Association between common cardiovascular drugs and depression.

OBJECTIVE: Cardiovascular diseases are associated with an increased risk of depression, but it remains unclear whether treatment with cardiovascular agents decreases or increases this risk. The effects of drugs on individual usage are also often unknown. This review aimed to examine the correlation between depression and common cardiovascular drugs, develop more potent interventions for depression in cardiovascular patients, and further research on the bio-behavioural mechanisms linking cardiovascular drugs to depression. DATA SOURCES: The data in this review were obtained from articles included in PubMed, EMBASE, and Web of Science. STUDY SELECTION: Clinical trials, observational studies, review literature, and guidelines about depression and cardiovascular drugs were selected for the article. RESULTS: We systematically investigated whether the seven most used cardiovascular drugs were associated with altered risk of incident depression in this literature review. Statins have been proven to have antidepressant effects. Some studies believe angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin receptor blocker (ARB) can exert an antidepressant influence by acting on the renin-angiotensin system, but further clinical trials are needed to confirm this. Beta-blockers have previously been associated with depression, but the current study found no significant association between beta blockers and the risk of depression. Aspirin may have antidepressant effects by suppressing the immune response, but its role as an antidepressant remains controversial. calcium channel blockers (CCBs) can regulate nerve signal transduction by adjusting calcium channels, but whether this effect is beneficial or harmful to depression remains unclear. Finally, some cases have reported that nitrates and diuretics are associated with depression, but the current clinical evidence is insufficient. CONCLUSIONS: Statins have been proven to have antidepressant effect, and the antidepressant effects of ACEIs/ARB and aspirin are still controversial. CCBs are associated with depression, but it is unclear whether it is beneficial or harmful. No association has been found with ß-blockers, diuretics, and nitrates.

Coronavirus Disease 2019 Related Clinical Studies: A Cross-Sectional Analysis.

OBJECTIVE: The quality and rationality of many recently registered clinical studies related to coronavirus disease 2019 (COVID-19) needs to be assessed. Hence, this study aims to evaluate the current status of COVID-19 related registered clinical trial. METHODS: We did an electronic search of COVID-19 related clinical studies registered between December 1, 2019 and February 21, 2020 (updated to May 28, 2020) from the ClinicalTrials.gov, and collected registration information, study details, recruitment status, characteristics of the subjects, and relevant information about the trial implementation process. RESULTS: A total of 1,706 studies were included 10.0% of which (n=171) were from France, 943 (55.3%) used an interventional design, and 600 (35.2%) used an observational design. Most of studies (73.6%) aimed to recruit fewer than 500 people. Interferon was the main prevention program, and antiviral drugs were the main treatment program. Hydroxychloroquine and chloroquine (230/943, 24.4%) were widely studied. Some registered clinical trials are incomplete in content, and 37.4% of the 1,706 studies may have had insufficient sample size. CONCLUSION: The quality of COVID-19 related studies needs to be improved by strengthening the registration process and improving the quality of clinical study protocols so that these clinical studies can provide high-quality clinical evidence related to COVID-19.

Chemoprophylaxis, diagnosis, treatments, and discharge management of COVID-19: An evidence-based clinical practice guideline (updated version).

The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of a rapidly spreading illness, coronavirus disease 2019 (COVID-19), affecting more than seventeen million people around the world. Diagnosis and treatment guidelines for clinicians caring for patients are needed. In the early stage, we have issued "A rapid advice guideline for the diagnosis and treatment of 2019 novel coronavirus (2019-nCoV) infected pneumonia (standard version)"; now there are many direct evidences emerged and may change some of previous recommendations and it is ripe for develop an evidence-based guideline. We formed a working group of clinical experts and methodologists. The steering group members proposed 29 questions that are relevant to the management of COVID-19 covering the following areas: chemoprophylaxis, diagnosis, treatments, and discharge management. We searched the literature for direct evidence on the management of COVID-19, and assessed its certainty generated recommendations using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach. Recommendations were either strong or weak, or in the form of ungraded consensus-based statement. Finally, we issued 34 statements. Among them, 6 were strong recommendations for, 14 were weak recommendations for, 3 were weak recommendations against and 11 were ungraded consensus-based statement. They covered topics of chemoprophylaxis (including agents and Traditional Chinese Medicine (TCM) agents), diagnosis (including clinical manifestations, reverse transcription-polymerase chain reaction (RT-PCR), respiratory tract specimens, IgM and IgG antibody tests, chest computed tomography, chest x-ray, and CT features of asymptomatic infections), treatments (including lopinavir-ritonavir, umifenovir, favipiravir, interferon, remdesivir, combination of antiviral drugs, hydroxychloroquine/chloroquine, interleukin-6 inhibitors, interleukin-1 inhibitors, glucocorticoid, qingfei paidu decoction, lianhua qingwen granules/capsules, convalescent plasma, lung transplantation, invasive or noninvasive ventilation, and extracorporeal membrane oxygenation (ECMO)), and discharge management (including discharge criteria and management plan in patients whose RT-PCR retesting shows SARS-CoV-2 positive after discharge). We also created two figures of these recommendations for the implementation purpose. We hope these recommendations can help support healthcare workers caring for COVID-19 patients.

