A novel dual-target Septin9 methylation assay for improved detection of early-stage colorectal cancer and high-grade intraepithelial neoplasia.

BACKGROUND: Colorectal cancer (CRC) ranks as the third most common malignancies in the world, and periodic examination of the patient is advantageous in reducing the mortality of CRC. The first blood-based Septin9 gene methylation assay which recognized by the US FDA for CRC examination was Epi proColon. However, this assay was not broadly applied in the current clinical guideline because of its relatively lower sensitivity in the detection of early-stage CRC. METHODS: This study aimed at developing a new multiplex Septin9 methylation assay (ColonUSK) which simultaneously evaluates two CpG-rich subregions in the promoter of the Septin9 gene and an internal control in a single reaction. ColonUSK proved increased sensitivity, with a detection limit as low as 12pg of the positive DNA compared with the Septin9 assay targeting one CpG-rich subregion. 1366 subjects were prospectively recruited from four comprehensive hospitals in China in an opportunistic screening study for assessing its value in CRC detection. Blind testing was developed to evaluate ColonUSK in comparison with clinical examination using clinical gold standard such as colonoscopy. RESULTS: The assay demonstrates clinical sensitivity for diagnosing colorectal cancer (CRC) and advanced adenoma at rates of 77.34% and 25.26%, respectively. Furthermore, ColonUSK exhibits a high degree of specificity for non-CRC cases (95.95%) clinically. Significantly, the detection rate of cases in high-grade intraepithelial neoplasia increased to 54.29%. The value for the assay in the Kappa test was 0.76, showing a high degree of consistency between ColonUSK and clinical gold standard. CONCLUSIONS: ColonUSK indicated moderate diagnostic value and could become a non-invasive detection way for CRC. The implementation of the ColonUSK assay has the capacity to markedly enhance CRC screening practices.

Current status and continuing medical education need for general practitioners in Tibet, China: a cross-sectional study.

BACKGROUND: The Tibetan area is one of China's minority regions with a shortage of general practice personnel, which requires further training and staffing. This research helps to understand the current condition and demand for general practitioner (GP) training in Tibetan areas and to provide a reference for promoting GP education and training. METHODS: We conducted a cross-sectional survey using stratified sampling targeting 854 GPs in seven cities within the Tibetan Autonomous Region, utilizing an online questionnaire. Achieving a high response rate of 95.1%, 812 GPs provided invaluable insights. Our meticulously developed self-designed questionnaire, available in both Chinese and Tibetan versions, aimed to capture a wide array of data encompassing basic demographics, clinical skills, and specific training needs of GPs in the Tibetan areas. Prior to deployment, the questionnaire underwent rigorous development and refinement processes, including expert consultation and pilot testing, to ensure its content validity and reliability. In our analysis, we employed descriptive statistics to present the characteristics and current training needs of GPs in the Tibetan areas. Additionally, chi-square tests were utilized to examine discrepancies in training needs across various demographic groups, such as age, job positions, and educational backgrounds of the participating GPs. RESULTS: The study was completed by 812 (812/854, 95.1%) GPs, of whom 62.4% (507/812) were female. The top three training needs were hypertension (81.4%, 661/812), pregnancy management (80.7%, 655/812), and treatment of related patient conditions and events (80.5%, 654/812). Further research shows that the training required by GPs of different ages in "puncturing, catheterization, and indwelling gastric tube use" (64.6% vs. 54.8%, p = 9.5 × 10- 6) varies statistically. GPs in various positions have different training needs in "community-based chronic disease prevention and management" (76.6% vs. 63.9%, p = 0.009). The training needs of GPs with different educational backgrounds in "debridement, suturing, and fracture fixation" (65.6% vs. 73.2%, p = 0.027) were also statistically significant. CONCLUSIONS: This study suggests the need for targeted continuing medical education activities and for updating training topics and content. Course developers must consider the needs of GPs, as well as the age, job positions, and educational backgrounds of GPs practicing in the Tibetan Plateau region. TRIAL REGISTRATION: Not applicable.

Dual inhibition of MYC and SLC39A10 by a novel natural product STAT3 inhibitor derived from Chaetomium globosum suppresses tumor growth and metastasis in gastric cancer.

