Objective To assess the efficacy and the treatment-induced side effects of intravesically administered Epirubicin (EPI) following TUR in patients with Ta and T1 superficial bladder cancer compared to TUR alone. Methods According to the Cochrane reviewer’s handbook, included studies were those on patients with histologically confirmed Ta and T1 bladder cancer. EPI and EPI derivatives, dose and schedule would be considerd appropriate for inclusion. The search strategy was developed according to the Collaborative Review Group search strategy. Medline, EMbase, CBMdisc and the Cochrane library, articles of conference proceedings, and academic collections were searched for randomised controlled trials (RCTs) and quasi-RCT comparing intravesical EPI following TUR with TUR alone. Data were extracted from each identified paper independently by two reviewers. Trials were assessed for quality according to the method of Jadad scale. RevMan4.2 software developed by the Cochrane Collaboration was used for satistical analysis. Results Two hundred and thirteen related articles were identified, but only 10 were included in our systematic review. 3 articles were high quality and the rest were low. The pooled RR=1.51 (95%CI 1.32 to 1.72) and the pooled RR=1.49 (95%CI 1.35 to 1.66) in patients with Ta and T1 bladdercancer at 1 and 2 years respectively; The pooled RR=1.34 (95%CI 1.22 to 1.48) when comparing relative efficacy of intravesical EPI (drug doselt;50 mg) following TUR with TUR alone; The pooled RR=1.63 (95%CI 1.48 to 1.79) when comparing relative efficacy of intravesical EPI (drug dosegt;50 mg) following TUR with TUR alone. RR=1.49 (95%CI 1.33 to 1.66) and RR=1.56 (95%CI 1.36 to 1.84) when comparing relative efficacy of single intravesical EPI following TUR with TUR alone respectively. RR=0.79 (95%CI 0.53 to 1.17) when comparing the incidence of disease progression of intravesical doxorubicin following TUR with TUR alone. RR=4.34 (95%CI 2.62 to 7.19) when comparing side effect of intravesical EPI following TUR with TUR alone. Conclusions Intravesically administered EPI following TUR in patients with Ta and T1 superficial bladder cancer may reduce the incidence of tumour recurrence, but cannot reduce the incidence of disease progreesion. Intravesically administered EPI following TUR has some side effects but can be tolerated and has no influence on the life of patients.
Synergistic drug combinations enable enhanced therapeutics. Their discovery typically involves the measurement and assessment of drug combination index (CI), which can be facilitated by the development and applications of in-silico CI predictive tools. In this work, we developed and tested the ability of a mathematical model of drug-targeted EGFR-ERK pathway in predicting CIs and in analyzing multiple synergistic drug combinations against observations. Our mathematical model was validated against the literature reported signaling, drug response dynamics, and EGFR-MEK drug combination effect. The predicted CIs and combination therapeutic effects of the EGFR-BRaf, BRaf-MEK, FTI-MEK, and FTI-BRaf inhibitor combinations showed consistent synergism. Our results suggest that existing pathway models may be potentially extended for developing drug-targeted pathway models to predict drug combination CI values, isobolograms, and drug-response surfaces as well as to analyze the dynamics of individual and combinations of drugs. With our model, the efficacy of potential drug combinations can be predicted. Our method complements the developed in-silico methods (e.g. the chemogenomic profile and the statistically-inferenced network models) by predicting drug combination effects from the perspectives of pathway dynamics using experimental or validated molecular kinetic constants, thereby facilitating the collective prediction of drug combination effects in diverse ranges of disease systems.
ObjectiveThis study examined the pattern of adjunctive antidepressant use in schizophrenia patients and its demographic and clinical correlates in a nationwide survey in China. MethodsFourteen thousand and thirteen patients in 45 Chinese psychiatric hospitals or centers were interviewed (4,486 in 2002, 5,288 in 2006, and 4,239 in 2012). Patients' sociodemographic and clinical characteristics were recorded using a standardized protocol and data collection procedure. Chi-square test, independent-samples t test, Mann-Whitney U test, and multiple logistic regression analysis were used in data analyses. ResultsAntidepressant use was found in 5.2% of the study population with 4.6% in 2002, 4.3% in 2006, and 6.9% in 2012, respectively. A significant increase in use from 2006 to 2012 was found (p<.001). Multiple logistic regression analyses in the whole population revealed that patients receiving adjunctive antidepressants were more likely to be outpatients in tertiary referral centers (level-III hospitals) and who had an earlier age of onset, less severe global illness, but more depressive symptoms. They were less likely to receive first-generation antipsychotics but more likely to receive benzodiazepines (R-2=0.255, p<.001). ConclusionsDespite an increasing trend, the frequency of antidepressant use in schizophrenia in China was considerably lower than in Western countries. The benefits and risks associated with concomitant use of antidepressants in schizophrenia need to be studied further.
