A Targeted and Responsive Nanoprodrug Delivery System for Synergistic Glioma Chemotherapy.

Doxorubicin (DOX) is widely used as a chemotherapeutic agent for both hematologic and solid tumors and is a reasonable candidate for glioma treatment. However, its effectiveness is hindered by significant toxicity and drug resistance. Moreover, the presence of the blood-brain barrier (BBB) brings a crucial challenge to glioma therapy. In response, a GSH-responsive and actively targeted nanoprodrug delivery system (cRGD/PSDOX-Cur@NPs) are developed. In this system, a disulfide bond-bridged DOX prodrug (PEG-SS-DOX) is designed to release specifically in the high glutathione (GSH) tumor environment, markedly reducing the cardiotoxicity associated with DOX. To further address DOX resistance, curcumin, serving as a P-glycoprotein (P-gp) inhibitor, effectively increased cellular DOX concentration. Consequently, cRGD/PSDOX-Cur@NPs exhibited synergistic anti-tumor effects in vitro. Furthermore, in vivo experiments validated the superior BBB penetration and brain-targeting abilities of cRGD/PSDOX-Cur@NPs, showcasing the remarkable potential for treating both subcutaneous and orthotopic gliomas. This research underscores that this nanoprodrug delivery system presents a novel approach to inhibiting glioma while addressing resistance and systemic toxicity.

Real-world application of nirmatrelvir/ritonavir in hospitalized COVID-19 patients with onset of symptoms beyond 5 days: a comparative study.

PURPOSE: Physicians may administer Nirmatrelvir-ritonavir to patients who have been symptomatic for more than 5 days. There is currently no clear evidence to support this approach. METHODS: A real-world study was conducted to investigate the potential relationship between the administration of Nirmatrelvir-ritonavir and the rates of intubation or in-hospital mortality among COVID-19 patients who experienced symptoms for more than 5 days. The end point was a composite event of intubation or in-hospital mortality. The outcomes between those patients who received Nirmatrelvir-ritonavir and those who did not were compared. RESULTS: A total of 847 patients were included in the analysis. Among them, 312 patients (36.84%) received Nirmatrelvir-ritonavir. Within the entire population, 86 patients (10.15%) experienced intubation or in-hospital mortality. The main analysis indicated that there was a significant association between the application of Nirmatrelvir-ritonavir and intubation or in-hospital mortality, with an odds ratio of 0.50 (95% confidence interval, 0.28 to 0.87; P = 0.0153) using inverse probability of treatment weighting. The finding was consistent with multiple sensitivity analyses. CONCLUSIONS: The application of Nirmatrelvir-ritonavir was associated with a significantly reduced risk of intubation or death in hospitalized COVID-19 patients who experienced symptoms for more than 5 days as compared to those who did not receive the treatment.

Comprehensive Analysis on Prognostic Signature Based on T Cell-Mediated Tumor Killing Related Genes in Gastric Cancer.

Although immunotherapy is a valuable treatment for gastric cancer (GC), identifying the patients who would benefit most from this approach presents a challenge. In this study, GC patients were divided into two subtypes by consensus clustering according to T cell-mediated tumor killing related genes (TTKRGs), and there were significant differences in tumor-infiltrating immune cells, signaling pathways, and gene expression of immunomodulators and inhibitory immune checkpoints between the two subtypes. Then, we developed an individualized signature based on TTKRGs, and its clinical and predictive value in GC patients for chemotherapeutic and immunotherapeutic responses was assessed. We confirmed the expression levels of signature genes in GC tumor tissue using quantitative real-time polymerase chain reaction (qRT-PCR). Additionally, to improve the accuracy of GC prognosis predictions, we established a nomogram. We further identified some compounds as sensitive drugs targeting GC risk groups. The signature showed significant predictive ability across RNA-seq, microarray, and qRT-PCR cohorts, which could assist in predicting survival, immunotherapeutic and chemotherapeutic outcomes in GC patients.

Career Adaptability and Academic Achievement Among Chinese High School Students: A Person-centered Longitudinal Study.

