RPL41 sensitizes retinoblastoma cells to chemotherapeutic drugs via ATF4 degradation.

Retinoblastoma is the most common intraocular cancer with metastatic potential affecting infants and children. Although chemotherapy is available for retinoblastoma, side effects and drug resistance are frequent. Rpl41, encoding ribosomal protein L41 (RPL41), has been identified as a tumor suppressor gene, and its targeted degradation of activating transcription factor 4 (ATF4) produces an antitumor effect. The goal of the present study is to provide experimental evidence for the clinical application of a small peptide regimen in combination with chemotherapy for the treatment of retinoblastoma and to investigate the mechanism of their combined cytotoxicity. It was observed that treatment with the RPL41 peptide alone decreased the viability, migration, and invasion of retinoblastoma Y79 and Weri-Rb1 cells, in addition to promoting cell apoptosis and cell cycle arrest. Furthermore, RPL41 protein levels showed a significantly decreased trend in retinoblastoma specimens, whereas ATF4 protein levels tended to be increased. Mechanistically, ATF4 degradation as a result of RPL41 peptide treatment was observed in retinoblastoma Y79 and Weri-Rb1 cells. Most important, low-dose administration of the RPL41 peptide significantly enhanced the antitumor effect of carboplatin, and further analysis confirmed their synergistic effect as anti-retinoblastoma therapy, indicating that RPL41 sensitized Y79 and Weri-Rb1 retinoblastoma cells to carboplatin. Thus, our data provide a preclinical rationale for the exploration of the RPL41 peptide as a potential adjuvant to carboplatin treatment in retinoblastoma.

Impaired VEGF Signaling in Lungs with Hypoplastic Esophageal Atresia and Effects on Branching Morphogenesis.

BACKGROUND/AIMS: Patients with esophageal atresia (EA) and tracheoesophageal fistula (TEF) often suffer chronic respiratory tract disease. We previously reported that primary lung maldevelopment caused by deficient branching of embryonal airways in experimental EA-TEF was induced by Adriamycin. In this study, we investigated the Vascular endothelial growth factor (VEGF) pathway in the developing lung in an EA-TEF rat model. We further analyzed the effect of recombinant VEGF treatment in vitro on branching morphogenesis of embryo lungs in experimental EA-TEF. METHODS: Pregnant rats received either Adriamycin or vehicle on E7, E8 and E9. Lungs were recovered at E15, E18 and E21. Expression of VEGF and receptors (Flk-1 and Flt-1) were assessed by quantitative PCR, immunohistochemistry and immunoblotting. E13 lungs were cultured for 72 hours with 50 ng/mL of recombinant rat VEGF in serum-free medium. The rates of increase in bud count and airway contour were evaluated. RESULTS: Our results showed a significant downregulation of VEGF during pseudoglandular and canalicular stages. In contrast, there were significantly higher levels of the Flt-1 receptor in the canalicular stage, which may represent a compensatory response to decreased VEGF. However, both variables returned to normal levels at the saccular stage. Exogenous VEGF treatment enhanced hypoplastic lung growth, evidenced by the increase in bud count and airway contour. CONCLUSIONS: A VEGF signaling defect possibly plays an important role in defective embryonic airway branching. Additionally, VEGF treatment may accelerate lung growth in EA-TEF lungs.

Maternal protein restriction induces alterations in insulin signaling and ATP sensitive potassium channel protein in hypothalami of intrauterine growth restriction fetal rats.

It is well recognized that intrauterine growth restriction leads to the development of insulin resistance and type 2 diabetes mellitus in adulthood. To investigate the mechanisms behind this "metabolic imprinting" phenomenon, we examined the impact of maternal undernutrition on insulin signaling pathway and the ATP sensitive potassium channel expression in the hypothalamus of intrauterine growth restriction fetus. Intrauterine growth restriction rat model was developed through maternal low protein diet. The expression and activated levels of insulin signaling molecules and K(ATP) protein in the hypothalami which were dissected at 20 days of gestation, were analyzed by western blot and real time PCR. The tyrosine phosphorylation levels of the insulin receptor substrate 2 and phosphatidylinositol 3'-kinase p85α in the hypothalami of intrauterine growth restriction fetus were markedly reduced. There was also a downregulation of the hypothalamic ATP sensitive potassium channel subunit, sulfonylurea receptor 1, which conveys the insulin signaling. Moreover, the abundances of gluconeogenesis enzymes were increased in the intrauterine growth restriction livers, though no correlation was observed between sulfonylurea receptor 1 and gluconeogenesis enzymes. Our data suggested that aberrant intrauterine milieu impaired insulin signaling in the hypothalamus, and these alterations early in life might contribute to the predisposition of the intrauterine growth restriction fetus toward the adult metabolic disorders.

