Methods and clinical biomarker discovery for targeted proteomics using Olink technology.

PURPOSE: This paper is to offer insights for designing research utilizing Olink technology to identify biomarkers and potential therapeutic targets for disease treatment. EXPERIMENTAL DESIGN: We discusses the application of Olink technology in oncology, cardiovascular, respiratory and immune-related diseases, and Outlines the advantages and limitations of Olink technology. RESULTS: Olink technology simplifies the search for therapeutic targets, advances proteomics research, reveals the pathogenesis of diseases, and ultimately helps patients develop precision treatments. CONCLUSIONS: Although proteomics technology has been rapidly developed in recent years, each method has its own disadvantages, so in the future research, more methods should be selected for combined application to verify each other.

Examining the impact of COVID-19 on Maori:non-Maori health inequities in Aotearoa, New Zealand: an observational study protocol.

INTRODUCTION: The COVID-19 pandemic has had both direct and indirect impacts on the health of populations worldwide. While racial/ethnic health inequities in COVID-19 infection are now well known (and ongoing), knowledge about the impact of COVID-19 pandemic management on non-COVID-19-related outcomes for Indigenous peoples is less well understood. This article presents the study protocol for the Health Research Council of New Zealand funded project 'Ma te Mohio ka Marama: Impact of COVID-19 on Maori:non-Maori inequities'. The study aims to explore changes in access to healthcare, quality of healthcare and health outcomes for Maori, the Indigenous peoples of Aotearoa New Zealand (NZ) and non-Maori during the COVID-19 outbreak period across NZ. METHODS AND ANALYSIS: This observational study is framed within a Kaupapa Maori research positioning that includes Kaupapa Maori epidemiology. National datasets will be used to report on access to healthcare, quality of healthcare and health outcomes between Maori and non-Maori during the COVID-19 pandemic in NZ. Study periods are defined as (a) prepandemic period (2015-2019), (b) first pandemic year without COVID-19 vaccines (2020) and (c) pandemic period with COVID-19 vaccines (2021 onwards). Regional and national differences between Maori and non-Maori will be explored in two phases focused on identified health priority areas for NZ including (1) mortality, cancer, long-term conditions, first 1000 days, mental health and (2) rheumatic fever. ETHICS AND DISSEMINATION: This study has ethical approval from the Auckland Health Research Ethics Committee (AHREC AH26253). An advisory group will work with the project team to disseminate the findings of this project via project-specific meetings, peer-reviewed publications and a project-specific website. The overall intention of the project is to highlight areas requiring health policy and practice interventions to address Indigenous inequities in health resulting from COVID-19 pandemic management (both historical and in the future).

Construction of a prognostic model for triple-negative breast cancer based on immune-related genes, and associations between the tumor immune microenvironment and immunological therapy.

BACKGROUND: Triple-negative breast cancer (TNBC) is the subtype of breast cancer with the worst prognosis, and it is highly heterogeneous. There is growing evidence that the tumor immune microenvironment (TIME) plays a crucial role in tumor development, maintenance, and treatment responses. Notably however, the full effects of the TIME on prognosis, TIME characteristics, and immunotherapy responses in TNBC patients have not been fully elucidated. METHODS: Gene Expression Omnibus and The Cancer Genome Atlas data were used to data analysis. Single-cell sequencing and tissue microarray analysis were used to investigate gene expression. The concentrations and distributions of immune cell types were determined and analyzed using the CIBERSORT strategy. Tumor immune dysfunction and exclusion score and the IMvigor210 cohort were used to estimate the sensitivity of TNBC patients with different prognostic statuses to immune checkpoint treatment. RESULTS: Five immune-related genes associated with TNBC prognosis (IL6ST, NR2F1, CKLF, TCF7L2, and HSPA2) was identified and a prognostic evaluation model was constructed based on those genes. The respective areas under the curve of the prognostic nomogram model at 3 and 5 years were 0.791 and 0.859. The group with a lower nomogram score, with a better prognosis survival status and clinical treatment benefit rate. CONCLUSION: A prognostic model for TNBC that was closely related to the immune landscape and therapeutic responses was constructed. This model may help clinicians to make more precise and personalized treatment decisions pertaining to TNBC patients.

The hub genes and their potential regulatory mechanisms in chronic spontaneous urticaria revealed by integrated transcriptional expression analysis.

