Integrated Database Research Articles

CREAMMIST: an integrative probabilistic database for cancer drug response prediction.

Extensive in vitro cancer drug screening datasets have enabled scientists to identify biomarkers and develop machine learning models for predicting drug sensitivity. While most advancements have focused on omics profiles, cancer drug sensitivity scores precalculated by the original sources are often used as-is, without consideration for variabilities between studies. It is well-known that significant inconsistencies exist between the drug sensitivity scores across datasets due to differences in experimental setups and preprocessing methods used to obtain the sensitivity scores. As a result, many studies opt to focus only on a single dataset, leading to underutilization of available data and a limited interpretation of cancer pharmacogenomics analysis. To overcome these caveats, we have developed CREAMMIST (https://creammist.mtms.dev), an integrative database that enables users to obtain an integrative dose-response curve, to capture uncertainty (or high certainty when multiple datasets well align) across five widely used cancer cell-line drug-response datasets. We utilized the Bayesian framework to systematically integrate all available dose-response values across datasets (>14 millions dose-response data points). CREAMMIST provides easy-to-use statistics derived from the integrative dose-response curves for various downstream analyses such as identifying biomarkers, selecting drug concentrations for experiments, and training robust machine learning models.

Functional characterization of secologanin synthase-like homologous genes suggests their involvement in the biosynthesis of diverse metabolites in the secoiridoid biosynthetic pathway of Camptotheca acuminata Decne

The assignment of functions based on homology has recently been challenged by the frequent discovery of functional divergence among homologous gene family members of enzymes involved in plant secondary metabolism. Secologanin synthase (SLS) is the key CYP450 enzyme that acts critically in the biosynthesis of Strychnos alkaloid scaffold. In this study, to fully elucidate the mechanism that underlies metabolic variation, the CYP450 paralogs that participate in oxidative transformation of the secoiridoid pathway were functionally characterized by combining multitiered strategies of metabolite profiling, phylogenetic analyses, biochemistry assays and reverse genetics techniques. Five CaSLSs-like homologous genes were mined and isolated from an integrative multi-omics database of Camptotheca acuminata. Protein sequences, structural comparisons, and phylogenetic analyses confirmed that CaSLS1–2 and CaSLS4–5 were grouped into the SLS clade, and only CaSLS3 clustered into the 7DLH clade. Five homologs, including two previously identified enzymatic genes, were thus designated as CaSLAS1, CaSLAS2, Ca7DLH, CaSLS4 and CaSLS5. Enzymatic assays of the recombinant proteins in yeast showed that CaSLAS1 and CaSLAS2 displayed multi-catalytic activities of SLS, secologanic acid synthase (SLAS) and secoxyloganin synthase (SXS). Additionally, the reactions of CaSLASs enzymes generated stereospecific isomers of secoiridoid products, and a new product of secoxyloganin was observed. CaSLS5, a third SLS enzyme isoform that catalyzes the formation of secologanin, was reported for the first time. However, CaSXS enzymatic activities in vitro had little physiological impact on the biosynthesis of camptothecin (CPT) in Camptotheca acuminata. The primary and secondary roles of CaSLSs-like genes in secoiridoid metabolism were confirmed by virus-induced gene silencing (VIGS) in plant leaves. Efficient silencing and transcriptional downregulation of CaSLAS2, compared with the CaSLAS1 homologs, resulted in a greater reduction of the accumulation of CPT within silenced plants, and CaSLS5 had barely any effect on the contents of metabolites in planta. Thus, CaSLAS2, rather than CaSLAS1, appeared to function as a major participant in the biosynthesis of CPT, and there were redundant functions in the CaSLSs-like enzymes. Consistent with such roles, CaSLAS2 was ubiquitously expressed at very high levels in Camptotheca tissues, and CaSLAS2 was specifically expressed in young leaves. In contrast, CaSLS5 was poorly expressed in every tissue tested. Our findings demonstrate that homologs that belong to the CYP72 gene family are functionally diverse and exhibit divergence and thereby uncover an expanding group of enzymatic genes that determine the chemo-diversity of the iridoid pathway.

