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Background: Traditional Chinese medicine (TCM) has been used to treat various diseases for thousands of years. However, the uncertainty of dosage as well as the lack of systemic evaluation of pharmacology and toxicology is one major reason why TCM remains mysterious and is not accepted worldwide. Hence, we aimed to propose an integrated dose–response metabolomics strategy based on both therapeutic effects and adverse reactions to guide the TCM dosage in treatment. Methods: The proposed methodology of integrated dose–response metabolomics includes four steps: dose design, multiple comparison of metabolic features, response calculation and dose–response curve fitting. By comparing the changes of all metabolites under different doses and calculating these changes through superposition, it is possible to characterize the global disturbance and thus describe the overall effect and toxicity of TCM induced by different doses. Rhubarb, commonly used for constipation treatment, was selected as a representative TCM. Results: This developed strategy was successfully applied to rhubarb. The dose–response curves clearly showed the efficacy and adverse reactions of rhubarb at different doses. The rhubarb dose of 0.69 g/kg (corresponding to 7.66 g in clinic) was selected as the optimal dose because it was 90% of the effective dose and three adverse reactions were acceptable in this case. Conclusion: An integrated dose–response metabolomics strategy reflecting both therapeutic effects and adverse reactions was established for the first time, which we believe is helpful to uncover the mysterious veil of TCM dosage. In addition, this strategy benefits the modernization and internationalization of TCM, and broadens the application of metabolomics. [ABSTRACT FROM AUTHOR]

Simple Summary: Epithelial ovarian cancer (EOC) is the deadliest cancer in the female reproductive system. Currently, there are no effective early detection methods for this disease, and the treatments for advanced stages of EOC have a low success rate. Circular RNAs (circRNAs) are noncoding RNAs generated from the "back-splicing" of precursor messenger RNAs. Recent studies have shown that many circRNAs are aberrantly expressed in tumor tissues and/or plasma of EOC patients, and they regulate EOC cell activity and tumor growth. In this review, we provide an overview of EOC and circRNA biology. We then summarize circRNAs that are dysregulated and exert tumor-promoting or tumor-suppressive effects in EOC. We also discuss the possibility of using circRNAs as diagnostic/prognostic markers and therapeutic targets. Epithelial ovarian cancer (EOC) is the most lethal gynecological cancer, and more than 70% of patients are diagnosed at advanced stages. Despite the application of surgery and chemotherapy, the prognosis remains poor due to the high relapse rate. It is urgent to identify novel biomarkers and develop novel therapeutic strategies for EOC. Circular RNAs (circRNAs) are a class of noncoding RNAs generated from the "back-splicing" of precursor mRNA. CircRNAs exert their functions via several mechanisms, including acting as miRNA sponges, interacting with proteins, regulating transcription, and encoding functional proteins. Recent studies have identified many circRNAs that are dysregulated in EOC and may be used as diagnostic and prognostic markers. Increasing evidence has revealed that circRNAs play a critical role in ovarian cancer progression by regulating various cellular processes, including proliferation, apoptosis, metastasis, and chemosensitivity. The circRNA-based therapy may be a novel strategy that is worth exploring in the future. Here, we provide an overview of EOC and circRNA biogenesis and functions. We then discuss the dysregulations of circRNAs in EOC and the possibility of using them as diagnostic/prognostic markers. We also summarize the role of circRNAs in regulating ovarian cancer development and speculate their potential as therapeutic targets. [ABSTRACT FROM AUTHOR]

Objectives. The purpose of this study was to identify the molecular mechanism and prognosis-related genes of Jianpi Jiedu decoction in the treatment of hepatocellular carcinoma. Methods. The gene expression data of hepatocellular carcinoma samples and normal tissue samples were downloaded from TCGA database, and the potential targets of drug composition of Jianpi Jiedu decoction were obtained from TCMSP database. The genes were screened out in order to obtain the expression of these target genes in patients with hepatocellular carcinoma. The differential expression of target genes was analyzed by R software, and the genes related to prognosis were screened by univariate Cox regression analysis. Then, the LASSO model was constructed for risk assessment and survival analysis between different risk groups. At the same time, independent prognostic analysis, GSEA analysis, and prognostic analysis of single gene in patients with hepatocellular carcinoma were performed. Results. 174 compounds of traditional Chinese medicine were screened by TCMSP database, corresponding to 122 potential targets. 39 upregulated genes and 9 downregulated genes were screened out. A total of 20 candidate prognostic related genes were screened out by univariate Cox analysis, of which 12 prognostic genes were involved in the construction of the LASSO regression model. There was a significant difference in survival time between the high-risk group and low-risk group (p < 0.05). Among the genes related to prognosis, the expression levels of CCNB1, NQO1, NUF2, and CHEK1 were high in tumor tissues (p < 0.05). Survival analysis showed that the high expression levels of these four genes were significantly correlated with poor prognosis of HCC (p < 0.05). GSEA analysis showed that the main KEGG enrichment pathways were lysine degradation, folate carbon pool, citrate cycle, and transcription factors. Conclusions. In the study, we found that therapy target genes of Jianpi Jiedu decoction were mainly involved in metabolism and apoptosis in hepatocellular carcinoma, and there was a close relationship between the prognosis of hepatocellular carcinoma and the genes of CCNB1, NQO1, NUF2, and CHEK1. [ABSTRACT FROM AUTHOR]

