Assessment of Multidimensional Health Care Parameters Among Adults in Japan for Developing a Virtual Human Generative Model: Protocol for a Cross-sectional Study.

BACKGROUND: Human health status can be measured on the basis of many different parameters. Statistical relationships among these different health parameters will enable several possible health care applications and an approximation of the current health status of individuals, which will allow for more personalized and preventive health care by informing the potential risks and developing personalized interventions. Furthermore, a better understanding of the modifiable risk factors related to lifestyle, diet, and physical activity will facilitate the design of optimal treatment approaches for individuals. OBJECTIVE: This study aims to provide a high-dimensional, cross-sectional data set of comprehensive health care information to construct a combined statistical model as a single joint probability distribution and enable further studies on individual relationships among the multidimensional data obtained. METHODS: In this cross-sectional observational study, data were collected from a population of 1000 adult men and women (aged ≥20 years) matching the age ratio of the typical adult Japanese population. Data include biochemical and metabolic profiles from blood, urine, saliva, and oral glucose tolerance tests; bacterial profiles from feces, facial skin, scalp skin, and saliva; messenger RNA, proteome, and metabolite analyses of facial and scalp skin surface lipids; lifestyle surveys and questionnaires; physical, motor, cognitive, and vascular function analyses; alopecia analysis; and comprehensive analyses of body odor components. Statistical analyses will be performed in 2 modes: one to train a joint probability distribution by combining a commercially available health care data set containing large amounts of relatively low-dimensional data with the cross-sectional data set described in this paper and another to individually investigate the relationships among the variables obtained in this study. RESULTS: Recruitment for this study started in October 2021 and ended in February 2022, with a total of 997 participants enrolled. The collected data will be used to build a joint probability distribution called a Virtual Human Generative Model. Both the model and the collected data are expected to provide information on the relationships between various health statuses. CONCLUSIONS: As different degrees of health status correlations are expected to differentially affect individual health status, this study will contribute to the development of empirically justified interventions based on the population. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/47024.

Phospholipase Cδ1 induces E-cadherin expression and suppresses malignancy in colorectal cancer cells.

Colorectal cancer (CRC) is one of the most common causes of cancer-related deaths worldwide, and Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations in CRC predict the ineffectiveness of EGF receptor-targeted therapy. Previous transcriptional microarray analysis suggests the association between phospholipase Cδ1 (PLCδ1) expression and KRAS mutation status in CRC. However, both the roles and the regulatory mechanisms of PLCδ1 in CRC are not known. Here, we found that the expression of PLCδ1, one of the most basal PLCs, is down-regulated in CRC specimens compared with normal colon epithelium by immunohistochemistry. Furthermore, we examined the roles of PLCδ1 in CRC cell lines that harbor an activating KRAS mutation. Ectopic expression of PLCδ1 in CRC cells induced the expression of E-cadherin, whereas knockdown of PLCδ1 repressed the expression of E-cadherin. Moreover, the overexpression of PLCδ1 suppressed the expression of several mesenchymal genes and reduced cell motility, invasiveness, and in vivo tumorigenicity of SW620 CRC cells. We also showed that PLCδ1 expression is repressed by the KRAS/mitogen-activated protein kinase kinase (MEK) pathway. Furthermore, PLCδ1 suppressed the phosphorylation of extracellular signal-regulated kinase (ERK)1/2 through E-cadherin induction in CRC cells, suggesting the presence of a negative regulatory loop between KRAS/MEK/ERK signaling and PLCδ1. These data indicate that PLCδ1 has tumor-suppressive functions in CRC through E-cadherin induction and KRAS/MEK/ERK signal attenuation.

Identification of novel small compounds that restore E-cadherin expression and inhibit tumor cell motility and invasiveness.

Tumor dissemination and invasive behavior are associated with a majority of cancer-related mortality cases. Loss of E-cadherin, which is caused by several tumor-promoting factors, is associated with metastasis and poor prognosis in many neoplasms. In this study, we aimed to identify small molecule compounds that restore the expression of E-cadherin, because these molecules are most likely to suppress tumor malignancy by restoring E-cadherin function and/or by inhibiting signals that suppress E-cadherin expression. Here, we developed a fluorescence screen system based on E-cadherin expression. A pilot drug library screen revealed that methotrexate (MTX) strongly induces E-cadherin expression in a colorectal cancer cell line, SW620. From the screen for 9600 compounds, we identified 9 hit compounds, which restored the expression of E-cadherin in SW620 and/or a melanoma cell line, SK-MEL-28. We confirmed that MTX and the other identified compounds transcriptionally promote E-cadherin expression. Among these, 2 compounds suppressed migration/invasion capacity in colorectal cancer cells and 3 in melanoma cells. A compound reduced SW620 migration and invasion with subtle effects on cell viability in SW620, SK-MEL-28, and a non-tumor cell line, HaCaT, with decrease in AKT and ERK1/2 protein levels. One of the other compounds reduced SK-MEL-28 cell migration and invasion and affected the viability only of SW620 and SK-MEL-28 cells but not HaCaT cells. These results suggest that these compounds would be attractive lead molecules as anti-metastasis agents.