In recent years, submucosal tunneling endoscopic resection (STER) has emerged as a novel therapeutic endoscopic technique for upper gastrointestinal submucosal tumors (SMTs). The aim of this study was to evaluate the safety and efficacy of STER for upper gastrointestinal SMTs. A systematic search of both English and Chinese databases was performed until November 15, 2015. Complete resection and en bloc resection rates were considered the primary outcome measures. Prevalence of complications was considered the secondary outcome measure. A random-effects model was used to generate conservative estimates of the prevalence of the main outcome variables. All data analyses were performed using Meta-Analyst software (version beta 3.13). A total of 28 studies were included in the final meta-analysis. The pooled complete resection and en bloc resection rates were 97.5 % (95 % CI 96.0-98.5 %) and 94.6 % (95 % CI 91.5-96.7 %), respectively. The common complications associated with STER were air leakage symptoms and perforation. The pooled prevalence of air leakage symptoms was 14.8 % (95 % CI 10.5-20.5 %) for subcutaneous emphysema and pneumomediastinum, 6.1 % (95 % CI 4.0-9.0 %) for pneumothorax and 6.8 % (95 % CI 4.7-9.6 %) for pneumoperitoneum. Additionally, the pooled prevalence of perforation was 5.6 % (95 % CI 3.7-8.2 %). Only a few cases of bleeding were reported in two studies. STER is a highly feasible and safe treatment option for upper gastrointestinal SMTs.
Cancer-associated fibroblasts (CAFs) are one major type of component identified in the tumor microenvironment. Studies have focused on the genetic and epigenetic status of CAFs, since they are critical in tumor progression and differ phenotypically and functionally from normal fibroblasts. The present review summarizes the recent achievements in understanding the gene profiles of CAFs and pays special attention to their possible epigenetic alterations. A total of 7 possible genetic alterations and epigenetic changes in CAFs are discussed, including gene differential expression, karyotype analysis, gene copy number variation, loss of heterozygosis, allelic imbalance, microsatellite instability, post-transcriptional control and DNA methylation. These genetic and epigenetic characteristics are hypothesized to provide a deep understanding of CAFs and a perspective on their clinical significance.
Background: With the increase in the amount of DNA methylation and gene expression data, the epigenetic mechanisms of cancers can be extensively investigate. Available methods integrate the DNA methylation and gene expression data into a network by specifying the anti-correlation between them. However, the correlation between methylation and expression is usually unknown and difficult to determine. Results: To address this issue, we present a novel multiple network framework for epigenetic modules, namely, Epigenetic Module based on Differential Networks (EMDN) algorithm, by simultaneously analyzing DNA methylation and gene expression data. The EMDN algorithm prevents the specification of the correlation between methylation and expression. The accuracy of EMDN algorithm is more efficient than that of modern approaches. On the basis of The Cancer Genome Atlas (TCGA) breast cancer data, we observe that the EMDN algorithm can recognize positively and negatively correlated modules and these modules are significantly more enriched in the known pathways than those obtained by other algorithms. These modules can serve as bio-markers to predict breast cancer subtypes by using methylation profiles, where positively and negatively correlated modules are of equal importance in the classification of cancer subtypes. Epigenetic modules also estimate the survival time of patients, and this factor is critical for cancer therapy. Conclusions: The proposed model and algorithm provide an effective method for the integrative analysis of DNA methylation and gene expression. The algorithm is freely available as an R-package at https://github.com/william0701/EMDN.
Tooth development involves epithelium invagination, mesenchyme aggregation, and epithelium-mesenchyme communication. A sophisticated signaling pathway network regulates the differentiation and crosstalk of multiple cell types in tooth germs and coordinates the broad spectrum of complex processes. MicroRNAs (miRNAs), a class of small non-coding RNA species that have been relatively well studied over the last few years, are now proposed as important regulators of tooth developmental signaling pathways as they repress cellular protein levels to provide a posttranscriptional gene regulation. In this review, we summarize the current knowledge of miRNA characteristics in regulating morphogenesis, amelogenesis, dentin formation, and tooth eruption and how they interplay with the signaling molecules during these processes. (C) 2016 Elsevier Ltd. All rights reserved.