Tea consumption and the risks of osteoporosis and hip fracture: a population-based longitudinal follow-up study

SummaryThis population-based longitudinal follow-up study showed a protective effect of tea consumption against osteoporosis, particularly among women and middle-aged people. High tea consumption was also associated with a reduced risk of hip fracture.IntroductionTo investigate the association of tea consumption with the risks of osteoporosis and hip fracture.MethodsThis study used the Keelung Community-based Integrated Screening database and Taiwan’s National Health Insurance Research Database. A total of 42,742 subjects aged 45 to 74 years were enrolled. Each was classified as no tea consumption, low tea consumption, and high tea consumption, according to the results of an eating habits questionnaire. The diagnosis of osteoporosis and hip fracture was based on BMD measured by dual-energy X-ray absorptiometry and the X-ray findings. The median follow-up time was 8.5 years.ResultsAs compared with the no tea consumption group, the osteoporosis HRs for the low tea consumption and high tea consumption groups were 0.88 (95% confidence interval (CI) 0.80–0.96) and 0.87 (95% CI 0.80–0.94), respectively. Among those participants aged 59 or below, the osteoporosis HRs for low tea consumption and high tea consumption (vs. no tea consumption) were 0.85 (95% CI 0.74–0.96) and 0.79 (95% CI 0.69–0.90). The HRs of hip fracture for the low tea consumption and high tea consumption groups (vs. no tea consumption) were 0.85 (95% CI 0.67–1.08) and 0.69 (95% CI 0.55–0.86), respectively.ConclusionTea consumption was linked to a lower risk of osteoporosis, particularly among women and middle-aged people. High tea consumption was also associated with a reduced risk of hip fracture.

On the Application of Multidimensional Statistical Procedures in the Analysis of the Prospects for Cooperation between the EAEU and ASEAN

This study discusses the results of using multidimensional statistical procedures in the analysis of development prospects and the state of regional integration of the countries of the Association of Southeast Asian Nations (ASEAN) and the countries of the Eurasian Economic Union (EAEU) in the horizon of 2030.Aim. Determine the development prospects and effectiveness of regional organizations, ASEAN and EAEU, as of 2030.Tasks. To identify the current trend in the development of the processes of regional cooperation and integration of the ASEAN countries and the EAEU countries, to determine and predict the state of the processes of regional cooperation and integration of the discussed regional associations in the context of the types and scenarios for the development of regional organizations proposed by the Eurasian Development Bank.Methods. The study used the work of the Eurasian Development Bank, the Regional Integration Database (RIDB), the open data of the World Bank, and the data of the ASEAN statistical portal. The research methodology was based on the assumption that, based on multivariate statistical procedures, it is possible to establish a different in time, the position of a regional organization in its relatively homogeneous group. The group (cluster) was taken (taken) in accordance with a typology provided by the Center for Integration Studies of the Eurasian Development Bank. The construction of time series models was carried out in accordance with the ARIMA methodology.Results. With the help of cluster analysis, similarities and differences were determined in relation to the distance of the object under study to the center of a homogeneous reference group. Thus, it was possible to establish the position of regional international organizations, ASEAN and EAEU, differing in time in their relatively homogeneous group. In addition, the processes of regional cooperation and integration are non-linear and non-unidirectional, accompanied byboth convergence and divergence.Conclusion. With regard to ASEAN, the possibility of reducing its effectiveness as a regional organization in the perspective of 2030 has been established, this situation is explained by the implementation of the hedging policy by the key actors in the region in the context of the growing competition between the United States and China.With regard to the EAEU, it has been established that the organization in the horizon of 2030 has significant opportunities for its development as an active organization in the post-Soviet space. However, such a prospect will depend on timely actions of the Russian Federation that meet the challenges and threats of sanctions pressure.

Premature discontinuation among individuals with epilepsy participating in epilepsy self-management research interventions

ObjectiveThe Managing Epilepsy Well (MEW) Network conducts epilepsy self-management (ESM) intervention development, testing, and archival clinical trials data analyses in the MEW Network Integrated Database (MEW-DB). However, not all trial participants fully benefit from ESM due to prematurely discontinuing program participation. This analysis sought to identify demographic and clinical predictors of premature discontinuation (PD) of ESM interventions available in the MEW-DB. MethodsData from prior studies were included if: 1) they were prospective trials testing an ESM intervention, 2) included baseline assessment and at least one post-intervention assessment, and 3) included data on PD. Dependent variables were all-cause PD, categorized as a binary variable (yes/no) and time to PD for the intervals between baseline and follow-up visit 1 (V1; approximately week 12) and visit two (V2; approximately week 24). Multivariable Cox proportional hazard models were used to identify factors affecting PD time-point. Explanatory variables included age, gender, race/ethnicity, education, employment, income, marital status, psychiatric comorbidities, depressive severity, anxiety symptoms, self-efficacy, number of anti-seizure medications (ASMs), health status, seizure frequency, and study design. ResultsSix prior MEW-DB studies were included, consisting of 627 people, where 624 were assigned to ESM or to control. PD among randomized individuals was 14.3 % by V1 and 15.7 % by V2. Predictors for V1 PD were treatment (ESM) vs. control arm, more severe depressive symptoms and having schizophrenia. Predictors for V2 PD were younger age, white race, more severe depressive symptoms and having schizophrenia. SignificanceWhile ESM approaches can improve multiple health outcomes among people with epilepsy, nearly one in six individuals prematurely discontinues their program. These findings suggest that ESM interventionists need to be particularly attentive to program retention over the first 3 months after ESM initiation. Younger people with epilepsy, those who self-identify as white, those with schizophrenia, and/or more severe depressive symptoms may need additional support for engagement.