Career adaptability, essential for high school students' career development, is closely associated with academic achievement. However, it is still unclear whether there exist multiple subgroups among Chinese high school students that exhibit distinct combinations of the career adaptability dimensions and whether these subgroups display significant differences in academic achievement. Using latent profile analysis, this study identified career adaptability profiles in Chinese high school students and examined their effects on academic achievement through a longitudinal design. Chinese high school students (Wave 1: N = 1783, 42.9% boys, Mage = 15.17, SD = 0.86; Wave 2: N = 1395, 42.9% boys, 82.4% science students, Mage = 16.19, SD = 0.88) completed a packet of measures on two occasions at eight-month intervals. Career adaptability was assessed at Wave 1, and academic achievement was assessed at Wave 2. Five distinct career adaptability profiles were identified: (1) Low control and confidence; (2) Below average; (3) Control dominant and low confidence; (4) Above average; (5) High. Profiles of career adaptability displayed significant differences in academic achievement. High, Above average, and Control dominant and low confidence students' achievements were significantly higher than Low control and confidence students. These findings indicate that students with an overall high level of career adaptability or more robust career control are more likely to achieve higher academic achievement. In addition, level (average scores of all dimensions across different profiles) and shape (distinct forms displayed by the specific combination of dimensions) effects exist in the influence of career adaptability profiles on academic achievement. This highlights the dynamic and diverse nature of adolescent career development within the Chinese high school context.

Chaperone-mediated autophagy degrade Dicer to promote breast cancer metastasis.

Metastasis in breast cancer usually lead to the majority of deaths on clinical patients. Accordingly, diagnosis of metastasis at the early stage in breast cancer is important to improve the prognosis. We observed that Dicer protein levels are significant decrease in highly invasive breast cancer cells and usually correlated with poor clinical outcomes. Following, we aim to clarify the molecular regulatory mechanism of this phenomenon in breast cancer to provide a new therapeutic target. In this study, we obtained that Dicer expression correlated with metastasis and invasion without affect cell stability in breast cancer cells. Importantly, we identified the regulatory mechanism of Dicer protein degradation, the chaperone-mediated autophagy (CMA)-mediated degradation that is major mechanism to decrease Dicer protein expression and lead to cancer metastasis. We discovered that heat shock cognate 71-kDa protein (Hsc70) which as a CMA-related factor interacts with the CMA-targeting motif I333A/K334A on Dicer to promote degradation through CMA. Taken together, our findings hint that Dicer highly correlated with cancer metastasis, we reveal the tumor-promoting effect of CMA-mediated Dicer degradation in breast cancer.

KOtBu-Promoted, Three-Component Domino Reaction of Arenes(indoles/phenols), C60, and (Per/poly)fluoroarenes: Achieving Direct C-C Cross-Coupling of Fullerene with (Per/poly)fluoroarenes.

A KOtBu-promoted, three-component cross-coupling of arenes(indoles/phenols), C60, and (per/poly)fluoroarenes has been established for the one-pot efficient synthesis of various 1,4-arene-bridged bis(polyfluoroaryl)-functionalized [60]fullerenes. This developed reaction system demonstrates good functional group compatibilities with broad substrate scope, which exhibits high regio- and chemoselectivities. Further control experiment succeeded in providing a one-pot protocol for the synthesis of various 1,2-N-(per/poly)fluoroarene-substituted 1,2-(3-indole)(hydro)fullerenes.

Risk and Prognosis of Second Primary Cancers among Ovarian Cancer Patients, Based on SEER Database.

The purposes of the present study were to elucidate the risk and prognostic effect of second primary cancers (SPCs) development, as well as the factors influencing the prognosis of OC patients with SPCs. A statistically significant increase in SPCs risk was observed among OC patients during 2004-2015. The independent factors were used to construct the SPCs-prediction nomogram and the OS-prediction nomogram. Both nomogram were subjected to internal validation and performed well. OC patients with SPCs have a better prognosis than patients without SPCs. Propensity score matching (PSM) was applied to reduce confounding.

Procyanidins and Their Therapeutic Potential against Oral Diseases.