The Effects of Deregulated Ribosomal Biogenesis in Cancer.

Ribosomes are macromolecular ribonucleoprotein complexes assembled from RNA and proteins. Functional ribosomes arise from the nucleolus, require ribosomal RNA processing and the coordinated assembly of ribosomal proteins (RPs), and are frequently hyperactivated to support the requirement for protein synthesis during the self-biosynthetic and metabolic activities of cancer cells. Studies have provided relevant information on targeted anticancer molecules involved in ribosome biogenesis (RiBi), as increased RiBi is characteristic of many types of cancer. The association between unlimited cell proliferation and alterations in specific steps of RiBi has been highlighted as a possible critical driver of tumorigenesis and metastasis. Thus, alterations in numerous regulators and actors involved in RiBi, particularly in cancer, significantly affect the rate and quality of protein synthesis and, ultimately, the transcriptome to generate the associated proteome. Alterations in RiBi in cancer cells activate nucleolar stress response-related pathways that play important roles in cancer-targeted interventions and immunotherapies. In this review, we focus on the association between alterations in RiBi and cancer. Emphasis is placed on RiBi deregulation and its secondary consequences, including changes in protein synthesis, loss of RPs, adaptive transcription and translation, nucleolar stress regulation, metabolic changes, and the impaired ribosome biogenesis checkpoint.

GPR12 Inhibits Apoptosis in Epithelial Ovarian Cancer via the Activation of ERK1/2 Signaling.

Epithelial ovarian cancer (EOC) is one of the most lethal gynecological malignancies in women worldwide. G protein-coupled receptor 12 (GPR12) is a member of G protein-coupled receptors (GPCRs) and plays an important role in the regulation of cell proliferation and survival. However, its role in EOC is underappreciated. In this study, we found that GPR12 is highly expressed in the EOC tissues and can be an ideal biomarker to predict the prognosis of patients with EOC. GPR12 knockdown obviously inhibits the proliferation of EOC cells by inducing cellular apoptosis in vitro and in vivo. Meanwhile, bioinformatic analysis showed that the inhibitory effect of GPR12 knockdown on the cell viability is closely related with Extracellular signal-regulated kinases 1/2 (ERK1/2) pathway, which has been confirmed by the fact that the activity of ERK1/2 pathway has been significantly blocked in the GPR12 knockdown cells. LM22B-10, ERK1/2 pathway activator, could reverse the inhibited proliferation caused by GPR12 knockdown in the EOC cells. Our findings suggest that GPR12 is involved in the EOC process and is a potential therapeutic target for EOC.

High-Risk Human Papillomavirus Oncogenic E6/E7 mRNAs Splicing Regulation.

High-risk human papillomavirus infection may develop into a persistent infection that is highly related to the progression of various cancers, including cervical cancer and head and neck squamous cell carcinomas. The most common high-risk subtypes are HPV16 and HPV18. The oncogenic viral proteins expressed by high-risk HPVs E6/E7 are tightly involved in cell proliferation, differentiation, and cancerous transformation since E6/E7 mRNAs are derived from the same pre-mRNA. Hence, the alternative splicing in the E6/E7-coding region affects the balance of the E6/E7 expression level. Interrupting the balance of E6 and E7 levels results in cell apoptosis. Therefore, it is crucial to understand the regulation of E6/E7 splice site selection and the interaction of splicing enhancers and silencers with cellular splicing factors. In this review, we concluded the relationship of different E6/E7 transcripts with cancer progression, the known splicing sites, and the identified cis-regulatory elements within high-risk HPV E6/E7-coding region. Finally, we also reviewed the role of various splicing factors in the regulation of high-risk HPV oncogenic E6/E7 mRNA splicing.

