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Background: Gastric intestinal metaplasia (IM) is a precancerous stage spanning a morphological spectrum that is poorly represented by human cell line models., Objective: We aim to establish and characterise human IM cell models to better understand IM progression along the cancer spectrum., Design: A large human gastric IM organoid (IMO) cohort (n=28), their clonal derivatives and normal gastric organoids (n=42) for comparison were established. Comprehensive multi-omics profiling and functional characterisation were performed., Results: Single-cell transcriptomes revealed IMO cells spanning a spectrum from hybrid gastric/intestinal to advanced intestinal differentiation. Their lineage trajectories connected different cycling and quiescent stem and progenitors, highlighting differences in gastric to IM transition and the potential origin of IM from STMN1 cycling isthmus stem cells. Hybrid IMOs showed impaired differentiation potential, high lineage plasticity beyond gastric or intestinal fates and reactivation of a fetal gene programme.Cell populations in gastric IM and cancer tissues were highly similar to those derived from IMOs and exhibited a fetal signature. Genomically, IMOs showed elevated mutation burden, frequent chromosome 20 gain and epigenetic deregulation of many intestinal and gastric genes. Functionally, IMOs were FGF10 independent and showed downregulated FGFR2. Several IMOs exhibited a cell-matrix adhesion independent subpopulation that displayed chromosome 20 gain but lacked key cancer driver mutations, potentially representing the earliest neoplastic precursor of IM-induced gastric cancer., Conclusions: Overall, our IMO biobank captured the heterogeneous nature of IM, revealing mechanistic insights on IM pathogenesis and progression, offering an ideal platform for studying early gastric neoplastic transformation and chemoprevention., Competing Interests: Competing interests: SYL and STY have received research sponsorships from Pfizer, Merck, Servier. HC is an inventor on multiple patents related to organoid technology and one patent on a Matrigel replacement. He is also currently head of Roche’s R&D in Basel, as a member of the executive board. His full disclosures can be found on the following website: www.uu.nl/staff/JCClevers/Additional functions. The other authors declare no competing interests., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: Uterine leiomyosarcoma (LMS) is an aggressive sarcoma and a subset of which exhibits DNA repair defects. Polo-like kinase 4 (PLK4) precisely modulates mitosis, and its inhibition causes chromosome missegregation and increased DNA damage. We hypothesize that PLK4 inhibition is an effective LMS treatment., Experimental Design: Genomic profiling of clinical uterine LMS samples was performed, and homologous recombination (HR) deficiency scores were calculated. A PLK4 inhibitor (CFI-400945) with and without an ataxia telangiectasia mutated (ATM) inhibitor (AZD0156) was tested in vitro on gynecologic sarcoma cell lines SK-UT-1, SKN, and SK-LMS-1. Findings were validated in vivo using the SK-UT-1 xenograft model in the Balb/c nude mouse model. The effects of CFI-400945 were also evaluated in a BRCA2-knockout SK-UT-1 cell line. The mechanisms of DNA repair were analyzed using a DNA damage reporter assay., Results: Uterine LMS had a high HR deficiency score, overexpressed PLK4 mRNA, and displayed mutations in genes responsible for DNA repair. CFI-400945 demonstrated effective antitumor activity in vitro and in vivo. The addition of AZD0156 resulted in drug synergism, largely due to a preference for nonhomologous end-joining DNA repair. Compared with wild-type cells, BRCA2 knockouts were more sensitive to PLK4 inhibition when both HR and nonhomologous end-joining repairs were impaired., Conclusions: Uterine LMS with DNA repair defects is sensitive to PLK4 inhibition because of the effects of chromosome missegregation and increased DNA damage. Loss-of-function BRCA2 alterations or pharmacologic inhibition of ATM enhanced the efficacy of the PLK4 inhibitor. Genomic profiling of an advanced-stage or recurrent uterine LMS may guide therapy., (©2024 The Authors; Published by the American Association for Cancer Research.)

