Androgen receptor-mediated apoptosis in bovine testicular induced pluripotent stem cells in response to phthalate esters.

The androgen receptor (AR) has a critical role in promoting androgen-dependent and -independent apoptosis in testicular cells. However, the molecular mechanisms that underlie the ligand-independent apoptosis, including the activity of AR in testicular stem cells, are not completely understood. In the present study, we generated induced pluripotent stem cells (iPSCs) from bovine testicular cells by electroporation of octamer-binding transcription factor 4 (OCT4). The cells were supplemented with leukemia inhibitory factor and bone morphogenetic protein 4, which maintained and stabilized the expression of stemness genes and pluripotency. The iPSCs were used to assess the apoptosis activity following exposure to phthalate esters, including di (2-ethyhexyl) phthalates, di (n-butyl) phthalate, and butyl benzyl phthalate. Phthalate esters significantly reduced the expression of AR in iPSCs and induced a higher ratio of BAX/BCL-2, thereby favoring apoptosis. Phthalate esters also increased the expression of cyclin-dependent kinase inhibitor 1 (p21(Cip1)) in a p53-dependent manner and enhanced the transcriptional activity of p53. The forced expression of AR and knockdown of p21(Cip1) led to the rescue of the phthalate-mediated apoptosis. Overall, this study suggests that testicular iPSCs are a useful system for screening the toxicity of environmental disruptors and examining their effect on the maintenance of stemness and pluripotency, as well as for identifying the iPSC signaling pathway(s) that are deregulated by these chemicals.

Breast tumor-associated osteoblast-derived CXCL5 increases cancer progression by ERK/MSK1/Elk-1/snail signaling pathway.

The skeleton is the most common metastatic site for breast cancer, with bone metastasis causing pain as well as risk of pathological fractures. Interaction between tumors and the bone microenvironment creates a vicious cycle that accelerates both bone destruction and cancer progression. This study is the first to analyze the soluble factors secreted by breast tumor-associated osteoblasts (TAOBs), which are responsible for promoting cancer progression. The addition of CXCL5 (chemokine (C-X-C motif) ligand 5), present in large amounts in TAOB-condition medium (TAOB-CM), mimicked the inductive effect of TAOB-CM on breast cancer epithelial-mesenchymal transition, migration and invasion. In contrast, inhibition of CXCL5 in OBs decreased TAOB-mediated cancer progression. Inducement of MCF-7 and MDA-MB-231 cancer progression by TAOB-derived CXCL5 is associated with increased Raf/MEK/ERK activation, and mitogen- and stress-activated protein kinase 1 (MSK1) and Elk-1 phosphorylation, as well as Snail upregulation. Activation of Elk-1 facilitates recruitment of phosphorylated MSK1, which in turn enhances histone H3 acetylation and phosphorylation (serine 10) of Snail promoter, resulting in Snail enhancement and E-cadherin downregulation. Moreover, mice treated with anti-CXCL5 antibodies showed decreased metastasis of 4T1 breast cancer cells. Our study suggests that inhibition of CXCL5-mediated ERK/Snail signaling is an attractive therapeutic target for treating metastases in breast cancer patients.

Three-dimensional ultrasonographic assessment of compression effect on urethra following tension-free vaginal tape and transobturator tape procedures.

OBJECTIVE: To compare the anatomical difference using three-dimensional (3D) ultrasound between the urethra at rest and during straining, in women who have undergone a tension-free vaginal tape (TVT) or TVT-obturator tape (TVT-O) procedure for stress urinary incontinence (SUI). METHODS: We reviewed retrospectively 48 women with SUI who had undergone either a TVT (n = 24) or a TVT-O (n = 24) procedure. All women underwent urinalysis, pelvic examination, pad test, 3D perineal ultrasonography and personal interview about urinary symptoms within 1 year after surgery. RESULTS: After both TVT and TVT-O procedures, the area and longest and shortest diameters of the hypoechoic core of the mid-urethra were significantly smaller during straining than during resting (P < 0.01). The distance between tape and urethra was similarly smaller during straining in both groups. Analysis of ultrasound measurements in women reporting success (n = 40) and those reporting failure (n = 8) of the procedure showed the area and longest and shortest diameters of the hypoechoic core of the mid-urethra to be significantly smaller during straining than during resting in both groups (P < 0.01). However, the shortest diameter of the proximal and distal urethra during straining were significantly smaller only in the successful group (P < 0.01). CONCLUSION: There are differences in urethral morphology during straining compared with during resting in women with TVT and those with TVT-O, regardless of tape procedure. A urethral compression effect of slings may have an important role in the continence mechanism.