PHGDH Inhibitor CBR-5884 Inhibits Epithelial Ovarian Cancer Progression via ROS/Wnt/ß-Catenin Pathway and Plays a Synergistic Role with PARP Inhibitor Olaparib.

PHGDH attaches importance to serine biosynthesis in cancer cells and maintaining mitochondrial redox homeostasis. However, the role of PHGDH inhibitor CBR-5884 in cell ROS level and its downstream pathways has not been explored in epithelial ovarian cancer. Thus, we investigated the function and possible mechanism of PHGDH inhibitor CBR-5884 on epithelial ovarian cancer in vitro and in vivo. A2780, OVCAR3, and ES-2 were treated with CBR-5884 at different concentrations or different time points. Results showed that CBR-5884 inhibited epithelial ovarian cancer cell proliferation, migration, and invasion and increases cell ROS level. Meanwhile, CBR-5884 exerts antitumor effect through activating ROS/Wnt/ß-catenin pathway. Besides, CBR-5884 exerts antitumor effect in vivo. What's more, we explored the effect of CBR-5884 with or without PARP inhibitor Olaparib, which showed that the two together had a larger effect. In conclusion, PHGDH inhibitor CBR-5884 inhibits epithelial ovarian cancer proliferation, migration, and invasion through activating ROS/Wnt/ß-catenin pathway and plays a synergistic role with PARP inhibitor olaparib, which provided a theoretical basis for PHGDH inhibitor CBR-5884 in clinical treatment.

Gynecologists Need to Be Vigilant-Two Case Reports of Intravascular Leiomyomatosis and Literature Review.

BACKGROUND: Intravascular leiomyomatosis is a rare benign lesion with malignant potential. The cases are sporadic. Most patients have no clinical symptoms, and the preoperative diagnostic rate is low. Case 1 was misdiagnosed, passively managed during operation, recurred quickly, and underwent a secondary operation. We learned lessons from case 1 and treated the case 2 patient differently. The case 2 patient had a good prognosis. We hope the report will be helpful to other gynecologists. CASE SUMMARY: Case 1: a 49-year-old woman complained of dysmenorrhea. Traditional ultrasound showed adenomyosis and a solid mass 6 * 3 cm in the right appendix. After routine examination, the patient underwent transabdominal total hysterectomy + bilateral salpingectomy + IVL tumor resection, with both ovaries kept. No medication was used after operation. Routine ultrasound was performed every 3 months. The disease recurred, and the patient underwent a secondary surgery 9 months after the first time. So far, 25 months after the secondary surgery, there is no sign of recurrence. Case 2: a 41-year-old woman underwent a routine body examination, where a left adnexal mass 7 cm was found. The patient underwent contrast-enhanced ultrasonography and was diagnosed and prepared well preoperatively. The patient underwent transabdominal total hysterectomy + bilateral salpingectomy + IVL tumor resection. GnRH-a drugs were used after operation for 3 cycle. Now, there is no sign of recurrence after operation for 23 months. CONCLUSION: The incidence rate of IVL is low, and there are no typical clinical symptoms. It is easy to be ignored by gynecologists. Contrast-enhanced ultrasound is helpful to diagnose preoperatively and reduce misdiagnosis. Good preparation, full exploration of the pelvic and abdominal vessels, removal of lesions completely as much as possible, and anti-estrogen therapy after operation can reduce the recurrence of disease.

Pre-diagnosis Dietary One-Carbon Metabolism Micronutrients Consumption and Ovarian Cancer Survival: A Prospective Cohort Study.

Background and Aims: Epidemiological evidence on the relation between one-carbon metabolism (OCM) micronutrients intake and ovarian cancer (OC) survival are limited and conflicting. We evaluated the aforementioned associations in a prospective cohort-the Ovarian Cancer Follow-Up Study. Methods: A total of 635 newly diagnosed OC patients aged 18-79 y were enrolled in the present study. Dietary intake related to one-carbon metabolism, including methionine, vitamins B2, B3, B6, B9, B12, choline, and betaine, was assessed using a validated 111-item food frequency questionnaire. Deaths were ascertained until March 31, 2021, via medical records and active follow-up. Cox proportional hazards regression model was used to evaluate the hazard ratios (HRs) and 95% confidence intervals (CIs) for these aforementioned associations. Results: During a median follow-up of 37.2 months (interquartile: 24.7-50.2 months), 114 deaths were identified. We observed an improved survival with the highest compared with the lowest tertile of dietary vitamin B6 (HR = 0.52, 95%CI: 0.32-0.84, P-trend <0.05) and choline intake (HR = 0.50, 95%CI: 0.30-0.83, P-trend <0.05). No significant associations with OC survival were observed for dietary vitamins B2, B3, B9, B12, methionine, and betaine intake. We also observed a curvilinear association between vitamin B6 intake and OC survival (P non-linear <0.05). Conclusion: Our study suggests that pre-diagnosis higher intake of vitamin B6 and choline may improve OC survival. Further clarification of these associations is warranted.