Chemoprophylaxis, diagnosis, treatments, and discharge management of COVID-19: an evidence-based clinical practice guideline (updated version)

The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of a rapidly spreading illness, coronavirus disease 2019 (COVID-19), affecting more than seventeen million people around the world. Diagnosis and treatment guidelines for clinicians caring for patients are needed. In the early stage, we have issued "A rapid advice guideline for the diagnosis and treatment of 2019 novel coronavirus (2019-nCoV) infected pneumonia (standard version)"; now there are many direct evidences emerged and may change some of previous recommendations and it is ripe for develop an evidence-based guideline. We formed a working group of clinical experts and methodologists. The steering group members proposed 29 questions that are relevant to the management of COVID-19 covering the following areas: chemoprophylaxis, diagnosis, treatments, and discharge management. We searched the literature for direct evidence on the management of COVID-19, and assessed its certainty generated recommendations using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach. Recommendations were either strong or weak, or in the form of ungraded consensus-based statement. Finally, we issued 34 statements. Among them, 6 were strong recommendations for, 14 were weak recommendations for, 3 were weak recommendations against and 11 were ungraded consensus-based statement. They covered topics of chemoprophylaxis (including agents and Traditional Chinese Medicine (TCM) agents), diagnosis (including clinical manifestations, reverse transcription-polymerase chain reaction (RT-PCR), respiratory tract specimens, IgM and IgG antibody tests, chest computed tomography, chest x-ray, and CT features of asymptomatic infections), treatments (including lopinavir-ritonavir, umifenovir, favipiravir, interferon, remdesivir, combination of antiviral drugs, hydroxychloroquine/chloroquine, interleukin-6 inhibitors, interleukin-1 inhibitors, glucocorticoid, qingfei paidu decoction, lianhua qingwen granules/capsules, convalescent plasma, lung transplantation, invasive or noninvasive ventilation, and extracorporeal membrane oxygenation (ECMO)), and discharge management (including discharge criteria and management plan in patients whose RT-PCR retesting shows SARS-CoV-2 positive after discharge). We also created two figures of these recommendations for the implementation purpose. We hope these recommendations can help support healthcare workers caring for COVID19 patients

Developments, Evolution, and Implications of National Diagnostic Criteria for COVID-19 in China.

Recently WHO has characterized COVID-19 as a pandemic. Diagnosing the disease accurately and decreasing misdiagnoses and missed diagnoses is very important for management. Therefore, we have analyzed the seven versions of China's national guidelines to examine how the diagnostic criteria roadmap has developed and evolved, in order to share our experience worldwide. In this article, we present the developments from the first to seventh versions, involving changes of case classification, changes to "suspected case," changes in "confirmed case," changes in clinical classifications, changes in "severe case," and unchanged criteria. We have also discussed the reasons and implications for these changes and are looking forward to providing suggestions for worldwide understanding and management of this pandemic. A nucleic acid test is currently accepted as the gold standard method to confirm diagnosis. In addition, imaging examination and epidemiological history should also be considered as auxiliary diagnosis methods.

Updating the diagnostic criteria of COVID-19 "suspected case" and "confirmed case" is necessary.

On 6 February 2020, our team had published a rapid advice guideline for diagnosis and treatment of 2019 novel coronavirus (2019-nCoV) infection, and this guideline provided our experience and make well reference for fighting against this pandemic worldwide. However, the coronavirus disease 2019 (COVID-19) is a new disease, our awareness and knowledge are gradually increasing based on the ongoing research findings and clinical practice experience; hence, the strategies of diagnosis and treatment are also continually updated. In this letter, we answered one comment on our guideline and provided the newest diagnostic criteria of "suspected case" and "confirmed case" according to the latest Diagnosis and Treatment Guidelines for COVID-19 (seventh version) that issued by the National Health Committee of the People's Republic of China.