Suppression of cell-cycle progression by Jun dimerization protein-2 (JDP2) involves downregulation of cyclin-A2.

We report here a novel role for Jun dimerization protein-2 (JDP2) as a regulator of the progression of normal cells through the cell cycle. To determine the role of JDP2 in vivo, we generated Jdp2-knockout (Jdp2KO) mice by targeting exon-1 to disrupt the site of initiation of transcription. The epidermal thickening of skin from the Jdp2KO mice after treatment with 12-O-tetradecanoylphorbol 13-acetate (TPA) proceeded more rapidly than that of control mice, and more proliferating cells were found at the epidermis. Fibroblasts derived from embryos of Jdp2KO mice proliferated faster and formed more colonies than fibroblasts from wild-type mice. JDP2 was recruited to the promoter of the gene for cyclin-A2 (ccna2) at the AP-1 site. Cells lacking Jdp2 had elevated levels of cyclin-A2 mRNA. Furthermore, reintroduction of JDP2 resulted in the repression of transcription of ccna2 and of cell-cycle progression. Thus, transcription of the gene for cyclin-A2 appears to be a direct target of JDP2 in the suppression of cell proliferation.

Malignant mixed müllerian tumor of primary mesenteric origin associated with a synchronous ovarian cancer: case report and literature review.

Malignant mixed müllerian tumor (MMMT) is a rare tumor in females and extragenital MMMT is even more so. We report a patient with MMMT primarily in the mesentery with synchronous ovarian cancer. In the English literature, 42 cases of extragenital MMMT have been reported other than the presented case, and this is only the second MMMT arising from the mesentery. Furthermore, among the cases reviewed, MMMTs tend to be associated with synchronous or metachronous colonic cancer or gynecologic tumors originating from the müllerian duct, including ovarian tumors, fallopian tube cancer, endometrial cancer, cervical cancer, and serous carcinoma of the peritoneum (14 out of 43 patients; 32.6%). The risk factors for MMMT include obesity, nulliparity, exogenous estrogen, and long-term tamoxifen use. The prognosis of MMMT is catastrophic and the treatment is based on the experience of those of uterine sarcomas, which is composed of operation, radiotherapy and chemotherapy.

CYP17, CYP1A1 and COMT polymorphisms and the risk of adenomyosis and endometriosis in Taiwanese women.

BACKGROUND: The aim of the study was to test whether the COMT, CYP1A1 and CYP17 genes influence the risk of developing adenomyosis and endometriosis. METHODS: We conducted two case-control studies, where the cases (n = 198) had either of the two diseases, and controls (n = 312) were disease-free women. For the COMT gene, we selected the G/A nonsynonymous single-nucleotide polymorphism (SNP) that leads to valine-to-methionine (Val/Met) substitution. For the CYP1A1 gene, we used a functional T/C SNP in the 3'-noncoding region, and we genotyped a T/C functional SNP in the 5' region of the CYP17 gene for the present study. Hardy-Weinberg equilibrium was checked in both cases and controls. Logistic regression models were used to evaluate the genetic effect, with adjustment for other covariates. RESULTS: We found that the homozygous COMT genotype that encodes low enzyme activity had an increased risk for adenomyosis with an age-adjusted odds ratio of 3.2 (95% confidence interval 1.3-7.8; P = 0.006). The COMT gene, however, was not associated with endometriosis. Neither the CYP1A1 nor CYP17 genes had any significant association with either of the two diseases. CONCLUSION: The COMT gene significantly influences the risk of adenomyosis but not endometriosis. The present study does not provide evidence to support any of the three genes exerting pleiotropic effects on both diseases.