Targeting HSP90 in ovarian cancers with multiple receptor tyrosine kinase coactivation.

BACKGROUND: Ovarian cancer has the highest mortality rate of all gynecologic malignancy. The receptor tyrosine kinases (RTKs), including EGFR, ERBB2, PDGFR, VEGFR and MET, are activated in subsets of ovarian cancer, suggesting that these kinases might represent novel therapeutic targets. However, clinical trials have not or just partially shown benefit to ovarian cancers treated with EGFR, ERBB2, or PDGFR inhibitors. Despite multiple RTK activation in ovarian cancer pathogenesis, it is unclear whether transforming activity is dependent on an individual kinase oncoprotein or the coordinated activity of multiple kinases. We hypothesized that a coordinated network of multi-RTK activation is important for the tumorigenesis of ovarian cancers. RESULTS: Herein, we demonstrate co-activation of multiple RTKs (EGFR, ERBB2, ERBB4, MET and/or AXL) in individual ovarian cancer cell lines and primary tumors. We also show that coordinate inhibition of this multi-kinase signaling has substantially greater effect on ovarian cancer proliferation and survival, compared to inhibition of individual activated kinases. The inhibition of this multi-RTK signaling by HSP90 suppression results in profound pro-apoptotic and anti-proliferative effects, and is associated with the inactivation of RTK downstream PI3-K/AKT/mTOR and RAF/MAPK signaling. CONCLUSION: These studies suggest that anti-multiple RTK strategy could be useful in the treatment of ovarian cancer.

Peroxisome Deficiency Dysregulates Fatty Acid Oxidization and Exacerbates Lipotoxicity in ß Cells.

An adverse intrauterine environment impairs the development of pancreatic islets in the fetus and leads to insufficient ß cell mass and ß cell dysfunction. We previously reported that Pex14, a peroxin protein involved in the biogenesis and degradation of peroxisomes, is markedly reduced in the pancreas of an intrauterine growth restriction fetus and last into adulthood. Peroxisomes function in a wide range of metabolic processes including fatty acid oxidization, ROS detoxification, and anti-inflammatory responses. To elucidate the impact of downregulation of the Pex14 gene on ß cell, Pex14 was knocked down by siRNA in INS-1 cells. Pex14 knockdown disturbed peroxisomal biogenesis and dysregulated fatty acid metabolism and lipid storage capability, thereby increased ROS level and blunted insulin secretion. Moreover, Pex14 knockdown upregulated inflammation factors and regulators of endoplasmic reticulum stress. The lipotoxicity of fatty acid (including palmitic acid and linoleic acid) in ß cells was exacerbated by knockdown of Pex14, as indicated by H2O2 accumulation and increased programmed cell death. The present results demonstrate the vital role of Pex14 in maintaining normal peroxisome function and ß cell viability and highlight the importance of a functional peroxisomal metabolism for the detoxification of excess FAs in ß cells.

[Acetylation of hepatic histone H3 in rats with intrauterine growth retardation].

