Functional polymorphism in H2BFWT-5'UTR is associated with susceptibility to male infertility.

H2B histone family, member W, testis-specific (H2BFWT) gene encodes a testis-specific histone that becomes incorporated into sperm chromatin. A male infertility-associated single nucleotide polymorphism (-9C > T) within the 5' untranslated region (5'UTR) of the H2BFWT gene was identified by direct sequencing. Statistical association studies showed the polymorphism significantly associated with male infertility (n = 442, P = 0.0157), especially in non-azoospermia (n = 262, P = 0.018). Furthermore, this polymorphism is also associated with sperm parameters, especially sperm count (n = 164, P = 0.0127) and vitality (n = 164, P = 0.0076). We investigated how the genetic variant at 5'UTR confers susceptibility to non-azoospermia. Western blotting of His-tag H2BFWT revealed a difference at the translational level between -9T and the wild-type -9C in the absence of change at the transcriptional level. Reporter assays showed that this reducing translational change originated from an upstream open reading frame (uORF) generated by the -9C to -9T change. Finally, in vivo H2BFWT expression in sperm was significantly dependent on the -9C > T genotype from non-azoospermia (P = 0.0061). Therefore, this polymorphism could affect the translational efficiency of a quantitatively important histone protein by the uORF. Our data implicate H2BFWT as a susceptibility factor for male infertility, possibly with other genetic and environmental factors.

Synergistic Activity of Paclitaxel, Sorafenib, and Radiation Therapy in advanced Renal Cell Carcinoma and Breast Cancer.

Advanced cancer has been shown to be associated with a higher percentage of epigenetic changes than with genetic mutations. Preclinical models have shown that the combination of paclitaxel, sorafenib, and radiation therapy (RT) plays a crucial role in renal cell carcinoma (RCC) and breast cancer. This study aimed to investigate the involvement of mitochondrial cytochrome c-dependent apoptosis in the mechanism of action of a combination of paclitaxel, sorafenib, and RT in RCC and breast cancer. RCC and breast cancer cell lines were exposed to paclitaxel and sorafenib alone or combined in the presence of radiation, and cell viability was determined using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. The synergistic anticancer effects of the combination therapy on cell cycle and intracellular signaling pathways were estimated using flow cytometry and immunoblot analysis. RCC and breast cancer cell line xenograft models were used to examine the antitumor activity in vivo. Our results suggest that paclitaxel, sorafenib, and RT synergistically decreased the viability of RCC and breast cancer cells and significantly induced their apoptosis, as shown by caspase-3 cleavage. Paclitaxel, sorafenib, and radiation cotreatment reduced antiapoptotic factor levels in these cells and, thereby, significantly reduced the tumor volume of RCC and breast cancer cell xenografts. The current study suggests that paclitaxel, sorafenib, and radiation cotreatment was more effective than cotreatment with paclitaxel or sorafenib and radiation. These findings may offer a new therapeutic approach to RCC and breast cancer.

Comparing epidural surgical anesthesia and spinal anesthesia following epidural labor analgesia for intrapartum cesarean section: a prospective randomized controlled trial.

BACKGROUND: The conversion of epidural labor analgesia (ELA) to epidural surgical anesthesia (ESA) for intrapartum cesarean section (CS) often fails, resulting in intraoperative pain. Spinal anesthesia (SA) can provide a denser sensory block than ESA. The purpose of this prospective, non-blinded, parallel-arm, randomized trial was to compare the rate of pain-free surgery between ESA and SA following ELA for intrapartum CS. METHODS: Both groups received continuous epidural infusions for labor pain at a rate of 10 ml/h. In the ESA group (n = 163), ESA was performed with 17 ml of 2% lidocaine mixed with 100 µg fentanyl, 1 : 200,000 epinephrine, and 2 mEq bicarbonate. In the SA group (n = 160), SA was induced with 10 mg of 0.5% hyperbaric bupivacaine and 15 µg fentanyl. We investigated the failure rate of achieving pain-free surgery and the incidence of complications between the two groups. RESULTS: The failure rate of achieving pain-free surgery was higher in the ESA group than the SA group (15.3% vs. 2.5%, P < 0.001). There was no statistical difference between the two groups in the rate of conversion to general anesthesia; however, the rate of analgesic requirement was higher in the ESA group than in the SA group (12.9% vs. 1.3%, P < 0.001). The incidence of high block, nausea, vomiting, hypotension, and shivering and Apgar scores were comparable between the two groups. CONCLUSIONS: SA after ELA can lower the failure rate of pain-free surgery during intrapartum CS compared to ESA after ELA.

The association of 4a4b polymorphism of endothelial nitric oxide synthase (eNOS) gene with the sperm morphology in Korean infertile men.

OBJECTIVE: To investigate the association between three polymorphism sites of endothelial nitric oxide synthase (eNOS; -786T>C, 4a4b, and 894G>T) with nonobstructive male infertility. DESIGN: Prospective case-control study. SETTING: University-based hospital. PATIENT(S): Three hundred seventy-one nonobstructive infertile men in azoospermia (n = 184) or ejaculate semen (n = 187) group were enrolled in this study. Two hundred twenty fertile men who had at least one child without any history of requiring assisted reproductive technology were included as the nationwide control group. INTERVENTION(S): Semen analysis according to the World Health Organization guidelines and cytogenetic and Y chromosome microdeletion assay. MAIN OUTCOME MEASURE(S): Three eNOS polymorphisms were investigated to assess its association with male infertility by pyrosequencing and gel electrophoresis. RESULT(S): The statistical analysis of three eNOS polymorphisms showed no significant association between the polymorphisms of the control and infertile group. We investigated the sperm parameters depending on the genotypes of the ejaculate semen group. The sperm morphology was found to be significantly associated with the 4a4b polymorphism of eNOS. CONCLUSION(S): Endothelial nitric oxide synthase may be important to sperm morphology in infertile men.

Preliminary analysis of the G178A polymorphism of insulin-like factor 3 in male infertility.

We investigated the association of nonsynonymous insulin-like factor 3 (INSL3) G178A polymorphism with nonobstructive male infertility. The common INSL3 G178A polymorphism was not statistically significantly associated with male infertility (P>.05), even though INSL3 is essential for the occurrence of bilateral cryptorchidism.