Immune landscape of advanced gastric cancer tumor microenvironment identifies immunotherapeutic relevant gene signature

Background Advanced gastric cancer (AGC) is a disease with poor prognosis due to the current lack of effective therapeutic strategies. Immune checkpoint blockade treatments have shown effective responses in patient subgroups but biomarkers remain challenging. Traditional classification of gastric cancer (GC) is based on genomic profiling and molecular features. Therefore, it is critical to identify the immune-related subtypes and predictive markers by immuno-genomic profiling. Methods Single-sample gene-set enrichment analysis (ssGSEA) and ESTIMATE algorithm were used to identify the immue-related subtypes of AGC in two independent GEO datasets. Weighted gene co-expression network analysis (WGCNA) and Molecular Complex Detection (MCODE) algorithm were applied to identify hub-network of immune-related subtypes. Hub genes were confirmed by prognostic data of KMplotter and GEO datasets. The value of hub-gene in predicting immunotherapeutic response was analyzed by IMvigor210 datasets. MTT assay, Transwell migration assay and Western blotting were performed to confirm the cellular function of hub gene in vitro. Results Three immune-related subtypes (Immunity_H, Immunity_M and Immunity_L) of AGC were identified in two independent GEO datasets. Compared to Immunity_L, the Immuntiy_H subtype showed higher immune cell infiltration and immune activities with favorable prognosis. A weighted gene co-expression network was constructed based on GSE62254 dataset and identified one gene module which was significantly correlated with the Immunity_H subtype. A Hub-network which represented high immune activities was extracted based on topological features and Molecular Complex Detection (MCODE) algorithm. Furthermore, ADAM like decysin 1 (ADAMDEC1) was identified as a seed gene among hub-network genes which is highly associated with favorable prognosis in both GSE62254 and external validation datasets. In addition, high expression of ADAMDEC1 correlated with immunotherapeutic response in IMvigor210 datasets. In vitro, ADAMDEC1 was confirmed as a potential protein in regulating proliferation and migration of gastric cancer cell. Deficiency of ADAMDEC1 of gastric cancer cell also associated with high expression of PD-L1 and Jurkat T cell apoptosis. Conclusions We identified immune-related subtypes and key tumor microenvironment marker in AGC which might facilitate the development of novel immune therapeutic targets.

Strategies to Assure Optimal Trade-Offs Among Competing Objectives for the Genetic Improvement of Soybean

Plant breeding is a decision-making discipline based on understanding project objectives. Genetic improvement projects can have two competing objectives: maximize the rate of genetic improvement and minimize the loss of useful genetic variance. For commercial plant breeders, competition in the marketplace forces greater emphasis on maximizing immediate genetic improvements. In contrast, public plant breeders have an opportunity, perhaps an obligation, to place greater emphasis on minimizing the loss of useful genetic variance while realizing genetic improvements. Considerable research indicates that short-term genetic gains from genomic selection are much greater than phenotypic selection, while phenotypic selection provides better long-term genetic gains because it retains useful genetic diversity during the early cycles of selection. With limited resources, must a soybean breeder choose between the two extreme responses provided by genomic selection or phenotypic selection? Or is it possible to develop novel breeding strategies that will provide a desirable compromise between the competing objectives? To address these questions, we decomposed breeding strategies into decisions about selection methods, mating designs, and whether the breeding population should be organized as family islands. For breeding populations organized into islands, decisions about possible migration rules among family islands were included. From among 60 possible strategies, genetic improvement is maximized for the first five to 10 cycles using genomic selection and a hub network mating design, where the hub parents with the largest selection metric make large parental contributions. It also requires that the breeding populations be organized as fully connected family islands, where every island is connected to every other island, and migration rules allow the exchange of two lines among islands every other cycle of selection. If the objectives are to maximize both short-term and long-term gains, then the best compromise strategy is similar except that the mating design could be hub network, chain rule, or a multi-objective optimization method-based mating design. Weighted genomic selection applied to centralized populations also resulted in the realization of the greatest proportion of the genetic potential of the founders but required more cycles than the best compromise strategy.

Immune Landscape of Advanced Gastric Cancer Tumor Microenvironment Identifies Immunotherapeutic Relevant Gene Signature

Background: Advanced gastric cancer (AGC) is a disease with poor prognosis due to the current lack of effective therapeutic strategies. Immune checkpoint blockade treatments have shown effective responses in patient subgroups but biomarkers remain challenging. Traditional classification of gastric cancer (GC) is based on genomic profiling and molecular features. Therefore, it is critical to identify the immune-related subtypes and predictive markers by immuno-genomic profiling. Methods: Single-sample gene-set enrichment analysis (ssGSEA) and ESTIMATE algorithm were used to identify the immue-related subtypes of AGC in two independent GEO datasets. Weighted gene co-expression network analysis (WGCNA) and Molecular Complex Detection (MCODE) algorithm were applied to identify hub-network of immune-related subtypes. Hub genes were confirmed by prognostic data of KMplotter and GEO datasets. MTT assay, Transwell migration assay and Western blotting were performed to confirm the cellular function of hub gene in vitro. Results: Three immune-related subtypes (Immunity_H, Immunity_M and Immunity_L) of AGC were identified in two independent GEO datasets. Compared to Immunity_L, the Immuntiy_H subtype showed higher immune cell infiltration and immune activities with favorable prognosis. A weighted gene co-expression network was constructed based on GSE62254 dataset and identified one gene module which was significantly correlated with the Immunity_H subtype. A Hub-network which represented high immune activities was extracted based on topological features and Molecular Complex Detection (MCODE) algorithm. Furthermore, ADAM like decysin 1 (ADAMDEC1) was identified as a seed gene among hub-network genes which is highly associated with favorable prognosis in both GSE62254 and external validation datasets. In vitro, ADAMDEC1 was confirmed as a potential protein in regulating proliferation and migration of gastric cancer cell. Deficiency of ADAMDEC1 of gastric cancer cell also associated with high expression of PD-L1 and Jurkat T cell apoptosis. Conclusions: We identified immune-related subtypes and key tumor microenvironment marker in AGC which might facilitate the development of novel immune therapeutic targets.

Two-Stage Distributionally Robust Optimization for a Two-Allocation p-Hub Median Problem

This paper presents a novel two-stage distributionally robust optimization model of the two-allocation p-hub median problem with different hub link scales. With the objective of minimizing overall costs of building and operating the hub network, the choices of hub locations and hub link scales are decided in the first stage, while the optimal flows are determined in the second stage once the uncertain demands have been realized. Before establishing the hub network, we just have partial distribution information about the uncertain flow demands, which can be described by a given perturbation set based on the historical information. Due to the ambiguous distributions leading to a computationally intractable model, we reformulate the proposed model into the tractable robust counterpart forms under two types of uncertainty sets (Box[Formula: see text]ellipsoidal perturbation set and Generalized ellipsoidal perturbation set). Finally, to demonstrate the effectiveness and applicability for our model, we conduct a case study for the express network system in the Beijing–Tianjin–Hebei region.