Increased Factor VIII Activity Is Predictive of the Occurrence of Portal Vein Thrombosis in Cirrhosis.

BACKGROUND: The aim of this study was to identify the role of factor VIII (FVIII) in portal vein thrombosis (PVT) occurrence in cirrhotic patients with gastroesophageal variceal bleeding. METHODS: A total of 453 cirrhotic patients with gastroesophageal varices were enrolled. Computed tomography was performed at baseline and patients were divided into PVT and non-PVT groups (n = 131 vs. 322). Individuals without PVT at baseline were followed up for the development of PVT. Time-dependent receiver operating characteristic analysis of FVIII for PVT development was performed. The Kaplan-Meier methodology was used to analyze the predictive ability of FVIII for PVT incidence at 1 year. RESULTS: FVIII activity (177.00 vs. 153.70, p = 0.001) was significantly increased in the PVT group compared with the non-PVT group in cirrhotic patients with gastroesophageal varices. FVIII activity was positively correlated with the severity of PVT (161.50 vs. 171.07 vs. 187.05%, p = 0.001). Furthermore, FVIII activity (hazard ratio [HR]: 3.48, 95% confidence interval [CI]: 1.14-10.68, p = 0.029 in model 1; HR: 3.29, 95% CI: 1.03-10.51, p = 0.045 in model 2) was an independent risk factor of 1-year PVT development in patients without PVT at baseline, which was confirmed by two separate Cox regression analysis and competing risk models. Patients with elevated FVIII activity exhibit a higher incidence of PVT in the non-PVT group at 1 year (15.17 vs. 3.16%, p < 0.001). The predictive value of FVIII remains significant in individuals who have never received splenectomy (14.76 vs. 3.04%, p = 0.002). CONCLUSION: Elevated FVIII activity was potentially associated with the occurrence and the severity of PVT. It might be helpful to identify cirrhotic patients at risk of PVT.

Relationship between indwelling site and peripheral venous catheter-related complications in adult hospitalized patients: A systematic review and meta-analysis.

AIMS AND OBJECTIVES: This systematic review and meta-analysis aimed to compare the incidence of PVC-related complications between catheterisation in the forearm and back of the hand in adult patients. BACKGROUND: A peripheral intravenous catheter (PVC) is often inserted as part of care during patients' hospitalisation. The catheter is typically inserted in the forearm or at the back of the hand in usual practice. Studies have not yet reached a consensus on the optimal insertion site in any clinical setting. DESIGN: We performed a systematic review and meta-analysis based on PRISMA guidelines. METHODS: We searched the following electronic databases: PubMed, Cochrane Library, Embase, and CINAHL. Randomised controlled trials, cohort studies, case-control studies and cross-sectional studies from inception to July 2021 reporting the incidence of PVC-related complications at the forearm and back of the hand were included. Fixed-effects models and random-effects models were used to derive the pooled risk ratios. RESULTS: Twenty-four studies involving 16562 PVCs met our inclusion criteria. The meta-analysis showed that compared with PVC placement in the back of the hand, placement in the forearm was associated with a higher incidence of total complications and infiltration/extravasation. However, the differences between the PVC indwelling sites were not significant (total complications: P = 0.43; phlebitis: P = 0.35; infiltration/extravasation: P = 0.51). Both incidence of total complications and infiltration/extravasation analyses showed high heterogeneity (total complications: I2  = 60%; infiltration/extravasation: I2  = 58%). CONCLUSION: Available evidence suggests that there is no significant difference between PVC placement in the forearm and at the back of the hand in terms of the incidence of complications, thus making both approaches suitable. RELEVANCE TO CLINICAL PRACTICE: For patients who need indwelling PVC, medical staff can choose the best indwelling site, and both forearm and back of the hand are suitable.

Successful management of chronic urticaria and food allergies in a pediatric population using integrative traditional Chinese medicine therapy: a case series.