Triple negative breast cancer (TNBC) has received increasing attention from oncologists worldwide due to its poor prognosis and paucity of targeted therapies. MicroRNAs (miRs) are a group of small non‑coding RNAs that are responsible for the post‑transcriptional regulation of various target genes. The present study demonstrated that the expression of miR‑199b‑5p in breast cancer tissue was significantly reduced compared with that in normal breast tissues by reverse transcription‑quantitative polymerase chain reaction. In addition, western blot analysis and luciferase reporter assays revealed that miR‑199b‑5p in TNBC cells inhibited discoidin domain receptor tyrosine kinase 1 expression by directly targeting its 3'‑untranslated region. Furthermore, miR‑199b‑5p markedly suppressed the proliferation and invasion of TNBC cells, as demonstrated by using wound‑healing, migration, invasion and proliferation assays. Collectively, these results indicate that miR‑199b‑5p may be a novel alternative therapeutic target for TNBC. [ABSTRACT FROM AUTHOR]

Objective: This study explored the protective effects of the microRNA-126 (miR-126)- mediated PI3K/Akt/eNOS signaling pathway on human cardiac microvascular endothelial cells (HCMECs) against hypoxia/reoxygenation (H/R)-induced injury and the inflammatory response. Methods: Untreated HCMECs were selected for the control group. After H/R treatment and cell transfection, the HCMECs were assigned to the H/R, miR-126 mimic, mimicnegative control (NC), miR-126 inhibitor, inhibitor-NC, wortmannin (an inhibitor of PI3K) and miR-126 mimic + wortmannin groups. Super oxide dismutase (SOD), nitric oxide (NO), vascular endothelial growth factor (VEGF) and reactive oxygen species (ROS) were measured utilizing commercial kits. Quantitative real-time polymerase chain reaction (qRT-PCR) and enzyme-linked immunosorbent assay (ELISA) were performed to detect miR-126 expression and the mRNA and protein expression of inflammatory factors. Western blotting was used to determine the expression of key members in the PI3K/Akt/eNOS signaling pathway. ACCK- 8 assay and flow cytometry were employed to examine cell proliferation and apoptosis, respectively. The angiogenic ability in each group was detected by the lumen formation test. Results: Compared to the control group, p/t-PI3K, p/t-Akt and p/t-eNOS expression, NO, VEGF and SOD levels, cell proliferation and in vitro lumen formation ability were decreased, while the ROS content, interleukin (IL)-6, IL-10 and tumor necrosis factor (TNF)-α expression and cell apoptosis were significantly increased in the H/R, mimic-NC, miR-126 inhibitor, inhibitor- NC, wortmannin and miR-126 mimic + wortmannin groups. Additionally, in comparison with the H/R group, the miR-126 mimic group had elevated p/t-PI3K, p/t-Akt and p/t-eNOS expression, increased NO, VEGF and SOD contents, and strengthened cell proliferation and lumen formation abilities but also exhibited decreased ROS content, reduced IL-6, IL-10 and TNF-α expressions, and weakened cell apoptosis, while the miR-126 inhibitor and wortmannin group exhibited the opposite results. Furthermore, decreased p/t-PI3K, p/t-Akt and p/t-eNOS expressions, decreased NO, VEGF and SOD contents, cell proliferation and lumen formation abilities, as well as increased ROS content, increased IL-6, IL-10 and TNF-α expression, and increased cell apoptosis were observed in the miR-126 mimic + wortmannin group compared to themiR-126 mimic group. Conclusions: These findings indicated that miR-126 protects HCMECs from H/R-induced injury and inflammatory response by activating the PI3K/Akt/ eNOS signaling pathway. [ABSTRACT FROM AUTHOR]

