LARP4B promotes hepatocellular carcinoma progression and impairs sorafenib efficacy by activating SPINK1-mediated EGFR pathway.

La-related proteins (LARPs) regulate gene expression by binding to RNAs and exhibit critical effects on disease progression, including tumors. However, the role of LARP4B and its underlying mechanisms in the progression of hepatocellular carcinoma (HCC) remain largely unclear. In this study, we found that LARP4B expression is upregulated and correlates with poor prognosis in patients with HCC. Gain- and loss-of-function assays showed that LARP4B promotes stemness, proliferation, metastasis, and angiogenesis in vitro and in vivo. Furthermore, LARP4B inhibition enhances the antitumor effects of sorafenib and blocks the metastasis-enhancing effects of low sorafenib concentrations in HCC. Mechanistically, LARP4B expression is upregulated by METTL3-mediated N6-methyladenosine (m6A)-IGF2BP3-dependent modification in HCC. RNA- and RNA immunoprecipitation (RIP)- sequencing uncovered that LARP4B upregulates SPINK1 by binding to SPINK1 mRNA via the La motif and maintaining mRNA stability. LARP4B activates the SPINK1-mediated EGFR signaling pathway, which supports stemness, progression and sorafenib resistance in HCC. Additionally, a positive feedback loop with the LARP4B/SPINK1/p-AKT/C/EBP-ß axis is responsible for the sorafenib-therapeutic benefit of LARP4B depletion. Overall, this study demonstrated that LARP4B facilitates HCC progression, and LARP4B inhibition provides benefits to sorafenib treatment in HCC, suggesting that LARP4B might be a potential therapeutic target for HCC.

Does Religious Participation Predict Future Expectations About Health? Using a Life Course Framework to Test Multiple Mechanisms.

Though an impressive array of health outcomes has been studied, research within the field of religion and health has not yet considered how religious involvement may affect future expectations about health. This is a significant shortcoming because the teachings of many religions direct adherent's focus to the distant future, and future self-ratings of health are a known predictor of subjective life expectancy and eventual mortality risk. Recognizing the need for a life course approach to conceptualizing patterns of religious involvement, we assess how stability or change in religious attendance from childhood to adulthood structures individual expectations of future health. Drawing on data from the 2017 Values and Beliefs of the American Public Study (Baylor Religion Survey Wave 5), we find that stable high (weekly) attendance between childhood and adulthood is associated with higher future health expectations. Parametric mediation analyses conducted in the counterfactual framework suggest that this association is explained by the tendency of frequent stable attenders to have (a) higher levels of beliefs in the sense of divine control and (b) a lower likelihood of engaging in harmful health behaviors (smoking).

Gastrointestinal Microbiota Changes in Patients With Gastric Precancerous Lesions.

Background: Gastric microbiota may be involved in gastric cancer. The relationship between gastrointestinal microbes and the risk of gastric cancer is unclear. This study aimed to explore the gastric and intestinal bacteria associated with gastritis and gastric precancerous lesions. We conducted a case-control study by performing 16S rRNA gene analysis of gastric biopsies, juices, and stool samples from 148 cases with gastritis or gastric precancerous lesions from Anhui and neighboring provinces, China. And we validated our findings in public datasets. Results: Analysis of microbial sequences revealed decreased bacterial alpha diversity in gastric bacteria during the progression of gastritis. Helicobacter pylori was the main contributor to the decreased microbial composition and diversity in the gastric mucosa and had little influence on the microbiota of gastric juice and feces. The gastric mucosal genera Gemella, Veillonella, Streptococcus, Actinobacillus, and Hemophilus had the higher degree of centrality across the progression of gastric precancerous lesions. And Acinetobacter may contribute to the occurrence of intraepithelial neoplasia. In addition, the microbial model of H. pylori-positive gastric biopsies and feces showed value in the prediction of gastric precancerous lesions. Conclusions: This study identified associations between gastric precancerous lesions and gastric microbiota, as well as the changes in intestinal microbiota, and explored their values in the prediction of gastric precancerous lesions.

