Background & Aims Little is known about the mechanisms of gastric carcinogenesis, partly because it has been a challenge to identify characterize gastric stem cells. Runx genes regulate development ...and their products are transcription factors associated with cancer development. A Runx1 enhancer element, eR1, is a marker of hematopoietic stem cells. We studied expression from eR1 in the stomach and the roles of gastric stem cells in gastric carcinogenesis in transgenic mice. Methods We used in situ hybridization and immunofluorescence analyses to study expression of Runx1 in gastric tissues from C57BL/6 (control) mice. We then created mice that expressed enhanced green fluorescent protein (EGFP) or CreERT2 under the control of eR1 (eR1-CreERT2;Rosa-Lox-Stop-Lox LSL-tdTomato, eR1-CreERT2;Rosa-LSL-EYFP mice). Gastric tissues were collected and lineage-tracing experiments were performed. Gastric organoids were cultured from eR1-CreERT2(5-2);Rosa-LSL-tdTomato mice and immunofluorescence analyses were performed. We investigated the effects of expressing oncogenic mutations in stem cells under control of eR1 using eR1-CreERT2;LSL-KrasG12D/+ mice; gastric tissues were collected and analyzed by histology and immunofluorescence. Results Most proliferation occurred in the isthmus; 86% of proliferating cells were RUNX1-positive and 76% were MUC5AC-positive. In eR1-EGFP mice, EGFP signals were detected mainly in the upper part of the gastric unit, and 83% of EGFP-positive cells were located in the isthmus/pit region. We found that eR1 marked undifferentiated stem cells in the isthmus and a smaller number of terminally differentiated chief cells at the base. eR1 also marked cells in the pyloric gland in the antrum. Lineage-tracing experiments demonstrated that stem cells in the isthmus and antrum continuously gave rise to mature cells to maintain the gastric unit. eR1-positive cells in the isthmus and pyloric gland generated organoid cultures in vitro. In eR1-CreERT2;LSL-Kras G12D/+ mice, MUC5AC-positive cells rapidly differentiated from stem cells in the isthmus, resulting in distinct metaplastic lesions similar to that observed in human gastric atrophy. Conclusions Using lineage-tracing experiments in mice, we found that a Runx1 enhancer element, eR1, promotes its expression in the isthmus stem cells of stomach corpus as well as pyloric gland in the antrum. We were able to use eR1 to express oncogenic mutations in gastric stem cells, proving a new model for studies of gastric carcinogenesis.
Tissue stem cells are central regulators of organ homoeostasis. We looked for a protein that is exclusively expressed and functionally involved in stem cell activity in rapidly proliferating isthmus ...stem cells in the stomach corpus.
We uncovered the specific expression of Iqgap3 in proliferating isthmus stem cells through immunofluorescence and in situ hybridisation. We performed lineage tracing and transcriptomic analysis of Iqgap3 +isthmus stem cells with the
mouse model. Depletion of Iqgap3 revealed its functional importance in maintenance and proliferation of stem cells. We further studied Iqgap3 expression and the associated gene expression changes during tissue repair after tamoxifen-induced damage. Immunohistochemistry revealed elevated expression of Iqgap3 in proliferating regions of gastric tumours from patient samples.
Iqgap3 is a highly specific marker of proliferating isthmus stem cells during homoeostasis. Iqgap3+isthmus stem cells give rise to major cell types of the corpus unit. Iqgap3 expression is essential for the maintenance of stem potential. The Ras pathway is a critical partner of Iqgap3 in promoting strong proliferation in isthmus stem cells. The robust induction of Iqgap3 expression following tissue damage indicates an active role for Iqgap3 in tissue regeneration.
IQGAP3 is a major regulator of stomach epithelial tissue homoeostasis and repair. The upregulation of IQGAP3 in gastric cancer suggests that IQGAP3 plays an important role in cancer cell proliferation.
To evaluate cost-effectiveness of a novel screening strategy using a microRNA (miRNA) blood test as a screen, followed by endoscopy for diagnosis confirmation in a 3-yearly population screening ...program for gastric cancer.
A Markov cohort model has been developed in Microsoft Excel 2016 for the population identified to be at intermediate risk (Singaporean men, aged 50-75 years with Chinese ethnicity). The interventions compared were (1) initial screening using miRNA test followed by endoscopy for test-positive individuals and a 3-yearly follow-up screening for test-negative individuals (proposed strategy), and (2) no screening with gastric cancer being diagnosed clinically (current practice). The model was evaluated for 25 years with a healthcare perspective and accounted for test characteristics, compliance, disease progression, cancer recurrence, costs, utilities, and mortality. The outcomes measured included incremental cost-effectiveness ratios, cancer stage at diagnosis, and thresholds for significant variables.