Procyanidins, as a kind of dietary flavonoid, have excellent pharmacological properties, such as antioxidant, antibacterial, anti-inflammatory and anti-tumor properties, and so they can be used to treat various diseases, including Alzheimer's disease, diabetes, rheumatoid arthritis, tumors, and obesity. Given the low bioavailability of procyanidins, great efforts have been made in drug delivery systems to address their limited use. Nowadays, the heavy burden of oral diseases such as dental caries, periodontitis, endodontic infections, etc., and their consequences on the patients' quality of life indicate a strong need for developing effective therapies. Recent years, plenty of efforts are being made to develop more effective treatments. Therefore, this review summarized the latest researches on versatile effects and enhanced bioavailability of procyanidins resulting from innovative drug delivery systems, particularly focused on its potential against oral diseases.

Combination of Modified NS1 and NS3 as a Novel Vaccine Strategy against Dengue Virus Infection.

Dengue virus (DENV) causes a range of illness, including dengue fever, dengue hemorrhagic fever, and dengue shock syndrome. DENV nonstructural protein (NS) 1 has been considered to be a desirable vaccine candidate for its ability to induce Ab and complement-dependent cytolysis of DENV-infected cells as well as to block the pathogenic effects of NS1. However a potential drawback of NS1 as a vaccine is that anti-DENV NS1 Abs can lead to endothelial cell damage and platelet dysfunction by antigenic cross-reactivity. Therefore, we modified the DENV NS1 by replacing the C-terminal cross-reactive epitopes with the corresponding region of Japanese encephalitis virus NS1 to generate a chimeric DJ NS1 protein. Active immunization with DJ NS1 induced a strong Ab response. To enhance cellular immunity, we further combined DJ NS1 with DENV NS3 to immunize mice and showed activation of Ag-specific CD4+ and CD8+ T cells in addition to Ab responses. We further detected NS3-specific CTL activities as well as CD107a expression of effector cells. Importantly, the protective effects attributed by DJ NS1 and NS3 immunization were demonstrated in a DENV-infected mouse model by reduced viral titers, soluble NS1 levels, mouse tail bleeding time, and vascular leakage at skin injection sites. Collectively, the results from this study reveal the humoral and cellular immune responses and the protective effects conferred by DJ NS1 and NS3 immunization in the mouse model of DENV infection and provide a potential strategy for dengue vaccine design.

Effects of vitamin E supplementation on the risk and progression of AD: a systematic review and meta-analysis.

Objective: The association between vitamin E supplementation and Alzheimer's disease (AD) was controversial because of conflicting data in the literature. This study was designed to systematically evaluate evidence about the efficacy of vitamin E supplementation not only on the risk but also on the progression of AD. Design: Five electronic databases were searched for studies published up to June 2017. Articles reporting vitamin E supplementation and AD were included, and the random-effect model was performed for the meta-analysis about the relationship between vitamin E supplementation and AD. Results: Five cohort studies and three randomized controlled trial (RCT) studies (total n = 14,262) involving 1313 cases about vitamin E effects on the risk of AD and 244 cases about effects on progression of AD. The pooled RR for vitamin E supplemental and risk of AD was 0.81 [95% CI: 0.50-1.33, I 2 = 69.2%]. Suitable data could not be extracted to do meta-analysis as there was no unified standard of outcome measure for studies on AD progression. We carefully analyzed and evaluated the authenticity and accuracy of every single trial, while reliable evidence could not be obtained. Conclusions: From what we do, neither the synthetic data on risk of AD nor the critical review on progression of AD could provide enough evidence on our research. Thus, we cannot draw a specific conclusion on the association or correlation between Vitamin E and AD.

Reduction and stabilization of Cr(VI) in soil by using calcium polysulfide: Catalysis of natural iron oxides.