BACKGROUND: Food allergy is becoming increasingly common among the pediatric population. Despite strict avoidance of food allergens, a subgroup of sensitive individuals still develops frequent, persistent, and difficult to treat hives (FPDTH) for which there is no curative therapy. Although these cases are rare, these patients are in most need of therapy. CASE PRESENTATIONS: This is a retrospective review of 3 pediatric patients with highly sensitive food allergies who initially presented with hives daily or every other day, or multiple times a day, but achieved marked remission after traditional Chinese medicine (TCM) therapies. Patient 1 (P1) is a 5-year-old who has experienced 140 reactions in his lifetime. Reactions were mostly hives with 4 episodes of anaphylaxis. P1 had used Prednisone 20 times, had an Epinephrine injection 4 times, and had 3 emergency room (ER) visits. Patient 2 (P2) is a 12-year-old who had experienced hives since age 3. Despite daily antihistamine use, P2 had > 730 reactions in his lifetime at the time of presentation including 2 episodes of anaphylaxis. He had been prescribed prednisone 4 times, an Epinephrine injection 2 times, and had 1 ER visit. Patient 3 (P3) is a 20-month-old girl who had experienced > 120 reactions including 1 episode of anaphylaxis. She was on daily desonide and frequently used an antihistamine, yet still had required a course of prednisone once, an Epinephrine injection once, and had 1 ER visit to manage her reaction. After presenting to our clinic, patients received internal and external TCM treatments, including herbal baths and creams (Remedy A-D) as basic remedies to reduce food reactions, including but not limited to frequent hives. Within 7-9 months of TCM treatment, remarkably all patients had complete remission of atopic symptoms. All three patients also experienced an improvement in other conditions including food intolerance, diarrhea, anxiety, eczema, and environmental allergies. After 1 year of treatment, all three patients had reductions in food-specific IgE levels that had been previously elevated, and additionally, P1 and P3, who initially had high total IgE levels, experienced a marked decrease in total IgE levels as well. All three patients continued to introduce foods into their diet that they previously had reactions to, and all 3 patients remain symptom-free. CONCLUSIONS: Three pediatric patients with a known history of multiple food sensitivities and physician-diagnosed food allergies that presented with FPDTH underwent a TCM regimen and experienced dramatic improvement in symptoms and reduction in their IgE levels. This regimen appears to be effective in FPDTH population although a further study in a controlled clinical setting is required.

Comparative Research on Metabolites of Different Species of Epichloë Endophytes and Their Host Achnatherum sibiricum.

Achnatherum sibiricum can be infected by two species of fungal endophytes, Epichloë gansuensis (Eg) and Epichloë sibirica (Es). In this study, the metabolites of Eg, Es, and their infected plants were studied by GC−MS analysis. The results showed that the metabolic profiles of Eg and Es were similar in general, and only six differential metabolites were detected. The direct effect of endophyte infection on the metabolites in A. sibiricum was that endophyte-infected plants could produce mannitol, which was not present in uninfected plants. Epichloë infection indirectly caused an increase in the soluble sugars in A. sibiricum related to growth and metabolites related to the defense against pathogens and herbivores, such as α-tocopherol, α-linolenic acid and aromatic amino acids. Epichloë infection could regulate galactose metabolism, starch and sucrose metabolism, tyrosine metabolism and phenylalanine metabolism of host grass. In addition, there was a significant positive correlation in the metabolite contents between the endophyte and the host.

Risk factors for peripheral venous catheter failure: A prospective cohort study of 5345 patients.

PURPOSE: The objective of this study was to determine the independent risk factors associated with peripheral venous catheter (PVC) failure and develop a model that can predict PVC failure. METHODS: This prospective, multicenter cohort study was carried out in nine tertiary hospitals in Suzhou, China between December 2017 and February 2018. Adult patients undergoing first-time insertion of a PVC were observed from catheter insertion to removal. Logistic regression was used to identify the independent risk factors predicting PVC failure. RESULTS: This study included 5345 patients. The PVC failure rate was 54.05% (n = 2889/5345), and the most common causes of PVC failure were phlebitis (16.3%) and infiltration/extravasation (13.8%). On multivariate analysis, age (45-59 years: OR, 1.295; 95% CI, 1.074-1.561; 60-74 years: OR, 1.375; 95% CI, 1.143-1.654; ⩾75 years: OR, 1.676; 95% CI, 1.355-2.073); department (surgery OR, 1.229; 95% CI, 1.062-1.423; emergency internal/surgical ward OR, 1.451; 95% CI, 1.082-1.945); history of venous puncture in the last week (OR, 1.298, 95% CI 1.130-1.491); insertion site, number of puncture attempts, irritant fluid infusion, daily infusion time, daily infusion volume, and type of sealing liquid were independent predictors of PVC failure. Receiver operating characteristic curve analysis indicated that a logistic regression model constructed using these variables had moderate accuracy for the prediction of PVC failure (area under the curve, 0.781). The Hosmer-Lemeshow goodness of fit test demonstrated that the model was correctly specified (χ2 = 2.514, p = 0.961). CONCLUSION: This study should raise awareness among healthcare providers of the risk factors for PVC failure. We recommend that healthcare providers use vascular access device selection tools to select a clinically appropriate device and for the timely detection of complications, and have a list of drugs classified as irritants or vesicants so they can monitor patients receiving fluid infusions containing these drugs more frequently.