Background: The association between hyperinsulinemia and obesity is well known. However, it is uncertain especially in childhood obesity, if initial fasting hyperinsulinemia predicts obesity, or obesity leads to hyperinsulinemia through insulin resistance. Objective: To investigate the predictive effect of fasting plasma insulin on subsequent weight change after a 5-year interval in childhood. Methods: 424 Children from Da Qing city, China, were recruited at 5 years of age and followed up for 5 years. Blood pressure, anthropometric measurements, fasting plasma insulin, glucose and triglycerides were measured at baseline and 5 years later. Results: Fasting plasma insulin at 5 years of age was significantly correlated with change of weight from 5 to 10 years (ΔWeight). Children in the lowest insulin quartile had ΔWeight of 13.08±0.73 kg compare to 18.39±0.86 in the highest insulin quartile (P<0.0001) in boys, and similarly 12.03±0.71 vs 15.80±0.60 kg (P<0.0001) in girls. Multivariate analysis showed that the predictive effect of insulin at 5 years of age on subsequent weight gain over 5 years remained statistically significant even after the adjustment for age, sex, birth weight, TV-viewing time and weight (or body mass index) at baseline. By contrast, the initial weight at 5 years of age did not predict subsequent changes in insulin level 5 years later. Children who had both higher fasting insulin and weight at 5 years of age showed much higher levels of systolic blood pressures, fasting plasma glucose, the homeostasis model assessment for insulin resistance (HOMA-IR) and triglycerides at 10 years of age. Conclusions: Fasting plasma insulin at 5 years of age predicts weight gain and cardiovascular risk factors 5 year later in Chinese children of early childhood, but the absolute weight at 5 years of age did not predict subsequent change in fasting insulin. [ABSTRACT FROM AUTHOR]

Cancer stem cells (CSCs) are characterized by intrinsic self-renewal and tumorigenic properties, and play important roles in tumor initiation, progression, and resistance to diverse forms of anticancer therapy. Accordingly, targeting signaling pathways that are critical for CSC maintenance and biofunctions, including the Wnt, Notch, Hippo, and Hedgehog signaling cascades, remains a promising therapeutic strategy in multiple cancer types. Furthermore, advances in various cancer omics approaches have largely increased our knowledge of the molecular basis of CSCs, and provided numerous novel targets for anticancer therapy. However, the majority of recently identified targets remain 'undruggable' through small-molecule agents, whereas the implications of exogenous RNA interference (RNAi, including siRNA and miRNA) may make it possible to translate our knowledge into therapeutics in a timely manner. With the recent advances of nanomedicine, in vivo delivery of RNAi using elaborate nanoparticles can potently overcome the intrinsic limitations of RNAi alone, as it is rapidly degraded and has unpredictable off-target side effects. Herein, we present an update on the development of RNAi-delivering nanoplatforms in CSC-targeted anticancer therapy and discuss their potential implications in clinical trials. [ABSTRACT FROM AUTHOR]

Advances in methodologies and tools often lead to new insights into cardiovascular diseases. Intravascular ultrasound (IVUS) is a well-established diagnostic method that provides high-resolution images of the vessel wall and atherosclerotic plaques. High-frequency (>50 MHz) ultrasound enables the spatial resolution of IVUS to approach that of optical imaging methods. However, the penetration depth decreases when using higher imaging frequencies due to the greater acoustic attenuation. An imaging method that improves the penetration depth of high-resolution IVUS would, therefore, be of major clinical importance. Modulated excitation imaging is known to allow ultrasound waves to penetrate further. This paper presents an ultrasound system specifically for modulated-excitation-based IVUS imaging. The system incorporates a high-voltage waveform generator and an image processing board that are optimized for IVUS applications. In addition, a miniaturized ultrasound transducer has been constructed using a Pb(Mg1/3Nb2/3)O3–PbTiO3 single crystal to improve the ultrasound characteristics. The results show that the proposed system was able to provide increases of 86.7% in penetration depth and 9.6 dB in the signal-to-noise ratio for 60 MHz IVUS. In vitro tissue samples were also investigated to demonstrate the performance of the system. [ABSTRACT FROM PUBLISHER]