Effects of hydrogen rich water and pure water on periodontal inflammatory factor level, oxidative stress level and oral flora: a systematic review and meta-analysis

Hydrogen rich water (HRW) was used as an auxiliary treatment for periodontitis and peri-implantitis due to its good antioxidant properties. However, the stability of artificially added active hydrogen was far less than that of pure natural active hydrogen, which greatly reduced active hydrogen molecules number in HRW. Meanwhile, the effect of HRW was relatively slow. Finally, long-term drinking of HRW may cause abnormal liver function. Hence, this study sought to summarize and analyze the effects of HRW on oral inflammation and oral flora in various studies to determine whether HRW can be used to inhibit dental plaque formation and aliviate oral inflammation. Randomized controlled trials (RCTs) of HRW and pure water (PW) in the treatment of periodontal diseases published before March 2022 in the PubMed, Web of science, EMBASE, Cochrane, China Knowledge Resource Integrated, Wanfang, and Weipu databases were searched. Changes in the inflammatory factor levels, oxidative stress response, and oral flora were summarized and used as outcome indicators. The quality of included studies was assessed by Cochrane risk of bias assessment tool, and the standardized mean differences (SMD) and the 95% confidence intervals (CIs) were calculated using Review Manager 5.3. In total, 17 studies, comprising 304 subjects, were included in this meta-analysis. Among them, 5 studies had a high risk of bias, and the rest had a certain risk of bias, thus, the total risk of bias was medium to low. The levels of interleukin (IL)-1β (SMD =-0.73; 95% CI: -1.29 to -0.18; P=0.009), tumor necrosis factor alpha (SMD =-2.51; 95% CI: -3.56 to -1.46; P<0.00001), IL-6 (SMD =-1.31; 95% CI: -1.96 to -0.67; P<0.0001), 8-hydroxyguanosine (SMD =-1.61; 95% CI: -2.35 to -0.87; P<0.0001), and reactive oxygen metabolites (SMD =-0.49; 95% CI: -0.91 to -0.06; P=0.02) in the HRW group decreased significantly, while the glutathione peroxidase level increased (SMD =2.5; 95% CI: 1.85 to 3.15; P<0.00001). Additionally, HRW was shown to effectively inhibit oral pathogenic bacteria activity (SMD =-0.91; 95% CI: -1.16 to -0.66; P<0.00001). HRW effectively inhibits the inflammatory reaction, oxidative stress level, and bacterial proliferation activity in patients with periodontal disease.

ProtPathDB: A Web-based Resource of Parasite Proteases

Background: Proteases regulate cell proliferation, cell growth, biological processes, and overall homeostasis. Several proteases are extensively annotated and well-characterized in pathogenic organisms such as bacteria, parasites, and microbial species as anti-bacterial, anti-parasitic and antimicrobial. Several of these proteins are being explored as viable targets for various drug discovery researches in various microbial diseases. Despite multiple studies on pathogen proteases, comprehensive information on pathogen proteases is scattered or redundant, if available. Methods: We have developed a comprehensive and integrative protease database resource, Prot- PathDB, for 23 pathogen species distributed among five taxa, Amoebozoa, Apicomplexa, Heterolob osea, Kinetoplastida and Fungi. ProtPathDB collects and organizes sequences, class division, signal peptides, localization, post-translational modifications, three-dimensional structure and related structural information regarding binding sites, and binding scores of annotated proteases. Results: The ProtPathDB is publicly available at http://bioinfo.icgeb.res.in/ProtPathDB. Conclusion: We believe that the database will be a one-stop resource for integrative and comparative analysis of pathogen proteases to better understand the functions of the microbial proteases and help drug discovery efforts targeting proteases.

