Search

Background Renal cell carcinoma (RCC) contributed to 403,262 new cases worldwide in 2018, which constitutes 2.2% of global cancer, nevertheless, sunitinib, one of the major targeted therapeutic agent for RCC, often developed invalid due to resistance. Emerging evidences suggested sunitinib can impact tumor environment which has been proven to be a vital factor for tumor progression. Methods In the present study, we used ssGSEA to extract the immune infiltrating abundance of clear cell RCC (ccRCC) and normal control samples from GSE65615, TCGA, and GTEx; key immune cells were determined by Student's t‐test and univariable Cox analysis. Co‐expression network combined with differentially expressed analysis was then applied to derive key immune‐related genes for ccRCC, followed by the identification of hub genes using differential expression analysis. Subsequently, explorations and validations of the biological function and the immune‐related and sunitinib‐related characteristics were conducted in KEGG, TISIDB, Oncomine, ICGC, and GEO databases. Results We refined immature dendritic cells and central memory CD4 T cells which showed associations with sunitinib and ccRCC. Following, five hub genes (CRYBB1, RIMBP3C, CEACAM4, HAMP, and LYL1) were identified for their strong relationships with sunitinib and immune infiltration in ccRCC. Further validations in external data refined CRYBB1, CEACAM4, and HAMP which play a vital role in sunitinib resistance, immune infiltrations in ccRCC, and the development and progression of ccRCC. In conclusion, our findings could shed light on the resistance of sunitinib in ccRCC and provide novel biomarkers or drug targets for ccRCC., We identified five hub genes (CRYBB1, RIMBP3C, CEACAM4, HAMP, and LYL1) related to immune infiltration, sunitinib in renal carcinoma. External validation refined CRYBB1, CEACAM4 and HAMP which played a vital role in the development and progression of ccRCC and implicated in sunitinib resistance and immune infiltrations in ccRCC.

To evaluate the expression, potential functions and mechanisms of long noncoding RNAs (lncRNAs) in the pathogenesis of varicocele (VC)-induced spermatogenic dysfunction.We established a rat model with left experimental VC and divided rats into the sham group, the VC group, and the surgical treatment group (each group, n = 10). Haematoxylin and eosin (HE) staining and sperm quality were analysed to evaluate spermatogenesis function. LncRNA expression profiles were analysed using lncRNA-Seq (each group n = 3) and validated using quantitative real-time polymerase chain reaction (each group n = 10). Correlation analysis and gene target miRNA prediction were used to construct competing endogenous RNA network. The regulated signalling pathway and spermatogenic dysfunction of differentially expressed lncRNAs (DE lncRNAs) were validated by Western blot.HE detection and sperm quality analysis showed that VC could induce spermatogenic dysfunction. Eight lncRNAs were upregulated and three lncRNAs were downregulated in the VC group compared with the sham group and surgical treatment group. The lncRNA of NONRATG002949.2, NONRATG001060.2, NONRATG013271.2, NONRATG022879.2, NONRATG023424.2, NONRATG005667.2 and NONRATG010686.2 were significantly negatively related to sperm quality, while NONRATG027523.1, NONRATG017183.2 and NONRATG023747.2 were positively related to sperm quality. The lncRNAs promote spermatogenic cell apoptosis and inhibit spermatogonia and spermatocyte proliferation and meiotic spermatocytes by regulating the PI3K-Akt signalling pathway.DE lncRNAs may be potential biomarkers for predicting the risk of spermatogenic dysfunction in VC and the effect of surgical repair. These DE lncRNAs promote spermatogenic dysfunction by regulating the PI3K-Akt signalling pathway.

