OBJECTIVE: To assess the association of gene expression with development potential of early embryos derived from patients with polycystic ovary syndrome (PCOS). METHODS: Three pairs of infertile patients with respectively matched age, body mass index, ovarian reserve and treatment with gonadotrophin-releasing hormone (GnRH) antagonists were selected. Patients with fewer embryos were assigned as the case group (n = 3), whilst the remainders were assigned as the control group (n = 3). Ovarian granulosa cells from patients were collected for the extraction of total RNA and subjected to RNA sequencing. The results were subjected to differential gene expression and functional enrichment analyses. RESULTS: Compared with the control group, 76 genes were up-regulated and 110 genes were down-regulated in the case group. The level of estradiol (E₂) was significantly higher in the control group on the trigger day with the injection of human chorionic gonadotrophin (HCG). Compared with the control group, the KRT7 gene was most significantly up-regulated, whilst the CCNYL2 gene was most significantly down-regulated in the case group. Gene ontology (GO) entries enrichment has found those associated with chromosome segregation, cell cycle regulation, and fatty acid metabolism to be significantly enriched. The genes participating in the regulation of cell assembly, differentiation, negative regulation of cell cycle, negative regulation of development, extracellular regulated protein kinases (ERK), ERK1 and ERK2 signaling pathways to be significantly down-regulated. KEGG enrichment analysis of cell signaling pathways revealed that steroid hormone biosynthesis-related genes were enriched. CONCLUSION Among patients treated with GnRH antagonists, the significant difference in the number of oocytes fertilized in vitro and the number of available embryos are associated with the difference in the expression of genes of ovarian granulosa cells.
Female ; Humans ; Pregnancy ; Embryonic Development ; Gene Expression ; Gonadotropin-Releasing Hormone/antagonists & inhibitors* ; Granulosa Cells ; Polycystic Ovary Syndrome/genetics*

The present study analyzed the predictive value of combined analysis of collapsin response mediator protein 4 (CRMP4) methylation levels and the Cancer of the Prostate Risk Assessment (CAPRA-S) Postsurgical score of patients who required adjuvant hormone therapy (AHT) after radical prostatectomy (RP). We retrospectively analyzed 305 patients with prostate cancer (PCa) who received RP and subsequent androgen deprivation therapy (ADT). Two hundred and thirty patients with clinically high-risk PCa underwent immediate ADT, and 75 patients with intermediate risk PCa underwent deferred ADT. CRMP4 methylation levels in biopsies were determined, and CAPRA-S scores were calculated. In the deferred ADT group, the values of the hazard ratios for tumor progression and cancer-specific mortality (CSM) in patients with ≥15% CRMP4 methylation were 6.81 (95% CI: 2.34-19.80) and 12.83 (95% CI: 2.16-26.10), respectively. Receiver-operating characteristic curve analysis indicated that CRMP4 methylation levels ≥15% served as a significant prognostic marker of tumor progression and CSM. In the immediate ADT group, CAPRA-S scores ≥6 and CRMP4 methylation levels ≥15% were independent predictors of these outcomes (uni- and multi-variable Cox regression analyses). The differences in the 5-year progression-free survival between each combination were statistically significant. Combining CAPRA-S score and CRMP4 methylation levels improved the area under the curve compared with the CRMP4 or CAPRA-S model. Therefore, CRMP4 methylation levels ≥15% were significantly associated with a poor prognosis and their combination with CAPRA-S score accurately predicted tumor progression and metastasis for patients requiring AHT after RP.
Aged ; Androgen Antagonists/therapeutic use* ; Biomarkers, Tumor/blood* ; Female ; Hormone Replacement Therapy ; Humans ; Male ; Methylation ; Middle Aged ; Muscle Proteins/metabolism* ; Neoplasm Grading ; Neoplasm Metastasis ; Neoplasm Staging ; Prognosis ; Progression-Free Survival ; Prostatectomy ; Prostatic Neoplasms/metabolism* ; Retrospective Studies ; Risk Assessment ; Treatment Outcome