Identification of significant genes as prognostic markers and potential tumor suppressors in lung adenocarcinoma via bioinformatical analysis.

BACKGROUND: Lung adenocarcinoma (LAC) is the predominant histologic subtype of lung cancer and has a complicated pathogenesis with high mortality. The purpose of this study was to identify differentially expressed genes (DEGs) with prognostic value and determine their underlying mechanisms. METHODS: Gene expression data of GSE27262 and GSE118370 were acquired from the Gene Expression Omnibus database, enrolling 31 LAC and 31 normal tissues. Common DEGs between LAC and normal tissues were identified using the GEO2R tool and Venn diagram software. Next, the Database for Annotation, Visualization, and Integrated Discovery (DAVID) was used to analyze the Gene Ontology and Kyoto Encyclopedia of Gene and Genome (KEGG) pathways. Then, protein-protein interaction (PPI) network of DEGs was visualized by Cytoscape with Search Tool for the Retrieval of Interacting Genes and central genes were identified via Molecular Complex Detection. Furthermore, the expression and prognostic information of central genes were validated via Gene Expression Profiling Interactive Analysis (GEPIA) and Kaplan-Meier analysis, respectively. Finally, DAVID, real-time PCR and immunohistochemistry were applied to re-analyze the identified genes, which were also further validated in two additional datasets from ArrayExpress database. RESULTS: First, 189 common DEGs were identified among the two datasets, including 162 downregulated and 27 upregulated genes. Next, Gene Ontology and KEGG pathway analysis of the DEGs were conducted through DAVID. Then, PPI network of DEGs was constructed and 17 downregulated central genes were identified. Furthermore, the 17 downregulated central genes were validated via GEPIA and datasets from ArrayExpress, and 12 of them showed a significantly better prognosis. Finally, six genes were identified significantly enriched in neuroactive ligand-receptor interactions (EDNRB, RXFP1, P2RY1, CALCRL) and Rap1 signaling pathway (TEK, P2RY1, ANGPT1) via DAVID, which were further validated to be weakly expressed in LAC tissues via RNA quantification and immunohistochemistry analysis. CONCLUSIONS: The low expression pattern and relation to prognosis indicated that the six genes were potential tumor suppressor genes in LAC. In conclusion, we identified six significantly downregulated DEGs as prognostic markers and potential tumor suppressor genes in LAC based on integrated bioinformatics methods, which could act as potential molecular markers and therapeutic targets for LAC patients.

The Inhibitory Effect of Endophyte-Infected Tall Fescue on White Clover Can Be Alleviated by Glomus mosseae Instead of Rhizobia.

In artificial ecosystems, mixed planting of gramineous and leguminous plants can have obvious advantages and is very common. Due to their improved growth performances and stress tolerance, endophyte-infected grasses are considered to be ideal plant species for grasslands. However, endophytic fungi can inhibit the growth of neighboring nonhost leguminous plants. In this study, we chose endophyte-infected and endophyte-free tall fescue (Lolium arundinaceum Darbyshire ex. Schreb.) and clover (Trifolium repens) as the experimental materials to explore whether arbuscular mycorrhizal fungi and rhizobium can alleviate the inhibitory effect of endophyte infection on clover. The results showed that endophytic fungi significantly reduced clover biomass. Arbuscular mycorrhizal fungi inoculation significantly increased the biomass of clover in both endophyte-infected tall fescue/clover and endophyte-free tall fescue/clover systems but the beneficial contribution of arbuscular mycorrhizal fungi was more obvious in the endophyte-infected tall fescue/clover system. Rhizobia inoculation could alleviate the detrimental effect of tall fescue on the growth of clover but did not alleviate the detrimental effect of endophyte infection on the growth of clover.

