Risk of uterine, ovarian and breast cancer following pelvic inflammatory disease: a nationwide population-based retrospective cohort study.

BACKGROUND: Pelvic inflammatory disease (PID) is characterized by infection and inflammation of the upper genital tract in women and is associated with health sequelae. We used a nationwide population-based retrospective cohort study to explore the relationship between PID and the subsequent development of gynecological cancers including ovarian, breast or uterine cancer. METHODS: We identified subjects diagnosed with PID between January 1st, 2000 and December 31st, 2002 in the Taiwan National Health Insurance Research Database. A comparison cohort constructed for patients without PID were matched according to age and sex. All PID patients and control groups were observed until diagnosed with ovarian, breast or uterine cancer, or until death, withdrawal from the NHI system, or until December 31st, 2009. RESULTS: The PID cohort consisted of 32,268 patients, and an equal number of matched controls without PID. The adjusted hazard ratio (HR) of ovarian, breast or uterine cancer in subjects with PID were: HR 1.326 (95 % confidence interval: 0.775-2.269), HR: 1.039 (95 % confidence interval: 0.862-1.252), and HR: 1.439 (95 % confidence interval: 0.853-2.426) respectively in comparison with controls during follow-up. CONCLUSIONS: This large nationwide population-based cohort study suggests that there is no increased risk for ovarian, breast or uterine cancer among women who have PID compared to a matching population.

Risk of Psychiatric Disorders following Ankylosing Spondylitis: A Nationwide Population-based Retrospective Cohort Study.

OBJECTIVE: Ankylosing spondylitis (AS) is a common inflammatory rheumatic disease. A higher prevalence of psychiatric comorbidities, including depressive disorder, has been proven in patients with AS. However, a clear temporal causal relationship between AS and psychiatric disorders has not been well established. We performed a nationwide population-based retrospective cohort study to analyze the relationship between AS and the subsequent development of psychiatric disorders, including schizophrenia, bipolar disorder, depressive disorders, anxiety disorders, and sleep disorders. METHODS: We identified subjects who were newly diagnosed with AS between January 1, 2000, and December 31, 2008, in the Taiwan National Health Insurance (NHI) Research Database. A comparison cohort was constructed of patients without AS who were matched according to age and sex. All patients with AS and control patients were observed until diagnosed with psychiatric disorders, or until death or withdrawal from the NHI system, or until December 31, 2009. RESULTS: The AS cohort consisted of 2331 patients and the comparison cohort consisted of 9324 matched control patients without AS. The adjusted HR for depressive disorders, anxiety disorders, and sleep disorders in subjects with AS were higher than those of the controls during followup (HR 1.718, 95% CI 1.303-2.265; HR 1.848, 95% CI 1.369-2.494; and HR 1.494, 95% CI 1.031-2.162, respectively). CONCLUSION: AS might increase the risk of a subsequent newly diagnosed depressive disorder, anxiety disorder, or sleep disorder, but not schizophrenia or bipolar disorder. These observations highlight the need for psychiatric evaluation and intervention for patients with AS.

Risk of Psychiatric Disorders Following Symptomatic Menopausal Transition: A Nationwide Population-Based Retrospective Cohort Study.

Menopausal transition is highly symptomatic in at least 20% of women. A higher prevalence of psychiatric symptoms, including depression, anxiety, and sleep disturbance, has been shown in women with symptomatic menopausal transition. However, a clear correlation between symptomatic menopausal transition and psychiatric disorders has not been established.We explored the association between symptomatic menopausal transition and subsequent newly diagnosed psychiatric disorders, including schizophrenia as well as bipolar, depressive, anxiety, and sleep disorders.We investigated women who were diagnosed with symptomatic menopausal transition by an obstetrician-gynecologist according to the data in the Taiwan National Health Insurance Research Database. A comparison cohort comprised age-matched women without symptomatic menopausal transition. The incidence rate and the hazard ratios of subsequent newly diagnosed psychiatric disorders were evaluated in both cohorts, based on the diagnoses of psychiatrists.The symptomatic menopausal transition and control cohorts each consisted of 19,028 women. The incidences of bipolar disorders (hazard ratio [HR] = 1.69, 95% confidence interval [CI] = 1.01-2.80), depressive disorders (HR = 2.17, 95% CI = 1.93-2.45), anxiety disorders (HR = 2.11, 95% CI = 1.84-2.41), and sleep disorders (HR = 2.01, 95% CI = 1.73-2.34) were higher among the symptomatic menopausal transition women than in the comparison cohort. After stratifying for follow-up duration, the incidence of newly diagnosed bipolar disorders, depressive disorders, anxiety disorders, and sleep disorders following a diagnosis of symptomatic menopausal transition remained significantly increased in the longer follow-up groups (1-5 and ≥ 5 years).Symptomatic menopausal transition might increase the risk of subsequent newly onset bipolar disorders, depressive disorders, anxiety disorders, and sleep disorders. A prospective study is necessary to confirm these findings.