OBJECTIVE: To investigate the effects of intrauterine growth retardation (IUGR) caused by malnutrition during pregnancy on the acetylation of histone H3 and expression of histonedeacetylase1(HDAC1) in the hepar of the adult offspring and to explore the relationship between them. METHODS: Male 8-week-old offspring from maternal protein-malnutrition dams were studied. The expression of HDAC1 mRNA in the hepar was measured by fluorescent quantization RT-PCR. The levels of hepatic nuclear HDAC1 protein and acetylation of histone H3/K9 were assessed by Western blot. RESULTS: The hepatic HDAC1 mRNA expression in IUGR rats was reduced to 54% of that of normal control rats (t=2.042, p<0.05). A decline in nuclear expression of HDAC1 protein (438 +/- 47) was also noted when compared with normal controls (1,128 +/- 110) (t=2.179, p<0.05). In contrast, the percentage of acetylated histone H3/K9 in IUGR rats (17.3 +/- 1.6%) increased significantly compared with that of normal control rats (10.5 +/- 1.2%) (t=3.597, p<0.01). The level of acetylated histone H3/K9 was negatively correlated with the HDAC1 protein concentration (r=-0.781, p<0.01). CONCLUSIONS: Increased hepatic acetylation of histone H3 in the IUGR offspring might be caused by decreased HDAC1 expression in nuclear protein. This may contribute to the transcription change of some genes in the hepar.

[Perturbed hepatic phosphoinositol 3-kinase signaling pathway in the rat with intrauterine growth restriction].

OBJECTIVE: To determine the molecular mechanisms linking intrauterine growth restriction (IUGR) to adult type 2 diabetes mellitus, the effect of IUGR on the hepatic post-receptor insulin-signaling pathway was investigated in the adult offspring. METHODS: The IUGR model was prepared by maternal protein-malnutrition. Western blotting analysis was undertaken to assess hepatic expression of insulin receptor substrate (IRS-2), phosphoinositol 3-kinase (PI-3K), protein kinase B (PKB), phosphorylated PKB-Ser473 and glycogen synthase kinase (GSK) 3 in 8-week-old male IUGR rats. RESULTS: The basal levels of PI-3K protein decreased in IUGR rats compared with normal controls (p<0.01), whereas GSK-3beta protein level significantly increased in IUGR rats (p<0.01). Both PKB and phosphorylated PKB-Ser473 protein levels significantly decreased in the liver of IUGR rats compared with normal controls (p<0.01)). After insulin administration, phosphorylated PKB-Ser473 significantly increased to 182% of basal level in control rats(p<0.01); However, phosphorylation of PKB which responded to insulin was markedly blunted in IUGR rats compared with controls and only increased to 123% of basal level (p<0.05). CONCLUSIONS: The level of PI-3K and PKB and phosphorylated PKB-Ser473 expression decreased in the liver of IUGR rats, whereas the levels of GSK-3beta protein increased. It may contribute to the pathogenesis of insulin resistance in the IUGR rats.

Maternal Protein Restriction Induces Alterations in Hepatic Unfolded Protein Response-Related Molecules in Adult Rat Offspring.

Intrauterine growth restriction (IUGR) leads to the development of metabolic syndrome in adulthood. To explore the potential mechanisms of metabolic imprinting, we investigated the effect of malnutrition in utero on hepatic unfolded protein response (UPR)-related genes in IUGR offspring. An IUGR rat model was developed by feeding a low-protein diet to pregnant rats. The expression levels and activity of hepatic UPR genes were analysed by quantitative PCR (qPCR) arrays and western blotting. The hepatic UPR molecules heat-shock 70-kDa protein 4l (Hspa4l), mitogen-activated protein kinase 10 (Mapk10), and endoplasmic reticulum to nucleus signalling 2 (Ern2) were markedly downregulated in IUGR foetuses, but the expression of Mapk10 and Ern2 returned to normal levels at 3 weeks postnatal. In contrast, cAMP responsive element binding protein 3-like 3 (Creb3l3) was upregulated in hepatic tissues at embryo 20(E20), then restored to normal in adulthood (12 weeks). The protein levels of activating transcription factor 2 (Atf2) and Atf6, two key factors of the UPR pathway, were upregulated in the livers of IUGR foetuses, and the latter remained upregulated until 12 weeks. Combined with our previous findings showing an increase in hepatic gluconeogenesis enzymes in IUGR offspring, we speculated that aberrant intrauterine milieu impaired UPR signalling in hepatic tissues; these alterations early in life might contribute to the predisposition of IUGR foetuses to adult metabolic disorders.

Prognostic Influence of the Time Interval between Surgery and Chemotherapy in Epithelial Ovarian Cancer.

