Cell suspension culture extract of Eriobotrya japonica attenuates growth and induces apoptosis in prostate cancer cells via targeting SREBP-1/FASN-driven metabolism and AR.

BACKGROUND: Castration-resistant prostate cancer (CRPC) is one of the main causes of male cancer mortality. There is currently no effective treatment to cure this deadly prostate cancer (PCa) progression. However, recent research showed that activation of lipogenesis leads to CRPC progression. It provides a rationale to target the highly lipogenic activity as a novel and promising therapy against lethal CRPC. PURPOSES: The present study aims to evaluate the anticancer efficacy and the molecular mechanism of cell suspension culture extract from Eriobotrya japonica (EJCE) in PCa, including CRPC. METHODS: Cell growth, migration and invasion analyses were performed by MTT method, a wound healing assay and the transwell method, respectively. Apoptosis was assessed by a flow cytometry-based Annexin V-FITC/PI assay, caspase enzymatic activity and Western blot analyses. Lipogenesis was determined by a Fatty Acid Quantification Kit and an Oil Red O staining. The in vivo experiment was conducted by a xenograft mouse model. RESULTS: PCa cell growth, migration and invasion were significantly affected by EJCE. EJCE decreased expression of sterol regulatory element-binding protein-1 (SREBP-1) and fatty acid synthase (FASN) in PCa cells, two main factors for lipogenesis. By inhibiting SREBP-1/FASN, EJCE reduced the intracellular fatty acid levels and lipid droplet accumulation in PCa. Moreover, EJCE down-regulated the androgen receptor (AR) and prostate-specific antigen (PSA) in PCa cells. Significantly, EJCE exhibited the potential anticancer activity by suppressing the growth and leading to apoptosis of CRPC tumors in a xenograft mouse model. CONCLUSION: These results reveal a novel therapeutic molecular mechanism of EJCE in PCa. Blockade of SREBP-1/FASN-driven metabolism and AR by EJCE could be employed as a potent opportunity to cure malignant PCa.

Is maternal serum inhibin A a good predictor in preterm labor? - Experience from a community hospital in Taiwan.

BACKGROUND: We aimed to determine whether inhibin A could be a reliable and accurate predictor of preterm birth, and discuss the possible pathogenic processes of inhibin A leading to preterm birth. METHODS: A retrospective cohort study was conducted on consecutive singleton pregnant women who underwent the second-trimester quad screen test at a gestational age of 15-20 weeks at Keelung Chang-Gung Memorial Hospital from March 2011 to May 2015. Data including maternal characteristics and pregnancy outcomes were collected from an electric medical record database. Data regarding pregnancy terminations before a gestational age of 24 weeks and regarding pregnancies that involved chromosomal or congenital anomalies were excluded from this analysis. One-way analysis of variance was used to compare second-trimester α-fetoprotein, human chorionic gonadotropin, unconjugated estriol, and inhibin A in women with preterm deliveries versus those with term deliveries. RESULTS: Although a total of 935 women with singleton pregnancies were enrolled, pregnancy outcome and complete maternal data were obtained from only 770 (82.3%)of them. In total, 687 (89.2%) women delivered at or after 37 weeks of gestation and 83 (10.8%) women delivered before 37 weeks of gestation. The results showed that the inhibin A level was significantly increased in the preterm labor group (p = 0.009). A cutoff inhibin A value above 2.25 was identified statistical significantly in the preterm labor group. CONCLUSIONS: From our results, an inhibin A level above 2.25 multiples of the median in the quad screen test may be associated with preterm labor afterward. Closely monitoring for uterine contractions or cervical length measurement in the second trimester may be indicated in patients with unexplained elevated inhibin A levels.

Emerging Therapeutic Activity of Davallia formosana on Prostate Cancer Cells through Coordinated Blockade of Lipogenesis and Androgen Receptor Expression.