Androgen deprivation therapy (ADT) is widely being applied in men who suffered from prostate cancer. Whether androgen deprivation therapy (ADT) is associated with an increased risk of developing cardiovascular-related disease is poorly defined.The aim of the present meta-analysis is to explore the relationship between ADT and the risk of cardiac events. MATERIALS AND METHODS: For this systematic review and meta-analysis, we searched databases from inception to April 2019 for randomized controlled trials (RCT) or observational studies that reported data on ADT administration and cardiac event incidence. The connection was evaluated through estimating relative risk ratio (RR) and 95% confidence intervals (CIs).A significantly increased acute myocardial infarction (AMI) was detected in the ADT group compared with the control group (RR = 1.19, 95% confidence interval (CI), 1.02-1.39, P .05). A significant difference between cardiovascular disease (CVD) and ADT was also observed, with summary RR = 1.25, 95% CI, 1.11-1.40, P .05. Furthermore, our study also suggested ADT was not related to increased incidence of sudden cardiac death (SCD) (RR = 1.13, 95% CI, 0.92-1.38, P = .24); AMI and CVD were not connected with the duration of ADT (AMI: RR = 1.31; 95% CI, 0.66-2.63, P = .44, for 5 year group; CVD: RR = 1.12, 95% CI, 0.97-1.30, P = .12, for 5 year group). In addition, the RR for risk of CVD was 1.28 (95% CI, 1.01-1.62, P .05) for men with PCa on new hormonal agents.Various ADT modalities have different impact on cardiovascular disease risk in different level. Long-term application of ADT is not associated with increased risk of AMI and CVD. Both abiraterone and enzalutamide could significantly increase the incidence of cardiac events in patients who suffered from prostate cancer. Cautions and periodic cardiovascular elevation are necessary for patients before the ADT starting.Androgen deprivation therapy is associated with increased risk of AMI, CHD, in contrast, this association is not detected in SCD.

Drug resistance is a major hurdle for the effectiveness of tamoxifen (TAM) to provide clinical benefit. Therefore, it is essential to identify a sensitizer that could be used to improve TAM efficacy in treating TAM‐resistant breast cancer. Here, we investigated the ability of baicalein to reverse TAM resistance. We found that baicalein increased the efficacy of TAM in inhibiting proliferation and inducing apoptosis of TAM‐resistant cells. It also enhanced the TAM‐induced growth reduction of resistant cells from NOD/SCID mouse mammary fat pads, without causing obvious systemic toxicity. Analyses using the CellMiner tool and the Kaplan–Meier plotter database showed that HIF‐1α expression was inversely correlated with TAM therapeutic response in NCI‐60 cancer cells and breast cancer patients. HIF‐1α expression was increased in TAM‐resistant cells due to an increase in mRNA levels and reduced ubiquitin‐mediated degradation. Baicalein reduced HIF‐1α expression by promoting its interaction with PHD2 and pVHL, thus facilitating ubiquitin ligase‐mediated proteasomal degradation and thereby suppressing the nuclear translocation, binding to the hypoxia‐response element, and transcriptional activity of HIF‐1α. As a result, baicalein downregulated aerobic glycolysis by restricting glucose uptake, lactate production, ATP generation, lactate/pyruvate ratio and expression of HIF‐1α‐targeted glycolytic genes, thereby enhancing the antiproliferative efficacy of TAM. Furthermore, baicalein interfered with HIF‐1α inhibition of mitochondrial biosynthesis, which increased mitochondrial DNA content and mitochondrial numbers, restored the generation of reactive oxygen species in mitochondria, and thus enhanced the TAM‐induced mitochondrial apoptotic pathway. The HIF‐1α stabilizer dimethyloxallyl glycine prevented the baicalein‐induced downregulation of glycolysis and mitochondrial biosynthesis and reduced the effects of baicalein on reversing TAM resistance. Our results indicate that baicalein is a promising candidate to help overcome TAM resistance by sensitizing resistant cells to TAM‐induced growth inhibition and apoptosis. The mechanism underlying the effects of baicalein consists of inhibition of HIF‐1α–mediated aerobic glycolysis and mitochondrial dysfunction., • Baicalein possesses the ability to reverse TAM resistance. • Baicalein reduces the expression and activity of HIF‐1α via the promotion of its interaction with PHD2 and pVHL and facilitates the ubiquitin ligase‐mediated proteasomal degradation in TAM‐resistant cells. • Baicalein inhibits HIF‐1α–mediated aerobic glycolysis and relieves HIF‐1α–restrained mitochondrial biosynthesis and reactive oxygen species generation, thereby enhancing TAM‐induced proliferation and mitochondrial‐mediated apoptosis.

Transcriptomics is an established powerful tool to identify potential mRNAs and ncRNAs (non‐coding RNAs) for endometrial receptivity. In this study, the goat endometrium at estrus day 5 (ED5) and estrus day 15 (ED15) were selected to systematically analyse the differential expressed genes (DEGs) what were induced by the embryo. There were 1,847 genes which were significantly differential expressed in endometrium induced by the embryo at ED5, and 1,346 at ED15 (p‐value, In this study, the goat endometrium at estrus day 5 and estrus day 15 were selected to systematically analyse the DEGs induced by the embryo in the endometrium of dairy goats, and there were 1,847 genes that were differential expressed at ED5, and 1,346 at ED15. In a word, this resulting view of the transcriptome greatly uncovered the global trends in mRNAs expression induced by the embryo in the endometrium of dairy goats.