Gastric cancer remains one of the most common deadly diseases and lacks effective targeted therapies. In the present study, we confirmed that the signal transducer and activator of transcription 3 (STAT3) is highly expressed and associated with a poor prognosis in gastric cancer. We further identified a novel natural product inhibitor of STAT3, termed XYA-2, which interacts specifically with the SH2 domain of STAT3 (Kd= 3.29 µM) and inhibits IL-6-induced STAT3 phosphorylation at Tyr705 and nuclear translocation. XYA-2 inhibited the viability of seven human gastric cancer cell lines with 72-h IC50 values ranging from 0.5 to 0.7 µΜ. XYA-2 at 1 µΜ inhibited the colony formation and migration ability of MGC803 (72.6% and 67.6%, respectively) and MKN28 (78.5% and 96.6%, respectively) cells. In the in vivo studies, intraperitoneal administration of XYA-2 (10 mg/kg/day, 7 days/week) significantly suppressed 59.8% and 88.8% tumor growth in the MKN28-derived xenograft mouse model and MGC803-derived orthotopic mouse model, respectively. Similar results were obtained in a patient-derived xenograft (PDX) mouse model. Moreover, XYA-2 treatment extended the survival of mice bearing PDX tumors. The molecular mechanism studies based on transcriptomics and proteomics analyses indicated that XYA-2 might exert its anticancer activity by synergistically inhibiting the expression of MYC and SLC39A10, two downstream genes of STAT3 in vitro and in vivo. Together, these findings suggested that XYA-2 may be a potent STAT3 inhibitor for treating gastric cancer, and dual inhibition of MYC and SLC39A10 may be an effective therapeutic strategy for STAT3-activated cancer.

Impact of health literacy and social support on medication adherence in patients with hypertension: a cross-sectional community-based study.

BACKGROUND: Previous studies have examined the associations of health literacy and social support with medication adherence among patients with hypertension. However, limited evidence exists regarding the mechanisms underlying the relationship between these factors and medication adherence. PURPOSE: To explore the prevalence of medication adherence and its determinants in patients with hypertension in Shanghai. METHODS: A community-based cross-sectional study was conducted among 1697 participants with hypertension. We collected sociodemographic and clinical characteristics as well as data regarding health literacy, social support, and medication adherence using questionnaires. We examined interactions among the factors using a structural equation model. RESULTS: The participants included 654 (38.54%) patients with a low degree of medication adherence and 1043 (61.46%) patients with a medium/high degree of adherence. Social support directly influenced adherence (ß = 0.165, P < 0.001) and indirectly influenced adherence through health literacy (ß = 0.087, P < 0.001). Health literacy directly influenced adherence (ß = 0.291, P < 0.001). Education indirectly affected adherence through both social support (ß = 0.048, P < 0.001) and health literacy (ß = 0.080, P < 0.001). Moreover, there was a sequential mediating effect of social support and health literacy on the association between education and adherence (ß = 0.025, P < 0.001). After controlling for age and marital status, similar results were also obtained, indicating a good model fit. CONCLUSIONS: The degree of medication adherence among hypertensive patients needs to improve. Health literacy and social support had both direct and indirect effects on adherence, and thus, these factors should be considered as tools to improve adherence.

Targeting E2 ubiquitin-conjugating enzyme UbcH5c by small molecule inhibitor suppresses pancreatic cancer growth and metastasis.

BACKGROUND: Pancreatic cancer is one of the most lethal cancers worldwide. The IAPs function as E3 ubiquitin ligases and contribute to pancreatic cancer initiation, progression, and metastasis. Although IAP-targeted therapies have been developed and shown anticancer efficacy in preclinical settings, none of them has been approved yet. METHODS: Transcriptome data from public datasets were used to analyze the correlation of IAPs and E2s, and the biological function of E2 UbcH5c in pancreatic cancer. A structure-based virtual screen was used to identify UbcH5c inhibitor, and surface plasmon resonance analysis and cellular thermal shift assays were employed to evaluate the binding affinity. The anticancer activities were demonstrated through in vitro and in vivo assays, while the related mechanisms were explored through transcriptomic and proteomic analyses and confirmed by western blot, immunofluorescence, and qRT-PCR. RESULTS: UbcH5c is positively correlated with the expression of IAPs in pancreatic cancer. We further found that UbcH5c is overexpressed and associated with a poor prognosis in pancreatic cancer. We identified a small-molecule UbcH5c inhibitor, termed DHPO, which directly bound to UbcH5c protein. DHPO inhibited cell viability and colony formation, induced apoptosis, and suppressed migration and invasion of pancreatic cancer cells in vitro. The compound inhibited UbcH5c-mediated IκBα degradation and NF-κB activation, which is critical for its anticancer activity. Furthermore, DHPO suppressed the tumor growth and metastasis in two orthotopic pancreatic tumor mouse models. CONCLUSIONS: These results indicated that inhibiting UbcH5c is a novel and effective strategy for treating pancreatic cancer and DHPO represents a new class of UbcH5c inhibitor and may be further developed as an anti-pancreatic cancer therapeutic agent.