BACKGROUND: Prostate cancer (PCa) is the most prevalent malignancy diagnosed in men in Western countries. There is currently no effective therapy for advanced PCa aggressiveness, including castration-resistant progression. The aim of this study is to evaluate the potential efficacy and determine the molecular basis of Davallia formosana (DF) in PCa. Methods: LNCaP (androgen-sensitive) and C4-2 (androgen-insensitive/castration-resistant) PCa cells were utilized in this study. An MTT-based method, a wound healing assay, and the transwell method were performed to evaluate cell proliferation, migration, and invasion. Intracellular fatty acid levels and lipid droplet accumulation were analyzed to determine lipogenesis. Moreover, apoptotic assays and in vivo experiments were conducted. RESULTS: DF ethanol extract (DFE) suppressed proliferation, migration, and invasion in PCa cells. DFE attenuated lipogenesis through inhibition of the expression of sterol regulatory element-binding protein-1 (SREBP-1) and fatty acid synthase (FASN). Moreover, DFE decreased androgen receptor (AR) and prostate-specific antigen (PSA) expression in PCa cells. We further showed the potent therapeutic activity of DFE by repressing the growth and leading to apoptosis of subcutaneous C4-2 tumors in a xenograft mouse model. CONCLUSIONS: These data provide a new molecular basis of DFE in PCa cells, and co-targeting SREBP-1/FASN/lipogenesis and the AR axis by DFE could be employed as a novel and promising strategy for the treatment of PCa.

Decreased placental apoptosis and autophagy in pregnancies complicated by gestational diabetes with large-for-gestational age fetuses.

INTRODUCTION: Dysregulation of placental apoptosis and autophagy are observed in pregnancy complications including preeclampsia and fetal growth restriction. However, studies of their changes in the placentas of women with gestational diabetes mellitus (GDM) show inconsistent results. We aimed to compare the changes in apoptosis, autophagy, and Bcl-2 family proteins in the placentas from women with normal pregnancies and those with GDM, with or without large-for-gestational age (LGA) infants and to investigate the effect of hyperglycemia on the changes in apoptosis, autophagy, and Bcl-2 family proteins in primary cytotrophoblastic cells. METHODS: Villous tissues were obtained from normal pregnant women and those with GDM, with or without LGA infants. Primary cytotrophoblast cells were isolated from normal term placentas and cultured under standard, hyperglycemic, or hyperosmotic conditions. RESULTS: Compared to placentas from normal pregnant women, those from GDM women with LGA infants were heavier, had lower beclin-1 and DRAM levels, less M30 and cleaved PARP immunoreactivity, and increased Ki-67 immunoreactivity. These changes were associated with increased Bcl-xL and decreased Bak levels. Increased glucose concentration led to lower ATG5, beclin-1, LC3B-II, p62, and DRAM levels, lower annexin V and M30-positive cell percentages, and less cleaved PARP changes compared with standard culture conditions. Hyperglycemia caused higher Bcl-xL levels and lower Bak and Bad levels than did standard culture conditions. DISCUSSION: There were differential changes in apoptosis and autophagy between placentas from normal pregnant women and those from GDM women with LGA infants. Bcl-2 family proteins are likely involved in the regulation of these changes.

Chinese Herbal Medicine Ganoderma tsugae Displays Potential Anti-Cancer Efficacy on Metastatic Prostate Cancer Cells.

Resistance to the current therapies is the main clinical challenge in the treatment of lethal metastatic prostate cancer (mPCa). Developing novel therapeutic approaches with effective regimes and minimal side effects for this fatal disease remain a priority in prostate cancer study. In the present study, we demonstrated that a traditional Chinese medicine, quality-assured Ganoderma tsugae ethanol extract (GTEE), significantly suppressed cell growth and metastatic capability and caused cell cycle arrest through decreasing expression of cyclins in mPCa cells, PC-3 and DU145 cells. GTEE also induced caspase-dependent apoptosis in mPCa cells. We further showed the potent therapeutic efficacy of GTEE by inhibiting subcutaneous PC-3 tumor growth in a xenograft model. The in vitro and in vivo efficacies on mPCa cells were due to blockade of the PI3K/Akt and MAPK/ERK signaling pathways associated with cancer cell growth, survival and apoptosis. These preclinical data provide the molecular basis for a new potential therapeutic approach toward the treatment of lethal prostate cancer progression.

Osajin displays potential antiprostate cancer efficacy via impairment of fatty acid synthase and androgen receptor expression.