Cr(VI)-contaminated soils could be remediated by using calcium polysulfide (CPS), while natural iron oxides as a main composition of soil would influence the pathways of the remediation. Through kinetic batch tests, the kinetics of Cr(VI) removal from soil, the effects of the contents of natural iron oxides, soil environmental conditions and mechanisms of Cr(VI) removal by using CPS with the presence of natural iron oxides were investigated. The results show that the removal of Cr(VI) by using CPS in soil fitted the pseudo-second-order model best, and the appearance of goethite increased the apparent rate constant from 0.0002 kg mg-1 h-1 to 0.0005 kg mg-1 h-1. The presence of iron oxides enhanced the removal of Cr(VI) by using CPS, and an extended reductive atmosphere of soil was created. The enhancement of Cr(VI) removal increased with the contents of iron oxides from 0 to 9 g kg-1, and declined from 9 to 12 g kg-1. Acidic environment favored the removal of Cr(VI) from soil by using CPS with or without the iron oxides compared to neutral soil and increased it from 87% to 100% because of proton-consuming reactions and electrostatic attraction. Twenty-nine percent of exchangeable and bound-to-carbonates species of chromium declined after the remediation, while 24% bound-to-iron-and-manganese-oxide species increased simultaneously. The findings of the study indicate that natural iron oxides in soils catalyze the reduction of Cr(VI) in soil and facilitate significantly the remediation of Cr(VI)-contaminated soil by using CPS.

Long-term and short-term surgical outcomes of single-incision laparoscopic hepatectomy on anterolateral liver segments.

BACKGROUND: Laparoscopic liver resection yields improved short-term surgical outcomes, whereas the reports about clinical benefits of single-incision laparoscopic hepatectomy (SILH) are scarce. This retrospective study is to compare the surgical outcomes of SILH with those of multi-incision laparoscopic hepatectomy (MILH). METHODS: The study included 54 patients who had undergone SILH and 184 patients who had undergone MILH between January 2010 and December 2017. Short-term outcomes were compared in those of patients who underwent left lateral sectionectomy and partial hepatectomy of segment 5-6. A subgroup analysis of hepatocellular carcinoma (HCC) was also performed for long-term outcome comparisons. RESULTS: In those of patients who underwent left lateral sectionectomy, SILH group had less chronic hepatitis B (15.2 vs. 45.8%; p = 0.004), less liver cirrhosis (12.1 vs. 50.0%; p = 0.002), less tumor proximal to major vessel (6.1 vs. 29.2%; p = 0.018), shorter surgical time (113.2 ± 37.9 vs. 146.0 ± 50.5 min; p = 0.007), and shorter postoperative hospital stays (4.4 ± 1.1 vs. 5.4 ± 1.3 days; p = 0.002) compared with MILH group. In those of patients with tumor located at segment 5-6, no significant differences were observed in surgical time, blood loss, complications, and mortality. Single-incision laparoscopic partial hepatectomy was only associated with wider surgical margins (11.8 ± 7.0 vs. 5.3 ± 5.2 mm; p = 0.003). In the HCC subgroup, SILH had similar 1-, 3-, and 5-year overall survival and 1-, 3-, and 5-year recurrence-free survival rates compared with patients who had undergone MILH. CONCLUSIONS: The study demonstrates the safety and feasibility of single-incision laparoscopic liver resection for left lateral sectionectomy and partial hepatectomy for segment 5-6. In selected patients within the group and by experienced surgical team, the SILH technique results in comparable short-term surgical outcomes and long-term oncological outcomes.

Comparison of sputum induction and bronchoscopy in diagnosis of sputum smear-negative pulmonary tuberculosis: a systemic review and meta-analysis.

