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Gene-environment and nutrition-environment studies often involve testing of high-dimensional interactions between two sets of variables, each having potentially complex nonlinear main effects on an outcome. Construction of a valid and powerful hypothesis test for such an interaction is challenging, due to the difficulty in constructing an efficient and unbiased estimator for the complex, nonlinear main effects. In this work, we address this problem by proposing a cross-validated ensemble of kernels (CVEK) that learns the space of appropriate functions for the main effects using a cross-validated ensemble approach. With a carefully chosen library of base kernels, CVEK flexibly estimates the form of the main-effect functions from the data, and encourages test power by guarding against over-fitting under the alternative. The method is motivated by a study on the interaction between metal exposures in utero and maternal nutrition on children's neurodevelopment in rural Bangladesh. The proposed tests identified evidence of an interaction between minerals and vitamins intake and arsenic and manganese exposures. Results suggest that the detrimental effects of these metals are most pronounced at low intake levels of the nutrients, suggesting nutritional interventions in pregnant women could mitigate the adverse impacts of in utero metal exposures on the children's neurodevelopment. for this article, including a standardized description of the materials available for reproducing the work, are available as an online supplement. [ABSTRACT FROM AUTHOR]

Cancer stem cells (CSCs) actively reprogram their tumor microenvironment (TME) to sustain a supportive niche, which may have a dramatic impact on prognosis and immunotherapy. However, our knowledge of the landscape of the gastric cancer stem-like cell (GCSC) microenvironment needs to be further improved. A multi-step process of machine learning approaches was performed to develop and validate the prognostic and predictive potential of the GCSC-related score (GCScore). The high GCScore subgroup was not only associated with stem cell characteristics, but also with a potential immune escape mechanism. Furthermore, we experimentally demonstrated the upregulated infiltration of CD206+ tumor-associated macrophages (TAMs) in the invasive margin region, which in turn maintained the stem cell properties of tumor cells. Finally, we proposed that the GCScore showed a robust capacity for prediction for immunotherapy, and investigated potential therapeutic targets and compounds for patients with a high GCScore. The results indicate that the proposed GCScore can be a promising predictor of prognosis and responses to immunotherapy, which provides new strategies for the precision treatment of GCSCs. [ABSTRACT FROM AUTHOR]

Gastric cancer (GC) is one of the most malignant tumors in the world. Growing evidence has highlighted the crucial role of long noncoding RNAs (lncRNAs) in the tumorigenesis of GC. The aim of the research was to elucidate the effects of lncRNA Fer-1-like family member 4 (FER1L4) in GC and identify the potential mechanisms. The present study investigated FER1L4 controlling cell survival and migration of SGC-7901 cells. Results indicated that the expression level of FER1L4 was distinctly decreased in GC cells, as evidenced by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) analysis. By using cell proliferation assay, Transwell assay, wound healing assay and western blotting, we found out that overexpression of FER1L4 in SGC-7901 cells hindered the capacities of cell proliferation, invasion, migration and lymphatic metastasis. Furthermore, results of the western blotting and immunofluorescence assay unveiled that overexpression of FER1L4 led to a notable reduction in the expression of C-X-C chemokine receptor type 4 (CXCR4) and C-X-C motif chemokine 12 (CXCL12) in SGC-7901 cells. Besides, activation of Hippo pathway by upregulating Yes-associated protein (YAP) expression or treatment of CXCR4 inhibitor WZ811 reversed the inhibitory effects of FER1L4 on proliferation and metastasis of SGC-7901 cells. Moreover, co-transfection with YAP and FER1L4 overexpression plasmids abrogated the repressive effects of FER1L4 overexpression on proliferation and metastasis. Taken together, these results demonstrated that lncRNA FER1L4 suppressed cell proliferation, invasion, migration and lymphatic metastasis of GC cells by inactivation of the Hippo-YAP pathway, providing novel insights into regulatory mechanism under GC and new strategies for clinical practice., Competing Interests: None., (AJTR Copyright © 2020.)