BACKGROUND: Currently, antiprostate cancer (PCa) drugs, including androgen deprivation therapy (ADT), are initially effective; however, most patients with PCa who receive ADT eventually progress to deadly aggressiveness. There is an urgent need to seek alternative strategies to cure this lethal disease. Activation of lipogenesis has been demonstrated to lead to PCa progression. Therefore, targeting the aberrant lipogenic activity could be developed therapeutically in PCa. The aim of this study is to investigate the molecular basis and efficacy of osajin, a bioactive prenylated isoflavonoid, in PCa. METHODS: PCa cells, LNCaP (androgen-sensitive) and C4-2 (androgen-insensitive/castration-resistant), were used in this study. Proliferation, migration, and invasion analyses were conducted by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method, a wound healing assay, and the transwell method. Lipogenesis was determined by a Fatty Acid Quantification Kit and oil red O staining. Apoptosis was assessed by annexin V-fluorescein isothiocyanate/propidium iodide staining, caspase enzymatic activity, and Western blot analyses. RESULTS: Osajin inhibited fatty acid synthase (FASN) expression, a key enzyme for lipogenesis, in PCa cells. By inhibiting FASN, osajin decreased the fatty-acid levels and lipid accumulation. Significantly, osajin downregulated androgen receptor (AR) and prostate-specific antigen (PSA) in PCa cells. Moreover, osajin suppressed PCa cell growth, migration, and invasion. Through activation of the caspase-dependent pathway, osajin induced apoptosis in PCa cells. CONCLUSIONS: These data provide a novel molecular basis of osajin in PCa cells, and cotargeting lipogenesis and the AR axis via impairment of FASN and AR expression by osajin could be applied as a new and promising approach for the treatment of malignant PCa.

Primary signet ring cell carcinoma of the cervix: A case report with review of the literature.

OBJECTIVE: Primary cervical signet ring cell carcinoma (PCSRCC) is extremely rare. In this paper, we describe a Case presenting with PCSRCC. CASE REPORT: The 48-year-old woman visited the gynecological department because of postmenopausal bleeding. A cervical mass was discovered through pelvic examination, and the biopsy results indicated a poorly differentiated adenocarcinoma with a signet ring cell pattern. Colonoscopy revealed external compression of the rectum without intraluminal mucosal lesions. Abdominal computed tomography revealed a suspicious malignant lesion at the cervicorectal junction and multiple metastases. Debulking surgery was performed and the final pathology report documented a FIGO stage IVb PCSRCC involving multiple sites. CONCLUSION: Complete tumor survey and staging are critical to differentiate primary from metastatic signet cell carcinoma of the cervix. Immunohistochemical studies cannot provide precise information. Because cases are rare, it is difficult to determine the proper treatment guidelines and prognosis.

Primary signet ring cell carcinoma of the cervix: A case report with review of the literature.

OBJECTIVE: Primary cervical signet ring cell carcinoma (PCSRCC) is extremely rare. In this paper, we describe a case presenting with PCSRCC. CASE REPORT: The 48-year-old woman visited the gynecological department because of postmenopausal bleeding. A cervical mass was discovered through pelvic examination, and the biopsy results indicated a poorly differentiated adenocarcinoma with a signet ring cell pattern. Colonoscopy revealed external compression of the rectum without intraluminal mucosal lesions. Abdominal computed tomography revealed a suspicious malignant lesion at the cervicorectal junction and multiple metastases. Debulking surgery was performed and the final pathology report documented a FIGO stage IVb PCSRCC involving multiple sites. CONCLUSION: Complete tumor survey and staging are critical to differentiate primary from metastatic signet cell carcinoma of the cervix. Immunohistochemical studies cannot provide precise information. Because cases are rare, it is difficult to determine the proper treatment guidelines and prognosis.

Ganoderma tsugae Inhibits the SREBP-1/AR Axis Leading to Suppression of Cell Growth and Activation of Apoptosis in Prostate Cancer Cells.

Recent research suggests that the activation of lipid biosynthesis (lipogenesis) is linked with prostate cancer (PCa) malignancy. Sterol regulatory element-binding protein-1 (SREBP-1) is a key transcriptional regulator controlling lipogenesis. Moreover, androgen receptor (AR) has been well defined to play an important role in lethal PCa aggressiveness from androgen-responsive to castration-resistant status. In this study, we showed that the quality-assured Ganoderma tsugae ethanol extract (GTEE), a Chinese natural and herbal product, significantly inhibited expression of SREBP-1 and its downstream genes associated with lipogenesis in PCa cells. Through inhibiting SREBP-1, GTEE reduced the levels of intracellular fatty acids and lipids in PCa cells. Importantly, GTEE also downregulated the expression of AR and prostate-specific antigen (PSA) in both androgen-responsive and castration-resistant PCa cells. By blocking the SREBP-1/AR axis, GTEE suppressed cell growth and progressive behaviors, as well as activating the caspase-dependent apoptotic pathway in PCa cells. These data provide a new molecular basis of GTEE for the development of a potential therapeutic approach to treat PCa malignancy.

