Polymorphism rs2327430 in TCF21 predicts the risk and prognosis of gastric cancer by affecting the binding between TFAP2A and TCF21.

BACKGROUND: Single nuclear polymorphisms (SNPs) have been published to be correlated with multiple diseases. Transcription Factor 21 (TCF21) is a critical transcription factor involved in various types of cancers. However, the association of TCF21 genetic polymorphisms with gastric cancer (GC) susceptibility and prognosis remains unclear. METHODS: A case-control study comprising 890 patients diagnosed with GC and an equal number of cancer-free controls was conducted. After rigorous statistical analysis, molecular experiments were carried out to elucidate the functional significance of the SNPs in the context of GC. RESULTS: TCF21 rs2327430 (OR = 0.78, P = 0.026) provides protection against GC, while rs4896011 (OR = 1.39, P = 0.005) exhibit significant associations with GC risk. Furthermore, patients with the (TC + CC) genotype of rs2327430 demonstrate a relatively favorable prognosis (OR = 0.47, P = 0.012). Mechanistically, chromatin immunoprecipitation assay and luciferase reporter assay revealed that the C allele of rs2327430 disrupts the binding of Transcription Factor AP-2 Alpha (TFAP2A) to the promoter region of TCF21, resulting in increased expression of TCF21 and inhibition of malignant behaviors in GC cells. CONCLUSION: Our findings highlight the significant role of TCF21 SNPs in both the risk and prognosis of GC and provide valuable insights into the underlying molecular mechanisms. Specifically, the disruptive effect of rs2327430 on TCF21 expression and its ability to modulate malignant cell behaviors suggest that rs2327430 may serve as a potential predictive marker for GC risk and prognosis.

Long non-coding RNA LGALS8-AS1 facilitates PLAGL2-mediated malignant phenotypes in gastric cancer.

BACKGROUND: Great progress has been made in studying the function of long non-coding RNA (lncRNA) in various tumors, including gastric cancer (GC). However, there are still numerous lncRNAs that have not yet been studied and explored for their roles in GC, and their important functions need to be further revealed. METHODS: Through analyzing The Cancer Genome Atlas (TCGA) database combined with bioinformatics survival tools, a novel GC-related lncRNA LGALS8-AS1 was identified. A quantitative real-time polymerase chain reaction and a series of in vitro or in vivo cell functional experiments were performed to determine the expression and the role of LGALS8-AS1/miR-138-5p/PLAGL2 in GC. RESULTS: LGALS8-AS1 was remarkably upregulated and correlated with the unfavorable prognosis in GC. Higher expression of LGALS8-AS1 was positively associated with higher lymph node metastasis rate, as well as larger tumor size. In addition, a series of cell functional experiments revealed that LGALS8-AS1 could facilitate GC cell proliferation, migration and metastasis in vitro or in vivo. A deeper mechanism exploration revealed that LGALS8-AS1 could function as the miR-138-5p molecular sponge and upregulate the PLAGL2 expression, thereby promoting the cell proliferation, migration and metastasis in GC. CONCLUSIONS: In brief, we revealed the tumor promoting role of the LGALS8-AS1/miR-138-5p/PLAGL2 molecular signaling axis in GC, and our findings provide enlightenment for further understanding of the mechanism of tumorigenesis and development of GC, making LGALS8-AS1 a possible new diagnostic or therapeutic target for GC.

Omicron-specific mRNA vaccine induced cross-protective immunity against ancestral SARS-CoV-2 infection with low neutralizing antibodies.

The major challenge in COVID-19 vaccine effectiveness is immune escape by SARS-CoV-2 variants. To overcome this, an Omicron-specific messenger RNA (mRNA) vaccine was designed. The extracellular domain of the spike of the Omicron variant was fused with a modified GCN4 trimerization domain with low immunogenicity (TSomi). After immunization with TSomi mRNA in hamsters, animals were challenged with SARS-CoV-2 virus. The raised nonneutralizing antibodies or cytokine secretion responses can recognize both Wuhan S and Omicron S. However, the raised antibodies neutralized SARS-CoV-2 Omicron virus infection but failed to generate Wuhan virus neutralizing antibodies. Surprisingly, TSomi mRNA immunization protected animals from Wuhan virus challenge. These data indicated that non-neutralizing antibodies or cellular immunity may play a more important role in vaccine-induced protection than previously believed. Next-generation COVID-19 vaccines using the Omicron S antigen may provide sufficient protection against ancestral or current SARS-CoV-2 variants.