Anti-rheumatoid arthritis mechanism of Sophorae Tonkinesis Radix et Rhizoma based on network pharmacology and experimental verification

Based on the network pharmacology, molecular docking, and animal experiment, this study explored the anti-rheumatoid arthritis(RA) mechanism of Sophorae Tonkinesis Radix et Rhizoma(STRR). The active components of STRR were retrieved from Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform(TCMSP), Traditional Chinese Medicine Integrative Database(TCMID), and previous research, main targets of STRR from TCMSP and SwissTargetPrediction, and targets of RA from GeneCards, DrugBank, Online Mendelian Inheritance in Man(OMIM), and Therapeutic Target Database(TTD). The common targets of the two were screened by Venny 2.1.0. Cytoscape 3.6.0 was used to generate the &quot;component-target&quot; network, and STRING and Cytoscape were used to construct the protein-protein interaction(PPI) network. DAVID 6.8 was employed for Gene Ontology(GO) term enrichment and Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment, and AutoDock Vina for molecular docking. Finally, collagen-induced rheumatoid arthritis(CIA) mouse model was constructed, and the expression of core target proteins was detected by Western blot. A total of 27 active components, including quercetin, genistein, kaempferol, subprogenin C, and daidzein, and 154 anti-RA targets, such as signal transducer and activator of transcription 3(STAT3), tumor necrosis factor(TNF), mitogen-activated protein kinase 1(MAPK1), AP-1 transcription factor subunit(JUN), and interleukin 6(IL6), of STRR were screened out. It was preliminarily indicated that STRR may regulate phosphatidylinositol-3-kinase-protein kinase B(PI3 K-AKT) signaling pathway and TNF signaling pathway to modulate the positive regulation of RNA polymerase Ⅱ promoter transcription, inflammatory response, and other biological processes, thus exerting the anti-RA effect. The results of molecular docking showed that the main active components in STRR had high binding affinity to the core targets. Animal experiment suggested that the water extract of STRR can significantly reduce the levels of p-STAT3, p-MAPK1, and TNF. This study demonstrated the multi-component, multi-target and multi-pathway synergistic effect of STRR in the treatment of RA, laying an experimental basis for clinical application of this medicine.

Immunotherapy combined with chemotherapy versus chemotherapy alone as the first-line treatment of PD-L1-negative and driver-gene-negative advanced nonsquamous non-small-cell lung cancer: An updated systematic review and meta-analysis.

This meta-analysis aimed to compare the efficacy of immunotherapy combined with chemotherapy versus chemotherapy alone as the first-line therapy for patients with programmed death ligand-1 (PD-L1)-negative and driver-gene-negative advanced nonsquamous non-small-cell lung cancer (NSCLC). Eligible randomized trials were identified following the systematic search of PubMed, Cochrane Library, Embase, Web of Science, Wanfang Data, and China Knowledge Resource Integrated Database from January 2000 to June 2022. Seven trials involving 1132 patients with PD-L1-negative and driver-gene-negative advanced nonsquamous NSCLC were included. Immunotherapy combined with chemotherapy showed significantly superior objective response rate (ORR) compared with chemotherapy alone (odds ratio 2.81, 95% confidence interval [CI] 1.69-4.65). Immunotherapy combined with chemotherapy also significantly prolonged the progression-free survival (PFS) (hazard ratio [HR] 0.63, 95% CI 0.55-0.74, p < 0.001) and overall survival (OS) (HR 0.68, 95% CI 0.56-0.82, p < 0.001) of patients with PD-L1-negative and driver-gene-negative advanced nonsquamous NSCLC compared to chemotherapy alone. In terms of ≥3 treatment-related adverse events, patients receiving immunotherapy combined with chemotherapy were at higher risk than chemotherapy alone (OR 1.73, 95% CI 1.47-2.05). This meta-analysis suggested that immunotherapy combined with chemotherapy yielded a better ORR, PFS, and OS, and a higher incidence of treatment-related adverse events as the first-line therapy for patients with PD-L1-negative and driver-gene-negative nonsquamous advanced NSCLC in comparison to chemotherapy alone. A rational treatment protocol should be selected according to the individual condition of the patients.

Decoding the Mechanism of CheReCunJin Formula in Treating Sjögren's Syndrome Based on Network Pharmacology and Molecular Docking.