Chronic spontaneous urticaria (CSU) is a recurrent disease characterized by wheals and or angioedema, and its pathogenesis is still unclear. The microarray datasets of skin tissue from CSU patients and healthy controls were integrated and analysed in Gene Expression Omnibus (GEO). Differentially expressed genes (DEGs) were identified using the NetworkAnalyst tool. Then, the Gene Ontology (GO) and Kyoto Encyclopaedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed. Subsequently, a protein-protein interaction (PPI) network of DEGs was constructed by STRING and the related hub genes were identified through the MOCDE tool. The potential miRNAs targeting hub genes were predicted based on the intersection of three online databases, namely TargetScanHuman, TargetBase and miRNet. Differentially expressed lncRNAs (DElncRNAs) was performed using the GEO2R tool. The potential miRNAs targeting DElncRNAs were predicted through miRNet. Finally, the shared miRNAs targeting both hub genes and DElncRNAs were used to construct an mRNA/miRNA/lncRNA regulatory network. A total of 296 DEGs were obtained, which were mainly enriched in inflammatory and immune responses. Further, 14 hub genes were identified by the PPI network of DEGs. Clinical correlation analysis showed that the mRNA expressions of S100A7, S100A8, S100A9, S100A12, IL6 and SOCS3 in CSU were positively correlated with the 7-day urticaria activity score (UAS7), and their potential diagnostic value was supported by the receiver operating characteristic curve (ROC) analysis. Five up-regulated lncRNAs in the cytoplasm were obtained by DElncRNAs analysis. The ROC analysis showed that PVT1, SNHG3 and ZBTB20 - AS1 was of potential diagnostic value for CSU. Eight shared miRNAs targeting both hub genes and DElncRNAs were identified and used to construct a competing endogenous RNA (ceRNA) network. It was found that the IL-6/miR - 149 - 5p/ZBTB20 - AS1 axis might play an important role in the activation of mast cells in CSU. IL-6 and its related regulatory molecules may be used as potential diagnostic markers and therapeutic targets for CSU.

Rugby Fans in Training New Zealand (RUFIT NZ): a randomized controlled trial to assess the effectiveness of a healthy lifestyle program for overweight men delivered through professional rugby clubs.

BACKGROUND: A healthy lifestyle program that appeals to, and supports, overweight and obese New Zealand (NZ) European, Maori (indigenous) and Pasifika men to achieve weight loss is urgently needed. A pilot program inspired by the successful Football Fans in Training program but delivered via professional rugby clubs in NZ (n = 96) was shown to be effective in weight loss, adherence to healthy lifestyle behaviors, and cardiorespiratory fitness in overweight and obese men. A full effectiveness trial is now needed. AIMS: To determine the effectiveness and cost effectiveness of Rugby Fans In Training-NZ (RUFIT-NZ) on weight loss, fitness, blood pressure, lifestyle change, and health related quality of life (HRQoL) at 12- and 52-weeks. METHODS: We conducted a pragmatic, two-arm, multi-center, randomized controlled trial in NZ with 378 (target 308) overweight and obese men aged 30-65 years, randomized to an intervention group or wait-list control group. The 12-week RUFIT-NZ program was a gender-sensitised, healthy lifestyle intervention delivered through professional rugby clubs. Each intervention session included: i) a 1-h workshop-based education component focused on nutrition, physical activity, sleep, sedentary behavior, and learning evidence-based behavior change strategies for sustaining a healthier lifestyle; and 2) a 1-h group-based, but individually tailored, exercise training session. The control group were offered RUFIT-NZ after 52-weeks. The primary outcome was change in body weight from baseline to 52-weeks. Secondary outcomes included change in body weight at 12-weeks, waist circumference, blood pressure, fitness (cardiorespiratory and musculoskeletal), lifestyle behaviors (leisure-time physical activity, sleep, smoking status, and alcohol and dietary quality), and health-related quality of life at 12- and 52-weeks. RESULTS: Our final analysis included 200 participants (intervention n = 103; control n = 97) who were able to complete the RUFIT-NZ intervention prior to COVID-19 restrictions. At 52-weeks, the adjusted mean group difference in weight change (primary outcome) was -2.77 kg (95% CI -4.92 to -0.61), which favored the intervention group. The intervention also resulted in favorable significant differences in weight change and fruit and vegetable consumption at 12-weeks; and waist circumference, fitness outcomes, physical activity levels, and health-related quality of life at both 12 and 52 weeks. No significant intervention effects were observed for blood pressure, or sleep. Incremental cost-effective ratios estimated were $259 per kg lost, or $40,269 per quality adjusted life year (QALY) gained. CONCLUSION: RUFIT-NZ resulted in sustained positive changes in weight, waist circumference, physical fitness, self-reported physical activity, selected dietary outcomes, and health-related quality of life in overweight/obese men. As such, the program should be recommended for sustained delivery beyond this trial, involving other rugby clubs across NZ. TRIAL REGISTRATION: Australia New Zealand Clinical Trials Registry, ACTRN12619000069156. Registered 18 January 2019, https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=376740 Universal Trial Number, U1111-1245-0645.

BMI-1 promotes breast cancer proliferation and metastasis through different mechanisms in different subtypes.