Risk of psychiatric disorders following pelvic inflammatory disease: a nationwide population-based retrospective cohort study.

Pelvic inflammatory disease (PID) a common infection in women that is associated with significant morbidity and is a major cause of infertility. A clear temporal causal relationship between PID and psychiatric disorders has not been well established. We used a nationwide population-based retrospective cohort study to explore the relationship between PID and the subsequent development of psychiatric disorders. We identified subjects who were newly diagnosed with PID between 1 January 2000 and 31 December 2002 in the Taiwan National Health Insurance Research Database. A comparison cohort was constructed for patients without PID. A total of 21 930 PID and 21 930 matched control patients were observed until diagnosed with psychiatric disorders, or until death, withdrawal from the NHI system, or until 31 December 2009. Adjusted hazard ratio (HR) of bipolar disorder, depressive disorder, anxiety disorder and sleep disorder in subjects with PID were significantly higher (HR: 2.671, 2.173, 2.006 and 2.251, respectively) than that of the controls during the follow-up. PID may increase the risk of subsequent newly diagnosed bipolar disorder, depressive disorder, anxiety disorder and sleep disorder, which will impair life quality. Our findings highlight that clinicians should pay particular attention to psychiatric comorbidities in PID patients.

Hepatocyte growth factor and HER2/neu downregulate expression of apoptosis-inducing factor in non-small cell lung cancer.

Our previous study showed that patients with advanced stages of non-small cell lung cancer (NSCLC) were frequently detected with upregulation of hepatocyte growth factor (HGF). In vitro, HGF reduced expression of apoptosis-inducing factor (AIF) and cisplatin sensitivity in NSCLC cells. The effect of HGF was via HGF receptor (c-MET) and the downstream effector, focal adhesion kinase (FAK). In this study, we determined the prognostic value of AIF in NSCLC patients. AIF expression was determined by immunohistochemistry and immunoblotting. Our data show that AIF expression was associated with better prognosis. Expression of AIF inversely correlated with that of positive NSCLC markers, e.g., dihydrodiol dehydrogenase (DDH), c-MET, short oncostatin M receptor (OSMRs), matrix metalloproteinase (MMP)-1, and HER2/neu, which were closely associated with drug resistance, tumor recurrence, metastasis and poor prognosis. Noteworthy, silence of HER2/neu gene expression increases AIF level and drug sensitivity. Addition of HGF inhibits AIF expression in HER2/neu-silenced cells. These results suggested that both HGF and HER2/neu affect drug resistance by regulating AIF expression in NSCLC.

Extracts of Koelreuteria henryi Dummer induce apoptosis and autophagy by inhibiting dihydrodiol dehydrogenase, thus enhancing anticancer effects.

Dihydrodiol dehydrogenase (DDH) is frequently detected in cancer cells, and its overexpression correlates with drug resistance, the downregulation of DNA repair mechanisms, increased frequency of tumor recurrence, cancer cell metastasis and poor prognosis. The silencing of DDH expression using siRNA, on the other hand, reduces drug resistance and cancer cell mobility. These data suggest that DDH may be an oncogene-related protein. However, no specific DDH inhibitor has been identified to date. Thus, in this study, we used DDH as a target enzyme in a live-cell enzyme-linked immunosorbent assay to screen Chinese medicinal herb extracts (CMHEs) with the aim of identifying a DDH inhibitor. Using this method, we found 49 among 796 CMHEs that inhibited DDH expression. We selected three potential extracts, which had the highest activity against DDH, for further fractionation using high-performance liquid chromatography. The active ingredient was identified by immunoblot analysis. The function of the active ingredient was characterized by cell function analysis. Our results revealed that the CMHE-purified compounds targeted DDH, inducing autophagy and reducing DNA repair, which in turn enhanced the cytotoxic effects of the anticancer drugs and irradiation.

Nuclear expression of dynamin-related protein 1 in lung adenocarcinomas.