Background Sjögren's syndrome (SS) is a chronic autoimmune disease characterized by progressive oral and ocular dryness that correlates poorly with autoimmune damage to the glands. CheReCunJin (CRCJ) formula is a prescription formulated according to the Chinese medicine theory for SS treatment. Objective This study aimed to explore the underlying mechanisms of CRCJ against SS. Methods The databases, including Traditional Chinese Medicine System Pharmacology, Encyclopedia of Traditional Chinese Medicine, Bioinformatics Analysis Tool for the molecular mechanism of Traditional Chinese Medicine, and Traditional Chinese Medicine Integrated Databases, obtained the active ingredients and predicted targets of CRCJ. Then, DrugBank, Therapeutic Target Database, Genecards, Comparative Toxicogenomics Database, and DisGeNET disease databases were used to screen the predicted targets of SS. Intersected targets of CRCJ and SS were visualized by using Venn diagrams. The overlapping targets were uploaded to the protein–protein interaction network analysis search tool. Cytoscape 3.8.2 software constructed a “compound-targets-disease” network. Gene Ontology and the Kyoto Encyclopedia of Genes and Genomes analyses characterized potential targets' biological functions and pathways. AutoDock Vina 1.1.2 software was used to research and verify chemical effective drug components and critical targets. Results From the database, we identified 878 active components and 2578 targets of CRCJ, and 827 SS-related targets. 246 SS-related genes in CRCJ were identified by intersection analysis, and then ten hub genes were identified as crucial potential targets from PPI, including ALB, IL-6, TNF, INS, AKT1, IL1B, VEGFA, TP53, JUN, and TLR4. The process of CRCJ action against SS was mainly involved in human cytomegalovirus infection and Th17 cell differentiation, as well as the toll-like receptor signaling and p53 signaling pathways. Molecular docking showed that the bioactive compounds of CRCJ had a good binding affinity with hub targets. Conclusions The results showed that CRCJ could activate multiple pathways and treat SS through multiple compounds and targets. This study lays a foundation for better elucidation of the molecular mechanism of CRCJ in the treatment of SS, and also provides basic guidance for future research on Chinese herbal compounds.

A novel pyroptosis-regulated gene signature for predicting prognosis and immunotherapy response in hepatocellular carcinoma.

Background: Pyroptosis, a newly discovered type of programmed cell death, has both anti-tumor and tumor-promoting effects on carcinogenesis. In hepatocellular carcinoma (HCC), however, the associations between pyroptosis-regulated genes and prognosis, immune microenvironment, and immunotherapy response remain unclear.Samples and methods: Sequencing data were collected from The Cancer Genome Atlas database, The International Cancer Genome Consortium (ICGC), and The Integrative Molecular Database of Hepatocellular Carcinoma (HCCDB). First, we investigated the expression levels and copy number variations (CNVs) of 56 pyroptosis genes in HCC and pan-cancer. Next, we identified 614 genes related to 56 pyroptosis-associated genes at the expression, mutation, and CNVs levels. Pathway enrichment analysis of 614 genes in the Hallmark, KEGG, and Reactome databases yielded a total of 253 significant signaling pathways. The pyroptosis-regulated genes (PRGs) comprised 108 genes that were derived from the top 20 signaling pathways, of which 57 genes had prognostic value in HCC. The least absolute shrinkage and selection operator (LASSO) analysis was performed to screen for PRGs with prognostic values. Ultimately, we constructed a risk score model with seven PRGs to predict HCC prognosis and validated its predictive value in three independent HCC cohorts. Risk scores were used to illustrate receiver operating characteristic (ROC) curves predicting 1, 3, and 5-years overall survival (OS). Single-sample gene set enrichment analysis (ssGSEA), was performed to study 28 types of immune cells infiltrated in HCC. The relationship between the risk signature and six immune checkpoint genes and immunotherapy was analyzed. Results: A total of seven PRGs were obtained following multiple screening steps. The risk score model containing seven PRGs was found to correlate significantly with the HCC prognosis of the training group. In addition, we validated the risk score model in two additional HCC cohorts. The risk score significantly correlated with infiltrating immune cells (i. e. CD4+ T cells, etc.), ICB key molecules (i. e. HAVCR2, etc.), and ICB response. Conclusions: This study demonstrated a vital role of PRGs in predicting the prognosis and immunotherapy response of HCC patients. The risk model could pave the way for drugs targeting pyroptosis and immune checkpoints in HCC.