Breast cancer is among the most common malignant cancers in women. B-cell-specific Moloney murine leukemia virus integration site 1 (BMI-1) is a transcriptional repressor that has been shown to be involved in tumorigenesis, the cell cycle, and stem cell maintenance. In our study, increased expression of BMI-1 was found in both human triple negative breast cancer and luminal A-type breast cancer tissues compared with adjacent tissues. We also found that knockdown of BMI-1 significantly suppressed cell proliferation and migration in vitro and in vivo. Further mechanistic research demonstrated that BMI-1 directly bound to the promoter region of CDKN2D/BRCA1 and inhibited its transcription in MCF-7/MDA-MB-231. More importantly, we discovered that knockdown of CDKN2D/BRCA1 could promote cell proliferation and migration after repression by PTC-209. Our results reveal that BMI-1 transcriptionally suppressed BRCA1 in TNBC cell lines whereas, in luminal A cell lines, CDKN2D was the target gene. This provides a reference for the precise treatment of different types of breast cancer in clinical practice.

TIM-3 shuttled by MV3 cells-secreted exosomes inhibits CD4+ T cell immune function and induces macrophage M2 polarization to promote the growth and metastasis of melanoma cells.

This study is sought to determine the physiological mechanisms by which exosomes-encapsulated TIM-3 derived from melanoma cells might mediate CD4+ T cell immune function and macrophage M2 polarization in melanoma. Initially, exosomes were isolated from the human skin-derived melanoma cell line MV3for analysis of TIM-3 expression pattern. Next, the exosomes sourced from MV3 cells manipulated with sh-TIM-3 were co-incubated with CD4+ T cells to detect CD4+ T cell proliferation and MV3 cell migration and invasion, to observe the macrophage M2 polarization, and to determine levels of several EMT-related factors. Finally, melanoma nude mouse models were established to study the in vivo modulatory effects of TIM-3 from MV3 cells-derived exosomes. MV3 cells-derived exosomes inhibited CD4+ T cell immune function and promoted macrophage M2 polarization in melanoma. Our results revealed the abundance of TIM-3 in MV3 cells-derived exosomes. Of importance, silencing of TIM-3 shuttled by MV3 cells-derived exosomes improved CD4+ T cell immune function and inhibited macrophage M2 polarization to attenuate the growth and metastasis of melanoma cells. Collectively, MV3 cells-derived exosomes-loaded TIM-3 suppressed CD4+ T cell immune function and induced macrophage M2 polarization to improve occurrence and development of melanoma, therefore providing us with a potential therapeutic target for effectively combating melanoma.

Fbxo21 regulates the epithelial-to-mesenchymal transition through ubiquitination of Nr2f2 in gastric cancer.

F-box protein 21 (Fbxo21), a member of the F-box family proteins, constitutes one of the four subunits of an E3 ubiquitin ligase complex called SCFs (SKP1-Cullin-F-box). Despite the effect on antivirus immune response and ubiquitination regulation of a few oncoproteins, such as EID1 and P-gp, little is known about the Fbxo21 function in tumors, including gastric cancer. In our study, we confirmed that Fbxo21 expression was decreased in gastric cancer tissues. Decreased expression of Fbxo21 was significantly associated with poor prognosis in gastric cancer. Fbxo21 inhibited gastric cancer progression by inducing growth arrest and inhibiting migration and invasion. The expression of various EMT markers, such as E-cadherin, N-cadherin and Vimentin were altered after Fbxo21 knockdown or overexpression. Moreover, we demonstrated that Fbxo21 inhibited the EMT via the down-regulation of Nr2f2. Fbxo21 expression was negatively correlated with Nr2f2 protein expression in gastric cancer tissues and cell lines. And the Nr2f2 protein abundance was regulated by Fbxo21 via ubiquitination and proteasomal degradation. At last, we demonstrated the effects of Nr2f2 re-expression and inhibition on stable Fbxo21-overexpression or Fbxo21-silenced cell lines. These results suggested that Fbxo21 inhibited the proliferation and EMT in part through down-regulating the Nr2f2.

Identification of biomarkers predicting the chemotherapeutic outcomes of capecitabine and oxaliplatin in patients with gastric cancer.

The capecitabine and oxaliplatin (CapeOX) regimen is a commonly used adjuvant chemotherapeutic regimen for gastric cancer (GC). However, some patients exhibit a poor chemotherapy response due to genetic differences among individuals. Therefore, finding an effective sensitization strategy for CapeOX is important in the treatment of GC. The present study aimed to investigate the predictive biomarkers of the CapeOX chemotherapeutic outcomes for patients with GC. A total of 30 differentially expressed genes (DEGs) were identified using the gene expression profiles from The Cancer Genome Atlas capecitabine and oxaliplatin treatment GC cases and seven key DEGs [uroplakin-1b (UPK1B), fatty acid-binding protein, heart (FABP3), cystatin-M, caspase-5 (CASP5), corticosteroid 11-ß-dehydrogenase isozyme 2, cytochrome P450 4X1 (CYP4X1) and epidermal growth factor receptor kinase substrate 8-like protein 3] were associated with survival. Gene validation was performed in clinical samples divided into recurrence and nonrecurrence groups. Patients with high or low expression of UPK1B, FABP3, CASP5 and CYP4X1 had markedly different overall survival rates. A model was established and the area under the curve of the receiver operating characteristic reached 0.875 (0.793-0.957), indicating that the model had good sensitivity and specificity.