Background. Cerebral infarction (CI) is a common brain disease in clinical practice, which is mainly due to the pathological environment of ischemia and hypoxia caused by difficult cerebral circulation perfusion function, resulting in ischemic necrosis of local brain tissue and neurological impairment. In traditional Chinese medicine (TCM) theory, CI is mainly due to blood stasis in the brain. Therefore, blood-activating and stasis-dissipating drugs are often used to treat CI in clinical practice. Salvia miltiorrhiza Bunge (SMB) is a kind of traditional Chinese medicine with good efficacy in promoting blood circulation and removing blood stasis, and treatment of CI with it is a feasible strategy. Based on the above analysis, we chose network pharmacology to investigate the feasibility of SMB in the treatment of CI and to study the possible molecular mechanisms by providing some reference for the treatment of CI with TCM. Methods. The active ingredients and related targets of SMB were obtained through the Traditional Chinese Medicine Systems Pharmacology (TCMSP) database, and CI-related targets were obtained from the GeneCards and DisGeNET databases. The target of SMB for the treatment of CI was obtained using Cytoscape software and visualized. GO and KEGG enrichment analysis was performed based on "clusterProfiler" within R, and the prediction results were validated by molecular docking technique. Results. By constructing a compound-target (C-T) network, it was found that the active components in SMB mainly treated CI by regulating key proteins such as AKT1, IL-6, and EGFR. These key proteins mainly involve in pathways such as immune regulation, cancer and lipid metabolism, such as lipid and atherosclerosis, chemical carcinogenesis-receptor activation pathways, and IL-17 signaling pathway. In the GO term, it mainly regulates the response to steroid hormones, membrane rafts, and G protein-amine receptor coupled activity. Eventually, we verified that the luteolin and tanshinone IIA components in SMB have a good possibility of action with AKT1 and IL-6 by in silico techniques, indicating that SMB has some scientificity in the treatment of CI. Conclusion. SMB mainly treats CI by regulating 94 proteins involved in lipid and atherosclerosis, chemical carcinogenesis-receptor activation, and IL-17 signaling pathway. Our research strategy provided a template for the drug development of TCM for the treatment of CI. [ABSTRACT FROM AUTHOR]

The present study aims to investigate the roles of herb pairs containing Angelicae Sinensis Radix (Danggui) in Xin-Sheng-Hua Granule (XSHG) on hemolytic and aplastic anemia (HAA) mice. HAA model mice were induced by acetyl phenylhydrazine and cyclophosphamide; then the samples of XSHG and its decomposed recipes (DY, DC, DT, DH, DJ, and DZ) were orally administrated to these mice. Indicators of peripheral blood routine, organ index, and ATPase activities were tested. Moreover, the main effective components in these samples were also analyzed by UHPLC-TQ-MS/MS. Clear separation between the control and model groups from score plot of principal component analysis (PCA) was easily seen, indicating that HAA model was successfully conducted. Afterwards, relative distance calculation method between dose groups and control group from PCA score plot was adopted to evaluate the integrated effects of hematinic function of different samples. And the orders of hematinic effects were as follows: XHSG > DJ > DT > DZ > DH > DC > DY. Further analysis of these samples by UHPLC-TQ-MS/MS revealed that XSHG underwent complicated changes when herb pairs containing Danggui were excluded from XSHG, respectively. Compared with XSHG, the vast majority of active compounds in sample DY (formula minus herb pair Danggui-Yimucao) decreased significantly, which could partly explain why herb pair Danggui-Yimucao made great contribution to XSHG. These findings showed that withdrawal analysis method is a valuable tool to analyze the impacts of herb pairs containing Danggui on XSHG, which could lay foundation to reveal the compatibility rules of this formula. [ABSTRACT FROM AUTHOR]

Objective. To systematically evaluate the efficacy of Chinese herbal medicine Qiju Dihuang Decoction (QDD) for hypertension. Methods. A comprehensive literature search of randomized controlled trials using QDD to treat hypertension was conducted in 7 electronic databases, including Chinese databases. Subjects and abstracts of the trials were read in NoteExpress for preliminary screening, and the full text was read for further screening. The data extraction table was made for the selected 19 trials, and risk of bias was assessed by using the Cochrane collaboration tool, followed by data analysis using Rev Man 5.3. Results. The antihypertensive efficacy of QDD is 1.45 times that of antihypertensive drugs and 1.56 times that of conventional therapies, which can also reduce the endothelin level. QPAD exhibits an antihypertensive effect, and its clinical efficacy is 1.34 times and 1.61 times that of antihypertensive drugs, which can not only significantly lower the diastolic blood pressure but also reduce the 24 h mean ambulate blood pressure. At the same time, it can decrease the TCM syndrome score, inhibit the inflammation, protect the renal function, reduce the insulin resistance, and improve the life quality of patients. Conclusion. QDD can effectively reduce blood pressure and improve the life quality of patients with hypertension, which plays a certain role in preventing hypertension complications. However, due to the methodological deficiencies, more rigorous randomized controlled trials will be needed in the future to provide stronger evidence. [ABSTRACT FROM AUTHOR]