Aged ; Aged, 80 and over ; Androgen Antagonists/pharmacology* ; Androgens/blood* ; Cohort Studies ; Gonadotropin-Releasing Hormone/antagonists & inhibitors* ; Hormones/blood* ; Humans ; Luteinizing Hormone/blood* ; Male ; Middle Aged ; Orchiectomy ; Prostatic Neoplasms/surgery* ; Toremifene/therapeutic use*

Hyponatremia is a commonly observed complication that is related to hypoalbuminemia and portal hypertension in patients with advanced liver cirrhosis. Hyponatremia in patients with liver cirrhosis is mostly dilutional hyponatremia and is defined when the serum sodium concentration is below 130 meq/L. The risk of complications increases significantly in cirrhotic patients with hyponatremia, which includes spontaneous bacterial peritonitis, hepatorenal syndrome, and hepatic encephalopathy. In addition, hyponatremia is associated with increased morbidity and mortality in patients with cirrhosis, and is an important prognostic factor before and after liver transplantation. The conventional therapies of hyponatremia are albumin infusion, fluid restriction and loop diuretics, but these are frequently ineffective. This review investigates the pathophysiology and various therapeutic modalities, including selective vasopressin receptor antagonists, for the management of hyponatremia in patients with liver cirrhosis.
Antidiuretic Hormone Receptor Antagonists ; Fibrosis ; Hepatic Encephalopathy ; Hepatorenal Syndrome ; Humans ; Hypertension, Portal ; Hypoalbuminemia ; Hyponatremia* ; Liver Cirrhosis* ; Liver Transplantation ; Liver* ; Mortality ; Peritonitis ; Sodium ; Sodium Potassium Chloride Symporter Inhibitors

ObjectiveTo explore the antagonistic effect of vitamin E (VE) on male reproductive toxicity induced by di-2-ethylhexyl phthalate (DEHP) in pubertal SD rats and its underlying mechanisms.

METHODSThirty 5-week-old male SD rats were randomly divided into five groups of equal number, corn oil control, low-dose (10 mg/kg/d), medium-dose (100 mg/kg/d) and high-dose DEHP exposure (500 mg/kg/d), and VE intervention (high-dose DEHP + VE ［100 mg/kg/d］), and treated respectively for 30 successive days. At 3 days after treatment, the testes of the animals were harvested for determination of the oxidative stress index, serum reproductive hormone levels, cauda epididymal sperm parameters, and expressions of cell apoptosis-related genes and proteins.

RESULTSCompared with the control group, the rats of the medium- and high-dose DEHP groups showed significant decreases in the levels of such serum reproductive hormones as follicle-stimulating hormone (FSH), luteinizing hormone (LH) and testosterone (T), sperm parameters as average path velocity (VAP), straight line velocity (VSL), curvilinear velocity (VCL), straightness (STR), linearity (LIN) and wobble (WOB), and the activities of superoxide dismutase (SOD) and glutathione peroxide (GSH-Px), but significant increases were observed in the latter two groups in the content of malondialdehyde (MDA)(［3.32±0.87］ nmol/mg pro vs ［2.13±0.49］ nmol/ mg pro), mRNA expressions of Bad, Bax, Cytochrome C, Caspase-3 and the Bax/Bcl-2 ratio, and protein expressions of Cytochrome C and Caspase-3. In comparison with the high-dose DEHP group, the VE intervention group exhibited remarkably increased serum LH and T levels, sperm VAP, VSL, VCL, STR and WOB, and activities of SOD and GSH-Px, but markedly decreased mRNA expressions of Bad, Bax, Cytochrome C, Caspase-3 and the Bax/Bcl-2 ratio as well as the protein expressions of Cytochrome C and Caspase-3 in the testis tissue (P<0.05).

CONCLUSIONSExposure to DEHP induces androgen secretion disorders, causes oxidative damage to the testicular tissue, activates the mitochondrial apoptosis pathway in the testis, and ultimately reduces the quality of epididymal sperm, while VE can protect the rat testis from DEHP-induced reproductive toxicity.

