The overall survival (OS) of patients with ovarian cancer is poor while epithelial ovarian cancer (EOC) is the most lethal gynecologic cancer. The aim of the present study was to evaluate the ...clinico-pathologic characteristics, especially the prognostic factors, for patients with epithelial ovarian cancer (EOC) in Taiwan. Information about newly diagnosed patients with EOC from 2009 to 2012 was retrieved from the database of the Taiwan Cancer Registry. Data from 2009 to 2013 for the respective cases from the claims database of Taiwan's National Health Insurance and National Death Registry were then retrieved. Potential prognostic factors were analyzed. The mean age at diagnosis of the 2,498 patients was 52.8 years. Serous carcinoma and clear cell carcinoma were diagnosed in 43.3% and 22.8% of the total patients, respectively. For patients with early-stage disease, taxane-based adjuvant chemotherapy, stage I, and younger age at diagnosis led to better overall survival (p = 0.030, p = 0.002, p<0.001, respectively) in multivariable analysis. For advanced-stage patients, histology (endometrioid type), taxane-based adjuvant chemotherapy, stage, and age at diagnosis had a significant impact on OS (p<0.001, p = 0.020, p<0.001, p<0.001, respectively). In conclusion, taxane-based chemotherapy impacts the outcome of patients with EOC. Personalized medicine may be needed for different histological types of EOC because of their different outcomes.
PD-L1 has been widely demonstrated to contribute to failed antitumor immunity. Blockade of PD-L1 with monoclonal antibody could modulate the tumor immune environment to augment immunotherapy. PD-L1 ...expression is also detected in several types of cancer and is associated with poor prognosis. However, the prognostic role of PD-L1 in oral squamous cell carcinoma (OSCC) is still controversial. Our aim was to determine the role of PD-L1 in the prognosis of OSCC patients to identify its potential therapeutic relevance. PD-L1 immunoreactivity was analyzed by immunohistochemistry in 305 cancer specimens from primary OSCC patients. The medium follow-up time after surgery was 3.8 years (range from 0.1 to 11.1 years). The prognostic value of PD-L1 on overall survival was determined by Kaplan-Meier analysis and Cox proportional hazard models. Higher PD-L1 expression is more likely in tumor tissues of female than male OSCC patients (P = 0.0062). Patients with distant metastasis also had high PD-L1 expression (P = 0.0103). Multivariate analysis identified high PD-L1 expression as an independent risk factor in males and smokers (males: hazard ratio = 1.556, P = 0.0077; smokers: hazard ratio = 2.058, P = 0.0004). We suggest that PD-L1 expression, determined by IHC staining, could be an independent prognostic marker for OSCC patients who are male or who have a smoking habit.
Microtubule‐associated protein Tau, abundant in the central nervous system (CNS), plays crucial roles in microtubule assembly and stabilization. Abnormal Tau phosphorylation and aggregation are a ...common pathogenic hallmark in Alzheimer's disease (AD). Hyperphosphorylation of Tau could change its conformation and result in self‐aggregation, increased oxidative stress, and neuronal death. In this study, we examined the potential of licochalcone A (a natural chalcone) and five synthetic derivatives (LM compounds) for inhibiting Tau misfolding, scavenging reactive oxygen species (ROS) and providing neuroprotection in human cells expressing proaggregant ΔK280 TauRD‐DsRed. All test compounds were soluble up to 100 μM in cell culture media and predicted to be orally bioavailable and CNS‐active. Among them, licochalcone A and LM‐031 markedly reduced Tau misfolding and associated ROS, promoted neurite outgrowth, and inhibited caspase 3 activity in ΔK280 TauRD‐DsRed 293 and SH‐SY5Y cells. Mechanistic studies showed that LM‐031 upregulates HSPB1 chaperone, NRF2/NQO1/GCLC pathway, and CREB‐dependent BDNF/AKT/ERK/BCL2 pathway in ΔK280 TauRD‐DsRed SH‐SY5Y cells. Decreased neurite outgrowth upon induction of ΔK280 TauRD‐DsRed was rescued by LM‐031, which was counteracted by knockdown of NRF2 or CREB. LM‐031 further rescued the downregulated NRF2 and pCREB, reduced Aβ and Tau levels in hippocampus and cortex, and ameliorated cognitive deficits in streptozocin‐induced hyperglycemic 3 × Tg‐AD mice. Our findings strongly indicate the potential of LM‐031 for modifying AD progression by targeting HSPB1 to reduce Tau misfolding and activating NRF2 and CREB pathways to suppress apoptosis and promote neuron survival, thereby offering a new drug development avenue for AD treatment.
Through upregulating HSPB1 chaperone to reduce Tau misfolding, and enhancing NRF2 and CREB pathways to reduce ROS and apoptosis in ΔK280 TauRD‐DsRed SH‐SY5Y cells, as well as promoting neuron survival and cognitive function in hyperglycemic 3×Tg‐AD mice, LM‐031 (3‐benzoyl‐5‐hydroxychromen‐2‐one) displays potential for Alzheimer’s disease treatment.