Mobile Social Network-Based Smoking Cessation Intervention for Chinese Male Smokers: Pilot Randomized Controlled Trial.

BACKGROUND: Around 2 million Chinese people, mostly men, die annually from tobacco-related diseases; yet, fewer than 8% of Chinese smokers ever receive any smoking cessation support. OBJECTIVE: This study aimed to test the preliminary effectiveness and feasibility for a mobile social network (WeChat)-based smoking cessation intervention (SCAMPI program) among Chinese male smokers. METHODS: Chinese male smokers aged 25-44 years were recruited online from WeChat, the most widely used social media platform in China. Individuals using other smoking cessation interventions or who lacked capacity to provide online informed consent were excluded. Participants were randomly assigned (1:1) to intervention or control groups. Neither participants nor researchers were masked to assignment. The trial was fully online. All data were collected via WeChat. The intervention group received access to the full-version SCAMPI program, a Chinese-language smoking cessation program based on the Behaviour Change Wheel framework and relevant cessation guidelines. Specific intervention functions used in the program include: planning to help users make quitting plans, calculator to record quitting benefits, calendar to record progress, gamification to facilitate quitting, information about smoking harms, motivational messages to help users overcome urges, standardized tests for users to assess their levels of nicotine dependence and lung health, as well as a social platform to encourage social support between users. The control group had access to a static WeChat page of contacts for standard smoking cessation care. Both groups received incentive credit payments for participating. The primary outcome was 30-day biochemically verified smoking abstinence at 6 weeks after randomization, with missing data treated as not quitting. Secondary outcomes were other smoking status measures, reduction of cigarette consumption, study feasibility (recruitment and retention rate), and acceptability of and satisfaction with the program. RESULTS: The program recorded 5736 visitors over a 13-day recruitment period. We recruited 80 participants who were randomly allocated to two arms (n=40 per arm). At 6 weeks, 36 of 40 (90%) intervention participants and 35 of 40 (88%) control participants provided complete self-reported data on their daily smoking status via WeChat. Biochemically verified smoking abstinence at 6 weeks was determined for 10 of 40 (25%) intervention participants and 2 of 40 (5%) control participants (RR=5, 95% CI 1.2-21.4, P=.03). In the intervention group, the calculator function, motivational messages, and health tests were underused (less than once per week per users). Participants rated their satisfaction with the intervention program as 4.56 out of 5.00. CONCLUSIONS: Our program is a novel, accessible, and acceptable smoking cessation intervention for Chinese male smokers. A future trial with a greater sample size and longer follow-up will identify if it is as effective as these preliminary data suggest. TRIAL REGISTRATION: ANZCTR registry, ACTRN12618001089224; https://tinyurl.com/y536n7sx. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-18071.

Visceral Adiposity and Glucoregulatory Peptides are Associated with Susceptibility to Type 2 Diabetes: The TOFI_Asia Study.

OBJECTIVE: Ethnic differences in fat deposition contribute to type 2 diabetes (T2D). Identification of biomarkers that underpin dysglycemia are needed for better-targeted prevention and treatment. METHODS: The cross-sectional thin-on-the-outside-fat-on-the-inside (TOFI)_Asia study investigated adipose depots and clinical biomarkers as predictors of fasting plasma glucose (FPG) and insulin resistance (IR; assessed using the updated homeostatic model assessment of IR) in lean and overweight normo- and dysglycemic Chinese (n = 199) and Caucasian (n = 158) individuals. Multivariate least-angle regression models were used to identify predictors of FPG and IR. RESULTS: At similar age and BMI, Chinese individuals had lower body weight but had a greater percentage of total abdominal adipose tissue and a greater percentage of total visceral adipose tissue (VAT) (all P < 0.005). In Chinese individuals, FPG, hemoglobin A1c , fasting insulin, and triglycerides were higher, whereas HDL cholesterol and total and high-molecular-weight adiponectin levels were lower (all P < 0.0001). Raised liver enzyme and peptide concentrations (P < 0.02) were consistent with increased T2D risk. Lean Chinese women (<25 kg/m2 ) had greater total abdominal adipose tissue (kilograms) and VAT (kilograms) than Caucasian women, exhibiting the TOFI profile, with raised FPG (P < 0.001) and IR (P = 0.01). Risk factors for elevated FPG specific to Chinese individuals included male gender, VAT, and triglycerides (R2 = 0.33), and risk factors for IR specific to Chinese individuals included amylin, C-peptide, and glucagon (R2 = 0.49). VAT, amylin, and C-peptide were predictors in Caucasian individuals. CONCLUSIONS: VAT contributed to dysglycemia in both ethnicities, particularly in Chinese individuals characterized by the TOFI phenotype, as did the glucoregulatory peptides amylin and C-peptide, providing targets for T2D prevention.