Rapid detection and classification of hongmu by atmospheric pressure ionization mass spectrometry.

Hongmu, a Chinese customary noun representing 29 kinds of wood species such as some Pterocarpus species (abbreviated as spp. hereinafter), Dalbergia spp. and Diospyros spp., is popular among Chinese people due to the furniture made from it. The slow regeneration of hongmu resources led to a decline in production, making hongmu prices high and illegal businesses profit from it. Therefore, it is necessary to identify and distinguish different varieties of hongmu for commercial trade. Herein, a cost-effective and rapid methodology was first developed via atmospheric pressure glow discharge mass spectrometry (APGD-MS) to classify three Dalbergia spp. and three Pterocarpus spp. Meanwhile, principal component analysis (PCA) was further applied to distinguish wood species and six kinds of hongmu extracts were able to be approximately separated into six units. Besides, hongmu could be clearly distinguished from their counterfeits, such as Guibourtia spp., using the method provided here. This method may provide a timely and necessary way for the determination of ingredients and identification of the authenticity of hongmu.

S3I-201 derivative incorporating naphthoquinone unit as effective STAT3 inhibitors: Design, synthesis and anti-gastric cancer evaluation.

Signal transducer and activator of transcription 3 (STAT3) is a key regulator of many human cancers and has been widely recognized as a promising target for cancer therapy. A variety of small-molecule inhibitors have been developed for targeting STAT3, and some of them are now undergoing clinical trials. S3I-201, a known STAT3 inhibitor, may block STAT3 function in cancer cells by binding to the STAT3 SH2 domain to disrupt STAT3 protein complex formation. Using S3I-201 as a starting point for drug development, we synthesized a series of new STAT3 inhibitors 9a-x in this study by introducing naphthoquinone unit, a privileged fragment in STAT3 inhibitors. Most of the compounds exhibited strong anti-proliferation activity of gastric cancer cells (MGC803, MKN28, MNK1, and AGS). The representative compound 9n (SIL-14) could effectively inhibit the colony formation and migration of gastric cancer cells MGC803, arrest the cell cycle and induce MGC803 cell apoptosis at low micromolar concentrations in vitro. In addition, SIL-14 can also inhibit the phosphorylation of STAT3 protein and significantly decrease the expression of total STAT3, suggesting that it may exert anticancer effects by blocking the STAT3 signaling pathway. These results support that SIL-14 may be a promising STAT3 inhibitor for the further development of potential anti-gastric cancer candidates.

Characterization of a bioactive meroterpenoid isolated from the marine-derived fungus Talaromyces sp.

A new meroterpenoid, taladrimanin A (1), was isolated from a marine-derived fungus Talaromyces sp. HM6-1-1, together with eleven biogenetically related compounds (2-12). A plausible biosynthetic pathway for the meroterpenoids (1-4) was proposed. The planar structure of 1 was assigned by HRESIMS and NMR. Its relative configuration was established by quantum chemical NMR calculation of two possible isomers and analyzed by DP4 + method. Finally, X-ray diffraction unambiguously confirmed the relative configuration and revealed the absolute configuration of compound 1. 2-12 were assigned by comparing their NMR data with those reported in the literature. 1 was the first drimane-type meroterpenoid with a C10 polyketide unit bearing an 8R-configuration. In the bioactive assay, 1 exhibited antitumor activity against gastric cancer cells MGC803 and MKN28; it also inhibited the colony formation and induced apoptosis in MGC803 cells both in a concentration-dependent manner. Additionally, 1 displayed selective antibacterial activity against Staphylococcus aureus 6538P, and low activities towards strains of Vibrio parahaemolyticus and Escherichia coli in this study. KEY POINTS: • Twelve compounds were obtained from Talaromyces sp., including four meroterpenoids, one of which was new. • The new compound taladrimanin A (1) inhibits the growth of gastric cancer cells MGC803 and MKN28 as well as the pathogenic bacteria Staphylococcus aureus 6538P. • The biosynthetic pathway of the meroterpenoids was proposed.

Perceived extrinsic barriers hinder community detection and management of mild cognitive impairment: a cross-sectional study of general practitioners in Shanghai, China.