Low-free triiodothyronine is associated with poor prognosis of portal hypertension in cirrhosis.

BACKGROUND AND AIMS: The role of thyroid function in the portal hypertension development and prognosis remains unclear. This study aimed to investigate the correlation between serum-free triiodothyronine (fT3) levels and the outcomes of cirrhotic portal hypertension. METHODS: A total of 385 cirrhotic patients with confirmed portal hypertension underwent computed tomography angiography and thyroid function test at a tertiary care referral center from January 2009 to December 2017. The patients were assigned to the low-fT3 (n = 98) and normal-fT3 groups (n = 287). RESULTS: Child-Pugh (8.88 ± 0.22 vs. 7.09 ± 0.12, P < 0.001) and model for end-stage liver disease (MELD) scores (14.75 ± 0.57 vs. 10.59 ± 0.23, P < 0.001) significantly increased in the low-fT3 group. The hemoglobin level correlated with fT3 (R = 0.299, P < 0.0001) and fT4 (R = 0.310, P < 0.0001), while only fT3 significantly correlated with the albumin level (R = 0.537, P < 0.001). The Kaplan-Meier analysis indicated that the two-year survival rate was 74.51% in the low-fT3 group vs. 94.25% in the normal-fT3 group (P < 0.0001). The Cox regression analysis demonstrated that the serum level of fT3 [hazard ratio: 0.478; 95% confidence interval (CI) 0.391-0.758; P = 0.002] and prothrombin time (hazard ratio: 2.247; 95% CI: 1.316-3.838; P = 0.003) were independent prognostic factors in cirrhotic patients. CONCLUSION: The low fT3 level was associated with poor prognosis and the progression of cirrhotic portal hypertension.

Systemic inflammation and portal vein thrombosis in cirrhotic patients with gastroesophageal varices.

BACKGROUND AND AIM: Cirrhotic patients with gastroesophageal varices and non-tumoral portal vein thrombosis have a higher risk of re-bleeding and poor prognosis. This study aimed to analyze inflammatory biomarkers and thromboelastography in cirrhotic patients with portal vein thrombosis. METHODS: A total of 385 consecutive cirrhotic patients with gastroesophageal varices were prospectively enrolled between 1 December 2016, and 31 August 2017. Of these, 231 were eligible for analysis and were divided into portal vein thrombosis (n = 103) and non-portal vein thrombosis (n = 128) groups based on computerized tomography angiography findings. RESULTS: Patients with portal vein thrombosis generally had higher Child-Pugh scores than those without portal vein thrombosis (6.38 ± 0.12 vs. 5.81 ± 0.09, P < 0.001). The serum albumin levels were significantly lower in patients with portal vein thrombosis (35.90 ± 0.52 vs. 38.52 ± 0.43, P < 0.001). The portal vein thrombosis group had significant higher serum levels of interleukin 6 [4.85 (3.15-6.99) vs. 3.09 (2.06-5.20) pg/ml, P < 0.001] and tumor necrosis factor alpha [10.70 (7.60-15.20) vs. 9.07 (7.03-11.60) pg/ml, P = 0.020]. The interleukin 6 level was 2.5-fold higher in patients with portal vein thrombosis (adjusted odds ratio: 2.574; 95% confidential interval: 1.248-5.310). Thromboelastography showed that TEG-R, the reaction time, was significantly lower in the portal vein thrombosis group [5.20 (4.80-6.30) vs. 6.00 (5.20-6.95), P = 0.009], indicating enhanced coagulation activity. CONCLUSION: This study confirmed the important role of systemic inflammation in portal vein thrombosis. Interleukin 6, an important inflammatory cytokine, is independently associated with portal vein thrombosis. The correlation between the interleukin 6 level and portal vein thrombosis requires further investigation.

Portal vein thrombosis prevalence and mortality among alcoholic cirrhosis in a nationwide inpatient cohort.