Effect of hormone replacement therapy on uterine fibroids in postmenopausal women--a 3-year study.

OBJECTIVE: The aim of this prospective 3-year clinical study was to examine the effect of hormone replacement therapy (HRT) on uterine fibroid growth among postmenopausal women. METHODS: Thirty-seven postmenopausal women with uterine solitary fibroids were recruited randomly for HRT in a 3-year program. All participants received 0.625 mg conjugated equine estrogen (CEE) and 5 mg medroxyprogesterone (MPA) daily. Fibroid volume was measured by transvaginal ultrasonography at baseline and then at 12-month intervals for 3 times. Clinically, significant fibroid growth was defined as an increase in volume of more than 25% compared with baseline. Also, 35 postmenopausal women with uterine fibroid were studied as control who did not receive HRT during the study period. RESULTS: Fibroid volume had increased significantly after 1 year both in HRT users and non-users. These increases continued to the second year significantly in HRT users but not in non-users. However, the volumes declined significantly at the third year to similar levels as those measured at baseline in control. In HRT users, fibroid volume though significantly increased at the third year (vs. baseline) but declined insignificantly in comparison with the second year. Clinically, at end of the third year study, one of 34 and three of 34 women increased fibroid volume over 25% compared with baseline in HRT non-users and users, respectively. CONCLUSIONS: HRT does increase uterine fibroid volume statistically. However, its effect appears in the first 2 years of use. The increased fibroid volume begins to decline at the third year both in HRT users and non-users. Clinically, the increased effect of HRT on uterine fibroid of postmenopausal women should be not over-emphasized at least for 3 years of usage.

Akt activation by estrogen in estrogen receptor-negative breast cancer cells.

It has been a common belief that estrogen regulates cellular responses through binding to its receptor, the estrogen receptor (ER). In the nucleus, estrogen modulates the expression of estrogen-responsive genes through the action of the ER at the transcriptional level. In the cytoplasm, the ER-dependent signaling pathway has been shown to be involved in the activation of Akt and the downstream molecules. It is not clear, however, whether estrogen can modulate cytoplasmic signaling in an ER-independent manner. Human breast cancer cell lines without detectable ERs such as MDA-MB-435 and MDA-MB-231 were treated in estrogen-depleted medium followed by a brief treatment with estrogen. The activation of Akt was evaluated by a phosphoserine antibody. Our results showed that estrogen stimulated Akt activation, as indicated by phosphorylation at Ser(473) of the oncoprotein, in ER-negative breast cancer cells. Activation of Akt by estrogen in these cells was time and dose dependent and could be blocked by inhibitors of phosphatidylinositol 3'-kinase and Src kinase but not by estrogen antagonists. Our results provide evidence as well as the mechanism of the receptor-independent function of estrogen, in which the antiapoptotic factor Akt is activated.

E1A inhibition of radiation-induced NF-kappaB activity through suppression of IKK activity and IkappaB degradation, independent of Akt activation.