BACKGROUND: General practitioners (GPs) play a critical role in community detection and management of mild cognitive impairment (MCI). Although adequate knowledge is essential, healthcare practice is shaped by intrinsic and extrinsic factors. This study aimed to test the mediating effect of perceived extrinsic barriers on the associations between knowledge, attitudes, and intended practice of GPs in community detection and management of MCI. METHODS: A cross-sectional study was conducted through an online survey of 1253 GPs sampled from 56 community health centres (CHCs) in Shanghai in 2021. Perceived extrinsic barriers were rated on a five-point Likert scale for patient engagement, working environment, and system context, respectively. A summed score was generated subsequently for each domain ranging from 0 to 100, with a higher score indicating higher barriers. The mediating effect of perceived extrinsic barriers (second-order) and the moderation effect of training on the association between MCI knowledge and practice scores, as well as the moderation effect of past experience on the association between MCI knowledge and extrinsic barriers, were tested through structural equation modelling (SEM) with a partial least square (PLS) approach. RESULTS: The study participants reported an average barrier score of 65.23 (SD = 13.98), 58.34 (SD = 16.95), and 60.37 (SD = 16.99) for patient engagement, working environment, and system context, respectively. Although knowledge had both direct and indirect (through attitudes) effects on intended practice, perceived extrinsic barriers negatively mediated (ß = - 0.012, p = 0.025) the association between knowledge and practice. Training moderated the effect of knowledge on practice (ß = - 0.066, p = 0.014). CONCLUSIONS: Perceived extrinsic barriers have a detrimental effect on the translation of knowledge into practice for community detection and management of MCI. The effect of training on practice declines when knowledge scores become higher.

An update on the prevalence of eating disorders in the general population: a systematic review and meta-analysis.

OBJECTIVE: To update the prevalence of eating disorders in the general population before 2021 and to analyze the distribution characteristics at different times and in different regions and sexes, as well as the diagnostic criteria. METHODS: Based on the method from a previous report by the authors, studies were identified from the following databases: PubMed/Medline, PsycINFO, ISI Web of Knowledge, Ovid and the 4 most important Chinese databases. Articles in English and Chinese before 2021 were retrieved. The data retrieved at this time were pooled with the data from a previous report for analyses. RESULTS: Thirty-three studies were identified, which included 18 studies supplemented in this retrieval. The pooled lifetime and 12-month prevalence of eating disorders were 0.91% (95% CI, 0.48-1.71) and 0.43% (95% CI, 0.18-0.78), respectively. The pooled lifetime and 12-month prevalence of the subgroup EDs (any), which covers all types of eating disorders, were 1.69% and 0.72%, respectively. The lifetime prevalence of AN, BN and BED was 0.16% (95% CI, 0.06-0.31), 0.63% (95% CI, 0.33-1.02) and 1.53% (95% CI, 1.00-2.17), respectively. The lifetime prevalence of EDs in Western countries was 1.89%, and was high at 2.58% in females. Prevalence studies using DSM-5 criteria were scarce. CONCLUSIONS: The prevalence of eating disorders might be underestimated thus far. Not all types of EDs were included in a majority of epidemiological surveys, and the prevalence rates of the new types of EDs were significantly higher. Eating disorders were especially common in Western countries and in females. New diagnostic criteria should be used to comprehensively assess all types of eating disorders. LEVEL OF EVIDENCE: 1, systematic review and meta-analysis.

Prevalence of mild cognitive impairment in community-dwelling Chinese populations aged over 55 years: a meta-analysis and systematic review.

BACKGROUND: Mild cognitive impairment (MCI) is an intermediate phase between normal cognitive ageing and overt dementia, with amnesic MCI (aMCI) being the dominant subtype. This study aims to synthesise the prevalence results of MCI and aMCI in community-dwelling populations in China through a meta-analysis and systematic review. METHODS: The study followed the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) protocol. English and Chinese studies published before 1 March 2020 were searched from ten electronic bibliographic databases. Two reviewers screened for relevance of the studies against the pre-defined inclusion and exclusion criteria and assessed the quality of the included studies using the Risk of Bias Tool independently. A random-effect model was adopted to estimate the prevalence of MCI and aMCI, followed by sub-group analyses and meta-regression. Sensitivity and publication bias tests were performed to verify the robustness of the meta-analyses. RESULTS: A total of 41 studies with 112,632 participants were included in the meta-analyses. The Chinese community-dwelling populations over 55 years old had a pooled prevalence of 12.2% [95% confidence interval (CI): 10.6, 14.2%] for MCI and 10.9% [95% CI, 7.7, 15.4%] for aMCI, respectively. The prevalence of MCI increased with age. The American Psychiatric Association's Diagnostic tool (DSM-IV) generated the highest MCI prevalence (13.5%), followed by the Petersen criteria (12.9%), and the National Institute on Aging Alzheimer's Association (NIA-AA) criteria (10.3%). Women, rural residents, and those who lived alone and had low levels of education had higher MCI prevalence than others. CONCLUSION: Higher MCI prevalence was identified in community-dwelling older adult populations in China compared with some other countries, possibly due to more broadened criteria being adopted for confirming the diagnosis. The study shows that aMCI accounts for 66.5% of MCI, which is consistent with findings of studies undertaken elsewhere. SYSTEMATIC REVIEW REGISTRATION NUMBER: PROSPERO CRD42019134686.