A rapid advice guideline for the diagnosis and treatment of 2019 novel coronavirus (2019-nCoV) infected pneumonia (standard version).

In December 2019, a new type viral pneumonia cases occurred in Wuhan, Hubei Province; and then named "2019 novel coronavirus (2019-nCoV)" by the World Health Organization (WHO) on 12 January 2020. For it is a never been experienced respiratory disease before and with infection ability widely and quickly, it attracted the world's attention but without treatment and control manual. For the request from frontline clinicians and public health professionals of 2019-nCoV infected pneumonia management, an evidence-based guideline urgently needs to be developed. Therefore, we drafted this guideline according to the rapid advice guidelines methodology and general rules of WHO guideline development; we also added the first-hand management data of Zhongnan Hospital of Wuhan University. This guideline includes the guideline methodology, epidemiological characteristics, disease screening and population prevention, diagnosis, treatment and control (including traditional Chinese Medicine), nosocomial infection prevention and control, and disease nursing of the 2019-nCoV. Moreover, we also provide a whole process of a successful treatment case of the severe 2019-nCoV infected pneumonia and experience and lessons of hospital rescue for 2019-nCoV infections. This rapid advice guideline is suitable for the first frontline doctors and nurses, managers of hospitals and healthcare sections, community residents, public health persons, relevant researchers, and all person who are interested in the 2019-nCoV.

Identification of key genes for predicting colorectal cancer prognosis by integrated bioinformatics analysis.

Colorectal cancer (CRC) is a life-threatening disease with a poor prognosis. Therefore, it is crucial to identify molecular prognostic biomarkers for CRC. The present study aimed to identify potential key genes that could be used to predict the prognosis of patients with CRC. Three CRC microarray datasets (GSE20916, GSE73360 and GSE44861) were downloaded from the Gene Expression Omnibus (GEO) database, and one dataset was obtained from The Cancer Genome Atlas (TCGA) database. The three GEO datasets were analyzed to detect differentially expressed genes (DEGs) using the BRB-ArrayTools software. Functional and pathway enrichment analyses of these DEGs were performed using the Database for Annotation, Visualization and Integrated Discovery tool. A protein-protein interaction (PPI) network of DEGs was constructed, hub genes were extracted, and modules of the PPI network were analyzed. To investigate the prognostic values of the hub genes in CRC, data from the CRC datasets of TCGA were used to perform the survival analyses based on the sample splitting method and Cox regression model. Correlation among the hub genes was evaluated using Spearman's correlation analysis. In the three GEO datasets, a total of 105 common DEGs were identified, including 51 down- and 54 up-regulated genes in CRC compared with normal colorectal tissues. A PPI network consisting of 100 DEGs and 551 edges was constructed, and 44 nodes were identified as hub genes. Among these 44 genes, the four hub genes TIMP metallopeptidase inhibitor 1 (TIMP1), solute carrier family 4 member 4 (SLC4A4), aldo-keto reductase family 1 member B10 (AKR1B10) and ATP binding cassette subfamily E member 1 (ABCE1) were associated with overall survival (OS) in patients with CRC. Three significant modules were extracted from the PPI network. The hub gene TIMP1 was present in Module 1, ABCE1 was involved in Module 2 and SLC4A4 was identified in Module 3. Univariate analysis revealed that TIMP1, SLC4A4, AKR1B10 and ABCE1 were associated with the OS of patients with CRC. Multivariate analysis demonstrated that SLC4A4 may be an independent prognostic factor associated with OS. Furthermore, the results from correlation analysis revealed that there was no correlation between TIMP1, SLC4A4 and ABCE1, whereas AKR1B10 was positively correlated with SLC4A4. In conclusion, the four key genes TIMP1, SLC4A4, AKR1B10 and ABCE1 associated with the OS of patients with CRC were identified by integrated bioinformatics analysis. These key genes may be used as prognostic biomarkers to predict the survival of patients with CRC, and may therefore represent novel therapeutic targets for CRC.

Nomogram for predicting the survival of gastric adenocarcinoma patients who receive surgery and chemotherapy.