Development and Validation of Nomograms to Predict Operative Link for Gastritis Assessment Any-Stage and Stages III-IV in the Chinese High-Risk Gastric Cancer Population.

Purpose: It is very essential to diagnose gastric atrophy in the area with high prevalence of gastric cancer. Operative link for gastritis assessment (OLGA) was developed to detect the severity of gastric atrophy. The aim of this study was to develop and validate nomograms for predicting OLGA any-stage and stages III-IV in the Chinese high-risk gastric cancer population. Methods: We retrospectively analyzed 7,945 participants obtained by a multicenter cross-sectional study. We randomly selected 55% individuals (4,370 participants, training cohort) to analyze and generate the prediction models and validated the models on the remaining individuals (3,575 participants, validation cohort). A multivariate logistic regression model was used to select variables in the training cohort. The corresponding nomograms were developed to predict OLGA any-stage and stages III-IV, respectively. The area under the receiver operating characteristic curves and the GiViTI calibration belts were used to estimate the discrimination and calibration of the prediction models. Results: There were 1,226 (28.05%) participants in the training sample and 970 (27.13%) in the validation sample who were diagnosed with gastric atrophy. The nomogram predicting OLGA any-stage had an area under the curve (AUC) of 0.610 for the training sample and 0.615 for the validation sample, with favorable calibrations in the overall population. Similarly, the nomogram predicting OLGA stages III-IV had an AUC of 0.702 and 0.714 for the training and validation samples, respectively, with favorable calibrations in the overall population. Conclusions: The prediction model can early identify the occurrence of gastric atrophy and the severity stage of gastric atrophy to some extent.

Global and regional overview of the inclusion of paediatric surgery in the national health plans of 124 countries: an ecological study.

OBJECTIVE: This study evaluates the priority given to surgical care for children within national health policies, strategies and plans (NHPSPs). PARTICIPANTS AND SETTING: We reviewed the NHPSPs available in the WHO's Country Planning Cycle Database. Countries with NHPSPs in languages different from English, Spanish, French or Chinese were excluded. A total of 124 countries met the inclusion criteria. PRIMARY AND SECONDARY OUTCOME MEASURES: We searched for child-specific and surgery-specific terms in the NHPSPs' missions, goals and strategies using three analytic approaches: (1) count of the total number of mentions, (2) count of the number of policies with no mentions and (3) count of the number of policies with five or more mentions. Outcomes were compared across WHO regional and World Bank income-level classifications. RESULTS: We found that the most frequently mentioned terms were 'child*', 'infant*' and 'immuniz*'. The most frequently mentioned surgery term was 'surg*'. Overall, 45% of NHPSPs discussed surgery and 7% discussed children's surgery. The majority (93%) of countries did not mention selected essential and cost-effective children's procedures. When stratified by WHO region and World Bank income level, the West Pacific region led the inclusion of 'pediatric surgery' in national health plans, with 17% of its countries mentioning this term. Likewise, low-income countries led the inclusion of surg* and 'pediatric surgery', with 63% and 11% of countries mentioning these terms, respectively. In both stratifications, paediatric surgery only equated to less than 1% of the total terms. CONCLUSION: The low prevalence of children's surgical search terms in NHPSPs indicates that the influence of surgical care for this population remains low in the majority of countries. Increased awareness of children's surgical needs in national health plans might constitute a critical step to scale up surgical system in these countries.

CST1 Promoted Gastric Cancer Migration and Invasion Through Activating Wnt Pathway.

INTRODUCTION: Gastric cancer is one of the main reasons of cancer-induced death, exploring the molecular mechanisms of gastric cancer progression is critical for gastric cancer therapy. Here, we studied the role of cysteine protease inhibitor CST1 in gastric cancer progression. METHODS: Matrigel-coated or -uncoated transwell assay was used to determine the effect of CST1 on gastric cancer invasion and migration, luciferase reporter system was used to determine the effect of CST1 on Wnt pathway activity. RESULTS: CST1 had high expression levels in gastric cancer tissues and cells, patients who had high CST1 expression had poor outcome. Overexpression of CST1 increased gastric cancer migration and invasion, while knockdown of CST1 suppressed gastric cancer migration invasion. Mechanism analysis showed CST1 promoted WNT signaling pathway activity, promoted the nuclear translocation of ß-catenin and the expression of Wnt signaling targets. Inhibition of Wnt pathway in CST1 overexpression cells inhibited migration and invasion, suggesting CST1 promoted gastric cancer cell migration and invasion through activating the Wnt pathway. CONCLUSION: In summary, we found CST1 promoted gastric cancer migration and invasion through activating Wnt signaling, providing a novel target for gastric cancer therapy.