Phthalate exposure promotes chemotherapeutic drug resistance in colon cancer cells.

Phthalates are widely used as plasticizers. Humans can be exposed to phthalates through ingestion, inhalation, or treatments that release di(2-ethylhexyl) phthalate (DEHP) and its metabolite, mono(2-ehylhexyl) phthalate (MEHP), into the body from polyvinyl chloride-based medical devices. Phthalate exposure may induce reproductive toxicity, liver damage, and carcinogenesis in humans. This study found that colon cancer cells exposed to DEHP or MEHP exhibited increased cell viability and increased levels of P-glycoprotein, CD133, Bcl-2, Akt, ERK, GSK3ß, and ß-catenin when treated with oxaliplatin or irinotecan, as compared to control. The P-glycoprotein inhibitor, tariquidar, which blocks drug efflux, reduced the viability of DEHP- or MEHP-treated, anti-cancer drug-challenged cells. DEHP or MEHP treatment also induced colon cancer cell migration and epithelial-mesenchymal transformation. Elevated stemness-related protein levels (ß-catenin, Oct4, Sox2, and Nanog) and increased cell sphere sizes indicated that DEHP- or MEHP-treated cells were capable of self-renewal. We also found that serum DEHP concentrations were positively correlated with cancer recurrence. These results suggest phthalate exposure enhances colon cancer cell metastasis and chemotherapeutic drug resistance by increasing cancer cell stemness, and that P-glycoprotein inhibitors might improve outcomes for advanced or drug-resistant colon cancer patients.

1p deletion syndrome: A prenatal diagnosis characterized by an abnormal 1st trimester combined screening test, yet a normal NIPT result.

OBJECTIVE: To present a case with prenatal diagnosis and cytogenetic characterization of 1p36 deletion syndrome whose first trimester combined testing is abnormal but a normal NIPT result. CASE REPORT: A 33-year-old had an abnormal 1st trimester fetal aneuploidy screening result, but no trisomies 13, 18, 21 were detected by the noninvasive prenatal testing. Amniocentesis was performed after ultrasound showed fetal ventriculomegaly and echogenic bowel. The final conventional cytogenetics revealed a karyotype of 46, XX, del(1)(p36). CONCLUSION: Every prenatal genetic screening test and diagnostic procedure has its benefit and risk. NIPT offers better sensitivity and specificity for trisomies 13, 18, and 21. Even so, for primary population screening, NIPT provides lower detection rate than sequential screening if considering detection of all chromosomal abnormalities. Diagnostic testing should be offered rather than cell-free DNA screening to pregnant women if a fetal structural anomaly is identified on ultrasound examination.

Sacrospinous ligament fixation for hysteropexy: does concomitant anterior and posterior fixation improve surgical outcome?

INTRODUCTION AND HYPOTHESIS: Uterine preservation in uterine prolapse is an option for young patients. We hypothesized that sacrospinous hysteropexy (SSH) with anchorage to both the anterior and posterior cervix (SSH-ap) would have a better outcome than SSH with anchorage to the posterior cervix only (SSH-p). METHODS: This was a retrospective study including 75 patients who underwent SSH at Chang Gung Memorial Hospital between March 2008 and August 2013. Five were excluded due to incomplete data. Of the remaining 70 patients, 35 underwent SSH-p between March 2008 and June 2011, and 35 underwent SSH-ap between June 2010 and August 2013. The primary outcome was the objective anatomical result, and a successful outcome was considered anatomical correction (POP-Q stage 1 or less) of anterior and apical prolapse. Subjective outcome was evaluated using the POPDI-6 questionnaire, and a patient response of "No or mild abdominal organ falling out sensation" together with "No or mild heaviness" was considered to indicate a successful outcome. Anterior fornix and cervical diameter measurements were included. The secondary outcome was quality of life according to the UDI-6, IIQ-7, POPDI-6, and PISQ-12 questionnaires. The 3-year outcome was used for comparison. RESULTS: The subjective overall cure rates were significantly different between the SSH-p and SSH-ap groups (74.3% and 94.3%, respectively; p = 0.023). However, the objective overall cure rates were not significantly different (74.3% and 82.9%, respectively). CONCLUSION: Anchorage of the anterior cervix and vaginal wall together with the usual posterior anchorage yield better subjective outcomes and apical suspension at 3 years after surgery than anchorage of the posterior cervix and vaginal wall only. The cervix position affected the subjective outcome. Concurrent trachelectomy did not affect the outcome.