General practitioners' perceptions of their practice of evidence-based chronic disease prevention interventions: a quantitative study in Shanghai, China.

BACKGROUND: Epidemic chronic diseases pose significant challenges to the improvement of healthcare in China and worldwide. Despite increasing international calls for the inclusion of evidence-based decision-making (EBDM) processes in chronic disease prevention and control programming as well as policymaking, there is relatively little research that assesses the current capacity of physicians and the factors that influence that capacity in China. METHOD: This cross-sectional study was conducted in community health centres (CHCs) in Shanghai, China, using multistage cluster sampling. An evidence-based chronic disease prevention (EBCDP) evaluation tool was employed to assess physician EBCDP awareness, adoption, implementation and maintenance based on the Reach, Effectiveness, Adoption, Implementation and Maintenance (RE-AIM) framework and using a 7-point Likert scale. Linear regression analysis was used to assess associations between each EBCDP aspect and overall EBCDP status with participant characteristics or organizational factors. RESULT: A total of 892 physicians from CHCs in Shanghai, China, were assessed. The physicians perceived their awareness (mean = 4.90, SD = 1.02) and maintenance (mean = 4.71, SD = 1.07) of EBCDP to be relatively low. Physicians with relatively lower job titles and monthly incomes (> 9000 RMB) tended to have relatively higher scores for the awareness, adoption, and implementation of EBCDP (P < 0.05). Those who had participated in one program for chronic disease prevention and control were less likely to adopt (b = - 0.284, P = 0.007), implement (b = - 0.292, P = 0.004), and maintain (b = - 0.225, P = 0.025) EBCDP than those who had participated in more programs. Physicians in general practice (Western medicine) had a lower level of awareness of EBCDP than those in other departments (P < 0.0001). Physician from CHCs located in suburban areas had lower scores for awareness (b = - 0.150, P = 0.047), implementation (b = - 0.171, P = 0.029), and maintenance (b = - 0.237, P = 0.002) that those from urban CHCs. Physicians in CHCs affiliated with universities had higher scores on all four EBCDP aspects that those in CHCs not affiliated with a university. CONCLUSIONS: This study provides quantitative evidence illustrating EBCDP practices among physicians in CHCs with various personal and organizational characteristics, respectively. More methods should be provided to increase the awareness of such physicians regarding EBCDP to stimulate the use of EBCDP for their patients and in connection with other public health priorities.

The quality of primary care in community health centers: comparison among urban, suburban and rural users in Shanghai, China.

OBJECTIVE: Following World Health Organization's initiatives to advance primary care, China put forth forceful policies including the Personal Family Doctor Contract to ensure that every family sign up with a qualified doctor in a community health center (CHC) ever since its 2009 New Health Reform. We used the Johns Hopkins-designed Primary Care Assessment Tool (PCAT) to assess primary care quality experienced by the contracted residents and compare this across different socioeconomic regions. METHODS: Using a multistage sampling method, four CHCs each were randomly selected from urban, suburban and rural districts of Shanghai, a metropolitan with 24 million residents. ANOVA and Multivariate analyses were used to assess the association between location of CHC and the quality of primary care experience. FINDINGS: A total of 2404 CHC users completed our survey. Except for the domain of coordination (information systems), users from suburban CHCs reported best primary care experiences in all other domains, followed by users of rural CHCs. After controlling for covariates, suburban CHC users were more likely to report higher total PCAT scores (ß = 1.57, P <  0.001) compared with those from urban CHCs. CONCLUSION: That contracted residents from suburban CHCs reporting better primary care experience than those from urban CHCs demonstrates the unique value of CHCs in relatively medical-underserved areas. In particular, urban CHCs could further strengthen first contact (utilization), first contact (accessibility), coordination (referral system), comprehensiveness (available), and community orientation aspects of primary care performance. However, all CHCs could improve coordination (information system).

Oncogenic HER2 fusions in gastric cancer.