Micro/Nanoscale Structured Superhydrophilic and Underwater Superoleophobic Hybrid-Coated Mesh for High-Efficiency Oil/Water Separation.

A novel micro/nanoscale rough structured superhydrophilic hybrid-coated mesh that shows underwater superoleophobic behavior is fabricated by spray casting or dipping nanoparticle-polymer suspensions on stainless steel mesh substrates. Water droplets can spread over the mesh completely; meanwhile, oil droplets can roll off the mesh at low tilt angles without any penetration. Besides overcoming the oil-fouling problem of many superhydrophilic coatings, this superhydrophilic and underwater superoleophobic mesh can be used to separate oil and water. The simple method used here to prepare the organic-inorganic hybrid coatings successfully produced controllable micro-nano binary roughness and also achieved a rough topography of micro-nano binary structure by controlling the content of inorganic particles. The mechanism of oil-water separation by the superhydrophilic and superoleophobic membrane is rationalized by considering capillary mechanics. Tetraethyl orathosilicate (TEOS) as a base was used to prepare the nano-SiO2 solution as a nano-dopant through a sol-gel process, while polyvinyl alcohol (PVA) was used as the film binder and glutaraldehyde as the cross-linking agent; the mixture was dip-coated on the surface of 300-mesh stainless steel mesh to form superhydrophilic and underwater superoleophobic film. Properties of nano-SiO2 represented by infrared spectroscopy and surface topography of the film observed under scanning electron microscope (SEM) indicated that the film surface had a coarse micro-nano binary structure; the effect of nano-SiO2 doping amount on the film's surface topography and the effect of such surface topography on hydrophilicity of the film were studied; contact angle of water on such surface was tested as 0° by the surface contact angle tester and spread quickly; the underwater contact angle to oil was 158°, showing superhydrophilic and underwater superoleophobic properties. The effect of the dosing amount of cross-linking agent to the waterproof swelling property and the permeate flux of the film were studied; the oil-water separation effect of the film to oil-water suspension and oil-water emulsion was studied too, and in both cases the separation efficiency reached 99%, which finally reduced the oil content to be lower than 50 mg/L. The effect of filtration times to permeate flux was studied, and it was found that the more hydrophilic the film was, the stronger the stain resistance would be, and the permeate flux would gradually decrease along with the increase of filtration times.

Analysis of Risk Factors of Gastric Low-Grade Intraepithelial Neoplasia in Asymptomatic Subjects Undergoing Physical Examination.

Secondary prevention is an important strategy in gastric cancer. Low-grade intraepithelial neoplasia (LGIN) is the last stage of precancerous lesion, and its timely diagnosis can greatly improve the detection rate of early gastric cancer. We performed a prospective study to analyze the risk factors of gastric LGIN in asymptomatic subjects undergoing physical examination. A total of 3437 subjects were included in this study, and 2259 asymptomatic subjects were investigated from March 2015 to April 2018. Risk factors were evaluated, and the endoscopic features of LGIN and prognosis were described. The overall incidence of LGIN was 19.73% (678/3437), while the incidence of LGIN in the asymptomatic and symptomatic groups was 19.65% (444/2259) and 19.86% (234/1178), respectively (P = 0.884). The rate of Helicobacter pylori infection in this physical examination population was 39.13% (35.8% asymptomatic group, 45.5% symptomatic group; P ≤ 0.001). Risk factors including age, H. pylori infection, history of antibiotic misuse, and spicy and high-fat diet (all P < 0.05) were further verified by multivariate analysis as independent risk factors. History of antibiotic misuse and H. pylori infection showed significant associations with LGIN (odds ratio (OR) = 6.767, 95% confidence interval (CI) 3.873-11.825 and OR = 3.803, 95% CI 3.009-4.808, respectively). The most common endoscopic classification of LGIN was erosive gastritis (50.78%), and the major endoscopic appearance was Paris IIa (flat with slight elevation located mostly in the antrum). During the mean follow-up period of 15.02 months, 49.4% of LGIN regressed, 0.61% of LGIN progressed, and 50% of LGIN remained unchanged. History of antibiotic misuse and H. pylori infection were predominant risk factors of LGIN in asymptomatic subjects, and those individuals should consider early screening for gastric cancer.