Activation of the transcription factor nuclear factor kappaB (NF-kappaB) has been implicated in the protection of cells from apoptosis. We have shown previously that the adenovirus type 5 E1A sensitizes cells to radiation-induced apoptosis by inhibiting NF-kappaB activity. However, the exact mechanism of inhibition is not known. In this study, we compared the activity of inhibitor of nuclear factor-kappaB (IkappaB) kinase (IKK) and the degradation of IkappaBalpha in E1A transfectants and parental human cancer cells after ionizing radiation treatment. We found that radiation-induced IKK activity and IkappaBalpha degradation were inhibited in the E1A transfectants. Recently, Akt has been implicated in NF-kappaB activation. To test whether Akt is regulated by E1A and is involved in radiation-induced NF-kappaB activity, we examined the phosphorylation status of Akt in the E1A transfectants and parental cells and in irradiated cells. The results indicated that radiation induced Akt phosphorylation and that E1A inhibited basal but not radiation-induced Akt phosphorylation. We additionally examined radiation-induced NF-kappaB activity in cells stably transfected with a dominant-negative, inactive Akt and in parental cancer cells treated with a phosphatidylinositol 3-kinase inhibitor, wortmannin. We found that dominant-negative Akt and wortmannin did not block radiation-induced NF-kappaB activity. Thus, our results suggest that inhibition of IKK activity and IkappaB degradation is the predominant mechanism for E1A-mediated inhibition of radiation-induced NF-kappaB activity and that radiation-induced Akt activation cannot be inhibited by E1A and is likely independent of radiation-induced NF-kappaB activity.

A case of pulmonary endometriosis--a rare case report and a successful treatment experience.

Endometriosis is a common disease found in reproductive age women, but pulmonary endometriosis is rare. We present a 21-year-old female with catamenial chest pain, chest tightness, severe cough, and hemoptysis. Though we could not find any definite intrapulmonary endometriotic lesion by computed tomography and bronchoscope, she was diagnosed to have pulmonary endometriosis due to the typical clinical symptoms. After 6 months of GnRH agonist application, the symptoms were completely relieved. She has been followed up and has been symptoms free for at least 6 months after administration of GnRH agonist.

Weekly and monthly regimens of paclitaxel and carboplatin in the management of advanced ovarian cancer. A preliminary report on side effects.

This preliminary study was carried out over 18 months to evaluate whether the side effects in patients with advanced ovarian cancer receiving chemotherapy using paclitaxel-carboplatin differed between weekly (98 cycles in 14 patients) and monthly (102 cycles in 15 patients) administrations. We used paclitaxel (60 mg/m2) and carboplatin (AUC of 2) in the weekly regimen and 175 mg/m2 of paclitaxel and carboplatin (AUC of 6) in the monthly regimen. All eligible patients received at least four cycles of treatment in both regimens. The results revealed significantly decreased hematological toxicity in weekly regimens relative to monthly ones, ie, 7.1% vs. 18.6% of anemia (> or = grade 2), 7.1% vs. 32.3% of grade 3/4 granulocytopenia, and 0% vs. 15.7% of >grade 2 thrombocytopenia. There was no significant difference in nonhematological toxicities between the two regimens. The incidence of unscheduled events was much less in the weekly regimen than in the monthly one; ie, delayed treatment (3 vs. 18 events), unanticipated hospitalizations (3 vs. 15 times), and supplemental support with G-CSF (7 vs. 33 times). Complete responses were observed in 6 of 14 patients in the weekly regimen and in five of 15 patients in the monthly regimen, while partial responses were seen in four and five patients in the weekly and monthly regimens, respectively. The present results demonstrate that the weekly regimen can achieve the benefits of tolerable toxicity with significantly reduced myelosuppression and improved cost-effectiveness in terms of unscheduled events.

Laparoscopically assisted vaginal hysterectomy using the light-endorsed transvaginal section technique versus the conventional method: a preliminary study.

Laparoscopically assisted vaginal hysterectomy (LAVH) is now being used by an increasing number of gynecologists. However, problems, such as the long operating time, the inherent difficulty of the technique, and limitations of the skills of the surgeons, still exist. Pelvic adhesion, especially in the vesicouterine reflection, may increase the difficulty and morbidity of the operation. We here describe a simple technique, called light-endorsed transvaginal section (LETS), which can facilitate the effectiveness and safety of LAVH. We have designed prospective studies to compare results obtained in 50 cases treated using LAVH plus LETS (study group) with those obtained in 50 cases treated by conventional LAVH (control group). We further divided the study group into 25 'complicated' cases (with pelvic adhesion) and 25 'easy' cases (without pelvic adhesion). The results show that the LETS technique is a simple, safe, and easy way of increasing the efficacy of LAVH, especially as a supplement to LAVH in the presence of pelvic adhesions.