Somatic copy number alterations (CNAs) are major mutations that contribute to the development and progression of various cancers. Despite a few computational methods proposed to detect CNAs from single-cell transcriptomic data, the technical sparsity of such data makes it challenging to identify allele-specific CNAs, particularly in complex clonal structures. In this study, we present a statistical method, XClone, that strengthens the signals of read depth and allelic imbalance by effective smoothing on cell neighborhood and gene coordinate graphs to detect haplotype-aware CNAs from scRNA-seq data. By applying XClone to multiple datasets with challenging compositions, we demonstrated its ability to robustly detect different types of allele-specific CNAs and potentially indicate whole genome duplication, therefore enabling the discovery of corresponding subclones and the dissection of their phenotypic impacts., (© 2024. The Author(s).)

Compared with analyzing omics data from a single platform, an integrative analysis of multi-omics data provides a more comprehensive understanding of the regulatory relationships among biological features associated with complex diseases. However, most existing frameworks for integrative analysis overlook two crucial aspects of multi-omics data. Firstly, they neglect the known dependencies among biological features that exist in highly credible biological databases. Secondly, most existing integrative frameworks just simply remove the subjects without full omics data to handle block missingness, resulting in decreasing statistical power. To overcome these issues, we propose a network-based integrative Bayesian framework for biomarker selection and disease outcome prediction based on multi-omics data. Our framework utilizes Dirac spike-and-slab variable selection prior to identifying a small subset of biomarkers. The incorporation of gene pathway information improves the interpretability of feature selection. Furthermore, with the strategy in the FBM (stand for "full Bayesian model with missingness") model where missing omics data are augmented via a mechanistic model, our framework handles block missingness in multi-omics data via a data augmentation approach. The real application illustrates that our approach, which incorporates existing gene pathway information and includes subjects without DNA methylation data, results in more interpretable feature selection results and more accurate predictions., (© The Author(s) 2024. Published by Oxford University Press.)

Background: Many ethnic minorities in Hong Kong seek medical tourism after encountering inequalities in access to local healthcare because of language barriers and cultural-religious differences. The present study explored the ethnic minorities' lived experiences of medical tourism and issues arising from cross-border health-seeking relevant to this specific population., Methods: Qualitative in-depth interviews with 25 ethnic minority informants from five South Asian countries in 2019., Results: The 19 informants out of the 25 have sought assistance from their international networks for home remedies, medical advice and treatments of traditional/Western medicines, for they are more costly or unavailable in Hong Kong and for issues related to racial discrimination, language barriers, transnationalism engagement, cultural insensitivity, and dissatisfaction with healthcare services in Hong Kong., Discussion: Medical tourism can relieve the host country's caring responsibilities from healthcare services, so the government might no longer be hard-pressed to fix the failing healthcare system. Consequently, it could cause public health concerns, such as having patients bear the risks of exposure to new pathogens, the extra cost from postoperative complications, gaps in medical documentation and continuum of care, etc. It also triggers global inequities in health care, exacerbating unequal distribution of resources among the affordable and non-affordable groups., Conclusion: Ethnic minorities in Hong Kong sought cross-border healthcare because of structural and cultural-religious issues. The surge of medical tourism from rich and developed countries to poor and developing countries may infringe upon the rights of residents in destination countries. To mitigate such negative impacts, policymakers of host countries should improve hospital infrastructure, as well as train and recruit more culturally sensitive healthcare workers to promote universal health coverage. Healthcare professionals should also strive to enhance their cultural competence to foster effective intercultural communication for ethnic minority groups., (© 2024. The Author(s).)