A national viral hepatitis therapy program was launched in Taiwan in October 2003. This study aimed to assess the impact of the program on reduction of end‐stage liver disease (ESLD) burden. Profiles ...of national registries of households, cancers, and death certificates were used to derive incidence and mortality of ESLDs from 2000 to 2011. Age‐gender–adjusted incidence and mortality rates of hepatocellular carcinoma (HCC) and chronic liver diseases (CLDs) and cirrhosis of adults ages 30‐69 years were compared before and after launching the program using Poisson's regression models. A total of 157,570 and 61,823 patients (15%‐25% of those eligible for reimbursed treatment) received therapy for chronic hepatitis B and C, respectively, by 2011. There were 42,526 CLDs and cirrhosis deaths, 47,392 HCC deaths, and 74,832 incident HCC cases occurred in 140,814,448 person‐years from 2000 to 2011. Male gender and elder age were associated with a significantly increased risk of CLDs and cirrhosis and HCC. Mortality and incidence rates of ESLDs decreased continuously from 2000 to 2003 (before therapy program) through 2004‐2007 to 2008‐2011 in all age and gender groups. The age‐gender–adjusted rate ratio (95% confidence interval; P value) in 2008‐2011 was 0.78 (0.76‐0.80; P < 0.001) for CLDs and cirrhosis mortality, 0.76 (0.75‐0.78; P < 0.005) for HCC mortality, and 0.86 (0.85‐0.88; P < 0.005) for HCC incidence using 2000‐2003 as the reference period (rate ratio = 1.0). Conclusions: The national viral hepatitis therapy program has significantly reduced the mortality of CLDs and cirrhosis and incidence and mortality of HCC. (Hepatology 2015;61:1154–1162)
Hypertension has been associated with Parkinson's disease (PD), but data on antihypertensive drugs and PD are inconclusive. We aim to evaluate antihypertensive drugs for an association with PD in ...hypertensive patients.
Hypertensive patients who were free of PD, dementia and stroke were recruited from 2005-2006 using Taiwan National Health Insurance Database. We examined the association between the use of calcium channel blockers (CCBs), angiotensin converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs) and the incidence of PD using beta-blockers as the reference. Cox regression model with time-varying medication use was applied.
Among 65,001 hypertensive patients with a mean follow-up period of 4.6 years, use of dihydropyridine CCBs, but not non-dihydropyridine CCBs, was associated with a reduced risk of PD (adjusted hazard ratio aHR = 0.71; 95% CI, 0.57-0.90). Additionally, use of central-acting CCBs, rather than peripheral-acting ones, was associated with a decreased risk of PD (aHR = .69 55-0.87. Further decreased association was observed for higher cumulative doses of felodipine (aHR = 0.54 0.36-0.80) and amlodipine (aHR = 0.60 0.45-0.79). There was no association between the use of ACEIs (aHR = 0.80 0.64-1.00) or ARBs (aHR = 0.86 0.69-1.08) with PD. A potentially decreased association was only found for higher cumulative use of ACEIs (HR = 0.52 0.34-0.80) and ARBs (HR = 0.52 0.33-0.80).
Our study suggests centrally-acting dihydropyridine CCB use and high cumulative doses of ACEIs and ARBs may associate with a decreased incidence of PD in hypertensive patients. Further long-term follow-up studies are needed to confirm the potential beneficial effects of antihypertensive agents in PD.
Depression, a psychiatric and dysthymic disorder, severely affects the learning, work and life quality. The main pathogenesis of depression is associated with central nervous system (CNS) ...dysfunction. Taurine has been demonstrated to exert protective effects on the brain development and can improve learning ability and memory. Our study investigated the antidepressant-like effects of taurine pre-treatment by examining the changes in depression-like behavior, hormones, neurotransmitters, inflammatory factors and neurotrophic factors in the hippocampus of a chronic unpredictable mild stress (CUMS)-induced depressive rat model. Taurine was found to inhibit the decrease of sucrose consumption and prevent the deficiency of spatial memory and anxiety in rats exposed to CUMS, suggesting a preventive effect of taurine on depression-like behavior. Furthermore, the decreased levels of 5-hydroxytryptamine, dopamine, noradrenaline; the increased levels of glutamate, corticosterone; and the decreased expressions of fibroblast growth factor-2, vascular endothelial growth factor and brain derived neurotrophic factor in depressive rats were hindered by taurine pre-administration. However, tumor necrosis factor-α and interleukin-1β levels were not significantly changed by taurine. The results demonstrated that the anti-depressive effect of taurine may be involved in the regulation of hypothalamic-pituitary-adrenal (HPA) axis and the promotion of neurogenesis, neuronal survival and growth in the hippocampus.