A Mobile Social Network-Based Smoking Cessation Intervention for Chinese Male Smokers: Protocol for a Pilot Randomized Controlled Trial.

BACKGROUND: Approximately 2 million Chinese people die annually from tobacco-related diseases, mostly men; yet, fewer than 8% of Chinese smokers ever receive any smoking cessation advice or support. A social network-based gamified smoking cessation intervention (SCAMPI: Smoking Cessation App for Chinese Male: Pilot Intervention) is designed to help Chinese male smokers to quit smoking. OBJECTIVE: This paper aims to present the protocol of a study examining the preliminary effectiveness of SCAMPI by comparing the prolonged abstinence rate of a group of users with a comparator group during a 6-week follow-up period. METHODS: A two-arm pilot randomized controlled trial was conducted to assess the preliminary effectiveness and acceptability of the SCAMPI program as a smoking cessation intervention. After initial web-based screening, the first 80 eligible individuals who had gone through the required registration process were registered as participants of the trial. Participants were randomly allocated to the intervention group (n=40) and the control group (n=40). Participants in the intervention group used the full version of the SCAMPI program, which is a Chinese smoking cessation program developed based on the Behavior Change Wheel framework and relevant smoking cessation and design guidelines with involvement of target users. The program delivers a range of smoking cessation approaches, including helping users to make quitting plans, calculator to record quitting benefits, calendar to record progress, gamification to facilitate quitting, providing information about smoking harms, motivational messages to help users overcome urges, providing standardized tests to users for assessing their levels of nicotine dependence and lung health, and providing a platform to encourage social support between users. Participants in the control group used the restricted version of the SCAMPI program (placebo app). RESULTS: Recruitment for this project commenced in January 2019 and proceeded until March 2019. Follow-up data collection was commenced and completed by June 2019. The primary outcome measure of the study was the 30-day bio-verified smoking abstinence at the 6-week follow-up (self-reported data verified by the Nicotine Cotinine Saliva Test). The secondary outcome measures of the study included participants' cigarette consumption reduction (compared baseline daily cigarette consumption with end-of-trial daily cigarette consumption), participants' 7-day smoking abstinence at 4-week and 6-week follow-up (self-reported), participants' 30-day smoking abstinence at 6-week follow-up (self-reported data only), and participants' acceptability and satisfaction levels of using the SCAMPI program (measured by the Mobile App Rating Scale questionnaire). CONCLUSIONS: If the SCAMPI program is shown to be preliminary effective, the study will be rolled out to be a future trial with a larger sample size and longer follow-up (6 months) to identify if it is an effective social network-based tool to support Chinese male smokers to quit smoking. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12618001089224; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=375381. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR1-10.2196/18071.

FLNA promotes chemoresistance of colorectal cancer through inducing epithelial-mesenchymal transition and smad2 signaling pathway.

Chemoresistance is a leading cause of tumor relapse and treatment failure in colorectal cancer (CRC) patients and is correlated with epithelial-mesenchymal transition (EMT). This study was aimed to explore the mechanism of EMT in chemoresistant CRC. Bioinformatic method was used to screen differentially expressed genes between 5-FU sensitive and resistant CRC cells. Immunohistochemistry staining was utilized to analyze the expression of FLNA in CRC tissues. The roles of FLNA in chemoresistance were validated via loss-of-function and gain-of-function experiments in vitro and in an orthotopic CRC animal model. The regulation of c-Met signaling by FLNA was explored via Co-Immunoprecipitation and luciferase reporter assays. Our results suggested FLNA directly regulated the metastasis and EMT of chemoresistant CRC cells. Moreover, c-Met-AKT mediated ser2152 phosphorylation of FLNA was demonstrated to be correlated with EMT. In turn, FLNA enhanced c-Met promoter activity by its interaction with smad2. Clinically, the expression of FLNA was significantly associated with c-Met protein levels in CRC tissues. These data established that FLNA could be a novel and reliable CRC marker and a potential therapeutic target against CRC.

Inhibition of Splicing Factor 3b Subunit 1 (SF3B1) Reduced Cell Proliferation, Induced Apoptosis and Resulted in Cell Cycle Arrest by Regulating Homeobox A10 (HOXA10) Splicing in AGS and MKN28 Human Gastric Cancer Cells.