BACKGROUND: Genetic amplification of HER2 drives tumorigenesis and cancer progression in a subset of patients with gastric cancer (GC), and treatment with trastuzumab, a humanized HER2-neutralizing antibody, improves the overall survival rate of HER2-positive patients. However, a considerable portion of the patients does not respond to trastuzumab and the molecular mechanisms underlying the intrinsic resistance to anti-HER2 therapy in GC is not fully understood. METHODS: We performed whole-transcriptome sequencing on 21 HER2-positive tumor specimens from Chinese GC patients. Whole genome sequencing was performed on the three samples with HER2 fusion to discover the DNA integration structure. A multicolor FISH assay for HER2 split screening was conducted to confirm HER2 fusion and IHC (HercepTest™) was used to detect the membranous expression of HER2. Fusion cDNA were transfected into NIH/3T3 cells and generate stable cell line by lentivirus. The expression of exogenous HER2 fusion proteins and pHER2 were examined by western blot analysis. In vitro efficacy studies were also conducted by PD assay and softagar assay in cell line expression wild type and fusion HER2. T-DM1 was used to assess its binding to NIH/3T3 cells ectopically expressing wild-type and fusion HER2. Finally, the anti-tumor efficacy of trastuzumab was tested in NIH/3 T3 xenografts expressing the HER2 fusion variants. RESULTS: We identified three new HER2 fusions with ZNF207, MDK, or NOS2 in 21 HER2-amplified GC samples (14%; 3/21). Two of the fusions, ZNF207-HER2, and MDK-HER2, which are oncogenic, lead to aberrant activation of HER2 kinase. Treatment with trastuzumab inhibited tumor growth significantly in xenografts expressing MDK-HER2 fusion. In contrast, trastuzumab had no effect on the growth of xenografts expressing ZNF207-HER2 fusion, due to its inability to bind to trastuzumab. CONCLUSIONS: Our results provide the molecular basis of a novel resistance mechanism to trastuzumab-based anti-HER2 therapy, supporting additional molecule stratification within HER2-positive GC patients for more effective therapy options.

Identification and validation of dysregulated MAPK7 (ERK5) as a novel oncogenic target in squamous cell lung and esophageal carcinoma.

BACKGROUND: MAPK7/ERK5 (extracellular-signal-regulated kinase 5) functions within a canonical three-tiered MAPK (mitogen activated protein kinase) signaling cascade comprising MEK (MAPK/ERK kinase) 5, MEKK(MEK kinase) 2/3 and ERK5 itself. Despite being the least well studied of the MAPK-modules, evidence supports a role for MAPK7-signaling in the pathology of several cancer types. METHODS AND RESULTS: Fluorescence in situ hybridization (FISH) analysis identified MAPK7 gene amplification in 4% (3/74) of non-small cell lung cancers (NSCLC) (enriched to 6% (3/49) in squamous cell carcinoma) and 2% (2/95) of squamous esophageal cancers (sqEC). Immunohistochemical (IHC) analysis revealed a good correlation between MAPK7 gene amplification and protein expression. MAPK7 was validated as a proliferative oncogenic driver by performing in vitro siRNA knockdown of MAPK7 in tumor cell lines. Finally, a novel MEK5/MAPK7 co-transfected HEK293 cell line was developed and used for routine cell-based pharmacodynamic screening. Phosphorylation antibody microarray analysis also identified novel downstream pharmacodynamic (PD) biomarkers of MAPK7 kinase inhibition in tumor cells (pMEF2A and pMEF2D). CONCLUSIONS: Together, these data highlight a broader role for dysregulated MAPK7 in driving tumorigenesis within niche populations of highly prevalent tumor types, and describe current efforts in establishing a robust drug discovery screening cascade.

Morita therapy for anxiety disorders in adults.