The influence of time to chemotherapy (TTC) on recurrence and survival among epithelial ovarian cancer (EOC) patients still remains unknown. This single center retrospective cohort study was conducted on 489 EOC patients who underwent surgery followed by taxane- plus platinum-based chemotherapy in the Shengjing Hospital of China Medical University between 2011 and 2015. The Multivariate cox proportional regression models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for progression-free survival (PFS) and overall survival (OS) after adjustment for potential confounders. The median follow-up duration was 2.97 years (inter-quartile range from 2.11 to 4.13 years). The recurrence and mortality rate of the all patients was 50.9% (249/489) and 43.6% (213/489), respectively. Having comorbidity, residual disease, ascites, and advanced FIGO stage (III-IV) was associated worse PFS and OS of EOC patients. Compared to TTC less than 14 days, delayed TTC (more than 28 days) was associated with a worse PFS (HR=1.36; 95%CI: 0.96-1.92) and OS (HR=1.38; 95%CI: 0.95-2.00). Notably, in EOC patients with advanced stage, delayed TTC (more than 28 days) was associated with worse PFS (HR=1.51; 95%CI: 1.02-2.24) and OS (HR=1.53; 95%CI: 1.01-2.32) when comparing to TTC less than 14 days. In conclusion, delayed TTC was associated with higher rates of EOC recurrence and survival among these patients with advanced stage. The findings of the present study may provide evidence for gynecologist as well as these ovarian cancer patients to make further decision for the treatment.

Combining situ-morcellation with continuous-fill-mattress suture in laparoscopic myomectomy: A surgical approach of choice for patients with large uterine fibroids.

BACKGROUND: To investigate the efficacy and advantage of combining situ-morcellation with continuous-fill-mattress suture compared with conventional morcellation and suture in laparoscopic myomectomy. METHODS: One hundred sixteen patients who underwent laparoscopic myomectomy from March 2014 to October 2016. INTERVENTIONS: Patients were divided into combining situ-morcellation with continuous-fill-mattress suture group (n = 62) and conventional group (n = 54), and subsequent statistical analysis the clinical data of the 2 groups. RESULTS: The combining situ-morcellation with continuous-fill-mattress suture group shows significantly decrease of surgery time, incision size, blood loss, postoperative drainage volume and time, postoperative vent time, hospital stay and the loss of hemoglobin value. Moreover, there is significant significance between the 2 groups in the surgery time (P = .018), the postoperative drainage volume (P = .000), and the loss of hemoglobin value (P = .000). CONCLUSIONS: The combining situ-morcellation with continuous-fill-mattress suture shows significant advantages in shortening surgery time and reducing blood loss compared with conventional group in laparoscopic myomectomy.

Relationship between initiation time of adjuvant chemotherapy and survival in ovarian cancer patients: a dose-response meta-analysis of cohort studies.

Although several studies have previously investigated the association between the initiation time of adjuvant chemotherapy and survival in ovarian cancer, inconsistencies remain about the issue. We searched PubMed and Web of Science through the May 24, 2017 to identify cohort studies that investigated the aforementioned topic. Fourteen studies with 59,569 ovarian cancer patients were included in this meta-analysis. We conducted meta-analyses comparing the longest and shortest initiation time of adjuvant chemotherapy and dose-response analyses to estimate summary hazards ratios (HRs) and 95% confidence intervals (CIs). A random-effects model was used to estimate HRs with 95% CIs. When comparing the longest with the shortest category of initiation time of adjuvant chemotherapy, the summary HR was 1.18 (95% CI: 1.06-1.32; I 2 = 17.6; n = 7) for overall survival. Additionally, significant dose-response association for overall survival was observed for each week delay (HR = 1.04; 95% CI: 1.00-1.09; I 2 = 9.05; n = 5). Notably, these findings were robust in prospective designed cohort studies as well as studies with advanced stage (FIGO III-IV) patients. No evidence of publication bias was observed. In conclusion, prolonged initiation time of adjuvant chemotherapy is associated with a decreased overall survival rate of ovarian cancer, especially in patients with advanced stage ovarian cancer.

Comorbidity and survival among women with ovarian cancer: evidence from prospective studies.