BACKGROUND: Pulmonary tuberculosis is one of the most common infectious diseases worldwide. Patients with suspected pulmonary tuberculosis with negative smear are recommended to undergo further tests including sputum induction and bronchoscopy. Our study is aimed to compare sputum induction and bronchoscopic specimens in the diagnosis of sputum smear-negative pulmonary tuberculosis. METHOD: PubMed, Web of Science, Cochrane Library and Embase were searched for eligible studies. The pooled sensitivities (SEN), specificities (SPE), positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR) and 95% confidence intervals (CI) were constructed, and the areas under the curves (AUCs) were calculated. RESULTS: Five studies with a total number of 586 cases were included. For mycobacterial culture, the SEN and SPE of sputum induction were 0.72(95% CI, 0.66-0.77) and 1.00(95%CI, 0.99-1.000) respectively, whereas the SEN and SPE of bronchoscopy were 0.70(95%CI, 0.64-0.75) and 1.00(95%CI, 0.99-1.00) respectively. Sputum induction had a similar AUC (0.9564, SE = 0.0749) with bronchoscopy (0.8618, SE = 0.1652) (P = 0.602). For specimen of acid-fast bacilli smear, the SEN and SPE of sputum induction were 0.35(95% CI, 0.29-0.42) and 0.99(95% CI, 0.96-1.00) respectively, whereas the SEN and SPE of bronchoscopy were 0.38(95% CI, 0.32-0.45) and 0.99(95% CI, 0.96-1.00) respectively. There is no statistically significant difference in the AUC for sputum induction (0.6016) compared with bronchoscopy (0.8163) (P = 0.792). CONCLUSIONS: For the diagnosis of sputum smear-negative pulmonary tuberculosis, the diagnosis yield of sputum induction and bronchoscopy is similar.

The Effects of Positioning on the Volume/Location of the Internal Jugular Vein Using 2-Dimensional Tracked Ultrasound.

OBJECTIVE: To investigate the effects of different positioning on the volume/location of the internal jugular vein (IJV) using 2-dimensional (2D) tracked ultrasound. DESIGN: This was a prospective, observational study. SETTING: Local research institute. PARTICIPANTS: Healthy volunteers. INTERVENTIONS: Twenty healthy volunteers were scanned in the following 6 positions: (1) supine with head neutral, rotated 15 and 30 degrees to the left and (2) 5-, 10-, and 15-degree Trendelenburg position with head neutral. In each position the volunteer's neck was scanned using a 2D ultrasound probe tracked with a magnetic tracker. These spatially tracked 2D images were collected and reconstructed into a 3D volume of the IJV and carotid artery. This 3D ultrasound volume then was segmented to obtain a 3D surface on which measurements and calculations were performed. MEASUREMENTS AND MAIN RESULTS: The measurements included average cross-section area (CSA), CSA along the length of IJV, and average overlap rate. CSA (mm2) in the supine and 5-, 10-, and 15-degree Trendelenburg positions were as follows: 86.7 ± 44.8, 104.3 ± 54.5, 119.1 ± 58.6, and 133.7 ± 53.3 (p < 0.0001). CSA enlarged with the increase of Trendelenburg degree. Neither Trendelenburg position nor head rotation showed a correlation with overlap rate. CONCLUSIONS: Trendelenburg position significantly increased the CSA of the IJV, thus facilitating IJV cannulation. This new 3D reconstruction method permits the creation of a 3D volume through a tracked 2D ultrasound scanning system with image acquisition and integration and may prove useful in providing the user with a "road map" of the vascular anatomy of a patient's neck or other anatomic structures.

Comparative efficacy and safety of phosphodiesterase type 5 inhibitors for erectile dysfunction in diabetic men: a Bayesian network meta-analysis of randomized controlled trials.

PURPOSE: To compare the efficacy and safety profiles of different phosphodiesterase-5 inhibitors (PDE5Is) administrations for erectile dysfunction (ED) in diabetic men, including on-demand (PRN) and regular regimens (OAD). MATERIALS AND METHODS: Searches were carried out in four electronic databases: PubMed (until April 17th, 2017); Scopus (until April 17th, 2017); Embase (until April 17th, 2017); and Cochrane (until April 18th, 2017). The outcomes for this study are as follows: (1) Global Assessment Question (GAQ) positive response rate; (2) changes from baseline to the end of the study in Erectile Function Domain of International Index of Erectile Function (IIEF-EF); and (3) treatment-related adverse events (TRAEs). The comparative effects of PDE5I regimens were analyzed with random-effect models in a Bayesian Framework using the GeMTC R package. RESULTS: We identified 1056 records, of which 15 randomized trials with 5274 patients were included. The included studies covered eight kinds of PDE5I administration: avanafil PRN; mirodenafil PRN; sildenafil PRN; tadalafil PRN; tadalafil OAD; udenafil PRN; udenafil OAD; vardenafil PRN; and placebo. In surface under the cumulative ranking curve analysis, vardenafil PRN ranked first, third and first, and mirodenafil PRN ranked second, first and second in GAQ, IIEF-EF, and TRAEs, respectively. CONCLUSIONS: PDE5I administrations were generally efficient and well-tolerated in diabetic men. Among these administrations, vardenafil PRN and mirodenafil PRN seem to have a possible advantage of efficacy and avoiding adverse effects compared to others. There is no significant difference between regular and on-demand regimens of PDE5Is.