Background. Qixuehe capsule (QXH), a Chinese patent medicine, has been demonstrated to be effective in the treatment of menstrual disorders. In traditional Chinese medicine (TCM) theory, qi stagnation and blood stasis syndrome (QS-BSS) is the main syndrome type of menstrual disorders. However, the pharmacodynamic effect of QXH in treating QS-BSS is not clear, and the main active compounds and underlying mechanisms remain unknown. Methods. A rat model of QS-BSS was established to evaluate the pharmacodynamic effect of QXH. Thereafter, a network pharmacology approach was performed to decipher the active compounds and underlying mechanisms of QXH. Results. QXH could significantly reduce the rising whole blood viscosity (WBV) and plasma viscosity (PV) but also normalize prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT), and fibrinogen (FIB) content in QS-BSS rats. Based on partial least-squares-discriminant analysis (PLS-DA), the low-dose QXH-intervened (QXH-L) and the high-dose QXH-intervened (QXH-H) groups seemed the most effective by calculating the relative distance to normality. Through network pharmacology, QXH may improve hemorheological abnormality mainly via 185 compounds-51 targets-28 pathways, whereas 184 compounds-68 targets-28 pathways were associated with QXH in improving coagulopathy. Subsequently, 25 active compounds of QXH were verified by UPLC-Q/TOF-MS. Furthermore, 174 active compounds of QXH were shared in improving hemorheological abnormality and coagulopathy in QS-BSS, each of which can act on multiple targets to be mainly involved in complement and coagulation cascades, leukocyte transendothelial migration, PPAR signaling pathway, VEGF signaling pathway, and arachidonic acid metabolism. The attribution of active compounds indicated that Angelicae Sinensis Radix (DG), Paeoniae Radix Rubra (CS), Carthami Flos (HH), Persicae Semen (TR), and Corydalis Rhizoma (YHS) were the vital herbs of QXH in treating QS-BSS. Conclusion. QXH can improve the hemorheology abnormality and coagulopathy of QS-BSS, which may result from the synergy of multiple compounds, targets, and pathways. [ABSTRACT FROM AUTHOR]

Purpose: This study aimed to assess the effects of transitional health management on adherence and prognosis in elderly patients with acute myocardial infarction undergoing percutaneous coronary intervention. Methods: We conducted the trial from June 2016 to December 2016. A total of one hundred and fifty patients with acute myocardial infarction after PCI who met the inclusion criteria were randomly divided into an experimental (n = 75) group and a control (n = 75) group. The participants in the experimental group received transitional health management for three months. The two groups of patients were evaluated for treatment adherence, quality of life, clinical indicators, adverse cardiovascular events and statistics regarding readmission rates at baseline and 6 months after discharge. Results: Compared with the controls, patients in the intervention group demonstrated better medication adherence, reexamination adherence, healthy lifestyle and clinical indicators (all P<0.05) and lower rates of adverse cardiovascular events and readmission (all P<0.05). Conclusion: Transitional health management effectively improved adherence in elderly patients with acute myocardial infarction after PCI, ameliorated clinical indicators, and effectively reduced the incidence of adverse cardiovascular events and readmission rates. Transitional health management was an effective intervention for PCI patients after discharge. [ABSTRACT FROM AUTHOR]

Calcitonin gene-related peptide (CGRP) has a potent protective action on the cardiovascular system; however, little is known about the role of CGRP in angiotensin II- (Ang II-) induced inflammation of vascular smooth muscle cells (VSMCs). This study is aimed at determining the anti-inflammatory effect of CGRP in Ang II-treated VSMCs and whether a disintegrin and metalloproteinase 17 (ADAM17) modulates this protective action. Small interference RNA (siRNA) and inhibitors of CGRP, epidermal growth factor receptor (EGFR), and extracellular signal-regulated kinase 1/2 (ERK1/2) were adopted to investigate their effect on Ang II-induced inflammation in VSMCs. Here, we found that CGRP could inhibit inflammation and decrease ADAM17 expression and activation of EGFR and ERK1/2 in VSMCs stimulated with Ang II. Results of siRNA demonstrated that ADAM17 siRNA attenuated Ang II-induced inflammation and up-regulation of activities of EGFR and ERK1/2 in VSMCs. Furthermore, the EGFR-ERK1/2 pathway promoted Ang II-induced VSMC inflammation. In summary, these findings identify the anti-inflammatory effect of CGRP in VSMCs stimulated by Ang II and suggest that ADAM17 is involved in the protective effect of CGRP against Ang II-induced inflammation via the EGFR-ERK1/2 pathway in VSMCs. [ABSTRACT FROM AUTHOR]