BACKGROUND: Surgery is the only way to cure gastric adenocarcinoma (GAC), and chemotherapy is the basic adjuvant management for GAC. A significant prognostic nomogram for predicting the respective disease-specific survival (DSS) rates of GAC patients who receive surgery and chemotherapy has not been established. OBJECTIVE: We were planning to establish a survival nomogram model for GAC patients who receive surgery and chemotherapy. METHODS: We identified 5764 GAC patients who had received surgery and chemotherapy from the record of Surveillance, Epidemiology, and End Results (SEER) database. About 70% (n = 4034) of the chosen GAC patients were randomly assigned to the training set, and the rest of the included ones (n = 1729) were assigned to the external validation set. A prognostic nomogram was constructed by the training set and the predictive accuracy of it was validated by the validation set. RESULTS: Based on the outcome of a multivariate analysis of candidate factors, a nomogram was developed that encompassed age at diagnosis, number of regional lymph nodes examined after surgery, number of positive regional lymph nodes, sex, race, grade, derived AJCC stage, summary stage, and radiotherapy status. The C-index (Harrell's concordance index) of the nomogram model was some larger than that of the traditional seventh AJCC staging system (0.707 vs 0.661). Calibration plots of the constructed nomogram displayed that the probability of DSS commendably accord with the survival rate. Integrated discrimination improvement (IDI) revealed obvious increase and categorical net reclassification improvement (NRI) showed visible enhancement. IDI for 3-, 5- and 10- year DSS were 0.058, 0.059 and 0.058, respectively (P > 0.05), and NRI for 3-, 5- and 10- year DSS were 0.380 (95% CI = 0.316-0.470), 0.407 (95% CI = 0.350-0.505), and 0.413 (95% CI = 0.336-0.519), respectively. Decision curve analysis (DCA) proved that the constructed nomogram was preferable to the AJCC staging system. CONCLUSION: The constructed nomogram supplies more credible DSS predictions for GAC patients who receive surgery and chemotherapy in the general population. According to validation, the new nomogram will be beneficial in facilitating individualized survival predictions and useful when performing clinical decision-making for GAC patients who receive surgery and chemotherapy.

IgG plasma cells initiate changes in the protein C system in mouse ulcerative colitis through CD14+CD64+ macrophage activation.

BACKGROUND: Inhibition of the protein C system (PCS) might be one of the mechanisms of ulcerative colitis (UC). OBJECTIVES: The aim of the study was to explore the role of IgG plasma cells in changes in the PCS in UC. MATERIAL AND METHODS: Dextran sulfate sodium (DSS) was chosen to induce mouse UC. Inflammation was assessed using hematoxylin & eosin (H&E) staining and immunofluorescence. The profiling of colonic plasma cells and macrophages from colitis mice was analyzed with flow cytometry. After stimulation of macrophages with IgG type immune complex (IgG-IC), western blot was used to determine tumor necrosis factor α (TNF-α) and interleukin 6 (IL-6) protein levels. After co-incubation of colonic mucosa microvascular endothelial cells (MVECs) with TNF-α or IL-6, mitogen-activated protein kinase (MAPK) expression was detected. RESULTS: The DSS-colitis mice showed higher inflammatory indexes (p < 0.05 or p < 0.01), accompanied by greater infiltration of CD38+IgG+ plasma cells (p < 0.01), CD14+CD64+ macrophages (p < 0.01) and IgG-IC than healthy mice. Enhancement of TNF-α and IL-6 protein expression was demonstrated in this subset of macrophages when stimulated by IgG-IC (p < 0.01). After MVECs were incubated with TNF-α or IL-6, the expression of ß-arrestin1, pP38 MAPK and pJNK MAPK exhibited an increase (p < 0.05 or p < 0.01), but downregulation of endothelial protein C receptor (EPCR) expression was observed (p < 0.05 or p < 0.01); this inhibition of EPCR expression was reversed by SB203580, SP600125 or U0126 (p < 0.05 or p < 0.01). In addition, changes in activated protein C (APC) presented results similar to those for EPCR expression (p < 0.05 or p < 0.01). CONCLUSIONS: These results reveal that the PCS is inhibited during UC processing. There is a possibility that the interaction between IgG plasma cells and CD14+CD64+ macrophages, as well as further secretion of cytokines from CD14+CD64+ macrophages by the formation and stimulation of IgG-IC, subsequently influence MVECs through the ß-arrestin-MAPK pathway. Enhancement of PCS activity may represent a novel approach for treating UC.