Impact of Computer-Based and Pharmacist-Assisted Medication Review Initiated in the Emergency Department.

OBJECTIVES: Whether early medication reconciliation and integration can reduce polypharmacy and potentially inappropriate medication (PIM) in the emergency department (ED) remains unclear. Polypharmacy and PIM have been recognized as significant causes of adverse drug events in older adults. Therefore, this pilot study was conducted to delineate this issue. DESIGN: An interventional study. SETTING: A medical center in Taiwan. PARTICIPANTS: Older ED patients (aged ≥65 years) awaiting hospitalization between December 1, 2017, and October 31, 2018 were recruited in this study. A multidisciplinary team and a computer-based and pharmacist-assisted medication reconciliation and integration system were implemented. MEASUREMENTS: The reduced proportions of major polypharmacy (≥10 medications) and PIM at hospital discharge were compared with those on admission to the ED between pre- and post-intervention periods. RESULTS: A total of 911 patients (pre-intervention = 243 vs post-intervention = 668) were recruited. The proportions of major polypharmacy and PIM were lower in the post-intervention than in the pre-intervention period (-79.4% vs -65.3%; P < .001, and - 67.5% vs -49.1%; P < .001, respectively). The number of medications was reduced from 12.5 ± 2.7 to 6.9 ± 3.0 in the post-intervention period in patients with major polypharmacy (P < .001). CONCLUSION: Early initiation of computer-based and pharmacist-assisted intervention in the ED for reducing major polypharmacy and PIM is a promising method for improving geriatric care and reducing medical expenditures. J Am Geriatr Soc 67:2298-2304, 2019.

Characterisation of fibroblast-like synoviocytes from a murine model of joint inflammation.

INTRODUCTION: Fibroblast-like synoviocytes (FLS) play a central role in defining the stromal environment in inflammatory joint diseases. Despite a growing use of FLS isolated from murine inflammatory models, a detailed characterisation of these cells has not been performed. METHODS: In this study, FLS were isolated from inflamed joints of mice expressing both the T cell receptor transgene KRN and the MHC class II molecule Ag7 (K/BxN mice) and their purity in culture determined by immunofluorescence and real-time reverse transcription polymerase chain reaction (real-time RT-PCR). Basal expression of proinflammatory genes was determined by real-time RT-PCR. Secreted interleukin 6 (IL-6) was measured by enzyme-linked immunosorbent assay (ELISA), and its regulation by tumor necrosis factor-alpha (TNF-α and corticosterone (the major glucocorticoid in rodents) measured relative to other mesenchymal cell populations. RESULTS: Purity of FLS culture was identified by positive expression of fibronectin, prolyl 4-hydroxylase, cluster of differentiation 90.2 (CD90.2) and 248 (CD248) in greater than 98% of the population. Cultured FLS were able to migrate and invade through matrigel, a process enhanced in the presence of TNF-α. FLS isolated from K/BxN mice possessed significantly greater basal expression of the inflammatory markers IL-6, chemokine ligand 2 (CCL-2) and vascular cell adhesion molecule 1 (VCAM-1) when compared to FLS isolated from non-inflamed tissue (IL-6, 3.6 fold; CCL-2, 11.2 fold; VCAM-1, 9 fold; P<0.05). This elevated expression was abrogated in the presence of corticosterone at 100 nmol/l. TNF-α significantly increased expression of all inflammatory markers to a much greater degree in K/BxN FLS relative to other mesenchymal cell lines (K/BxN; IL-6, 40.8 fold; CCL-2, 1343.2 fold; VCAM-1, 17.8 fold; ICAM-1, 13.8 fold; P<0.05), with secreted IL-6 mirroring these results (K/BxN; con, 169±29.7 versus TNF-α, 923±378.8 pg/ml/1×105 cells; P<0.05). Dose response experiments confirmed effective concentrations between 10 and 100 nmol/l for corticosterone and 1 and 10 ng/ml for TNF-α, whilst inflammatory gene expression in FLS was shown to be stable between passages four and seven. CONCLUSIONS: This study has established a well characterised set of key inflammatory genes for in vitro FLS culture, isolated from K/BxN mice and non-inflamed wild-type controls. Their response to both pro- and anti-inflammatory signalling has been assessed and shown to strongly resemble that which is seen in human FLS culture. Additionally, this study provides guidelines for the effective characterisation, duration and treatment of murine FLS culture.