Dynamin-related protein 1 (DRP1), an 80 kDa GTPase, is involved in mitochondrial fission and anticancer drug-mediated cytotoxicity, which implicate an association with disease progression of cancer. In this study we investigated the prognostic value of DRP1 in lung adenocarcinomas. Using immunohistochemistry, we measured the expression of DRP1 in 227 patients with lung adenocarcinomas. Expression of DRP1 was confirmed by immunoblotting. The correlation between DRP1 expression and clinicopathological parameters was analyzed by statistical analysis. Difference of survivals between different groups was compared by a log-rank test. The results showed that DRP1 expression was detected in 202 patients with lung adenocarcinomas. Among these, nuclear DRP1 (DRP1(nuc)) was detected in 184 patients. A significant difference was found in cumulative survival between patients with high DRP1(nuc) levels and those with DRP1(cyt) levels (P<0.001). In vitro, hypoxia increased DRP1(nuc) levels and cisplatin resistance. Antibodies specific to DRP1 co-precipitated a human homologue of yeast Rad23 protein A (hHR23A) and silencing of hHR23A decreased the nuclear DRP1 level and cisplatin resistance. In conclusion, DRP1(nuc) is highly expressed in lung adenocarcinomas, and correlates with poor prognosis. Nuclear DRP1 may increase drug resistance during hypoxia, and hHR23A is essential for nuclear transportation of DRP1. Our results suggest that other than the protein level alone, intracellular distribution of the protein is critical for determining the protein function in cells.

Hepatocyte growth factor induces hypoxia-related interleukin-8 expression in lung adenocarcinoma cells.

Rapid growth of cancer cells often creates insufficient supply of oxygen and nutrients in the tumour nest. The frequent detection of hypoxia-inducible factor (HIF) and interleukin-8 (IL-8) in afflicted tissues suggests that IL-8 expression could be associated with elevated levels of HIF. Recently, we found that hypoxia also upregulated the expression of hepatocyte growth factor (HGF) in lung adenocarcinoma (LAD) cells. However, the relationship between HGF and IL-8 has not been investigated in LAD cells. In this study, we found that HGF induced IL-8 expression in LAD. Interestingly, hypoxia also increased the level of prostaglandin F(2alpha) (PGF(2alpha)), a product of dihydrodiol dehydrogenase (DDH). When expression of DDH was suppressed by siRNA, the levels of PGF(2alpha), HGF and IL-8 were reduced; however, their levels returned to normal after DDH was reintroduced. These data suggest that hypoxia induces biosynthesis of PGF(2alpha), which then activates HGF and IL-8 expression. The results provide a reasonable explanation of how PGF(2alpha), HGF and IL-8 exert their effects on cancer cell metastasis.

Ischemic brain cell-derived conditioned medium protects astrocytes against ischemia through GDNF/ERK/NF-kB signaling pathway.

Conditioned medium (CM) collected from cultures of ischemic microglia, astrocytes, and neurons were protective to astrocytes under the in vitro ischemic condition (deprivation of oxygen, glucose and serum). Molecular and signaling pathway(s) responsible for the CMs protective activity were investigated. Results showed that CMs from the ischemic microglia (MCM), astrocytes (ACM) and neurons (NCM) contained glial cell line-derived neurotrophic factor (GDNF), which protects astrocytes against the in vitro ischemia. Expression of extra cellular signal-regulated kinase (ERK1/2) and nuclear factor-kappa B (NF-kB) by GDNF led to the inhibition of apoptosis of the ischemic astrocytes in a caspase 3-independent manner. However, CMs- and GDNF-mediated protection of the ischemic astrocytes was protein kinase B (Akt) independent. These results provided mechanistic data regarding how GDNF- and CMs-mediated protection of the ischemic astrocytes is taking place. These observations provide information for the use of GDNF and GDNF containing CMs in the control of cerebral ischemia.

HGF increases cisplatin resistance via down-regulation of AIF in lung cancer cells.

Our previous study had shown that advanced stages of lung adenocarcinomas (ADC) was frequently associated with overexpression of hepatocyte growth factor (HGF), which has multipotent and anti-apoptotic activities. In this study, we examined the effect of HGF on gene expression of apoptosis-inducing factor (AIF) and cisplatin sensitivity in lung ADC cells. Expression of AIF was determined by immunocytochemistry and confocal immunofluorescence microscopy. Our data show that addition of HGF suppressed AIF expression and increased cisplatin resistance. The effect could be through HGF receptor and its downstream effector, focal adhesion kinase (FAK). Interestingly, knockout of FAK gene increased AIF expression and drug sensitivity. Re-introduction of FAK gene, on the other hand, restored drug resistance. These results suggested that HGF might induce cisplatin resistance via c-Met to activate FAK and down-regulate AIF expression.