Serotonin Transporter (5-HTT) Gene Polymorphisms and Susceptibility to Chronic Periodontitis: A Case-Control Study.

Objective: The current study is aimed at exploring the relationship between chronic periodontitis and serotonin transporter (5-HTT) gene polymorphisms (rs6354 and rs12449783) in the Chinese Han population. Methods: This study included a total of 120 patients with chronic periodontitis and 125 healthy control subjects. The 5-HTT gene (rs6354 and rs12449783) was genotyped using oral mucosal tissue with a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Linkage disequilibrium was examined using Haploview. Genotype and allele frequencies were compared between the cases and controls using a χ2 test. Results: Genotype distribution of the 5-HTT gene polymorphisms rs6354 and rs12449783 in the control group conformed to Hardy-Weinberg equilibrium. The frequency of the AC genotype, the AC + CC genotype and C allele of the 5-HTT rs6354 polymorphism was higher in cases (P < 0.05) vs. the healthy control. The adjusted odds ratio (OR) was 1.910 (95%CI = 1.049-3.476) for the AC genotype, 2.026 (95%CI = 1.115-3.680) for the AC+CC genotype, and 1.875 for the C allele (95%CI = 1.089-3.228. Such an association was particularly strong in women for the AC genotype (OR = 2.167, 95%CI = 1.034-4.542). The genotype and allele frequencies of rs12449783 did not differ between the cases and controls. Haplotype C-C (rs6354-rs12449783) was also more frequent in the cases (OR = 2.372, 95%CI = 1.154-4.875, P = 0.016). Conclusion: Chronic periodontitis is associated with the 5-HTT gene rs6354 polymorphism, as well as rs6354/rs12449783 interaction.

Clinical Significance of TRMT6 in Hepatocellular Carcinoma: A Bioinformatics-Based Study.

BACKGROUND The purpose of this study was to investigate the correlation between TRMT6 mRNA expression levels and clinicopathological features in primary HCC patients and to evaluate their prognostic value. MATERIAL AND METHODS The clinical information and the mRNA sequencing data of the patients with primary hepatocellular carcinoma (HCC) were extracted from The Cancer Genome Atlas (TCGA) Liver Cancer database. The correlation between the clinicopathological features and the expression of TRMT6 was analyzed by t test and chi-square test. The overall survival (OS) and recurrence-free survival (RFS) were estimated using the Kaplan-Meier method and Cox regression models. Gene set enrichment analysis (GSEA) was used to explore the potential mechanisms of TRMT6 dysregulation in primary HCC patients. RESULTS Compared to normal tissues, TRMT6 was significantly upregulated in primary HCC tissues. Kaplan-Meier survival curves revealed that higher TRMT6 expression was associated with reduced RFS (p=0.0146) and OS (p=0.0224) in HCC patients. Moreover, multivariable Cox regression analysis indicated that TRMT6 upregulation independently predicted poor RFS (HR: 1.871, 95% CI: 1.204, 2.905, p=0.005) and OS (HR: 2.176, 95% CI: 1.234, 3.836, p=0.007). Gene Set Enrichment Analysis (GSEA) indicated that primary HCC samples in the TRMT6 high expression group were enriched for the G2M checkpoint, spermatogenesis, and MYC target genes. CONCLUSIONS TRMT6 was upregulated in HCC tissues, and higher TRMT6 expression levels was correlated with reduced OS and RFS in patients with primary HCC. TRMT6 might be a promising prognostic biomarker for poor clinical outcomes in primary HCC patients.

ZNF281 Regulates Cell Proliferation, Migration and Invasion in Colorectal Cancer through Wnt/ß-Catenin Signaling.

BACKGROUND/AIMS: Zinc Finger Protein 281 (ZNF281) was recently identified as a novel oncogene in several human carcinomas. However, the clinical significance of ZNF281 in colorectal cancer (CRC) and the molecular mechanisms by which ZNF281 promotes the growth and metastasis of CRC remain unknown. METHODS: ZNF281 expression in CRC tissues was assessed, and the outcomes were analyzed to determine the clinical importance of ZNF281 expression. Cell Transwell assays and a wound healing assay were performed to assess the effects of ZNF281 on CRC cell migration and invasion in vitro. Western blotting was applied to analyze the potential mechanisms. RESULTS: ZNF281 mRNA and protein levels were significantly increased in CRC tissues compared with normal colon tissues, and high ZNF281 expression was associated with advanced T stage, N stage, TNM stage and differentiation. Therefore, ZNF281 expression might be an independent prognostic indicator in CRC patients. Moreover, knockdown of ZNF281 expression suppressed cell proliferation, migration and invasion by inhibiting the Wnt/ß-catenin pathway. CONCLUSION: Our study indicates that ZNF281 plays a critical role in the progression and metastasis of CRC and could represent a potential therapeutic target for CRC.