OBJECTIVES: Portal vein thrombosis is commonly associated with cirrhosis. The effect of alcoholic cirrhosis on portal vein thrombosis prevalence and mortality has not been well studied. METHODS: We conducted a retrospective cohort study utilizing the 2000-2014 National Inpatient Sample Database. We included patients older than 18 years with decompensated cirrhosis without a history of liver transplantation or hepatocellular carcinoma. We further identified patients with alcoholic cirrhosis vs. non-alcoholic cirrhosis. Primary outcomes included the risk and mortality of portal vein thrombosis in alcoholic cirrhosis. Secondary outcomes included trends of portal vein thrombosis prevalence and mortality in alcoholic cirrhosis, implications of portal vein thrombosis on complications in alcoholic cirrhosis vs. non-alcoholic cirrhosis, and risk of venous thromboembolism in alcoholic cirrhosis. RESULTS: Among 1 892 271 patients with decompensated alcoholic cirrhosis, portal vein thrombosis prevalence was 1.3%. Alcoholic cirrhosis was associated with lower risk of portal vein thrombosis (odds ratio 0.76, P < 0.001) and venous thromboembolism (odds ratio 0.69, P < 0.001) compared to non-alcoholic cirrhosis. Portal vein thrombosis contributed to increased mortality (odds ratio 1.19, P < 0.001) in alcoholic cirrhosis. Portal vein thrombosis prevalence among alcoholic cirrhosis increased while mortality declined during the study period. CONCLUSION: Thrombotic events including portal vein thrombosis and venous thromboembolism were found in less frequent association with alcoholic cirrhosis compared with non-alcoholic cirrhosis. Despite this, the higher in-hospital mortality found among portal vein thrombosis with alcoholic cirrhosis should prompt careful consideration of management.

Colonic Mucosubmucosal Elongated Polyp in the Sigmoid Colon on Surveillance Colonoscopy.

Colonic mucosubmucosal elongated polyp (CMSEP) is a newly designated colorectal polyp. It has unique endoscopic features of a worm- or drumstick-shaped appearance. Histologically, it is composed of normal colonic mucosa and expanded submucosa with a prominent vascular component and no significant inflammation. CMSEP is usually detected incidentally on screening colonoscopy or colonoscopy for other causes. Differential diagnoses that need to be considered include mucosal prolapse syndrome, filiform polyposis, hamartomatous polyp, colon leiomyoma, inverted diverticulum, and residual stalk of a pedunculated adenoma. We present a case of CMSEP on surveillance colonoscopy and literature review.

Systemic Lupus Erythematosus and Angioedema: A Cross-Sectional Study From the National Inpatient Sample.

Objectives: This cross-sectional study aims to investigate the odds of developing angioedema (AE) in systemic lupus erythematosus (SLE) populations compared to non-SLE populations in hospital settings in the United States using a nationwide database. Materials and methods: We used the data from the National Inpatient Sample for the years 2012 to 2014. We constructed two models for multivariate logistic regression analysis. Model 1 was designed to adjust demographic information, while model 2 included each factor in model 1 and additionally accounted for AE-related comorbidities. Results: A total of 90,485 hospitalizations with an AE diagnosis were identified for the years 2012 to 2014, among which 1,505 hospitalizations had both SLE and AE. Compared to those without SLE, AE patients with SLE were younger and included more females. In AE hospitalizations, SLE was associated with higher odds of AE-related comorbidities including atopic disorder, leukocytoclastic vasculitis, eosinophilia, and infections. SLE was associated with higher odds of AE both as all inpatient diagnosis and as principal diagnosis (unadjusted odds ratio [OR] 3.24, 95% confidence interval [CI] 2.87-3.63, p<0.001, model 1 adjusted OR 2.54, 95% CI 2.26-2.86, p<0.001, model 2 adjusted OR 1.71, 95% CI 1.51-1.93, p<0.001). Conclusion: Our study demonstrates that SLE is associated with higher odds of having AE, including severe AE as the principal reason for inpatient admission. SLE is possibly an independent risk factor for AE.

Emerging trends and research foci in gastrointestinal microbiome.