BACKGROUND: Morita therapy, first proposed in 1919, is a systematic psychological therapy for anxiety disorders that is based on eastern philosophy. It is mainly used as an alternative therapy for anxiety disorders in Asian countries such as Japan and China. Varying foci of treatment outcomes have been reported. To date, there has been no systematic review to investigate the strength of evidence for Morita therapy in anxiety disorders. OBJECTIVES: To assess the effects of Morita therapy compared with pharmacological therapy, other psychological therapy, no intervention or wait list for anxiety disorders in adults. SEARCH METHODS: We searched The Cochrane Collaboration Depression, Anxiety and Neurosis Group's Specialised Register (CCDANCTR, which includes relevant randomised controlled trials from MEDLINE (1950 to date), EMBASE (1974 to date) and PsycINFO (1967 to date)), Dissertation Abstracts International (DAI) and four main Chinese medical databases (Chongqing VIP Database, Wanfang Database, China Hospital Knowledge Database, China Biology Medicine disc) as described in the protocol of this review to December 2014. Furthermore, we extended our search in the Cochrane Central Register of Controlled Trials (CENTRAL) and the World Health Organization International Clinical Trials Registry Platform (ICTRP) and the Sagace, a web-based search engine for biomedical databases in Japan. We applied no date or language restrictions. We contacted experts in the field for supplemental data. SELECTION CRITERIA: We included all relevant randomised controlled trials comparing Morita therapy with any other treatment in the treatment of anxiety disorders. DATA COLLECTION AND ANALYSIS: Two authors independently selected studies and extracted data. For homogenous dichotomous data, we calculated fixed-effect risk ratios (RR), 95% confidence intervals (CI) and, where appropriate, numbers needed to treat for an additional beneficial outcome (NNTB) on an intention-to-treat basis. For continuous data, we calculated fixed-effect standardised mean differences (SMD) and 95% CI. MAIN RESULTS: We found seven small Chinese studies (449 participants), six of which provided useable data for meta-analysis. No study compared Morita therapy with an inactive control. Unclear randomisation methods, lack of blinding and low quality reporting of outcomes were common in the included studies. We graded the overall risk of bias as high and the quality of the evidence as very low.Two social phobia studies (75 outpatients) directly compared Morita therapy with pharmacological therapy. In this comparison, the pooled RR of global state was 1.85 (95% CI 1.27 to 2.69) and the NNTB was 3 (95% CI 2 to 5), indicating a significant difference between groups favouring Morita therapy in the short term (up to 12 weeks' post-treatment). Data regarding drop-outs was insufficient and no description of adverse effects was provided. We graded the quality of the evidence for this comparison as very low, mainly due to high risk of bias in the studies and insufficient information in the results.Four studies (288 inpatients) investigated the effect of Morita therapy plus pharmacological therapy versus pharmacological therapy alone, three studies for the treatment of obsessive-compulsive disorder (OCD) (228 participants) and one study for generalised anxiety disorder (60 participants). One of the OCD studies reported incomplete data of global state while the outcome of global state was missing in the other three studies. There was no significant difference between groups for drop-outs for any reason in two OCD studies in the short term (RR 1.76, 95% CI 0.47 to 6.67; I(2) = 44%). Information pertaining to drop-outs for adverse effects was unclear. We rated the risk of bias of this comparison as high. We graded the quality of the evidence as very low. AUTHORS' CONCLUSIONS: The evidence base on Morita therapy for anxiety disorders was limited. All studies included in this review were conducted in China, and the results may not be applicable to Western countries. These included studies were small, provided insufficient information about drop-outs and adverse effects, and contained considerable risk of bias. Therefore, we graded the evidence as very low quality and were unable to draw conclusions on the effectiveness of Morita therapy in the treatment of anxiety disorders. Well-designed future studies that employ adequate allocation concealment, recruit large sample sizes, report drop-outs and adverse effects, and report outcomes clearly and consistently are needed to establish the effectiveness of Morita therapy for anxiety disorders.

Whole genome gene copy number profiling of gastric cancer identifies PAK1 and KRAS gene amplification as therapy targets.

Gastric cancer is the second leading cause of death from cancer worldwide, with an approximately 20% 5-year survival rate. To identify molecular subtypes associated with the clinical prognosis, in addition to genetic aberrations for potential targeted therapeutics, we conducted a comprehensive whole-genome analysis of 131 Chinese gastric cancer tissue specimens using whole-genome array comparative genomic hybridization. The analyses revealed gene focal amplifications, including CTSB, PRKCI, PAK1, STARD13, KRAS, and ABCC4, in addition to ERBB2, FGFR2, and MET. The growth of PAK1-amplified gastric cancer cells in vitro and in vivo was inhibited when the corresponding mRNA was knocked down. Furthermore, both KRAS amplification and KRAS mutation were identified in the gastric cancer specimens. KRAS amplification was associated with worse clinical outcomes, and the KRAS gene mutation predicted sensitivity to the MEK1/2 inhibitor AZD6244 in gastric cancer cell lines. In summary, amplified PAK1, as well as KRAS amplification/mutation, may represent unique opportunities for developing targeted therapeutics for the treatment of gastric cancer.

Trends and hotspots in gastrointestinal neoplasms risk assessment: A bibliometric analysis from 1984 to 2022.