The miRNA-based screening was found to be cost-effective with an incremental cost-effectiveness ratio of $40 971/quality-adjusted life-year. Key drivers included test costs, test accuracy, cancer incidence, and recurrence risk. Threshold analysis highlights the need for high accuracy of miRNA tests (threshold sensitivity: 68%; threshold specificity: 77%). A perfect compliance to screening would double the cancer diagnosis in early stages compared to the current practice. Probabilistic sensitivity analysis reported the miRNA-based screening to be cost-effective in >95% of iterations for a willingness to pay of $70 000/quality-adjusted life-year (approximately equivalent to 1 gross domestic product/capita)
The miRNA-based screening intervention was found to be cost-effective and is expected to contribute immensely in early diagnosis of cancer by improving screening compliance.
•Biomarker testing can offer effective cancer screening, enabling early diagnosis, but poses a risk of high testing costs and missed cases. Recently GastroClear, an in vitro test for gastric cancer–related microRNA, has been approved by the Singapore government. Nevertheless, there is a need to evaluate the cost-effectiveness of its implementation for population screening. This study addresses this evidence gap by:•Evaluating the cost-effectiveness of screening population every 3-years for the population at intermediate risk•Identifying the impact of screening on early diagnosis, significance of compliance, test accuracy, and testing costs•Studying outcomes to enable identification of the drivers/limitations that are crucial to achieve cost-effectiveness
In recent years, the tribology field has expanded with the advent of nanolubrication. Nanolubricants are the name given to the dispersion of nanoparticles in a base oil, and has attracted researchers ...due to its potential application. In addition to being used in the tribology field, nanoparticles are also used for medical, space, and composites purposes. The addition of nanoparticles in base oils is promising because it enhances specific tribological characteristics including wear-resistance and friction, and the most important reason is that the majority of them are environmentally friendly. This paper reviews the tribological effect of various nanoparticles as lubricant additives. Parameters of nanoparticles that affect tribological performance, the technique to enhance stability, and lubrication mechanism that is currently believed to function will be delineated in detail. Moreover, this review facilitates an understanding of the role of various nanoparticles, which helps in developing and designing suitable nanolubricants for various applications.
Genome rearrangements, a hallmark of cancer, can result in gene fusions with oncogenic properties. Using DNA paired-end-tag (DNA-PET) whole-genome sequencing, we analyzed 15 gastric cancers (GCs) ...from Southeast Asians. Rearrangements were enriched in open chromatin and shaped by chromatin structure. We identified seven rearrangement hot spots and 136 gene fusions. In three out of 100 GC cases, we found recurrent fusions between CLDN18, a tight junction gene, and ARHGAP26, a gene encoding a RHOA inhibitor. Epithelial cell lines expressing CLDN18-ARHGAP26 displayed a dramatic loss of epithelial phenotype and long protrusions indicative of epithelial-mesenchymal transition (EMT). Fusion-positive cell lines showed impaired barrier properties, reduced cell-cell and cell-extracellular matrix adhesion, retarded wound healing, and inhibition of RHOA. Gain of invasion was seen in cancer cell lines expressing the fusion. Thus, CLDN18-ARHGAP26 mediates epithelial disintegration, possibly leading to stomach H+ leakage, and the fusion might contribute to invasiveness once a cell is transformed.
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•Chromatin structure contributes to the shape of genome rearrangements in GC•CLDN18-ARHGAP26 is a recurrent fusion gene in 3% of Asian GCs•CLDN18-ARHGAP26 impairs epithelial barrier properties and wound healing•CLDN18-ARHGAP26 contributes to GC by loss of CLDN18 and gain of ARHGAP26 functions
Yao et al. identify somatic structural variations (SVs) in gastric cancer (GC) that create five recurrent fusion genes. Comparisons between chromatin interaction and SV data suggest chromatin structure contributes to the emergence of SVs. Comprehensive functional analyses reveal that CLDN18-ARHGAP26 impairs epithelial integrity and wound healing.
This study investigated the tribological behaviour of Pongamia oil (PO) and 15W–40 mineral engine oil (MO) with and without the addition of graphene nanoplatelets (GNPs). The friction and wear ...characteristics were evaluated in four-ball anti-wear tests according to the ASTM D4172 standard. The morphology of worn surfaces and the lubrication mechanism of GNPs were investigated via SEM and EDS. This study also focuses on the tribological effect of GNP concentration at various concentrations. The addition of 0.05 wt % GNPs in PO and MO exhibits the lowest friction and wear with 17.5% and 12.24% friction reduction, respectively, and 11.96% and 5.14% wear reduction, respectively. Through SEM and EDS surface analysis, the surface enhancement on the worn surface by the polishing effect of GNPs was confirmed. The deposition of GNPs on the friction surface and the formation of a protective film prevent the interacting surfaces from rubbing, resulting in friction and wear reduction.
Intestinal metaplasia (IM) is a pre-malignant condition of the gastric mucosa associated with increased gastric cancer (GC) risk. Analyzing 1,256 gastric samples (1,152 IMs) across 692 subjects from ...a prospective 10-year study, we identify 26 IM driver genes in diverse pathways including chromatin regulation (ARID1A) and intestinal homeostasis (SOX9). Single-cell and spatial profiles highlight changes in tissue ecology and IM lineage heterogeneity, including an intestinal stem-cell dominant cellular compartment linked to early malignancy. Expanded transcriptome profiling reveals expression-based molecular subtypes of IM associated with incomplete histology, antral/intestinal cell types, ARID1A mutations, inflammation, and microbial communities normally associated with the healthy oral tract. We demonstrate that combined clinical-genomic models outperform clinical-only models in predicting IMs likely to transform to GC. By highlighting strategies for accurately identifying IM patients at high GC risk and a role for microbial dysbiosis in IM progression, our results raise opportunities for GC precision prevention and interception.