LettuceGDB: The community database for lettuce genetics and omics

As a globally popular leafy vegetable and a representative plant of the Asteraceae family, lettuce has great economic and academic significance. In the last decade, high-throughput sequencing, phenotyping, and other multi-omics data in lettuce have accumulated on a large scale, thus increasing the demand for an integrative lettuce database. Here, we report the establishment of a comprehensive lettuce database, LettuceGDB (https://www.lettucegdb.com/). As an omics data hub, the current LettuceGDB includes two reference genomes with detailed annotations; re-sequencing data from over 1000 lettuce varieties; a collection of more than 1300 worldwide germplasms and millions of accompanying phenotypic records obtained with manual and cutting-edge phenomics technologies; re-analyses of 256 RNA sequencing datasets; a complete miRNAome; extensive metabolite information for representative varieties and wild relatives; epigenetic data on the genome-wide chromatin accessibility landscape; and various lettuce research papers published in the last decade. Five hierarchically accessible functions (Genome, Genotype, Germplasm, Phenotype, and O-Omics) have been developed with a user-friendly interface to enable convenient data access. Eight built-in tools (Assembly Converter, Search Gene, BLAST, JBrowse, Primer Design, Gene Annotation, Tissue Expression, Literature, and Data) are available for data downloading and browsing, functional gene exploration, and experimental practice. A community forum is also available for information sharing, and a summary of current research progress on different aspects of lettuce is included. We believe that LettuceGDB can be a comprehensive functional database amenable to data mining and database-driven exploration, useful for both scientific research and lettuce breeding.

Significant metabolic alterations in non-small cell lung cancer patients by epidermal growth factor receptor-targeted therapy and PD-1/PD-L1 immunotherapy.

Background: Cancer-related deaths are primarily attributable to lung cancer, of which non-small cell lung cancer (NSCLC) is the most common type. Molecular targeting therapy and antitumor immunotherapy have both made great strides in the treatment of NSCLC, but their underlying mechanisms remain unclear, especially from a metabolic perspective. Methods: Herein, we used a nontargeted metabolomics approach based on liquid chromatography-mass spectrometry to analyze the metabolic response of NSCLC patients to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) or PD-1/PD-L1 inhibitors. Multiple analyses, including principal component analysis (PCA), orthogonal partial least squares-discriminant analysis (OPLS-DA) and pathway analysis, were used for metabolic data analysis. Additionally, differential metabolites were analysed and identified by publically available and integrated databases. Results: After treatment with EGFR-TKIs or PD-1/PD-L1 inhibitors, glutamate/glutamine, phenylalanine, n-acetyl-l-leucine, n-acetyl-d-tryptophan, D-n-valine, arachidonic acid, and linoleic acid levels were significantly increased in patients with NSCLC, whereas carnitine, stearyl carnitine, palmitoyl carnitine, linoleic carnitine, and palmitic acid levels were markedly decreased. Compared with newly diagnosed, untreated patients, there were three shared metabolic pathways (phenylalanine metabolism, glycerophospholipid metabolism, and D-glutamine and D-glutamate metabolism) in the EGFR-TKIs or PD-1/PD-L1 inhibitor-treated groups, all of which were related to lipid and amino acid metabolism. Moreover, there were significant differences in lipid metabolism (glycerophospholipid metabolism and phosphatidylinositol signaling) and amino acid metabolism (tryptophan metabolism) between the EGFR-TKI and PD-1/PD-L1 inhibitor groups. Conclusion: Our results show that EGFR-TKIs and PD-1/PD-L1 inhibitors induce changes in carnitine, amino acids, fatty acids, and lipids and alter related metabolic pathways in NSCLC patients. Endogenous metabolism changes occur due to drug action and might be indicative of antitumor therapeutic effect. These findings will provide new clues for identifying the antitumor mechanism of these two treatments from the perspective of metabolism.

Cost-effectiveness of the add-on exenatide to conventional treatment in patients with Parkinson's disease when considering the coexisting effects of diabetes mellitus.

ObjectiveThis study aims to investigate the cost-effectiveness of the add-on exenatide to conventional pharmacotherapy in patients with Parkinson’s disease (PD) when considering the coexistence of diabetes mellitus (DM).MethodsWe used the Keelung and Community-based Integrated Screening databases to understand the medical utilisation in the Hoehn and Yahr stages of patients with PD. A Markov model with 1-year cycle length and 50-year time horizon was used to assess the cost-effectiveness of add-on exenatide to conventional pharmacotherapy compared to conventional pharmacotherapy alone. All costs were adjusted to the value of the new Taiwanese dollar (NT$) as of the year 2020. One-way sensitivity and probability analyses were performed to test the robustness of the results.ResultsFrom a societal perspective, the add-on exenatide brought an average of 0.39 quality-adjusted life years (QALYs) gained, and a cost increment of NT$104,744 per person in a 50-year horizon compared to conventional pharmacotherapy. The incremental cost-effectiveness ratio (ICER) was NT$268,333 per QALY gained. As the ICER was less than the gross domestic product per capita (NT$839,558), the add-on exenatide was considered to be very cost-effective in the two models, according to the World Health Organization recommendation. Add-on exenatide had a 96.9% probability of being cost-effective in patients with PD, and a 100% probability of being cost-effective in patients with PD and DM.ConclusionAdd-on exenatide is cost-effective in PD combined with DM. Considering that DM may be a risk factor for neurodegenerative diseases, exenatide provides both clinical benefits and cost-effectiveness when considering both PD and DM.