PEST-containing nuclear protein regulates cell proliferation, migration, and invasion in lung adenocarcinoma.

Lung cancer is the leading cause of cancer-related mortality worldwide. PEST-containing nuclear protein (PCNP) has been found in the nucleus of cancer cells. Whether PCNP plays a role in the growth of lung adenocarcinoma is still unknown. In the present study, the results indicated that the level of PCNP in lung adenocarcinoma tissue was significantly higher than that in corresponding adjacent non-tumor tissue. Over-expression of PCNP promoted the proliferation, migration, and invasion of lung adenocarcinoma cells, while down-regulation of PCNP exhibited opposite effects. PCNP over-expression decreased apoptosis through up-regulating the expression levels of phospho (p)-signal transducers and activators of transcription (STAT) 3 and p-STAT5 in lung adenocarcinoma cells, whereas PCNP knockdown showed opposite trends. PCNP overexpression enhanced autophagy by increasing the expression levels of p-phosphatidylinositol 3-kinase (PI3K), p-Akt, and p-mammalian target of rapamycin (mTOR) in lung adenocarcinoma cells, however an opposite trend was observed in the sh-PCNP group. In addition, overexpression of PCNP showed the tumor-promoting effect on xenografted lung adenocarcinoma, while PCNP knockdown reduced the growth of lung adenocarcinoma via regulating angiogenesis. Our study elucidates that PCNP can regulate the procession of human lung adenocarcinoma cells via STAT3/5 and PI3K/Akt/mTOR signaling pathways. PCNP may be considered as a promising biomarker for the diagnosis and prognosis in patients with lung adenocarcinoma. Furthermore, PCNP can be a novel therapeutic target and potent PCNP inhibitors can be designed and developed in the treatment of lung adenocarcinoma.

The Top-100 Highly Cited Original Articles on Drug Therapy for Ventilator-Associated Pneumonia.

Background: In recent decades, research on drug therapy for ventilator-associated pneumonia (VAP) remains one of the major hot-spots in the field of critical care medicine, but relevant data are not satisfactory. Our aim was to assess the status and trends of the most cited articles on drug therapy for VAP through bibliometric approaches. Methods: The Institute for Scientific Information (ISI) Web of Science core collection database was searched for the VAP-related articles. The time period for retrieval was from the beginning of the database to September 30, 2018. The top 100 most cited articles were selected to obtain their information on the authors, title, publication, number of citations, author's affiliations, country, etc. These general information and bibliometric data were collected for analysis. VOSviewer software was used to generate a term co-occurrence graph that visualized a reference pattern for different terms in the 100 articles. Results: The number of citations for the 100 selected articles ranged from 142 to 3,218. These articles were published in 31 different journals. The top three journals in terms of the number of our selected articles they published were "Critical Care Medicine" (17 articles), "American Journal of Respiratory and Critical Care Medicine" (11 articles) and "Clinical Infectious Diseases" (10 articles). The most frequently nominated author was Marin H. Kollef from the University of Washington, and of the top 100 articles, 16 listed his name. These top 100 articles were published after the year of 2000. The most common type of article in the top 100 was an original article (53%). The United States and France were the countries that contributed the most articles to the top 100. Gram-negative bacilli, pseudomonas aeruginosa, antibiotics, risk factors and other terms appeared more frequently, suggesting that attentions on this issue currently focused on the rational application and management of antibiotics. Conclusion: This study analyzed the 100 most cited articles on drug-treated VAP, and provided insights into the historical developments and characteristics of the most cited articles in the field of VAP.

Tumour necrosis factor-α-induced protein 8-like 2 is a novel regulator of proliferation, migration, and invasion in human rectal adenocarcinoma cells.