Rs15285, a functional polymorphism located in lipoprotein lipase, predicts the risk and prognosis of gastric cancer.

Lipoprotein lipase (LPL), a crucial gene in lipid metabolism, has a significant role in the progression of malignant tumors. The purpose of this research was to investigate the impact of rs15285 found in the LPL gene's 3'UTR region on the risk, biological behavior, and gastric cancer (GC) prognosis as well as to examine its potential function. Genotyping of rs15285 in 888 GC cases and 874 controls was conducted by SNaPshot technology. We used bioinformatics analysis and in vitro experiments to study the role of rs15285. First, this study revealed for the first time that polymorphism rs15285 increases the risk of GC (OR = 1.48, 95%CI = 1.16-1.89, P = 0.002). Although no relationship was found between rs12585 and the pathological features of GC, the prognosis of individuals with the rs12585 TT genotype was poorer than that of patients with the CC or CC+CT genotype (HR = 2.39 for TT vs. CC, P = 0.025; HR = 2.38 for TT vs. CC+CT, P = 0.025). In addition, bioinformatics analysis showed rs12585 may affect the binding of miRNAs to LPL, resulting in an increase of LPL expression to promote cancer progression. Ultimately, in vitro tests revealed that the rs15285 T allele increased LPL expression on the mRNA as well as the protein levels, promoting GC cell proliferation, invasion, and metastasis. The LPL rs12528 TT genotype increased the risk of GC and predicted a poor prognosis. Mechanistically, the rs15285 T allele could improve the expression of LPL, and thus promotes the malignant phenotype of GC. Therefore, our study may provide new biological predictors and a theoretical basis for the prognosis and customized therapy of stomach cancer patients. KEY POINTS: • Rs15285 polymorphism is a risk factor for GC. • Rs12585 TT genotype predicts a bad outcome in GC individuals. • Rs15285 T allele enhances GC cells malignant biological behavior.

Polymorphism rs1057147 located in mesothelin gene predicts lymph node metastasis in patients with gastric cancer.

Lymph node metastasis, a crucial factor in the spread of gastric cancer (GC), is strongly associated with a negative prognosis for patients. This study aimed to investigate the association of the mesothelin (MSLN) gene polymorphisms (rs3764247, rs3764246, rs12597489, rs1057147, and rs3765319) with the risk of lymph node metastasis of GC patients in a Chinese Han population. The PCR-LDR genotyping was used to detect the genotypes of MSLN polymorphisms in GC patients with lymph node metastasis (n = 610) or without (n = 356). Our research indicates that certain genetic markers, specifically rs3764247, rs3764246, rs12597489, and rs3765319, do not appear to be linked with an increased risk of lymph node metastasis in GC. However, we did observe that patients with the rs1057147 GA genotype exhibited a higher likelihood of lymph node metastasis in GC when compared to those with the GG genotype (OR = 1.33, 95% CI = 1.01 - 1.76, P = 0.045). Patients with rs1057147 GA + AA genotype were found to have a higher likelihood of lymph node involvement (OR = 1.35, 95% CI = 1.03 - 1.77, P = 0.029) when compared to those with GG genotype in the dominant model. The allelic model revealed that the A allele of rs1057147 exhibited a stronger correlation with lymph node metastasis compared to the G allele (OR = 1.28, 95% CI = 1.02 - 1.60, P = 0.031). In addition, we found that rs1057147 polymorphism revealed a poor prognosis for GC patients with lymph node metastasis. Further stratified analysis revealed that the prognostic effect of rs1057147 was more pronounced in patients with GC who had lymph node metastasis and had a tumor size of 4 cm or greater, as well as more than 2 lymph node metastases. Bioinformatics studies showed that the binding mode of miR-3144-5p or miR-3619-3p to MSLN was altered by the mutation of rs1057147. Our study confirmed the important role of MSLN rs1057147 polymorphism locus in GC lymph node metastases and suggested a potential prognostic factor during GC progression. KEY POINTS: • Rs1057147 GA genotype had an increased risk of lymph node metastasis in gastric cancer. • The A allele of rs1057147 had a stronger association with lymph node metastasis than the G allele. • The binding mode of miR-3144-5p or miR-3619-3p to MSLN was altered by the mutation of rs1057147.