A mullerian duct remnant myoma misdiagnosed as ovarian cancer in a woman with vaginal agenesis--a case report.

Leiomyoma are very common in the normal uterus; however, they are rather rare in mullerian duct remnant. We report a case of mullerian duct remnant leiomyoma associated with vaginal agenesis. The mass had papillary growth with cystic-solid components by ultrasound. Ovarian cancer was suspected preoperatively. Finally, a fibroid with hyalinization and chondroid metaplasia was diagnosed histopathologically. To the best of our knowledge, this is the first case of mullerian duct remnant leiomyoma with degeneration, mimicking ovarian cancer by ultrasound. We provide the clinical details of this case and discuss a diagnostic pitfall.

A huge pancreatic cystic adenoma misdiagnosed as an ovarian cyst.

Pancreatic cyst mimicking an ovarian cyst ultrasonographically has not yet been reported. We report an elderly woman with such a huge pancreatic cyst whose initial presentation was low abdominal pain. Ultrasound showed a hypoechoic cyst measuring 13.6 x 13.2 x 11.8 cm occupying pelvic cavity. She received laparotomy under the impression of ovarian cyst. Interestingly, the cyst was found to have originated from the pancreas. Total cyst excision was performed and pathologic report was pancreatic microadenoma. The patient's postoperative course was unremarkable.

Correlation of arterial and end-tidal carbon dioxide in spontaneously breathing patients during ambulatory gynecologic laparoscopy.

Laparoscopy can be performed while patients are under total intravenous anesthesia (TIVA), or sedated and breathing spontaneously through the normal airway. Respiratory monitoring is difficult when patients are sedated or anesthetized, however. The purposes of this study were to evaluate the reliability of end-tidal carbon dioxide (ETCO2) measurement for monitoring arterial carbon dioxide pressure (PaCO2), and to assess the PaCO2/ETCO2 gradient among patients receiving TIVA while breathing spontaneously through the normal airway. Sixty patients were divided into two groups: group 1 patients (n = 30) received general anesthesia with controlled ventilation, while group 2 patients (n = 30) received TIVA with spontaneous breathing through the normal airway; ETCO2 was sampled through a 10-French suction catheter inserted into the nasopharynx via the nasal airway. Arterial blood gas and ETCO2 were recorded at the time of preinduction, induction, CO2 insufflation, and change to Trendelenburg tilt position (20 degrees-30 degrees), and at 10-minute intervals thereafter. The results showed that ETCO2 was highly correlated with PaCO2 in group 1 (correlation coefficient r = 0.85), but not in group 2 (r = 0.55). In group 2, the PaCO2/ETCO2 gradient increased as time elapsed, with significant differences (p < 0.05) between the values at induction and those at 30 minutes after the change to the Trendelenburg position and thereafter. These results indicate that the ETCO2 and PaCO2 values correlate well during the first 20 minutes after the change to the Trendelenburg position in laparoscopy patients receiving TIVA with spontaneous breathing, but that PaCO2 monitoring is still necessary.

The experiences of rectosigmoid pouch as a continent urinary diversion after radical cystectomy.

Thirty-five patients receiving cystectomy underwent rectosigmoid pouch. The technique of ureteral submucous implantation was described. The follow-up results were analyzed. The relationship of postoperative voiding frequency and preoperative anal closure pressure was assessed. The day and night time continence rate is 97% (34/35). There were no hydronephrosis, no ureterocolonic stricture or reflux. The complications are not unique to rectosigmoid pouch and not high when compared with other forms of urinary diversion. When the preoperative anal closure pressure reaches nearly 100 cmH2O a postoperative outcome with good quality of life will be predicted. With the advantages of high continence rate and simplicity of performance the rectosigmoid pouch will become one of the alternative forms of continent urinary diversion. For obtaining the favorable results a patient with normal renal function, good hepatic function and anal closure pressure more than 50 cmH2O is required.