Objective: Local immune regulation therapy has been one of the therapeutic methods used for the treatment of autoimmune thyroid disease in patients with pretibial myxedema (PTM). However, the poor response rate and high recurrence rate are still major problems. Whether a premixed corticosteroid, compound betamethasone, could enhance remission rate and decrease recurrence rate in patients with PTM was investigated in the present study.Subjects and Methods: We have performed a clinical utility observation of compound betamethasone with intralesional injections based on basic thyroid disease treatment in 32 PTM patients between January 2008 and August 2016. The patients were followed up for 2 years, and the clinical outcomes and side effects were calculated and analyzed.Results: All patients had a complete remission after different times of injection. A total of 21.7% patients had complete remission with one time of injection, 34.8% with two times of injection, 17.4% with three times of injection, 4.3% with four times of injection, and 4.3% with five times of injection. In all, 56.3% patients with a disease duration of <6 months had complete remission after a 1-month treatment, 37.5% patients with a disease duration between 6 months and 12 months had complete remission after a 2-month treatment, 3.1% patients with a disease duration of 2 years had complete remission after a 5-month treatment, and 3.1% with a disease duration of 5 years had complete remission after a 7-month treatment.Conclusion: Compound betamethasone with multipoint intralesional injection is a feasible, effective, and secure novel strategy in the treatment of PTM. [ABSTRACT FROM AUTHOR]

Background: Cryptococcal infection has become a public health challenge globally. However, information about cryptococcal infection in patients with hematological diseases remains relatively rare.Methods: HIV-uninfected cryptococcosis cases with hematological diseases admitted to Huashan Hospital from January 2001 to December 2014 were reviewed.Results: In total, 33 cryptococcosis patients were enrolled, including 12 malignant and 21 non-malignant hematological cases. Twenty-six patients had central nervous system (CNS) involvement, which was observed more often in patients with non-malignancies than with malignancies (20/21 vs. 6/12, P = 0.001) Most patients (25/26) with CNS infection were confirmed by cerebrospinal fluid (CSF) culture or smear, and 100% (20/20) of them tested positive for the CSF cryptococcal antigen test. Eighteen out of 26 cryptococcal meningitis patients were treated with amphotericin B (AmB)-based therapy, 16 of them with AmB deoxycholate (d-AmB) and 2 patients with liposomal AmB. The clinical success rate was 55.6%. D-AmB was well-tolerated at 0.35-0.59 mg/kg/d (median 0.43 mg/kg/d) and only 12 patients had mild adverse events.Conclusions: CNS cryptococcal infection was more frequent in patients with hematological non-malignancies, and cryptococcal antigen test as well as the CSF fungal culture or smear are suggested for early diagnosis. D-AmB could be used as an alternative therapy for CNS-infected patients with hematological diseases. [ABSTRACT FROM AUTHOR]

Human induced pluripotent stem cells (hiPSCs) may provide potential resource for regenerative medicine research, including generation of insulin-producing cells for diabetes research and insulin production. Testosterone (T) is an androgen hormone which promotes protein synthesis and improves the management of type 2 diabetes in clinical studies. Concurrently, co-existed hyperandrogenism and hyperinsulinism is frequently observed in polycystic ovary syndrome, congenital adrenal hyperplasia and some of Wermer's syndrome. However, the relationship among androgens, insulin and the differentiation of pancreatic β cells is still not fully clear. Here we find that T improves the differentiation efficiency of insulin-producing cells from hiPSCs. The addition of T into routine differentiation formula for pancreatic β cells increases the differentiation efficiency from 12% to 35%. The administration of T promotes the expression of key genes associated with β cells differentiation including NGN3, NEUROD1 and INS. This finding benefits the ongoing process to optimize the differentiation protocol of pancreatic β cells from hiPSCs, and provides some degree of understanding the clinical management of T for type 2 diabetes. [ABSTRACT FROM AUTHOR]

Background: ALK rearrangement-advanced NSCLC patients respond to crizotinib. ALK rearrangement is currently determined with RT-PCR. VENTANA IHC is a standard method to identify ALK protein overexpression in NSCLC; however, VENTANA IHC has rarely been used to determine the response to crizotinib in Chinese patients with NSCLC and ALK overexpression. To better clarify the clinical implication of VENTANA IHC to detect ALK rearrangements, we conducted this study to analyze VENTANA IHC and RT-PCR in a large cohort of Chinese patients with NSCLC undergoing screening for ALK rearrangements.Methods: A total of 1720 patients with NSCLC who had ALK rearrangements detected by VENTANA IHC and/or RT-PCR were included in this analysis. We compared the efficacy and survival of ALK-positive patients detected by VENTANA IHC and RT-PCR. We used NGS to identify patients in whom the two methods were inconsistent.Results: Among 1720 patients, 187 (10.87%) were shown to be ALK-positive by VENTANA IHC and/or RT-PCR, and 66 received crizotinib treatment. We identified 10.27% (172/1674) of patients as ALK-positive by the VENTANA IHC method, and 12.73% (41/322) of patients had ALK rearrangements by the RT-PCR method. Twenty-nine of 276 (10.51%) ALK-positive patients were simultaneously analyzed using VENTANA IHC and RT-PCR. The overall response rates were 65.90% (29/44) by VENTANA IHC and 55.88% (19/34) by RT-PCR. The disease control rates were 86.36% (38/44) by VENTANA IHC and 76.47% (26/34) by RT-PCR. In contrast, the median progression-free survival for VENTANA IHC and RT-PCR was 8.5 and 9.2 months, respectively. The VENTANA IHC and RT-PCR results obtained for 6 of 17 ALK-positive patients were inconsistent based on NGS; specifically, 4 patients had EML4-ALK fusions, 2 patients had non EML4-ALK fusions, 1 patient had a KCL1-ALK fusion, and one patient had a FBXO36-ALK fusion.Conclusions: VENTANA IHC is a reliable and rapid screening tool used in routine pathologic laboratories for the identification of suitable candidates for ALK-targeted therapy. VENTANA IHC has moderate sensitivity and a slightly higher association with response to therapy with ALK inhibitors, and some VENTANA IHC-positive, but RT-PCR-negative cases may benefit from crizotinib. [ABSTRACT FROM AUTHOR]