A highly efficient and chemoselective one‐pot protocol for the diversity‐oriented synthesis of two types of coumarin‐based formal cross‐coupling adducts, furo3,2‐ccoumarins and 3‐benzofuranyl ...chromenones, is described. Key attributes of the methodology are an initial chemoselective acylation of functionalized phosphorus zwitterions and a subsequent chemoselective intramolecular Wittig reaction that preferentially resulted in one of the two coumarin derivatives in high yield, depending on relative reactivities and the addition sequence of the acylating agents.
Double agents without the mystery: In the efficient diversity‐oriented synthesis of two types of coumarin‐derived polyheterocycles, furo3,2‐ccoumarins and 3‐benzofuranyl chromenones, the chemoselective acylation of phosphorus zwitterions was followed by a chemoselective intramolecular Wittig reaction (see scheme). The judicious choice of acylating agents and their addition sequence created a difference in reactivity in the Wittig reaction.
Esophageal squamous dysplasia is believed to be the precursor lesion of esophageal squamous cell carcinoma (ESCC); however, the genetic evolution from dysplasia to ESCC remains poorly understood. ...Here, we applied multi-region whole-exome sequencing to samples from two cohorts, 45 ESCC patients with matched dysplasia and carcinoma samples, and 13 tumor-free patients with only dysplasia samples. Our analysis reveals that dysplasia is heavily mutated and harbors most of the driver events reported in ESCC. Moreover, dysplasia is polyclonal, and remarkable heterogeneity is often observed between tumors and their neighboring dysplasia samples. Notably, copy number alterations are prevalent in dysplasia and persist during the ESCC progression, which is distinct from the development of esophageal adenocarcinoma. The sharp contrast in the prevalence of the 'two-hit' event on TP53 between the two cohorts suggests that the complete inactivation of TP53 is essential in promoting the development of ESCC.The pathogenesis of oesophageal squamous cell carcinoma is a multi-step process but the genetic determinants behind this progression are unknown. Here the authors use multi-region exome sequencing to comprehensively investigate the genetic evolution of precursor dysplastic lesions and untransformed oesophagus.
High blood cholesterol has been associated with cardiovascular diseases. The enzyme HMG CoA reductase (HMGCR) is responsible for cholesterol synthesis, and inhibitors of this enzyme (statins) have ...been used clinically to control blood cholesterol. Sterol regulatory element binding protein (SREBP) -2 is a key transcription factor in cholesterol metabolism, and HMGCR is a target gene of SREBP-2. Attenuating SREBP-2 activity could potentially minimize the expression of HMGCR. Luteolin is a flavone that is commonly detected in plant foods. In the present study, Luteolin suppressed the expression of SREBP-2 at concentrations as low as 1 μM in the hepatic cell lines WRL and HepG2. This flavone also prevented the nuclear translocation of SREBP-2. Post-translational processing of SREBP-2 protein was required for nuclear translocation. Luteolin partially blocked this activation route through increased AMP kinase (AMPK) activation. At the transcriptional level, the mRNA and protein expression of SREBP-2 were reduced through luteolin. A reporter gene assay also verified that the transcription of SREBF2 was weakened in response to this flavone. The reduced expression and protein processing of SREBP-2 resulted in decreased nuclear translocation. Thus, the transcription of HMGCR was also decreased after luteolin treatment. In summary, the results of the present study showed that luteolin modulates HMGCR transcription by decreasing the expression and nuclear translocation of SREBP-2.
Background/Purpose Little is known about the annual changes in cancer incidence and survival that occurred after the establishment of the long-form cancer registry database in Taiwan. Therefore, this ...study aimed to investigate the updated incidence and stage-specific relative survival rates (RSRs) among adult cancer patients in Taiwan. Methods Cancer incidence data from 2002 to 2012 were collected using the Taiwan Cancer Registry Database. Age-standardized incidence rates, average annual percent changes (AAPCs), and sex ratios were calculated for adults. Five-year stage-specific RSRs were estimated for cases diagnosed between 2004 and 2008 and were followed up to 2013 for major cancers. Results The overall age-standardized incidence rates per 100,000 populations increased from 348.39 in 2002 to 401.18 in 2012, and the AAPC was 1.7% ( p < 0.05), whereas the male:female ratio was approximately 1:3 during the entire period. Most cancer sites showed a trend of increasing incidence, with the exception of common cancers such as cervix uteri (AAPC = −6.2%, p < 0.05), bladder (AAPC = −2.5%, p < 0.05), stomach (AAPC = −2.4%, p < 0.05), nasopharynx (AAPC = −1.2%, p < 0.05), and liver (AAPC = −1.1%, p < 0.05). The 5-year RSRs for Stage I cancers were greater than 93% for the colon and rectum, female breast, and cervix uteri, whereas RSRs for patients with Stage IV cancers ranged from 2.9% to 38.9%, with patients with liver cancer and those with oral cancer showing the lowest and highest RSRs, respectively. Conclusion Our study showed increased incidence in most cancers and provided baseline estimates of stage-specific RSRs among the Taiwanese adult population. Continuous surveillance may help politicians to improve health policies and cancer care in Taiwan.
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