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•Genomic profiling reveals 26 intestinal metaplasia (IM) driver genes including SOX9•IM lineage heterogeneity harbors a stem-cell subpopulation linked to malignancy•IM molecular subtypes are associated with inflammation and microbial communities•Genomic-clinical models improve identification of IMs at risk of GC progression
Intestinal metaplasia (IM) is a pre-malignant condition linked to gastric cancer (GC). Huang et al. analyze a large prospective IM cohort, identifying driver genes, stem cell populations linked to GC, and molecular subtypes associated with inflammation and oral microbes. These results facilitate the use of genomics in GC precision prevention.
Background & Aims Age, sex, smoking, and family history are risk factors for colorectal cancer in Asia. The Asia-Pacific Colorectal Screening (APCS) scoring system was developed to identify subjects ...with a high risk for advanced neoplasm (AN). We tested an algorithm that combined APCS scores with fecal immunochemical test (FIT) in colorectal cancer screening. Methods We performed a multicenter prospective study, enrolling asymptomatic individuals older than 40 years old in 12 Asia-Pacific regions from December 2011 to December 2013. APCS scores were calculated for each individual (0−1 = low risk LR, 2−3 = medium risk MR, and 4−7 = high risk HR for AN). LR and MR subjects were offered FIT and referred for early colonoscopies if FIT results were positive. HR subjects were offered colonoscopies. The proportions of subjects with ANs were determined for each group based on colonoscopy findings; odd ratios for LR and MR subjects were calculated compared to LR individuals. We calculated the sensitivity of the APCS-FIT algorithm in identifying subjects with AN. Results A total of 5657 subjects were recruited: 646 subjects (11.4%) were considered LR, 3243 subjects (57.3%) were considered MR, and 1768 subjects (31.3%) were considered HR for AN. The proportions of individuals with an AN in these groups were 1.5%, 5.1%, and 10.9%, respectively. Compared with LR group, MR and HR subjects had a 3.4-fold increase and a 7.8-fold increase in risk for AN, respectively. A total of 70.6% subjects with AN (95% confidence interval: 65.6%−75.1%) and 95.1% subjects with invasive cancers (95% confidence interval: 82.2%−99.2%) were correctly instructed to undergo early colonoscopy examination. Conclusions The APCS scoring system, which is based on age, sex, family history, and smoking, is a useful tool for determining risk for colorectal cancer and advanced adenoma in asymptomatic subjects. Use of the APCS score-based algorithm in triaging subjects for FIT or colonoscopy can substantially reduce colonoscopy workload.
Patients found to be at high risk of advanced proximal neoplasia (APN) after flexible sigmoidoscopy screening should be considered for colonoscopy examination. We developed and validated a scoring ...system to identify persons at risk for APN.
We collected data from 7954 asymptomatic subjects (age, 50-75 y) who received screening colonoscopy examinations at 14 sites in Asia. We randomly assigned 5303 subjects to the derivation cohort and the remaining 2651 to the validation cohort. We collected data from the derivation cohort on age, sex, family history of colorectal cancer, smoking, drinking, body mass index, medical conditions, and use of nonsteroidal anti-inflammatory drugs or aspirin. Associations between the colonoscopic findings of APN and each risk factor were examined using the Pearson χ
test, and we assigned each participant a risk score (0-15), with scores of 0 to 3 as average risk and scores of 4 or higher as high risk. The scoring system was tested in the validation cohort. We used the Cochran-Armitage test of trend to compare the prevalence of APN among subjects in each group.
In the validation cohort, 79.5% of patients were classified as average risk and 20.5% were classified as high risk. The prevalence of APN in the average-risk group was 1.9% and in the high-risk group was 9.4% (adjusted relative risk, 5.08; 95% CI, 3.38-7.62; P < .001). The score included age (61-70 y, 3; ≥70 y, 4), smoking habits (current/past, 2), family history of colorectal cancer (present in a first-degree relative, 2), and the presence of neoplasia in the distal colorectum (nonadvanced adenoma 5-9 mm, 2; advanced neoplasia, 7). The c-statistic of the score was 0.74 (95% CI, 0.68-0.79), and for distal findings alone was 0.67 (95% CI, 0.60-0.74). The Hosmer-Lemeshow goodness-of-fit test statistic was greater than 0.05, indicating the reliability of the validation set. The number needed to refer was 11 (95% CI, 10-13), and the number needed to screen was 15 (95% CI, 12-17).
We developed and validated a scoring system to identify persons at risk for APN. Screening participants who undergo flexible sigmoidoscopy screening with a score of 4 points or higher should undergo colonoscopy evaluation.
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