Despite the fact that long noncoding RNAs (lncRNAs) play roles in almost all biological processes, little is known about their biological function in the endometrium during the formation of endometrial receptivity. In this study, a comprehensive analysis of lncRNAs in goat endometrial tissues on Day 5 (prereceptive endometrium, PE) and Day 15 (receptive endometrium, RE) of pregnancy was performed by using RNA-Seq. As a result, 668 differentially expressed lncRNAs (DELs) were found between the PE and RE. Further study showed that lncRNA882, regulated by estrogen (E2) and progestin (P4), could act as competing endogenous RNAs (ceRNAs) for miR-15b, which inhibited the expression of transforming growth factor-b-activated kinase 1 binding protein 3 (TAB3) and then indirectly regulated the level of leukemia inhibitory factor (LIF). This was helpful for the formation of endometrial receptivity in dairy goats. In conclusion, we elucidated the endometrium lncRNA profiles of PE and RE in dairy goats; lncRNA882 acted as a ceRNA for miR-15b and then indirectly regulated the level of LIF in goat endometrial epithelium cells. Thus, this study helped us to better understand the molecular regulation of endometrial receptivity in dairy goats.

Circular RNAs (circRNAs) in various tissues and cell types from mammalian sources have been studied. However, present knowledge on circRNAs in the development of pre-receptive endometrium (PE) in dairy goats is limited. In the pre-receptive endometrium of dairy goats, higher circRNA3175 (ciR3175) levels, lower miR-182 levels and higher Testin (TES) levels were detected. And ciR3175 could decreased the miR-182 levels by acting as a miRNA sponge, and miR-182 could down-regulated the expression level of TES via the predicted target site in endometrial epithelial cells (EECs) in vitro. Via this way, ciR3175 functioned as a competing endogenous RNAs (ceRNA) that sequestered miR-182, thereby protecting TES transcripts from miR-182-mediated suppression in EECs in vitro. Further, TES inhibited EECs apoptosis by decreasing the expression level of BCL-2/BAX via the MAPK pathway. Thus, a ciR3175-miR182-TES pathway in the endometrium was identified in EECs, and the modulation of which could emerge as a potential target in regulating the pre-receptive endometrium development in dairy goats.

Xinong Saanen (n = 305) and Guanzhong (n = 317) dairy goats were used to detect SNPs in the caprine MTHFR 3'-UTR by DNA sequencing. One novel SNP (c.*2494GA) was identified in the said region. Individuals with the AA genotype had greater milk protein levels than did those with the GG genotype at the c.*2494 GA locus in both dairy goat breeds (P 0.05). Functional assays indicated that the MTHFR:c.2494GA substitution could increase the binding activity of bta-miR-370 with the MTHFR 3'-UTR. In addition, we observed a significant increase in the MTHFR protein level of AA carriers relative to that of GG carriers. These altered levels of MTHFR protein may account for the association of the SNP with milk protein level.

In this study, we report the analysis of INHA and INHβA gene polymorphisms in 786 goats of three breeds: Xinong Saanen (SN), Guanzhong (GZ) and Boer (BG). We identified three new allelic variants: P1-C80G and/126G (GenBank accession no. HQ202573) in the three goat breeds and P2-C936T (GenBank accession no. HQ202572) in SN and GZ goat breeds. At P1 locus, AA, AB and BB genotypes were found in the three goat breeds. At P2 locus, CC and CT genotypes were found in SN and GZ goat breeds. After comparing genotype distribution within the three goat breeds, BG had conspicuous differences from SN and GZ (P < 0.001) at P2 locus. The SNP locus was in Hardy-Weinberg disequilibrium at P1 locus in the three goat breeds (P < 0.05). At P2 locus, the SNP locus was in Hardy-Weinberg disequilibrium in SN and GZ goat breeds (P < 0.05). Association of polymorphisms with litter size was done at P1 locus in the three goat breeds. The result showed that AA genotype had remarkable litter size at P1 locus in the three goat breeds (P < 0.05). Therefore, these results suggest that INHA gene is a strong candidate gene that affects litter size in goats.