BACKGROUND: Gastrointestinal neoplasm (GN) significantly impact the global cancer burden and mortality, necessitating early detection and treatment. Understanding the evolution and current state of research in this field is vital. AIM: To conducts a comprehensive bibliometric analysis of publications from 1984 to 2022 to elucidate the trends and hotspots in the GN risk assessment research, focusing on key contributors, institutions, and thematic evolution. METHODS: This study conducted a bibliometric analysis of data from the Web of Science Core Collection database using the "bibliometrix" R package, VOSviewer, and CiteSpace. The analysis focused on the distribution of publications, contributions by institutions and countries, and trends in keywords. The methods included data synthesis, network analysis, and visualization of international collaboration networks. RESULTS: This analysis of 1371 articles on GN risk assessment revealed a notable evolution in terms of research focus and collaboration. It highlights the United States' critical role in advancing this field, with significant contributions from institutions such as Brigham and Women's Hospital and the National Cancer Institute. The last five years, substantial advancements have been made, representing nearly 45% of the examined literature. Publication rates have dramatically increased, from 20 articles in 2002 to 112 in 2022, reflecting intensified research efforts. This study underscores a growing trend toward interdisciplinary and international collaboration, with the Journal of Clinical Oncology standing out as a key publication outlet. This shift toward more comprehensive and collaborative research methods marks a significant step in addressing GN risks. CONCLUSION: This study underscores advancements in GN risk assessment through genetic analyses and machine learning and reveals significant geographical disparities in research emphasis. This calls for enhanced global collaboration and integration of artificial intelligence to improve cancer prevention and treatment accuracy, ultimately enhancing worldwide patient care.

The AKT inhibitor AZD5363 is selectively active in PI3KCA mutant gastric cancer, and sensitizes a patient-derived gastric cancer xenograft model with PTEN loss to Taxotere.

INTRODUCTION: Activation of the PI3K/AKT pathway is a common phenomenon in cancer due to multiple mechanisms, including mutation of PI3KCA, loss or mutation of PTEN, or over-expression of receptor tyrosine kinases. We recently developed a novel AKT kinase inhibitor, AZD5363, and demonstrated that HGC27, a cell line harboring both PI3KCA mutation and PTEN loss, displayed the greatest sensitivity to this AKT inhibitor in vitro and in vivo. CASE PREPARATION: To further elucidate the correlation between AZD5363 response and genetic alterations in gastric cancer (GC) and identify GC patients with both PI3KCA mutations and PTEN loss, we investigated the effects of pharmacological inhibition of AKT on a panel of 20 GC cell lines and genetic aberrations in tumor samples from a cohort of Chinese GC patients. We demonstrated that GC cells with PI3KCA mutations were selectively sensitive to AZD5363. Disease linkage studies showed that PI3KCA activating mutations or PTEN loss were found in 2.7% (4/150) and 23% (14/61) of Chinese GC patients respectively. To further dissect the role of PI3KCA mutation and PTEN loss in response to AKT inhibition, we tested the antitumor activity of AZD5363 in two patient-derived GC xenograft (PDGCX) models harboring either PI3KCA mutation or PTEN loss. Our data indicated that AZD5363 monotherapy treatment led to a moderate response in the PI3KCA mutant PDGCX model. Whilst monotherapy AZD5363 or Taxotere were ineffective in the PTEN negative PDGCX model, significant anti-tumor activity was observed when AZD5363 was combined with Taxotere. CONCLUSION: Our results indicated that PI3KCA mutation is an important determinant of response to AKT inhibition in GC and combination with AZD5363 can overcome innate resistance to Taxotere in a PTEN loss PDGCX model. It is suggested that AKT inhibitor is an attractive option for treatment of a new segment of GC patients with aberrant PI3K/AKT signaling.

MnOxHy-modified CoMoP/NF nanosheet arrays as hydrogen evolution reaction and oxygen evolution reaction bifunctional catalysts under alkaline conditions.

It is widely acknowledged that interface engineering strategies can significantly enhance the activity of catalysts. In this study, we developed a CoMoP nanoarray directly grown in situ on a nickel foam (NF) substrate, with the interface structure formed through the electrodeposition of MnOxHy. The resulting heterostructure MnOxHy/CoMoP/NF exhibited remarkable hydrogen evolution reaction (HER) activity, achieving overpotentials as low as 61 and 138 mV at 10 and 100 mA cm-2, respectively. Moreover, MnOxHy/CoMoP/NF demonstrated efficient oxygen evolution reaction (OER) activity with an overpotential of 330 mV at 100 mA cm-2. Remarkably, MnOxHy/CoMoP/NF maintained its catalytic properties and structural integrity even after working continuously for 20 h facilitating the HER at 10 mA cm-2 and the OER at 100 mA cm-2. The Tafel slopes of the HER and OER were determined to be as small as 14 and 55 mV dec-1, respectively, confirming that the coupled interface conferred fast reaction kinetics on the catalyst. When applied in overall water splitting, MnOxHy/CoMoP/NF delivered a voltage of 1.91 V at 100 mA cm-2 with excellent stability. This study demonstrated the feasibility of utilizing a simple electrodeposition technique to fabricate a heterogeneous structure with bifunctional catalytic activity, establishing a solid foundation for diverse industrial applications.