Hysteroscopic resection of vaginal septum in an adolescent virgin with obstructed hemivagina.

This article reports on one patient with a double uterus, unilateral vaginal obstruction, with hemi-haematocolpos and ipsilateral renal agenesis. Early accurate diagnosis followed by the excision of the obstructing vaginal septum offers complete relief of symptoms, while preserving reproductive capacity. Unlike conventional excision of vaginal septum, we used resectoscope excision with cutting electrode under continuous pure distilled water irrigation. The postoperative course was uneventful, and haematocolpos and severe dysmenorrhoea disappeared. The resected vaginal area revealed re-epithelialization by hysteroscope follow-up one year after resection. With advancements in resectoscopic operation, evaluation and treatment of vaginal disorders in babies and virgins is very feasible.

Adenosine-stimulated intracellular calcium increase in cultured human uterine myocyte.

The effect of adenosine on intracellular free calcium concentration ([Ca2+]i) was studied in human uterine myocyte. Adenosine 10(-6) M elicited a rapid followed by a maintained increase in [Ca2+]i in Fluo-3-loaded myocytes. Compared with basal [Ca2+]i level, adenosine induced a 2.6-fold increase in the absence of extracellular calcium, and a 2.4-fold increase in the presence of extracellular calcium. There was no significant difference between the two groups in the initial response. After depletion of intracellular calcium stores by repetitive caffeine (10 mM) applications, adenosine could not induce increase in [Ca2+]i. The initial rise could be induced in the absence of extracellular calcium, whereas the maintained phase after 120 s of adenosine application was dependent on the presence of extracellular calcium. The maintained phase response was 1.39- and 0.90-fold compared with basal [Ca2+]i level in the presence and absence of extracellular calcium respectively. There was significant (p < 0.01) maintenance of [Ca2+]i in the presence of extracellular calcium, which appeared to be associated with calcium influx. The data suggest that in human uterine myocytes, adenosine stimulates release of Ca2+ from intracellular stores and influx of extracellular Ca2+ through Ca2+ entry pathway.

Pilot study of transurethral needle ablation (TUNA) in treatment of nonbacterial prostatitis.

Transurethral needle ablation (TUNA) was performed on seven patients with chronic nonbacterial prostatitis who failed to respond to conventional treatments administered for more than half a year. The TUNA procedure heated the prostate to a temperature ranging from 90 degrees to 100 degrees C while the urethral temperature was maintained below 43 degrees C by a protective sheath and irrigation. After treatment, four patients showed complete resolution of symptoms and three a partial improvement. All patients had a decrease in the leukocyte count in expressed prostatic secretions (EPS) 1 month after treatment. Recurrence of abnormal inflammatory cells in the EPS was noted in two patients at 3 months after treatment. The subjective improvement has been maintained during the subsequent follow-up. From these results, TUNA is considered to be an effective, safe, and easy treatment for most patients with nonbacterial prostatitis.

Transurethral needle ablation of the prostate (TUNA) in the treatment of chronic urinary retention.

The transurethral needle ablation (TUNA) of the prostate was performed in 8 patients in chronic urinary retention, all of whom were a poor surgical risk. A special catheter device was used to deliver low-level radiofrequency energy to heat tissue within the prostate to 100 degrees C. After treatment, uroflowmetry, symptom score and quality of life score were evaluated. Tolerance of the procedure with topical anesthesia was satisfactory. Of the 8 patients, 6 (75%) resumed voiding within a mean time of 9.2 days (range 1-21). The mean maximal flow rate was 9.8 +/- 3.2 ml/s (range 5.9-14). Failure to void was associated with a decompensated detrusor function. We conclude that TUNA is effective for patients with urinary retention due to benign prostatic hyperplasia. It seems particularly suitable for treating elderly patients with a high surgical risk.