Tumour necrosis factor-α-induced protein 8-like 2 (TIPE2) is a tumour suppressor in many types of cancer. However, the mechanism of action of TIPE2 on the growth of rectal adenocarcinoma is unknown. Our results showed that the expression levels of TIPE2 in human rectal adenocarcinoma tissues were higher than those in adjacent non-tumour tissues. Overexpression of TIPE2 reduced the proliferation, migration, and invasion of human rectal adenocarcinoma cells and down-regulation of TIPE2 showed reverse effects. TIPE2 overexpression increased apoptosis through down-regulating the expression levels of Wnt3a, phospho (p)-ß-Catenin, and p-glycogen synthase kinase-3ß in rectal adenocarcinoma cells, however, TIPE2 knockdown exhibited reverse trends. TIPE2 overexpression decreased autophagy by reducing the expression levels of p-Smad2, p-Smad3, and transforming growth factor-beta (TGF-ß) in rectal adenocarcinoma cells, however, TIPE2 knockdown showed opposite effects. Furthermore, TIPE2 overexpression reduced the growth of xenografted human rectal adenocarcinoma, whereas TIPE2 knockdown promoted the growth of rectal adenocarcinoma tumours by modulating angiogenesis. In conclusion, TIPE2 could regulate the proliferation, migration, and invasion of human rectal adenocarcinoma cells through Wnt/ß-Catenin and TGF-ß/Smad2/3 signalling pathways. TIPE2 is a potential therapeutic target for the treatment of rectal adenocarcinoma.

Up-Regulation of Phosphatase in Regenerating Liver-3 (PRL-3) Contributes to Malignant Progression of Hepatocellular Carcinoma by Activating Phosphatase and Tensin Homolog Deleted on Chromosome Ten (PTEN)/Phosphoinositide 3-Kinase (PI3K)/AKT Signaling Pathway.

BACKGROUND The purpose of the study was to investigate the functional roles of phosphatase in regenerating liver-3 (PRL-3) in hepatocellular carcinoma (HCC), as well as the related molecular mechanisms. MATERIAL AND METHODS HCC tissues and adjacent normal tissues were collected from 124 HCC patients. The mRNA and protein levels of PRL-3 were detected using quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot assays, respectively. The relationship between PRL-3 expression and clinical characteristics of HCC patients was evaluated by chi-square test. MTT and Transwell assays were performed to estimate cell proliferation and motility, respectively. RESULTS The expression of PRL-3 was significantly increased in HCC tissues and cells at both protein and mRNA levels (P<0.01 for all). Furthermore, the up-regulation of PRL-3 was positively correlated with hepatic vascular invasion (P=0.019), lymph node metastasis (P=0.012), and TNM stage (P=0.001). The knockdown of PRL-3 suppressed HCC cell proliferation, migration, and invasion, and PR3K/AKT pathway activity was also obviously inhibited in HCC cells with PRL-3 deficiency. The levels of PTEN were negatively associated with PRL-3 expression. PRL-3 might inhibit the protein level of PTEN through enhancing its phosphorylation level. The transfection of si-PTEN can reverse the anti-tumor action caused by PRL-3 knockdown in HCC cells. CONCLUSIONS Up-regulation of PRL-3 may activate the PI3K/AKT signaling pathway and enhance malignant progression of HCC through targeting PTEN.

XRCC2-Deficient Cells are Highly Sensitive to 5-Fluorouracil in Colorectal Cancer.

BACKGROUND/AIMS: Inhibition of the repair of 5-fluorouracil (5-FU)-induced DNA lesions may improve the responses of tumors to anticancer agents. XRCC2 is a key factor in DNA repair. However, the role of XRCC2 in the chemoresistance of colorectal cancer (CRC) treated with 5-FU remains unclear. The aim of this study is to investigate whether XRCC2 expression affects the chemosensitivity of colorectal cancer. METHODS: XRCC2 expression in CRC tissues was assessed, and the outcomes were analyzed to determine the clinical importance of XRCC2 expression. Following treatment with 5-FU, the effect of XRCC2 on proliferation was evaluated via a CCK-8 assay, the effects on cell cycle distribution and apoptosis were analyzed using flow cytometry, and γH2AX foci formation assays were performed to examine the influence of 5-FU on DNA Double-strand breaks(DSBs) repair in CRC cells. RESULTS: XRCC2 expression in CRC tissues was significantly higher than that in normal tissues, and this increased XRCC2 expression was associated with advanced T staging, M staging, TNM staging, Duke's staging, and greater liver and lymph node metastases. XRCC2 expression might be an independent prognostic indicator for CRC patients. Patients with negative XRCC2 expression exhibit greater sensitivity to treatment with 5-FU-based chemotherapy than those with positive XRCC2 expression. Moreover, our observations revealed that the knockdown of XRCC2 in CRC cells increased the sensitivities to 5-FU in terms of cell proliferation, apoptosis and cell cycle arrest. DNA DSBs repair was slower in the XRCC2-deficient cells than in the XRCC2-wild type cells. CONCLUSION: Our study demonstrated that XRCC2 might play an important role in CRC and function as a novel prognostic indicator and that the down-regulation of XRCC2 may be useful for sensitizing CRC cells during 5-FU chemotherapy.