BACKGROUND: Gastrointestinal microbiome has drawn an increasing amount of attention over the past decades. There is emerging evidence that the gut flora plays a major role in the pathogenesis of certain diseases. We aimed to analyze the evolution of gastrointestinal microbiome research and evaluate publications qualitatively and quantitatively. METHODS: We obtained a record of 2891 manuscripts published between 1998 and 2018 from the Web of Science Core Collection (WoSCC) of Thomson Reuters; this record was obtained on June 23, 2018. The WoSCC is the most frequently used source of scientific information. We used the term "Gastrointestinal Microbiomes" and all of its hyponyms to retrieve the record, and restricted the subjects to gastroenterology and hepatology. We then derived a clustered network from 70,169 references that were cited by the 2891 manuscripts, and identified 676 top co-cited articles. Next, we used the bibliometric method, CiteSpace V, and VOSviewer 1.6.8 to identify top authors, journals, institutions, countries, keywords, co-cited articles, and trends. RESULTS: We identified that the number of publications on gastrointestinal microbiome is increasing over time. 112 journals published articles on gastrointestinal microbiome. The United States of America was the leading country for publications, and the leading institution was the University of North Carolina. Co-cited reference analysis revealed the top landmark articles in the field. Gut microbiota, inflammatory bowel disease (IBD), probiotics, irritable bowel disease, and obesity are some of the high frequency keywords in co-occurrence cluster analysis and co-cited reference cluster analysis; indicating gut microbiota and related digestive diseases remain the hotspots in gut microbiome research. Burst detection analysis of top keywords showed that bile acid, obesity, and Akkermansia muciniphila were the new research foci. CONCLUSIONS: This study revealed that our understanding of the link between gastrointestinal microbiome and associated diseases has evolved dramatically over time. The emerging new therapeutic targets in gut microbiota would be the foci of future research.

Generation of a long-acting fusion inhibitor against HIV-1.

AIDS has evolved from a fatal infectious disease to a manageable chronic disease under the treatment of anti-AIDS medications. HIV fusion inhibitors with high activity, low side effects and strong selectivity are promising drugs against HIV. Only one fusion inhibitor is currently approved, thereby highly active long-acting fusion inhibitors need to be developed for long-term AIDS treatment. Here, we synthesised MT-SC22EK (a small HIV fusion inhibitor) derivatives containing 1-2 staples to improve its stability. Antiviral activity studies showed that MT-SC22EK-2 with two staples exhibited potent inhibitory activity against HIV-1 standard strains and Chinese epidemic strains, and at the same time, MT-SC22EK-2 presented strong anti-T20 resistance. Surprisingly, MT-SC22EK-2 possessed excellent protease stability with a half-life of 3665 min. MT-SC22EK-2 is a potential HIV fusion inhibitor considered as a long-acting anti-HIV drug candidate.

Rheumatoid arthritis is associated with increased in-hospital mortality in asthma exacerbations: a nationwide study.

The relationship between RA and asthma has been yielding conflicting results, with most recent studies showing a possible positive association. The study aims at the outcomes of adult patients hospitalized for asthma exacerbation in those with and without RA. We used data from the National Inpatient Sample (NIS) for the period of 2012-2014. ICD 9 code was used to identify the diagnosis. Our primary outcome was in-hospital mortality. Our secondary outcome was total asthma exacerbation hospitalizations, length of stay, and total hospital charges. Compared to those without RA, RA was associated with increased hospitalizations for asthma exacerbation (unadjusted OR 1.29, p < 0.001; adjusted OR 1.06, p = 0.002), more respiratory and systemic comorbidities, increased in-hospital mortality (unadjusted OR 1.89, p = 0.001; adjusted OR 1.60, p = 0.020), length of stay (4.5 vs 3.8; unadjusted p < 0.001, adjusted p < 0.001), and total hospital charges (30,149 vs 26,247; unadjusted p < 0.001, adjusted p = 0.048). Our study was the first to demonstrate that RA is associated with increased in-hospital mortality, length of stay, and cost using a national inpatient database. We hypothesize that in asthmatic patients with concurrent RA, their asthma may represent a distinctive subgroup that is more severe and carries a poorer prognosis, which deserves more attention and future investigation.

miR-541 suppresses proliferation and invasion of squamous cell lung carcinoma cell lines via directly targeting high-mobility group AT-hook 2.