Earnings during adulthood in patients with childhood-onset inflammatory bowel disease: a nationwide population-based cohort study.

SummaryBackgroundIBD with onset during childhood seems to represent a severe disease phenotype with increased morbidity. We have previously demonstrated that children with IBD have significantly lower final grades in compulsory school compared to healthy peers.AimTo evaluate the association of childhood‐onset IBD with a later professional career and subsequent earningsMethodsWe identified 5404 individuals diagnosed with childhood‐onset (<18 years) IBD between 1990 and 2014 (2818 with ulcerative colitis and 2328 with Crohn's disease) in the Swedish National Patient Register. Patients were matched with 10 general population reference individuals by sex, birth year, and place of residence (n = 51,295). Data on earnings during 1992–2017 were obtained through the longitudinal integration database for health insurance and labour market studies. Earnings were converted into Euros (inflation‐adjusted to 2019). The differences in earnings between patients and general population reference individuals were calculated through quantile regression.ResultsPatients with childhood‐onset IBD had significantly lower annual taxable earnings from ages 20 to 30 (adjusted median annual income difference (AMAID) at age 30: −5.4% [95% CI −9.1% to −1.8%]). In particular, annual taxable earnings through early adult age were lower in patients who, during childhood, had had surgery or long‐term inpatient treatment for IBD (AMAID at age 30: −16.3% [95% CI ‐24.7% to −7.9%]).ConclusionsOverall, the negative influence of disease on earnings in early adult age was modest for patients with childhood‐onset IBD. The markedly larger negative income gap from ages 20 to 30 in patients with more severe IBD during childhood should be recognised.

The prevalence and risk factors of facial pressure injuries related to adult non-invasive ventilation equipment: A systematic review and meta-analysis.

To systematically assess the prevalence of facial pressure injuries related to adult non-invasive ventilation equipment, and risk factors of facial pressure injuries. PubMed, Cochrane Library, Web of Science, Embase, China Knowledge Resource Integrated Database, Wanfang Database, Chinese Biomedical Database and Weipu Database were comprehensively searched for observational studies investigating the prevalence and risk factors of facial pressure injuries related to adult non-invasive ventilation equipment from inception to May 16th, 2022. Filter articles based on inclusion and exclusion criteria. The quality of the included studies was evaluated independently by two investigators. Meta-analysis was conducted using Stata 16.0 software package. In total, 2835 articles were screened and data from 12 studies were used in meta-analysis. The prevalence of facial pressure injuries related to adult non-invasive ventilation equipment was 25% (95% confidence interval, CI:15% to 37%, I2 =97.34%, P < 0.0001). After controlling for confounding variables, the following risk factors of facial pressure injuries: use equipment form, with diabetes, fever, cumulative time of using equipment, facial skin oedema and Glasgow score. Understanding the risk factors of facial pressure injuries can provide the healthcare personnel with the theoretical basis for the management and treatment of the patients.

The Antidiabetic Activities of Neocryptotanshinone: Screened by Molecular Docking and Related to the Modulation of PTP1B.

The aim of this study was to provide a practical experimental basis for the development of Neocryptotanshinone (NCTS) as an effective hypoglycemic drug and a theoretical method for the rapid screening of natural compounds with hypoglycemic effects. Molecular docking was used to screen the most suitable ligand. Hematoxylin and eosin, immunohistochemical staining, enzyme-linked immunosorbent assay and Western Blotting approved the hypoglycemic effect of NCTS. According to the free energy of binding, among 180 active compounds from the Traditional Chinese Medicine Integrated Database, NCTS was finally chose for investigation its hypoglycemic effects. In db/db mice, NCTS significantly reduced body weight and plasma glucose, improved glucose tolerance and levels of fasting plasma glucose and glycated hemoglobin A1c, and decreased insulin resistance after six-week administration. NCTS restored the pathological state in the liver of db/db mice and significantly decreased protein tyrosine phosphatase 1B (PTP1B) expression in the liver and muscle of db/db mice, which is related to the regulatory effect of NCTS on insulin receptor substrate 1. In conclusion, we successfully explored the hypoglycemic effect of NCTS in db/db mice via regulating the expression of PTP1B.

Effects of 6-Hydroxykaempferol: A Potential Natural Product for Amelioration of Tendon Impairment.