Background: Previous studies have reported that natriuretic peptides in the blood and pleural fluid (PF) are effective diagnostic markers for heart failure (HF). These natriuretic peptides include N-terminal pro-brain natriuretic peptide (NT-proBNP), brain natriuretic peptide (BNP), and midregion pro-atrial natriuretic peptide (MR-proANP). This systematic review and meta-analysis evaluates the diagnostic accuracy of blood and PF natriuretic peptides for HF in patients with pleural effusion. Methods: PubMed and EMBASE databases were searched to identify articles published in English that investigated the diagnostic accuracy of BNP, NT-proBNP, and MR-proANP for HF. The last search was performed on 9 October 2014. The quality of the eligible studies was assessed using the revised Quality Assessment of Diagnostic Accuracy Studies tool. The diagnostic performance characteristics (sensitivity, specificity, and other measures of accuracy) were pooled and examined using a bivariate model. Results: In total, 14 studies were included in the meta-analysis, including 12 studies reporting the diagnostic accuracy of PF NT-proBNP and 4 studies evaluating blood NT-proBNP. The summary estimates of PF NT-proBNP for HF had a diagnostic sensitivity of 0.94 (95% confidence interval [CI]: 0.90–0.96), specificity of 0.91 (95% CI: 0.86–0.95), positive likelihood ratio of 10.9 (95% CI: 6.4–18.6), negative likelihood ratio of 0.07 (95% CI: 0.04–0.12), and diagnostic odds ratio of 157 (95% CI: 57–430). The overall sensitivity of blood NT-proBNP for diagnosis of HF was 0.92 (95% CI: 0.86–0.95), with a specificity of 0.88 (95% CI: 0.77–0.94), positive likelihood ratio of 7.8 (95% CI: 3.7–16.3), negative likelihood ratio of 0.10 (95% CI: 0.06–0.16), and diagnostic odds ratio of 81 (95% CI: 27–241). The diagnostic accuracy of PF MR-proANP and blood and PF BNP was not analyzed due to the small number of related studies. Conclusions: BNP, NT-proBNP, and MR-proANP, either in blood or PF, are effective tools for diagnosis of HF. Additional studies are needed to rigorously evaluate the diagnostic accuracy of PF and blood MR-proANP and BNP for the diagnosis of HF. [ABSTRACT FROM AUTHOR]

Angiogenesisis a key restorative mechanism in response to ischemia, and pro-angiogenic therapy could be beneficial in stroke. Accumulating experimental and clinical evidence suggest that human urinary kallidinogenase (HUK) improves stroke outcome, but the underlying mechanisms are not clear. The aim of current study was to verify roles of HUK in post-ischemic angiogenesis and identify relevant mediators. In rat middle cerebral artery occlusion (MCAO) model, we confirmed that HUK treatment could improve stroke outcome, indicated by reduced infarct size and improved neurological function. Notably, the 18F-FDG micro-PET scan indicated that HUK enhanced cerebral perfusion in rats after MCAO treatment. In addition, HUK promotespost-ischemic angiogenesis, with increased vessel density as well as up-regulated VEGF andapelin/APJ expression in HUK-treated MCAO mice. In endothelial cell cultures, induction of VEGF and apelin/APJ expression, and ERK1/2 phosphorylation by HUK was further confirmed. These changes were abrogated by U0126, a selective ERK1/2 inhibitor. Moreover, F13A, a competitive antagonist of APJ receptor, significantly suppressed HUK-induced VEGF expression. Furthermore, angiogenic functions of HUK were inhibited in the presence of selective bradykinin B1 or B2 receptor antagonist both in vitro and in vivo. Our findings indicate that HUK treatment promotes post-ischemic angiogenesis and cerebral perfusion via activation of bradykinin B1 and B2 receptors, which is potentially due to enhancement expression of VEGF and apelin/APJ in ERK1/2 dependent way. [ABSTRACT FROM AUTHOR]