Polymorphisms of an oncogenic gene, mesothelin, predict the risk and prognosis of gastric cancer in a Chinese Han population.

Mesothelin (MSLN) is a cell surface protein associated with tumor invasion and metastasis. This study aims to explore the biological function of MSLN in gastric cancer and to evaluate the association of MSLN polymorphism (rs3764247, rs3764246, rs12597489, rs1057147, rs3765319) with the risk and prognosis of gastric cancer. Small interfering RNA (siRNA) transfection and MSLN overexpression were performed in human gastric cancer cell lines, respectively. The proliferation of tumor cells was evaluated by Cell counting kit 8(CCK-8) and colony formation assay. Wound healing assay and transwell assay were used to elucidate gastric cancer cell migration and invasion rates. We conducted a case-control study involving 860 patients with gastric cancer and 870 controls. All mutation sites were genotyped by PCR-LDR sequencing. First, our study revealed the cancer-promoting role of MSLN in gastric cancer. Second, we also demonstrated that rs3764247 and rs3764246 were associated with a reduced risk of gastric cancer (OR = 0.83, p = 0.010; OR = 0.84, p = 0.011; respectively). The clinicopathological analysis further showed that rs3764247 was closely related to T stage, vascular infiltration, and HER2 expression. In addition, in the survival analysis of 392 patients with gastric cancer, patients with rs3764247 CC genotype had poorer survival than patients with AA + AC genotype after adjusting for age, sex, TNM stage, and Lauren classification (HR = 2.07, p = 0.029). Our findings indicated that MSLN could be an oncogene whose polymorphisms were closely related to the risk and prognosis of gastric cancer.

Obesity promotes lipid accumulation in lymph node metastasis of gastric cancer: a retrospective case‒control study.

BACKGROUND: The connection between obesity, lipid accumulation, and lymph node metastasis (LNM) in gastric cancer (GC) is unclear. METHODS: The association of body mass index (BMI) and serum lipid levels with LNM was measured by calculating the odds ratio (OR) and 95% confidence interval (CI) in 1,058 eligible GC patients with a mean age of 61.4 years. Meanwhile, differentially expressed genes (DEGs) were identified between lymph node metastasis-positive (N +) and -negative (N0) groups using public RNA-seq data. Neutral lipids in human GC samples were detected by Oil red O staining. The expression of cluster of differentiation 36 (CD36), fatty acid synthase (FASN), and lipoprotein lipase (LPL) was detected by immunohistochemistry (IHC) and quantitative real-time PCR. RESULTS: Compared with normal-weight patients, overweight (OR = 2.02, 95% CI = 1.26-3.23) and obese (OR = 1.83, 95% CI = 1.15-2.91) patients showed increased ORs for LNM. However, no significant results were obtained for serum lipids in the multivariable-adjusted model (P > 0.05). Subgroup analysis suggested that increased low-density lipoprotein cholesterol was a risk factor in females (OR = 1.27, 95% CI = 1.02-1.59). Functional enrichment analysis of DEGs revealed a connection between lipid metabolism and LNM. Meanwhile, lipid staining showed a mass of lipids in obese N + tumor samples, and IHC analysis indicated an increase in LPL and CD36 expression in N + cases, implying a crucial role for exogenous lipid supply in LNM. CONCLUSIONS: High BMI significantly increases the risk of LNM in GC and promotes lipid accumulation in GC cells in LNM.

Low-Dose SARS-CoV-2 S-Trimer with an Emulsion Adjuvant Induced Th1-Biased Protective Immunity.

