAP1 gene were selected for genotyping. Single marker based association analyses were conducted at both allelic and genotypic levels. SNPs that passed the Bonferroni correction in the discovery stage were genotyped in the replication dataset. Bioinformatics tools including PolymiRTS, GTEx, STRING and Gene Ontology database were utilized to investigate the functional consequences of the significant SNPs. SNP rs3177696 was identified to be significantly associated with risk of DVT in the study subjects. The G allele of SNP rs3177696 was significantly related to decreased risk of DVT. Functional consequences of SNP rs3177696 were obtained based on bioinformatics analyses. The G allele of SNP rs3177696 was related to the increased gene expression level of KEAP1. In summary, we have identified KEAP1 gene to be a potential susceptible locus for DVT in Han Chinese population. Further bioinformatics analyses have provided supportive evidence for the functional consequence of the significant SNP.

Postmenopausal osteoporosis (PMOP) is one of systemic bone degenerative diseases characterised by decreased bone mineral density (BMD). Previous studies suggest that the SPON1 gene may be associated with BMD and play an important role in the occurrence and development of PMOP. In this study, we aimed to investigate the potential association between PMOP and the SPON1 gene. A total of 8062 postmenopausal women comprising 2684 primary PMOP patients, and 5378 healthy controls were recruited. Forty tag SNPs were selected for genotyping to evaluate the association of the SPON1 gene with PMOP and BMD. Genetic association and bioinformatics analyses were performed for PMOP. SNP rs2697825 was identified to be significantly associated with the risk of PMOP at both allelic (T-statistics = −3.84, p = .0001) and genotypic levels (χ2=15.86, p = .0004). The G allele of SNP rs2697825 was significantly associated with a decreased risk of PMOP with an OR [95%] of 0.84 [0.77–0.92]. The G allele of SNP rs2697825 was associated with increased BMD at both the lumbar spine and femoral neck. Our results provide further evidence to support the important role for the SPON1 gene in the aetiology of PMOP, adding to the current understanding of the susceptibility to osteoporosis.

Osteoarthritis (OA) is a complex degenerative joint disorder, which is caused by both environmental and genetic factors. Previous studies have indicated that the GNL3 gene is associated with knee osteoarthritis (KOA) susceptibility in Europeans; however, the exact molecular mechanism is still unclear. In the present study, we investigated the potential genetic association of GNL3 with KOA in a two-stage sample of 6,704 individuals from the Han Chinese population. Subjects containing 1,052 KOA patients and 2,117 controls were considered the discovery dataset, while subjects consisting of 1,173 KOA patients and 2,362 controls were utilized as the replication dataset. Single-SNP association, imputation, and haplotypic association analyses were performed. The SNP of rs11177 in GNL3 was identified to be significantly associated with KOA after accounting for age, gender and BMI in both stages. The imputed SNP of rs6617 in SPCS1 was found to be strongly associated with KOA risk, and the significant association signal was confirmed in the replication stage. Moreover, a haplotype-based analysis also indicated a positive genetic effect of GNL3 on KOA susceptibility. In summary, our results proved that GNL3 plays an important role in the etiology of KOA, suggesting that GNL3 is a potential genetic modifier for KOA development.

Heat shock protein 47 (HSP47) is a collagen-specific molecular chaperone and is involved in tumor progression by promoting angiogenesis. However, the regulatory network of HSP47 in angiogenesis remains elusive. In this study, we report a novel mechanism of HSP47-induced angiogenesis in bladder cancer (BC). We find that HSP47 is abnormally overexpressed in BC and is correlated with poor prognosis. HSP47 down-regulation suppresses angiogenesis in BC cells. Mechanistically, activation of the ERK pathway and induction of C-C Motif Chemokine Ligand 2 (CCL2) are responsible for HSP47-induced angiogenesis. The correlation between HSP47 with CCL2 and angiogenesis is further confirmed in BC clinical samples. Taken together, our findings suggest that HSP47 contributes to BC angiogenesis by induction of CCL2 and provide a potential anti-angiogenesis target for BC therapy.