Background: Necrotizing enterocolitis (NEC) is the leading cause of neonatal gastrointestinal mortality; effective interventions are lacking with limited understanding of the pathogenesis of NEC. The importance of Toll-like receptor 4 (TLR4) signaling in NEC is well documented; however, the potential mechanisms that regulate enterocyte inflammation and apoptosis remain unclear. The aim of this study was to characterize the role of TLR4-mediated inflammation and apoptosis in the development of NEC and to determine the major apoptotic pathways and regulators in the process. Methods: TLR4-deficient C57BL/10ScNJ mice and lentivirus-mediated stable TLR4-silent cell line (IEC-6) were used. NEC was induced by formula gavage, cold, hypoxia, combined with lipopolysaccharide in vivo or lipopolysaccharide stimulation in vitro. Enterocyte apoptosis was evaluated by TUNEL or Annexin analysis. The expression of TLR4, caspase3, caspase8, caspase9, Bip, Bax, Bcl-2, and RIP was detected by Western blot and immunofluorescence. Inflammatory factors such as tumor necrosis factor-a and interleukin-2 were examined by Luminex. Results: Defect of TLR4 led to suppressed enterocytes apoptosis both in vitro and in vivo; the expression of caspase3, caspase8, Bip, and Bax was decreased; and caspase9 and Bcl-2 were increased. NEC severity was attenuated in TLR4-deficient mice compared with wild-type counterparts, and enterocytes apoptosis was correlated with NEC severity. RIP and cytokine level of tumor necrosis factor-a and interleukin-2 were also decreased. Conclusions: TLR4-induced inflammation and apoptosis play a critical role in the pathogenesis of NEC. TLR4 inhibition, combined with extrinsic (caspase8) and/or endoplasmic reticulum stress (Bip) apoptosis signaling blockade could serve as a potential effective treating strategy for NEC.
Epileptic seizures, the most common symptom accompanying glioma, are closely associated with tumor growth and patient quality of life. However, the association between glioma and glioma-related epilepsy is poorly understood. In fact, findings related to the location of epileptogenicity have been inconsistent in previous studies. We investigated seizure foci in patients with glioma and the corresponding association between glioma-related epilepsy and the tumoral and peritumoral microenvironment. Clinical characteristics, extracellular electrophysiology, immunohistochemistry, and western blots were conducted on 12 patients with glioma; nine patients had histories of preoperative seizures while three did not. Samples from included patients were used to identify seizure foci and mTOR pathway status. Electrophysiological recordings were conducted on 36 samples (tumor, peritumoral, and normal brain tissues) from 12 patients. Interictal-like discharges (ILDs) were observed in seven of nine peritumoral tissues obtained from patients with glioma that had experienced perioperative seizures. No ILDs were observed in any other sample groups. Western blots and immunohistochemistry for mTOR pathway proteins (mTOR and S6k) suggested that the mTOR pathway was activated in peritumoral tissues of patients with seizure history, but inactivated in patients without seizure history. Our results suggest that mTOR pathway expression in peritumoral tissues is associated with tumor-related seizures, thus providing a potential target for therapeutics aimed at simultaneously controlling gliomas and seizures.
Epilepsy has been recognized as a brain network disorder. Therefore, functional MRI (fMRI)-based connectivity is an ideal technique for exploring the complex effects of epilepsy on the brain. Functional connectivity studies have provided insights into the physiopathogenesis of the epileptic network underlying focal epilepsies, genetic generalized epilepsy, and specific epileptic syndromes. An increasing number of studies have focused on the deleterious effects of epilepsy on other brain networks to help to explain cognitive deficits and psychiatric symptoms. Anti-epileptic treatment studies have yielded information about the side effects and the restoration of functional abnormalities after using the drug. Researchers who have examined predictors of surgical outcomes have suggested that there might be identifiable pre-surgical patterns of functional connectivity that are associated with a greater likelihood of positive cognitive or seizure outcomes. However, knowledge regarding the role of fMRI connectivity remains limited in clinical settings. Further validation through invasive investigations and follow-up studies is required for its reliable application in the clinical management of individual patients. (C) 2016 Published by Elsevier Ltd on behalf of British Epilepsy Association.