Background: DEHP, a common plasticizer known for its hormone-disrupting properties, has been associated with asthma. However, a significant proportion of adult asthma cases are "non-atopic", lacking a clear etiology., Methods: In a case-control study conducted between 2011 and 2015, 365 individuals with current asthma and 235 healthy controls from Kaohsiung City were enrolled. The control group comprised individuals without asthma, Type 2 Diabetes Mellitus (T2DM), hypertension, or other respiratory/allergic conditions. The study leveraged asthma clusters (Clusters A to F) established in a prior investigation. Analysis involved the examination of urinary DEHP metabolites (MEHP and MEHHP), along with the assessment of oxidative stress, sphingolipid metabolites, and inflammatory biomarkers. Statistical analyses encompassed Spearman's rank correlation coefficients, multiple logistic regression, and multinomial logistic regression., Results: Asthma clusters (E, D, C, F, A) exhibited significantly higher ORs of MEHHP exposures compared to the control group. When considering asthma-related comorbidities (T2DM, hypertension, or both), patients without comorbidities demonstrated significantly higher ORs of the sum of primary and secondary metabolites (MEHP + MEHHP) and MEHHP compared to those with asthma comorbidities. A consistent positive correlation between urinary HEL and DEHP metabolites was observed, but a consistent negative correlation between DEHP metabolites and selected cytokines was identified., Conclusion: The current study reveals a heightened risk of MEHHP and MEHP + MEHHP exposure in specific asthma subgroups, emphasizing its complex relationship with asthma. The observed negative correlation with cytokines suggests a new avenue for research, warranting robust evidence from epidemiological and animal studies., (© 2024. The Author(s).)

Inflammatory bowel disease alters the gut microbiota, causes defects in mucosal barrier function, and leads to dysregulation of the immune response to microbial stimulation. This study investigated and compared the efficacy of a candidate probiotic strain, Bacillus coagulans BC198, and its heat-killed form in treating dextran sulfate sodium-induced colitis. Both live and heat-killed B. coagulans BC198 increased gut barrier-associated protein expression, reduced neutrophil and M1 macrophage infiltration of colon tissue, and corrected gut microbial dysbiosis induced by colitis. However, only live B. coagulans BC198 could alleviate the general symptoms of colitis, prevent colon shortening, and suppress inflammation and tissue damage. At the molecular level, live B. coagulans BC198 was able to inhibit Th17 cells while promoting Treg cells in mice with colitis, reduce pro-inflammatory MCP-1 production, and increase anti-inflammatory IL-10 expression in the colonic mucosa. The live form of B. coagulans BC198 functioned more effectively than the heat-killed form in ameliorating colitis by enhancing the anti-inflammatory response and promoting Treg cell accumulation in the colon., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

The three-dimensional (3D) tumor microenvironment (TME) comprises multiple interacting cell types that critically impact tumor pathology and therapeutic response. Efficient 3D imaging assays and analysis tools could facilitate profiling and quantifying distinctive cell-cell interaction dynamics in the TMEs of a wide spectrum of human cancers. Here, we developed a 3D live-cell imaging assay using confocal microscopy of patient-derived tumor organoids and a software tool, SiQ-3D (single-cell image quantifier for 3D), that optimizes deep learning (DL)-based 3D image segmentation, single-cell phenotype classification, and tracking to automatically acquire multidimensional dynamic data for different interacting cell types in the TME. An organoid model of tumor cells interacting with natural killer cells was used to demonstrate the effectiveness of the 3D imaging assay to reveal immuno-oncology dynamics as well as the accuracy and efficiency of SiQ-3D to extract quantitative data from large 3D image datasets. SiQ-3D is Python-based, publicly available, and customizable to analyze data from both in vitro and in vivo 3D imaging. The DL-based 3D imaging analysis pipeline can be employed to study not only tumor interaction dynamics with diverse cell types in the TME but also various cell-cell interactions involved in other tissue/organ physiology and pathology., Significance: A 3D single-cell imaging pipeline that quantifies cancer cell interaction dynamics with other TME cell types using primary patient-derived samples can elucidate how cell-cell interactions impact tumor behavior and treatment responses., (©2023 American Association for Cancer Research.)