PTFE/polyamide thin-film composite membranes using PTFE films modified with ethylene diamine polymer and interfacial polymerization: preparation and pervaporation application.

Plasma polymerization of ethylene diamine (EDA) on PTFE film surfaces is applied to modify PTFE surfaces to become hydrophilic and to incorporate amino groups onto PTFE surfaces. The surface-modified PTFE films are utilized as substrates for interfacial polymerization of EDA and trimesoyl chloride to prepare PTFE/polyamide thin-film composite (TFC) membranes. The effect of plasma power for plasma polymerization on the morphology and performances of the PTFE/PA TFC membranes are examined and discussed. The presence of amino groups on the PTFE substrates provides chemical linkages between PTFE and PA layers in interfacial polymerization to make the PTFE/PA TFC membranes are stable for pervaporation separations. A high permeation flux of 1910 g/hm(2) and a separation factor of 290 are observed with the PTFE/PA TFC membranes for pervaporation dehydration on a 70 wt% isopropanol aqueous solution at 70 degrees C. This approach explores a new method to prepare PTFE-based TFC membranes via interfacial polymerizations. The prepared TFC membranes could be potentially utilized in pervaporation and nanofiltration separations.

Selective inhibition of growth of tuberous sclerosis complex 2 null cells by atorvastatin is associated with impaired Rheb and Rho GTPase function and reduced mTOR/S6 kinase activity.

Inactivating mutations in the tuberous sclerosis complex 2 (TSC2) gene, which encodes tuberin, result in the development of TSC and lymphangioleiomyomatosis (LAM). The tumor suppressor effect of tuberin lies in its GTPase-activating protein activity toward Ras homologue enriched in brain (Rheb), a Ras GTPase superfamily member. The statins, 3-hydroxy-3-methylglutaryl CoA reductase inhibitors, have pleiotropic effects which may involve interference with the isoprenylation of Ras and Rho GTPases. We show that atorvastatin selectively inhibits the proliferation of Tsc2-/- mouse embryo fibroblasts and ELT-3 smooth muscle cells in response to serum and estrogen, and under serum-free conditions. The isoprenoids farnesylpyrophosphate (FPP) and geranylgeranylpyrophosphate (GGPP) significantly reverse atorvastatin-induced inhibition of Tsc2-/- cell growth, suggesting that atorvastatin dually targets a farnesylated protein, such as Rheb, and a geranylgeranylated protein, such as Rho, both of which have elevated activity in Tsc2-/- cells. Atorvastatin reduced Rheb isoprenylation, GTP loading, and membrane localization. Atorvastatin also inhibited the constitutive phosphorylation of mammalian target of rapamycin, S6 kinase, and S6 found in Tsc2-/- cells in an FPP-reversible manner and attenuated the high levels of phosphorylated S6 in Tsc2-heterozygous mice. Atorvastatin, but not rapamycin, attenuated the increased levels of activated RhoA in Tsc2-/- cells, and this was reversed by GGPP. These results suggest that atorvastatin may inhibit both rapamycin-sensitive and rapamycin-insensitive mechanisms of tuberin-null cell growth, likely via Rheb and Rho inhibition, respectively. Atorvastatin may have potential therapeutic benefit in TSC syndromes, including LAM.