Long-term and short-term surgical outcomes of laparoscopic versus open liver resection for hepatocellular carcinoma: might laparoscopic approach be better in early HCC?

BACKGROUND: This retrospective study compared the short- and long-term outcomes of laparoscopic liver resection (LLR) and open liver resection (OLR) and identified patients who might gain more benefits from LLR. METHODS: The demographic and perioperative data, short-term surgical outcomes, and long-term oncological results of all 313 patients who received elective liver resection for hepatocellular carcinoma (HCC) between January 2010 and June 2017 were analyzed. The patients were then divided into stage-specific subgroups according to the TNM staging system for comparison. RESULTS: LLR was performed in 153 patients and OLR in 160 patients. LLR is associated with less blood loss (p < 0.001), shorter surgical time (p = 0.001), shorter length of hospital stay (p < 0.001), and lower morbidity rate (p = 0.034). The 5-year overall survival (OS) rates in the LLR group were higher than those in the OLR group (78.1 vs. 57.6%; p = 0.002). Stage-specific subgroup analysis revealed similar 5-year OS in the two groups (stage I: 82.8 vs. 82.6%, p = 0.845; stage II: 80.3 vs. 69.2%, p = 0.638; stage III: 55.6 vs. 34.8%, p = 0.681), as did the 5-year recurrence-free survival. Moreover, the short-term outcomes were better in the LLR group in terms of surgical time, blood loss, and length of hospital stay, and these benefits attenuated with advancing tumor stage. CONCLUSIONS: LLR for HCC is a safe and feasible procedure that does not compromise long-term oncological outcomes. In early tumor stages, LLR might be better in terms of short-term surgical outcomes.

Risk Factors Analysis of Postoperative Pleural Effusion after Liver Resection.

BACKGROUND: Pulmonary complications remain relatively high in morbidities that arise after liver surgery and are associated with increased length of hospital stay and higher cost. Identification of possible risk factors in this retrospective analysis may help reduce operative morbidity and achieve better outcomes. METHODS: In all, 363 consecutive patients underwent elective hepatectomies between July 2008 and November 2013 and these were identified and analyzed retrospectively. Patient demographics and perioperative variables were collected. The main outcome was an analysis of risk factors associated with postoperative pleural effusion (PPE). RESULTS: Of 363 patients receiving hepatectomies, 80 patients (22.0%) developed pulmonary complications. The predominant pulmonary complication in this series is pleural effusion (76 patients, 95%). Univariate analysis found that older age, higher body mass index (BMI), chronic obstructive lung disease, asthma, heart disease, hepatitis C infection, heavy smoking, American Society of Anesthesiology class III and IV, hepatectomy site, combined surgeries, perioperative blood transfusion, and cirrhosis of liver were associated with PPE. Only older age, higher BMI, asthma, heavy smoker, combined gastrointestinal surgeries, and perioperative blood transfusion were identified as independent risk factors in multivariate analysis. CONCLUSION: This study identifies 6 risk factors for PPE. Identification and management of some of these factors could possibly reduce morbidity and improve short-term surgical outcomes.

The efficacy and safety of prophylactic use of levosimendan on patients undergoing coronary artery bypass graft: a systematic review and meta-analysis.