The relationship between comorbidity and ovarian cancer survival has been controversial so far. Therefore, we conducted a meta-analysis to summarize the existing evidence from prospective studies on this issue. Relevant studies were identified by searching the PubMed, EMBASE, and ISI Web of Science databases through the end of January 2015. Two authors independently performed the eligibility evaluation and data abstraction. Random-effects models were used to estimate summary hazard ratios (HRs) and 95% confidence intervals (CIs) for overall survival. Eight prospective studies involving 12,681 ovarian cancer cases were included in the present study. The summarized HR for presence versus absence of comorbidity was 1.20 (95% CI = 1.11-1.30, n = 8), with moderate heterogeneity (I(2) = 31.2%, P = 0.179). In addition, the summarized HR for the highest compared with the lowest category of the Charlson's comorbidity index was 1.68 (95% CI = 1.50-1.87, n = 2), without heterogeneity (I(2) = 0%, P = 0.476). Notably, a significant negative impact of comorbidity on ovarian cancer survival was observed in most subgroup analyses stratified by the study characteristics and whether there was adjustment for potential confounders. In conclusion, the findings of this meta-analysis suggest that underlying comorbidity is consistently associated with decreased survival in patients with ovarian cancer. Comorbidity should be taken into account when managing these patients.

Expression and role of the inhibitor of apoptosis protein livin in chemotherapy sensitivity of ovarian carcinoma.

Ovarian cancer has the highest mortality rate of all gynecological malignancies. Livin, a novel member of the inhibitor of apoptosis protein family, has been found to be expressed in various malignancies and is suggested to have poor prognostic significance. However, no data are available concerning the significance of livin in ovarian cancer. In the present study, we detected the expression of livin isoforms in human epithelial ovarian cancer (EOC) tissues using semi-quantitative RT-PCR and western blot assays. The data indicated that livin expression positive ratio was much higher in cancer tissues compared to those in benign ovarian tumors and normal ovarian specimens. To determine the role of livin in the process of ovarian cancer growth, RNA interference mediated by recombinant lentivirus vectors expressing livin shRNA was applied to induce a long-lasting downregulation of livin gene expression in SKOV3 human ovarian cancer cell line. Cell apoptosis and chemosensitivity were evaluated by MTT assay and flow cytometry, respectively, following downregulation of livin expression, and the cleavage of molecular markers of the mitochondrial apoptotic signaling pathway was investigated by immunoblotting. Livin knockdown with siRNA enhanced spontaneous and drug-induced apoptosis in SKOV3 cells. The inhibition of livin resulted in profound pro-apoptotic and antiproliferative effects, and was associated with the activation of caspase signaling. In conclusion, these data suggested that livin plays an important role in inhibiting the apoptosis of ovarian cancer cells. Specific silencing of livin expression could promote cell apoptosis, enhance chemotherapy sensitivity and may be a promising target for further research in clinical chemotherapy of epitheliod ovarian cancer.

Evaluation of loop ligation of larger myoma pseudocapsule combined with vasopressin on laparoscopic myomectomy.

OBJECTIVE: To study the effects of reducing hemorrhage by loop ligation of larger myoma pseudocapsules combined with vasopressin on laparoscopic myomectomy (LM). DESIGN: Prospective controlled clinical trial. SETTING: Sheng Jing Hospital, China Medical University. PATIENT(S): A total of 105 women with symptomatic single or multiple larger myomas (diameter 6-18 cm) in need of surgical intervention, who wished to retain their uteri, were randomly divided into three groups in our hospital from January 2006 to January 2008: A) loop ligation combined with vasopressin; B) vasopressin alone; and C) neither loop ligation nor vasopressin. All patients were treated by LM. Each group included 35 cases. INTERVENTION(S): Loop ligation of larger myoma (6-18 cm) pseudocapsule combined with vasopressin before thoroughly enucleating the myoma. MAIN OUTCOME MEASURE(S): Operating time, blood loss, blood transfusion, postoperative stay in hospital, symptom improvement. RESULT(S): Average blood loss, postoperative stay in hospital, number of conversions to laparotomy, and need for transfusion because of bleeding during operation in group A were significantly lower than in groups B and C. All patients in group A underwent technically successful laparoscopic operations. CONCLUSION(S): Loop ligation of larger myoma pseudocapsules combined with vasopressin is a safe, effective, and promising new method to reduce bleeding during laparoscopic myomectomy and makes the laparoscopic operations with larger myomas easier.