Probiotics for Preventing Ventilator-Associated Pneumonia in Mechanically Ventilated Patients: A Meta-Analysis with Trial Sequential Analysis.

Background and Objective: Ventilator-associated pneumonia (VAP) is still an important cause of morbidity and mortality in mechanically ventilated patients. The efficacy of the probiotics for preventing VAP is still controversial. Present study was conducted to comprehensively evaluate the effect of probiotics on VAP prevention in mechanically ventilated patients. Methods: PubMed, Embase, and CENTRAL were searched up to September 2016. Eligible trials designed with randomized controlled trials (RCTs) comparing probiotics with control in mechanically ventilated patients were included. Risk ratios (RRs) and mean differences (MDs) with 95% confidence intervals (CIs) were estimated with fixed or random effects models. Trial sequential analysis (TSA) was performed using TSA 0.9beta software. Results: Thirteen RCTs (N = 1969) were included. Overall, probiotics were associated with reduced incidence of VAP (RR = 0.73, 95% CI = 0.60-0.89; P = 0.002), which was confirmed by TSA (TSA adjusted 95% CI = 0.55-0.96). However, no significant difference was observed in 90-day mortality (RR = 1.00, 95% CI = 0.72-1.37; P = 0.99), overall mortality (RR = 0.84, 95% CI = 0.70-1.02; P = 0.09), 28-day mortality (RR = 1.06, 95% CI = 0.72-1.57; P = 0.99), intensive care unit (ICU) mortality (RR = 0.97, 95% CI = 0.74-1.27; P = 0.82), hospital mortality (RR = 0.81, 95% CI = 0.65-1.02; P = 0.07), diarrhea (RR = 0.99, 95% CI = 0.83-1.19; P = 0.92), length of ICU stay (MD = -2.40 days, 95% CI = -6.75 to 1.95; P = 0.28), length of hospital stay (MD = -1.34 days, 95% CI = -6.21 to 3.54; P = 0.59), and duration of mechanical ventilation (MD = -3.32 days, 95% CI = -6.74 to 0.09; P = 0.06). Conclusions: In this meta-analysis, we found that probiotics could reduce the incidence of VAP in mechanically ventilated patients. It seems likely that probiotics provide clinical benefits for mechanically ventilated patients.

LGR5 promotes hepatocellular carcinoma metastasis through inducting epithelial-mesenchymal transition.

The purpose of the present study was to investigate the prognostic value of Leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5) in hepatocellular carcinoma (HCC) and its role in promoting HCC metastasis. The expression level of LGR5 in liver tumor tissues and adjacent non-tumor tissues were detected adopting immunohistochemistry (IHC), real-time PCR (RT-PCR) and western blot assays. Chi-square test was used to evaluate the correlation between LGR5 expression and clinicopathological characteristics. In addition, we assessed the relationship between LGR5 and two epithelial-mesenchymal transition (EMT) markers (E-cadherin and N-cadherin) in HCC tissues and cell lines. Our results showed that the expression of LGR5 was significantly higher in liver tumor tissues than in adjacent non-tumor tissues. Moreover, up-regulated LGR5 was associated with larger tumor diameter (>5cm, P=0.001), higher TNM stage (P=0.021), increased recurrence (P=0.023) and growing metastasis (P=0.030). Besides, we found that the expression level of LGR5 was correlated with E-cadherin and N-cadherin. In conclusion, up-regulated LGR5 in HCC patients is associated with malignant clinicopathological characteristics. LGR5 may promote HCC metastasis through inducting EMT process, and thus can be regarded as a candidate biomarker for prognosis and as a target in therapy.