During cancer development, tumor suppressor genes were silenced by promoter methylation or histone deacetylation. Histone deacetylases (HDACs) are important to maintain histone deacetylation. HDAC inhibitors (HDACis) were thus proposed as a new therapeutic approach to cancer. The current study aims to understand the effect and molecular mechanisms of HDACis on gastric cancer cells. Trichostatin A (TSA) significantly inhibited the growth of gastric cancer cells by inducing apoptosis. Gene profiling results showed PUMA (p53 upregulated modulator of apoptosis) as one of 122 genes upregulated in TSA-treated gastric cancer cells. PUMA was downregulated in gastric cancer cell lines and primary gastric carcinoma tissues. Patients with low PUMA expression had significant decreases in overall survival (HR, 2.04; p = 0.047). Ectopic PUMA expression inhibited the growth of gastric cancer cells while PUMA depletion promoted cellular growth. The knockdown of HDAC3 but not other HDACs upregulated PUMA expression. HDAC3 could bind to PUMA promoter, which was abrogated after TSA treatment. In contrast to TSA and SB, HDAC3 siRNA failed to upregulate p53 expression but promoted the interaction of p53 with PUMA promoter. In summary, proapoptotic PUMA was downregulated in gastric cancer and its mRNA expression level is a valuable prognosis factor for gastric cancer. HDAC3 is important to downregulate PUMA expression in gastric cancer and HDACis, like TSA, promoted PUMA expression through stabilizing p53 in addition to HDAC3 inhibition. In combination with chemotherapy, targeting HDAC3 might be a promising strategy to induce apoptosis of gastric cancer cells. [ABSTRACT FROM AUTHOR]

Survivin is overexpressed in major types of cancer and is considered an ideal 'universal' tumor-associated antigen that can be targeted by immunotherapeutic vaccines. However, its anti-apoptosis function raises certain safety concerns. Here, a new truncated human survivin, devoid of the anti-apoptosis function, was generated as a candidate tumor vaccine. Interleukin 2 (IL-2) has been widely used as an adjuvant for vaccination against various diseases. Meanwhile, the DNA prime and recombinant adenovirus (rAd) boost heterologous immunization strategy has been proven to be highly effective in enhancing immune responses. Therefore, the efficacy of a new cancer vaccine based on a truncated form of survivin, combined with IL-2, DNA prime, and rAd boost, was tested. As prophylaxis, immunization with the DNA vaccine alone resulted in a weak immune response and modest anti-tumor effect, whereas the tumor inhibition ratio with the DNA vaccine administered with IL-2 increased to 89 % and was further increased to nearly 100 % by rAd boosting. Moreover, complete tumor rejection was observed in 5 of 15 mice. Efficacy of the vaccine administered therapeutically was enhanced by nearly 300 % when combined with carboplatin. These results indicated that vaccination with a truncated survivin vaccine using DNA prime-rAd boost combined with IL-2 adjuvant and carboplatin represents an attractive strategy to overcoming immune tolerance to tumors and has potential therapeutic benefits in melanoma cancer. [ABSTRACT FROM AUTHOR]

Active-fixation pacing leads allow the use of selective pacing sites. We evaluated their long-term performance versus passive-fixation leads in 199 newly implanted patients (n = 100 active and n = 99 passive). Postoperative pacing thresholds in the active group were higher than in the passive group (0.85 ± 0.31 V vs. 0.53 ± 0.21 V at baseline, P < 0.001). The active thresholds fell to 0.72 ± 0.23 V at 5 years with a significant drop at one month (0.68 ± 0.53 V, P = 0.003). The passive thresholds slightly increased to 0.72 ± 0.31 V at five years. Differences between groups were significant until three years (all P < 0.05). Active impedances were generally lower than passive impedances (600.44 ± 94.31Ω vs. 683.14 ± 110.98Ω at baseline), and both showed significant reductions at one month to 537.96 ± 147.43Ω in the active group, and after three months to 643.85 ± 82.40Ω in the passive group (both P < 0.01 vs. baseline). Impedance differences between groups were significant until four years (all P < 0.05). Adverse events included thresholds over 1 V, 5 of 6 active and 2 of 5 passive leads returned to below 1 V. One active left ventricular lead dislodged. One passive left subclavian lead insulation fracture occurred. Thus Active fixation pacing leads are stable in a five-year long-term follow up. There was no difference between active and passive leads in terms of electrical performance. [ABSTRACT FROM AUTHOR]