BACKGROUND Small nuclear ribonucleoproteins (snRNPs) complexes of protein and noncoding RNA accumulate in the cell nucleus and catalyze pre-mRNA splicing to form the spliceosome. This study aimed to investigate the role of the spliceosome, splicing factor 3b subunit 1 (SF3B1), in AGS and MKN28 human gastric cancer cells in vitro, including gene knockdown with small interfering RNA (siRNA), and the use of the selective mRNA splicing inhibitor of SF3B1, pladienolide B. MATERIAL AND METHODS In AGS and MKN28 human gastric cancer cells, SF3B1expression was inhibited with siRNA and pladienolide B. Following SF3B1 inhibition, the Cell Counting Kit-8 (CCK-8) assay measured cell proliferation, and flow cytometry was used to investigate cell apoptosis and cell cycle arrest. The downstream HOXA10 and AKT pathways were studied by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and Western blot. The presence of alternative splicing, or differential splicing, of single-gene coding for multiple proteins, was analyzed using The Cancer Genome Atlas (TCGA) SpliceSeq. RESULTS Inhibition of SF3B1 reduced the proliferation rate of AGS and MKN28 human gastric cancer cells by inducing apoptosis and G2/M phase arrest. SF3B1 knockdown resulted in reduced homeobox A10 (HOXA10) mRNA expression and expression of long noncoding RNA (lncRNA) isoforms of HOXA10 (exons 1 and 3) and HOXA10 (exons 2 and 3). SF3B1 inhibition increased PTEN levels and reduced AKT protein phosphorylation. CONCLUSIONS In AGS and MKN28 human gastric cancer cells in vitro, inhibition of SF3B1 reduced cell proliferation, induced apoptosis, and resulted in cell cycle arrest by regulating HOXA10 splicing.

Trends in length of stay following acute coronary syndrome hospitalisation in New Zealand 2006-2016: ANZACS-QI 32 study.

AIMS: Length of hospital stay (LOS) for acute coronary syndrome (ACS) has important clinical and cost implications. We report recent trends and predictors of ACS hospitalisation LOS in New Zealand. METHODS: Using routine national hospitalisation datasets, we calculated mean LOS for ACS admissions annually from 2006 to 2016, by demographics, ACS subtype and ACS procedures (coronary angiography, percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG)). We also identified predictors of longer LOS. RESULTS: Among 185,962 ACS hospitalisations, mean LOS decreased from 7.8 to 6.7 days between 2006 and 2016 (adjusted decrease = -0.18 days/year). Decline in LOS was observed for all demographic subgroups by age, sex, ethnicity and deprivation quintile. While coronary angiography and PCI rates increased during this time, LOS declined for all management strategies. However, the adjusted rate of decline was greater for patients receiving coronary angiography without revascularisation (-0.24 days/year), PCI (-0.22 days/year) and CABG (0.33 days/year)-than those not receiving angiography (-0.14 days/year), P<0.001. A greater decline occurred for NSTEMI and STEMI (9.4 to 7.5 days and 7.8 to 6.2 days, respectively) than UA (5.4 to 4.9 days). Predictors of longer LOS in 2016 were older age, female, Maori or Pacific ethnicity, not receiving coronary angiography, initial presentation to a non-interventional hospital and CABG. CONCLUSIONS: Mean LOS for ACS hospitalisations declined between 2006 and 2016. The decline was greatest in the increasing proportion of patients who received a coronary angiogram. Further reductions in LOS may be achieved by implementation of nationally agreed pathways for adequate and timely access to coronary angiography.

Proposed Modification of the 8th Edition of the AJCC Staging System for Gastric Cancer.

Background: The American Joint Committee on Cancer (AJCC) staging system has been the standardized staging system for malignancies since the first edition in 1987. The 8th edition of gastric cancer was released in 2016, and is expected to be used in clinical practice in 2018. The aim of this study was to improve this new gastric cancer staging system. Methods: We conducted median overall survival analyses in a cohort of 8359 gastric cancer patients from the Surveillance, Epidemiology, and End Results (SEER) database (2004-2014) via Kaplan-Meier curves and log-rank tests, and proposed a modified staging system based on median OS. The concordance index (C-index) was conducted to evaluate the predictive accuracy. Results: Using the 8th AJCC staging system, the median OS of patients at the same stage varied widely between the different substages, especially in stage III. Despite the definitions of T, N, and M, substages in the modified staging system were regrouped based on median OS. The C-index of stage III patients with the modified staging system [0.579, 95% confidence interval (CI) 0.564-0.593] was higher than the 8th AJCC staging system (0.567, 95% CI 0.552-0.581). Moreover, we divided these patients into two groups according to their examined lymph node counts (≥15 or 1-14), and studied the effectiveness of the modified staging system in the two groups. Conclusions: The modified 8th AJCC staging system for gastric cancer proposed in this study generates better prognostic stratifications and may be evaluated for further update. Abbreviations:AJCCAmerican Joint Committee on CancerOSOverall SurvivalSEERSurveillance, Epidemiology, and End Results.