Tendon impairment is a common injury associated with impairment of range of motion and pain. Currently, evidence has confirmed that natural herbs contribute to orthopedics and have shown excellent results in the clinical management of tendon impairment. Shujin Huoxue tablet (SHT) and its complex prescriptions are regularly used in tendon rupture therapy with positive results. This study aimed to discover the potential molecules that promote tendon healing. The Chinese traditional medicine system pharmacological database analysis platform (TCMSP) is the primary resource. The Traditional Chinese Medicine Integrated Database and Encyclopedia of Traditional Chinese Medicine database were used as secondary databases. The GeneCards database was used to search for reported tendinopathy-related genes by keywords. Functions of the targeted genes were analyzed using Gene Ontology enrichment analysis and Kyoto Encyclopedia of Genes and Genomes. Protein–protein interaction information was extracted from the STRING database. Docking study, MTT assay, quantitative real-time PCR, and migration assays were performed to obtain a better understanding of the herbs according to cell function to test the basic pharmacological action in vitro. A total of 104 disease nodes, 496 target gene nodes, 35 ingredient nodes, and one drug node were extracted. According to the TCMSP database, 6-hydroxykaempferol, which reportedly promotes the proliferation of microvascular endothelial cells, is a molecule found in SHT. We found that it promoted the proliferation and migration of tendon fibroblasts and elevated tendon repair-related gene expression. Purified 6-hydroxykaempferol promoted the proliferation and migration of tendon fibroblasts and increased their mRNA expression in tendon proliferation.

PCA Benchmark Analysis with ADVANTG3.0.1. and MCNP6.1.1b Codes

The Pool Critical Assembly Pressure Vessel (PCA) benchmark is a well known benchmark in the reactor shielding community which is described in the Shielding Integral Benchmark Archive and Database (SINBAD). It is based on the experiments performed at the PCA facility in the Oak Ridge National Laboratory (ORNL) and it can be used for the qualification of the pressure vessel fluence calculational methodology. The measured quantities to be compared against the calculated values are the equivalent fission fluxes at several experimental access tubes (A1 to A8) in front, behind, and inside the pressure-vessel wall simulator. This benchmark is particularly suitable to test the capabilities of the shielding calculational methodology and cross-section libraries to predict invessel flux gradients because only a few approximations are necessary in the overall analysis. This benchmark was analyzed using a modern hybrid stochastic-deterministic shielding methodology with ADVANTG3.0.1 and MCNP6.1.1b codes. ADVANTG3.0.1 is an automated tool for generating variance reduction (VR) parameters for Monte Carlo (MC) calculations with MCNP5v1.60 code (and higher versions). It is based on the multigroup, discrete ordinates solver Denovo, used for approximating the forward-adjoint transport fluxes to construct VR parameters for the final MC simulation. The VR parameters in form of the weight windows and the source biasing cards can be directly used with unmodified MCNP input. The underlining CADIS methodology in Denovo code was initially developed for biasing local MC results, such as point detector or a limited region detector. The FW-CADIS extension was developed for biasing MC results globally over a mesh tallies or multiple point/region detectors. Both CADIS and FW-CADIS are based on the concept of the neutron importance function, which is a solution of the adjoint Boltzmann transport equation. The equivalent fission fluxes calculated with MCNP are based on several highenergy threshold reactions from international dosimetry libraries IRDF-2002 and IRDFF-2014, distributed by the IAEA Nuclear Data Section. The obtained results show a good agreement with referenced PCA measurements. Visualization of the deterministic solution in 3D was done using the VisIt code from the Lawrence Livermore National Laboratory (LLNL).

Barriers and Supports in eHealth Implementation among People with Chronic Cardiovascular Ailments: Integrative Review.

eHealth interventions use information technology to provide attention to patients with chronic cardiovascular conditions, thereby supporting their self-management abilities. Objective: Identify barriers and aids to the implementation of eHealth interventions in people with chronic cardiovascular conditions from the perspectives of users, health professionals and institutions. Method: An integrative database review of WoS, Scopus, PubMed and Scielo of publications between 2016 and 2020 reporting eHealth interventions in people with chronic cardiovascular diseases. Keywords used were eHealth and chronic disease. Following inclusion and exclusion criteria application, 14 articles were identified. Results: Barriers and aids were identified from the viewpoints of users, health professionals and health institutions. Some notable barriers include users’ age and low technological literacy, perceived depersonalization in attention, limitations in technology access and usability, and associated costs. Aids included digital education and support from significant others. Conclusions: eHealth interventions are an alternative with wide potentiality for chronic disease management; however, their implementation must be actively managed.