Animals ; Antioxidants ; pharmacology ; Apoptosis ; genetics ; Autophagy-Related Protein 5 ; metabolism ; Caspase 3 ; metabolism ; Diethylhexyl Phthalate ; antagonists & inhibitors ; Epididymis ; Follicle Stimulating Hormone ; blood ; Luteinizing Hormone ; blood ; Male ; Malondialdehyde ; metabolism ; Mitochondria ; drug effects ; Oxidative Stress ; drug effects ; Oxidoreductases ; metabolism ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; Reproduction ; Spermatozoa ; drug effects ; physiology ; Superoxide Dismutase ; metabolism ; Testis ; drug effects ; Testosterone ; blood ; Vitamin E ; pharmacology

BACKGROUND: Adjuvant therapy after breast surgery, including tamoxifen or aromatase inhibitors, improves the postoperative outcomes and long-term survival of breast cancer patients. The aim of this study was to determine whether volume changes occurred in the contralateral breast during hormonal or other adjuvant therapies. METHODS: This study reviewed 90 patients who underwent unilateral breast reconstruction between September 2012 and April 2018 using tissue expanders and a permanent implant after the surgical removal of breast cancer. The volume of the contralateral breast was measured using a cast before the first (tissue expander insertion) and second (permanent implant change) stages of surgery. Changes in breast volume were evaluated to determine whether adjuvant therapy such as hormonal therapy, chemotherapy, and radiation therapy influenced the volume of the contralateral breast. RESULTS: The group receiving tamoxifen therapy demonstrated a significant decrease in volume compared with the group without tamoxifen (−7.8% vs. 1.0%; P=0.028). The aromatase inhibitor–treated group showed a significant increase in volume compared with those who did not receive therapy (−6.2% vs. 4.5%; P=0.023). There were no significant differences between groups treated with other hormonal therapy, chemotherapy, or radiation therapy. CONCLUSIONS: Patients who received tamoxifen therapy showed a significant decrease in volume in the contralateral breast, while no significant change in weight or body mass index was found. Our findings suggest that we should choose smaller implants for premenopausal patients, who have a high likelihood of receiving tamoxifen therapy.
Aromatase ; Aromatase Inhibitors ; Body Mass Index ; Breast Neoplasms ; Breast* ; Drug Therapy ; Female ; Hormone Antagonists ; Humans ; Mammaplasty* ; Reconstructive Surgical Procedures ; Surgery, Plastic ; Tamoxifen ; Tissue Expansion Devices

Glycogen synthase kinase3 (GSK3α and GSK3β) are serine/threonine protein kinases acting on numerous substrates and involved in the regulation of various cellular functions such as their proliferation, survival, glycogen metabolism, and autophagy. Accumulating evidence indicates that the expression of GSK3α is increased mainly in androgendependent while that of GSK3β in androgenindependent prostate cancer, and that GSK3β is also involved in the regulation of the transactivation of the androgen receptor (AR) and growth of prostate cancer. Animal experiments have proved that some GSK3 inhibitors, such as lithium, can significantly suppress tumor growth in different animal models of prostate cancer. The GSK3 inhibitor is promising to be an important agent for the clinical management of prostate cancer.
Androgens ; Animals ; Cell Line, Tumor ; Glycogen Synthase Kinase 3 ; antagonists & inhibitors ; metabolism ; Glycogen Synthase Kinase 3 beta ; antagonists & inhibitors ; metabolism ; Humans ; Male ; Neoplasm Proteins ; metabolism ; Neoplasms, Hormone-Dependent ; enzymology ; metabolism ; Prostatic Neoplasms ; drug therapy ; enzymology ; pathology ; Receptors, Androgen ; metabolism

Bipolar androgen therapy (BAT), as a new therapeutic strategy for castration-resistant prostate cancer (CRPC), can significantly reduce the level of prostate-specific antigen (PSA) for prostate cancer patients and has exhibited an excellent safety profile with no serious adverse events. Based on the clinical trials recently published at home and abroad, this article reviews the background, action mechanism, development, and prospect of BAT.
Androgen Antagonists ; therapeutic use ; Hormone Replacement Therapy ; methods ; Humans ; Male ; Prostate-Specific Antigen ; blood ; Prostatic Neoplasms, Castration-Resistant ; blood ; drug therapy ; Receptors, Androgen ; Testosterone ; administration & dosage ; blood

BACKGROUNDTwo recent whole-exome sequencing researches identifying somatic mutations in the ubiquitin-specific protease 8 (USP8) gene in pituitary corticotroph adenomas provide exciting advances in this field. These mutations drive increased epidermal growth factor receptor (EGFR) signaling and promote adrenocorticotropic hormone (ACTH) production. This study was to investigate whether the inhibition of USP8 activity could be a strategy for the treatment of Cushing's disease (CD).