Anthocyanidin attenuates myocardial ischemia induced injury via inhibition of ROS-JNK-Bcl-2 pathway: New mechanism of anthocyanidin action.

Despite treatment options available to date, myocardial ischemia (MI) remains the leading cause of death worldwide. Studies are focused on finding effective therapeutic strategies against MI injury. Growing interest has been developed in natural compounds possessing medicinal properties with scarcer side effects. Here, we have evaluated the cardioprotective potential of anthocyanidin against MI injury and explored its underlying protective mechanism. Left anterior descending coronary artery was ligated to induce MI in mice. Neonatal mice cardiomyocytes were treated with H2 O2 to induce oxidative stress (a major contributor to MI injury) in vitro. Anthocyanidin pretreatment significantly reduced the infarct size, preserved the cell viability, and protected against ischemia-induced cardiac injury in treatment groups compared with the H2 O2 -treated group in vitro. Measurement of reactive oxygen species (ROS) validated the strong antioxidant potential of anthocyanidin, as significant reduction in oxidative stress was observed in anthocyanidin-pretreated groups. Mechanistically, pretreatment with anthocyanidin significantly subdued the activation of JNK (to p-JNK) and elevated Bcl-2 levels. Both in vivo and in vitro findings suggest that anthocyanidin can induce a state of myocardial resistance against ischemic insult. We have provided the experimental evidence for inhibition of ROS/p-JNK/Bcl-2 pathway being the underlying mechanism of action of anthocyanidin. Our results support the use of anthocyanidin as therapeutic strategy against MI injury.

A co-designed mHealth programme to support healthy lifestyles in Maori and Pasifika peoples in New Zealand (OL@-OR@): a cluster-randomised controlled trial.

BACKGROUND: The OL@-OR@ mobile health programme was co-designed with Maori and Pasifika communities in New Zealand, to support healthy lifestyle behaviours. We aimed to determine whether use of the programme improved adherence to health-related guidelines among Maori and Pasifika communities in New Zealand compared with a control group on a waiting list for the programme. METHODS: The OL@-OR@ trial was a 12-week, two-arm, cluster-randomised controlled trial. A cluster was defined as any distinct location or setting in New Zealand where people with shared interests or contexts congregated, such as churches, sports clubs, and community groups. Members of a cluster were eligible to participate if they were aged 18 years or older, had regular access to a mobile device or computer, and had regular internet access. Clusters of Maori and of Pasifika (separately) were randomly assigned (1:1) to either the intervention or control condition. The intervention group received the OL@-OR@ mHealth programme (smartphone app and website). The control group received a control version of the app that only collected baseline and outcome data. The primary outcome was self-reported adherence to health-related guidelines, which were measured with a composite health behaviour score (of physical activity, smoking, alcohol intake, and fruit and vegetable intake) at 12 weeks. The secondary outcomes were self-reported adherence to health-related behaviour guidelines at 4 weeks; self-reported bodyweight at 12 weeks; and holistic health and wellbeing status at 12 weeks, in all enrolled individuals in eligible clusters; and user engagement with the app, in individuals allocated to the intervention. Adverse events were not collected. This study is registered with the Australian New Zealand Clinical Trials Registry, ACTRN12617001484336. FINDINGS: Between Jan 24 and Aug 14, 2018, we enrolled 337 Maori participants from 19 clusters and 389 Pasifika participants from 18 clusters (n=726 participants) in the intervention group and 320 Maori participants from 15 clusters and 405 Pasifika participants from 17 clusters (n=725 participants) in the control group. Of these participants, 227 (67%) Maori participants and 347 (89%) Pasifika participants (n=574 participants) in the intervention group and 281 (88%) Maori participants and 369 (91%) Pasifika participants (n=650 participants) in the control group completed the 12-week follow-up and were included in the final analysis. Relative to baseline, adherence to health-related behaviour guidelines increased at 12 weeks in both groups (315 [43%] of 726 participants at baseline to 329 [57%] of 574 participants in the intervention group; 331 [46%] of 725 participants to 369 [57%] of 650 participants in the control group); however, there was no significant difference between intervention and control groups in adherence at 12 weeks (odds ratio [OR] 1·13; 95% CI 0·84-1·52; p=0·42). Furthermore, the proportion of participants adhering to guidelines on physical activity (351 [61%] of 574 intervention group participants vs 407 [63%] of 650 control group participants; OR 1·03, 95% CI 0·73-1·45; p=0·88), smoking (434 [76%] participants vs 501 [77%] participants; 1·12, 0·67-1·87; p=0·66), alcohol consumption (518 [90%] participants vs 596 [92%] participants; 0·73, 0·37-1·44; p=0·36), and fruit and vegetable intake (194 [34%] participants vs 196 [30%] participants; 1·08, 0·79-1·49; p=0·64) did not differ between groups. We found no significant differences between the intervention and control groups in any secondary outcome. 147 (26%) intervention group participants engaged with the OL@-OR@ programme (ie, set at least one behaviour change goal online). INTERPRETATION: The OL@-OR@ mobile health programme did not improve adherence to health-related behaviour guidelines amongst Maori and Pasifika individuals. FUNDING: Healthier Lives He Oranga Hauora National Science Challenge.