An increasing number of studies have demonstrated that micro-ribonucleic acids (miRNAs) are important tumor suppressors during carcinogenesis. However, the function of miRNA-541 (miR-541) in malignancies, especially lung cancer, has not been widely reported. In this study, miR-541 expression was significantly decreased in squamous cell lung carcinoma (SCLC) cancerous tissue and SCLC cell lines. To analyze miR-541 function in SCLC, we overexpressed miR-541 in SCLC cell lines (SK-MES-1 and H226). According to the CCK8, wound scratch, and transwell invasion assay results, miR-541 overexpression significantly inhibited SCLC cell proliferation, migration, and invasion ability. Next, using RT-PCR, Western blotting, immunocytochemistry, and luciferase assays, HMGA2 was identified, for the first time, as a direct regulatory target of miR-541 in SK-MES-1 and H226 cells. Furthermore, upregulating HMGA2 expression significantly alleviated the suppressive effects of miR-541 on SK-MES-1 and H226 cell proliferation, migration, and invasion. In summary, our study revealed that miR-541 inhibited SCLC proliferation and invasion by directly targeting HMGA2.

Considerations and recent advances in QSAR models for cytochrome P450-mediated drug metabolism prediction.

Quantitative structure-activity relationships (QSAR) methods are urgently needed for predicting ADME/T (absorption, distribution, metabolism, excretion and toxicity) properties to select lead compounds for optimization at the early stage of drug discovery, and to screen drug candidates for clinical trials. Use of suitable QSAR models ultimately results in lesser time-cost and lower attrition rate during drug discovery and development. In the case of ADME/T parameters, drug metabolism is a key determinant of metabolic stability, drug-drug interactions, and drug toxicity. QSAR models for predicting drug metabolism have undergone significant advances recently. However, most of the models used lack sufficient interpretability and offer poor predictability for novel drugs. In this review, we describe some considerations to be taken into account by QSAR for modeling drug metabolism, such as the accuracy/consistency of the entire data set, representation and diversity of the training and test sets, and variable selection. We also describe some novel statistical techniques (ensemble methods, multivariate adaptive regression splines and graph machines), which are not yet used frequently to develop QSAR models for drug metabolism. Subsequently, rational recommendations for developing predictable and interpretable QSAR models are made. Finally, the recent advances in QSAR models for cytochrome P450-mediated drug metabolism prediction, including in vivo hepatic clearance, in vitro metabolic stability, inhibitors and substrates of cytochrome P450 families, are briefly summarized.

In vitro and in vivo studies on the complexes of vinpocetine with hydroxypropyl-beta-cyclodextrin.

The purpose of this study was to evaluate complexes of vinpocetine (VIN), a poorly water-soluble base type drug, with hydroxypropyl-beta-cyclodextrin (HP-beta-CD) in aqueous environment and in solid state, with or without citric acid (CA) as an acidifier of the complexation medium. The apparent stability constant (Kc) calculated by phase solubility was 282 M(-1) and the complexation in solution was structurally characterized by 1H-NMR which showed VIN was likely to fit into the cyclodextrin cavity with its phenyl ring and ethyl ester bond. Solid complexes of VIN and HP-beta-CD were prepared by kneading (KE), co-evaporating (CE) and freeze-drying (FD) methods. Physical mixtures were prepared for comparison. The study in the solid state included the differential scanning calorimetry (DSC), X-ray diffractometry (XRD) and infrared absorption spectroscopy (IR). From these analyses, CE and FD products were found in amorphous state, allowing to the conclusion of strong evidences of inclusion complex formation. However, the dissolution test showed that only VIN/HP-beta-CD+CA complexes by CE and FD method could provide satisfying dissolution behavior (rapid, complete and lasting) when compared to that of VIN/HP-beta-CD complexes. Interestingly, the addition of CA in inclusion complexes could significantly decrease the amount of HP-beta-CD needed to solubilize the same amount of VIN and thereby reducing the formulation bulk. Furthermore, in-vivo study revealed that the bioavailability of VIN after oral administration to rabbits (n=6) was significantly improved by VIN/HP-beta-CD+CA inclusion complex.