METHODSThe anticancer effect of USP8 inhibitor was determined by testing cell viability, colony formation, apoptosis, and ACTH secretion. The immunoblotting and quantitative reverse transcription polymerase chain reaction were conducted to explore the signaling pathway by USP8 inhibition.

RESULTSInhibition of USP8-induced degradation of receptor tyrosine kinases including EGFR, EGFR-2 (ERBB2), and Met leading to a suppression of AtT20 cell growth and ACTH secretion. Moreover, treatment with USP8 inhibitor markedly induced AtT20 cells apoptosis.

CONCLUSIONSInhibition of USP8 activity could be an effective strategy for CD. It might provide a novel pharmacological approach for the treatment of CD.

Adrenocorticotropic Hormone ; metabolism ; Animals ; Apoptosis ; drug effects ; Cell Proliferation ; drug effects ; physiology ; Cell Survival ; drug effects ; physiology ; Endopeptidases ; metabolism ; Endosomal Sorting Complexes Required for Transport ; antagonists & inhibitors ; metabolism ; Enzyme Inhibitors ; pharmacology ; Humans ; Indenes ; pharmacology ; Mice ; Pyrazines ; pharmacology ; Receptor, Epidermal Growth Factor ; metabolism ; Ubiquitin Thiolesterase ; antagonists & inhibitors ; metabolism

OBJECTIVETo investigate the effect of the non-PLC-dependent protein kinase C (PKC) pathway of parathyroid hormone (PTH) on the apoptosis and proliferation of osteoblast MC-3T3E1 cells.

METHODSMC-3T3E1 cells were seeded in 96-well plates at the density of 1.5×10(4) cells/mL and incubated for 3 day. The cells were then exposed to 100 nmol/L of [Gly(1), Arg(19)]hPTH(1-28), 100 nmol/L of [Gly(1), Arg(19)]hPTH(1-34), 100 nmol/L of [Gly(1), Arg(19)]hPTH(1-34)+1 µmol/L Go6983, 1 µmol/L Go6983, or deionized water (control) for 1, 24 or 48 h. After the treatments, cell counting kit-8 (CCK-8) and Caspase-Glo® 3/7 Assay (Caspase-3) were used to examine the proliferation and apoptosis of MC3T3-E1 cells.

RESULTSCCK-8 results showed that hPTH(1-34) increased the number of MC3T3-E1 cells compared with hPTH(1-34)+Go6983 at 1 h and 24 h, but this difference was not statistically different. At 48 h, treatment with hPTH(1-34), as compared with hPTH(1-28), significantly increased the number of MC3T3-E1 cells (P<0.05), and this effect was blocked by the PKC inhibitor Go6983 (P<0.05). hPTH(1-34) did not result in significant inhibition of MC3T3-E1 cell apoptosis at 1 h and 24 h as compared with hPTH(1-34)+Go6983, but significantly inhibited the cell apoptosis as compared with hPTH(1-28) (P<0.05); this inhibitory effect was blocked by Go6983 (P<0.05).

CONCLUSIONs A relatively long time (for 48 h) of exposure to PTH can inhibit apoptosis and promote the proliferation of MC3T3-E1cells through a non-PLC-dependent PKC pathway.

3T3 Cells ; Animals ; Apoptosis ; Cell Proliferation ; Indoles ; pharmacology ; Maleimides ; pharmacology ; Mice ; Osteoblasts ; Parathyroid Hormone ; pharmacology ; Protein Kinase C ; antagonists & inhibitors ; metabolism ; Signal Transduction