Indigenous health worker support for patients with poorly controlled type 2 diabetes: study protocol for a cluster randomised controlled trial of the Mana Tu programme.

INTRODUCTION: Type 2 diabetes mellitus (T2DM) and its complications are more common among Maori and Pacific people compared with other ethnic groups in New Zealand. Comprehensive and sustained approaches that address social determinants of health are required to address this condition, including culturally specific interventions. Currently, New Zealand has no comprehensive T2DM management programme for Maori or Pacific people. METHODS AND ANALYSIS: The Mana Tu programme was developed by a Maori-led collaborative of primary healthcare workers and researchers, and codesigned with whanau (patients and their families) in order to address this gap. The programme is based in primary care and has three major components: a Network hub, Kai Manaaki (skilled case managers who work with whanau with poorly controlled diabetes) and a cross-sector network of services to whom whanau can be referred to address the wider determinants of health. The Network hub supports the delivery of the intervention through training of Kai Manaaki, referrals management, cross-sector network development and quality improvement of the programme. A two-arm cluster randomised controlled trial will be conducted to evaluate the effectiveness of the Mana Tu programme among Maori, Pacific people or those living in areas of high socioeconomic deprivation who also have poorly controlled diabetes (glycated haemoglobin, HbA1c, >65 mmol/mol (8%)), compared with being on a wait list for the programme. A total of 400 participants will be included from 10 general practices (5 practices per group, 40 participants per practice). The primary outcome is HbA1c at 12 months. Secondary outcomes include blood pressure, lipid levels, body mass index and smoking status at 12 months. This protocol outlines the proposed study design and analysis methods. ETHICS AND DISSEMINATION: Ethical approval for the trial has been obtained from the New Zealand Health and Disability Ethics Committee (17/NTB/249). Findings will be presented to practices and their patients at appropriate fora, and disseminated widely through peer-reviewed publications and conference presentations. TRIAL REGISTRATION NUMBER: ACTRN12617001276347; Pre-result.

Compared with Cow Milk, a Growing-Up Milk Increases Vitamin D and Iron Status in Healthy Children at 2 Years of Age: The Growing-Up Milk-Lite (GUMLi) Randomized Controlled Trial.

Background: Iron deficiency (ID) and vitamin D deficiency (VDD) are significant pediatric health issues in New Zealand and Australia and remain prevalent micronutrient deficiencies in young children globally. Objective: We aimed to investigate the effect of a micronutrient-fortified, reduced-energy growing-up milk (GUMLi) compared with cow milk (CM) consumed for 1 y on dietary iron and vitamin D intakes and the status of New Zealand and Australian children at 2 y of age. Methods: The GUMLi Trial was a multicenter, double-blind, randomized controlled trial in 160 healthy 1-y-old New Zealand and Australian children conducted in 2015-2017. Participants were randomly assigned 1:1 to receive GUMLi (1.7 mg Fe/100 mL; 1.3 µg cholecalciferol/100 mL) or CM (0.02 mg Fe/100 mL; 0.06 µg cholecalciferol/100 mL) for 12 mo. Secondary outcomes, reported here, included change in dietary iron and vitamin D intakes, iron status, and 25-hydroxyvitamin D [25(OH)D] concentrations from blood samples at age 2 y. All regression models were adjusted for baseline outcome and study center. Results: GUMLi was a large contributor to dietary intakes of iron and vitamin D after 12 mo when compared with intakes from food and CM. The adjusted mean difference between groups for serum ferritin concentrations was 17.8 µg/L (95% CI: 13.6, 22.0 µg/L; P < 0.0001), and for 25(OH)D it was 16.6 nmol/L (95% CI: 9.9, 23.3 nmol/L; P < 0.0001). After 12 mo, ID was present in 16 (24%) participants in the CM group and 5 (7%) participants in the GUMLi group (P = 0.009), and the prevalence of VDD in the CM group increased to 14% (n = 10) and decreased to 3% (n = 2) (P = 0.03) in the GUMLi group. Conclusion: In comparison with CM, GUMLi significantly improved dietary iron and vitamin D intakes and the iron and vitamin D status of healthy children at 2 y of age. This trial was registered with the Australian New Zealand Clinical Trials Registry (www.anzctr.org.au) as ACTRN12614000918628.