Prophylactic use of levosimendan in cardiac surgery remains controversial and no meta-analysis has been done exclusively about that in patients undergoing coronary artery bypass graft (CABG) surgery. We conducted this systematic review and meta-analysis of levosimendan in CABG using PubMed, Embase, Scopus, and Cochrane Library (till April 20, 2018). Two-hundred and forty manuscripts were identified and 21 randomized trials (1727 patients in total) investigating the effect of levosimendan on the patients undergoing CABG surgery were finally included in this analysis. We found that levosimendan was an effective, well-tolerated inotropic agent in CABG, which was associated with a significantly reduced mortality rate [odds ratio (OR) 0.43, 95% confidence interval (CI) (0.26, 0.71), p = 0.001, I2 = 0%] and postoperative atrial fibrillation [OR 0.50, 95% CI (0.26, 0.97), p = 0.04, I2 = 76%], but a higher incidence of hypotension [OR 2.26, 95% CI (1.05, 4.85), p = 0.04, I2 = 79%]. Subgroup analyses revealed that such a benefit was mainly observed in the isolated CABG, the preoperative administration, with-bolus and on-pump subgroups. More high-quality and well-designed prospective studies are needed to confirm or disprove our findings in future.

Telmisartan protects chronic intermittent hypoxic mice via modulating cardiac renin-angiotensin system activity.

BACKGROUND: To explore the effects of chronic intermittent hypoxia (CIH), which mimics sleep apnea syndrome, on the cardiac renin angiotensin system (RAS), and to investigate the cardiac protection of an angiotensin receptor blocker (ARB)telmisartan (TERT) against CIH. METHODS: 32 healthy male C57B6J mice were randomly divided into CIH, ARB, blank and air control groups. CIH lasted for 12 weeks. Cardiac angiotensin converting enzyme (ACE), angiotensin converting enzyme 2 (ACE 2) and angiotensin II (Ang II) were evaluated by immunohistochemistry. Myocardial apoptosis were assessed by TUNEL assay and myocardial cell ultrastructure were observed under transmission electron microscope. RESULTS: Cardiac ACE expression was higher in the CIH group than in blank and air control groups, which was decreased with TERT treatment. TERT treatment elevated the expression of cardiac ACE 2 and Ang II compared with CIH group. Myocardial cell and capillary endothelial cell apoptosis, mitochondrial injury were most severe in CIH groups, which were mitigated with TERT treatment. CONCLUSIONS: CIH changes the expression of cardiac ACE, ACE2 and Ang II, which may cause myocardial damage. TERT protects mice from CIH-linked cardiac damage via modulating the activity of RAS in the hearts.

iTAR: a web server for identifying target genes of transcription factors using ChIP-seq or ChIP-chip data.

BACKGROUND: Chromatin immunoprecipitation followed by massively parallel DNA sequencing (ChIP-seq) or microarray hybridization (ChIP-chip) has been widely used to determine the genomic occupation of transcription factors (TFs). We have previously developed a probabilistic method, called TIP (Target Identification from Profiles), to identify TF target genes using ChIP-seq/ChIP-chip data. To achieve high specificity, TIP applies a conservative method to estimate significance of target genes, with the trade-off being a relatively low sensitivity of target gene identification compared to other methods. Additionally, TIP's output does not render binding-peak locations or intensity, information highly useful for visualization and general experimental biological use, while the variability of ChIP-seq/ChIP-chip file formats has made input into TIP more difficult than desired. DESCRIPTION: To improve upon these facets, here we present are fined TIP with key extensions. First, it implements a Gaussian mixture model for p-value estimation, increasing target gene identification sensitivity and more accurately capturing the shape of TF binding profile distributions. Second, it enables the incorporation of TF binding-peak data by identifying their locations in significant target gene promoter regions and quantifies their strengths. Finally, for full ease of implementation we have incorporated it into a web server ( http://syslab3.nchu.edu.tw/iTAR/ ) that enables flexibility of input file format, can be used across multiple species and genome assembly versions, and is freely available for public use. The web server additionally performs GO enrichment analysis for the identified target genes to reveal the potential function of the corresponding TF. CONCLUSIONS: The iTAR web server provides a user-friendly interface and supports target gene identification in seven species, ranging from yeast to human. To facilitate investigating the quality of ChIP-seq/ChIP-chip data, the web server generates the chart of the characteristic binding profiles and the density plot of normalized regulatory scores. The iTAR web server is a useful tool in identifying TF target genes from ChIP-seq/ChIP-chip data and discovering biological insights.