Caesarean Section is associated with reduced perinatal cytokine response, increased risk of bacterial colonization in the airway, and infantile wheezing.

The relationship between cesarean section (CS) and allergic disorders such as asthma and wheezing has been inconsistent, and the mechanisms for their connection remained largely unknown. We aimed to investigate whether CS is associated with infantile wheeze and to explore the connection between CS and several risk factors known to correlate with allergy development. Mononuclear cells were isolated from cord blood and assessed for cytokine responses by ELISA. Bacteria from nasopharyngeal specimens were identified with traditional culture methods. Infant lung function tests were performed at 6 and 12 months of age. IgE levels and clinical outcomes were assessed at 12 months. The result showed that children delivered by CS were associated with increased risk of wheezing (aHR 1.63; 95% CI: 1.01-2.62) and decreased compliance of the respiratory system at 12 months (p = 0.045). In addition, CS was associated with reduced TLR1-2- triggered TNF-α and IL-6 responses at birth. By12 months of age, children delivered by CS had significantly less airway bacterial clearance. Our findings suggested that CS was associated with decreased pro-inflammatory cytokine response to TLR1-2 stimulation, followed by higher abundance of bacterial colonization in the airway during late infancy, thus increasing the risk of infantile wheezing.

Maternal Vitamin D Level Is Associated with Viral Toll-Like Receptor Triggered IL-10 Response but Not the Risk of Infectious Diseases in Infancy.

Reports on the effect of prenatal vitamin D status on fetal immune development and infectious diseases in childhood are limited. The aim of this study was to investigate the role of maternal and cord blood vitamin D level in TLR-related innate immunity and its effect on infectious outcome. Maternal and cord blood 25 (OH)D level were examined from 372 maternal-neonatal pairs and their correlation with TLR-triggered TNF-α, IL-6, and IL-10 response at birth was assessed. Clinical outcomes related to infection at 12 months of age were also evaluated. The result showed that 75% of the pregnant mothers and 75.8% of the neonates were vitamin deficient. There was a high correlation between maternal and cord 25(OH)D levels (r = 0.67, p < 0.001). Maternal vitamin D level was inversely correlated with IL-10 response to TLR3 (p = 0.004) and TLR7-8 stimulation (p = 0.006). However, none of the TLR-triggered cytokine productions were associated with cord 25(OH)D concentration. There was no relationship between maternal and cord blood vitamin D status with infectious diseases during infancy. In conclusion, our study had shown that maternal vitamin D, but not cord vitamin D level, was associated with viral TLR-triggered IL-10 response.

Clinical Relevance and Treatment Selection of Ureteral Injury After Cesarean Section.

INTRODUCTION: The aim of this case series was to report the clinical relevance and management outcomes of ureteral injuries acquired secondary to cesarean section. METHODS: This was a retrospective case series from January 2007 to September 2014. Description of the patients' characteristics, diagnostic tools for investigation, management, and postoperative follow-up was conducted on postcesarean section patients who developed symptoms of urine leakage after cesarean section and necessitated secondary surgery for ureteral injury. Descriptive statistics was used for demographics and operative data. RESULTS: A total of 5619 cases were managed by cesarean section during the study period. Six (0.107%; 95% confidence interval [CI], 0.1069%-0.1071%) patients had ureteral injury related to the cesarean section. Of 6 cases, 3 (0.053%; 95% CI, 0.0529%-0.0531%) had ureterouterine fistula. Three cases were managed by ureteroneocystostomy, 1 by ureteroneocystostomy with Boari flap, 1 by transureteroureterostomy, and the other one by ureteral stenting via ureterocystoscopy. Three patients had immediate operation because of an acute abdomen and 3 patients had delayed operation. The left ureter was the most common site of ureteral injury (5/6). The postoperative course was uneventful for all cases. CONCLUSIONS: Continuous urinary leakage and acute abdominal distention associated with fluid accumulation after emergency cesarean section should be considered as "red flag" symptoms of ureteral injury and ureterouterine fistulae complications. Delayed management for ureteral repair may not be associated with bad outcomes for management of ureterouterine fistula. Delayed management was associated with less blood loss, less operating time, and acceptable outcome among patients with ureterouterine fistulae when the renal function is not compromised.