Summary Research shows a higher incidence of colorectal cancer in men. However, the molecular mechanisms for this gender disparity remain unknown. We report the roles of androgen in proliferation and differentiation of intestinal stem cells via targeting of the androgen receptor (AR) on intestinal stromal cells by negatively regulating BMP signaling. Orchidectomy (ORX) or the AR antagonist promotes expansion of intestinal epithelium but suppresses intestinal stem cell (ISC) proliferation. Conversely, the AR agonist inhibits ISC differentiation but augments proliferation in ovariectomized mice. Mechanistically, activation of the AR increases expression of BMP antagonists but lowers expression of BMP4 and Wnt antagonists in primary stromal cells, which promotes intestinal organoid growth. Interestingly, the BMP pathway inhibitor LDN-193189 reverses the ORX-induced effects. Our results highlight that stromal cells constitute the intestinal stem cell niche and provide a possible explanation for higher incidence rates of colorectal cancer in men., Highlights • Androgen receptor (AR) is expressed in intestinal stromal cells • Androgen regulates the renewal and differentiation of intestinal epithelial stem cells • Androgen regulates expression of BMP-related signal secretion in intestinal stromal cells • Selective inhibition of the BMP pathway reverses orchidectomy-induced effects, In this article, D. Chen, J. Li, and colleagues show that androgen promotes proliferation and inhibits differentiation of intestinal epithelial stem cells in mouse models. Mechanistically, they prove that activation of the androgen receptor regulates BMP-related signal secretion in intestinal stromal cells.

Multiple lines of evidence have confirmed the importance of genetic factors for hip osteoarthritis (HOA). Our study aimed to investigate the associations of TLR10 and NFKBIA with respect to the HOA risk in Han Chinese individuals. A total of 1,043 HOA patients and 2,664 controls were recruited. Then, 23 tag single-nucleotide polymorphisms (SNPs) in the TLR10 and NFKBIA genes were selected for genotyping. Genetic association analyses were conducted in both single-marker and haplotype-based ways. Gene by gene, two-way interactions were analysed using a case-only method. Multiple bioinformatics tools were utilised to examine the potential functional significance of the SNPs. Two significant SNPs, rs11096957 (OR = 1.26, P = 1.35 × 10−5) and rs2273650 (OR = 1.2, P = 1.57 × 10−3), were significantly associated with HOA risk. Rs11096957 was also associated with the severity of the HOA. Bioinformatics analysis indicated that the allele T of rs2273650 would create new miRNA/SNP target duplexes, which suggests that rs2273650 could alter the NFKBIA expression by affecting the miRNA/SNP target duplexes. Our study identified significant association signals from NFKBIA with HOA for the first time, and it also confirmed the contribution of TLR10 to the HOA risk. These findings would provide clues for identifying individuals at high risk of HOA.

The pathology of non-traumatic osteonecrosis of the femoral head (ONFH) is complex. Several studies have linked some polymorphisms of vascular endothelial growth factors A (VEGFA) with ONFH, but the results are not consistent and are even conflicting. In the study, 22 single nucleotide polymorphisms (SNPs) in VEGFA were genotyped in 1,762 subjects (489 cases and 1,273 controls). Genetic association analyses were performed in single markers and haplotype levels. Stratification analysis was conducted for ONFH patients. Gene by environment interactions were tested between VEGFA and the smoking status of the subjects. Gene expression and eQTL data of significant SNPs were extracted from GTEx to examine their potential biological function. The SNP, rs2010963, was identified to be significantly associated with ONFH (χ2 = 11.66, P = 0.0006, OR = 1.29). Haplotypes including rs2010963 were also identified to be correlated with ONFH in the haplotype-based analyses. After stratifying by the causes of ONFH, a significant signal from rs2010963 could only be identified in alcohol-induced patients (Pallelic = 0.0009) but not in steroid-induced patients (Pallelic = 0.055). No significant results were obtained from the gene by environmental interaction analyses. Significant expression differences of VEGFA were identified in multiple human tissues for different genotypes of rs2010963. Our findings indicate that SNP rs2010963 is significantly associated with ONFH.

Rheumatoid arthritis (RA) is a common, chronic autoimmune disease affecting 0.5–1.0% of adults worldwide, including approximately 4.5–5.0 million patients in China. The genetic etiology and pathogenesis of RA have not yet been fully elucidated. Recently, one new RA susceptibility gene (RAD51B) has been identified in Korean and European populations. In this study, we designed a two-stage case-control study to further assess the relationship of common variants in the RAD51B gene with increased risk of RA in a total of 965 RA patients and 2,511 unrelated healthy controls of Han Chinese ancestry. We successfully identified a common variant, rs911263, as being significantly associated with the disease status of RA (P = 4.8 × 10−5, OR = 0.64). In addition, this SNP was shown to be related to erosion, a clinical assessment of disease severity in RA (P = 2.89 × 10−5, OR = 0.52). These findings shed light on the role of RAD51B in the onset and severity of RA. More research in the future is needed to clarify the underlying functional link between rs911263 and the disease.