During the sustained COVID-19 pandemic, global mass vaccination to achieve herd immunity can prevent further viral spread and mutation. A protein subunit vaccine that is safe, effective, stable, has few storage restrictions, and involves a liable manufacturing process would be advantageous to distribute around the world. Here, we designed and produced a recombinant spike (S)-Trimer that is maintained in a prefusion state and exhibits a high ACE2 binding affinity. Rodents received different doses of S-Trimer (0.5, 5, or 20 µg) antigen formulated with aluminum hydroxide (Alum) or an emulsion-type adjuvant (SWE), or no adjuvant. After two vaccinations, the antibody response, T-cell responses, and number of follicular helper T-cells (Tfh) or germinal center (GC) B cells were assessed in mice; the protective efficacy was evaluated on a Syrian hamster infection model. The mouse studies demonstrated that adjuvating the S-Trimer with SWE induced a potent humoral immune response and Th1-biased cellular immune responses (in low dose) that were superior to those induced by Alum. In the Syrian hamster studies, when S-Trimer was adjuvanted with SWE, higher levels of neutralizing antibodies were induced against live SARS-CoV-2 from the original lineage and against the emergence of variants (Beta or Delta) with a slightly decreased potency. In addition, the SWE adjuvant demonstrated a dose-sparing effect; thus, a lower dose of S-Trimer as an antigen (0.5 µg) can induce comparable antisera and provide complete protection from viral infection. These data support the utility of SWE as an adjuvant to enhance the immunogenicity of the S-Trimer vaccine, which is feasible for further clinical testing.

Role of Solvation on Diffusion of Ions in Diblock Copolymers: Understanding the Molecular Weight Effect through Modeling.

Salt-doped diblock copolymers with microphase-separated domains of both an ion conductive and a mechanically strong polymer have been extensively studied due to their potential in transport applications. Several unusual or counterintuitive trends regarding their transport properties have been observed experimentally, such as increasing ion conduction as a function of molecular weight. A crucial feature of these systems is the strong solvation of ions in the conducting microphase due to its higher dielectric constant. Here, we perform molecular dynamics simulations using a coarse-grained model that includes a 1/r4 potential form to generically represent ion solvation, allowing us to reproduce experimentally observed trends and explore their molecular underpinnings. We find that increasing ion concentration can increase or decrease ion diffusion, depending on solvation strength. We also show that the trend of increasing diffusion with molecular weight becomes more dramatic as ions are solvated in one polymer block more strongly or as the ion-ion interactions get stronger. In contrast to expectations, the interfacial width or the overlap of ions with the nonconductive polymer block does not adequately explain this phenomenon; instead, local ion agglomeration best explains reduced diffusion. Interfacial sharpening, controlled by the Flory χ parameter and molecular weight, tends to allow ions to spread more uniformly, and this increases their diffusion.

Molecular mechanisms of TLR2-mediated antigen cross-presentation in dendritic cells.

Cross-presentation is a key function of dendritic cells (DCs), which present exogenous Ags on MHC class I molecules to prime CTL responses. The effects of TLR triggering on the cross-presentation of exogenous Ags by DCs remain unclear. In this study, we used synthetic dipalmitoylated peptides and TLR2 agonist-conjugated peptides as models to elucidate the mechanisms of TLR2-mediated cross-presentation. We observed that the internalization of dipalmitoylated peptides by bone marrow-derived DCs was facilitated by TLR2 via clathrin-mediated endocytosis. The administration of these dipalmitoylated peptide-pulsed bone marrow-derived DCs eliminated established tumors through TLR2 signaling. We further demonstrated that the induction of Ag-specific CTL responses and tumor regression by dipalmitoylated peptides was TAP independent. In addition, presentation of dipalmitoylated peptides by MHC class I molecules was blocked in the presence of an endosomal acidification inhibitor (chloroquine) or a lysosomal degradation inhibitor (Z-FL-COCHO). The endocytosed dipalmitoylated peptide also passed rapidly from early endosome Ag-1-positive endosomes to RAS-related GTP-binding protein 7 (Rab7)-associated late endosomes compared with their nonlipidated counterparts. Furthermore, we found that dipalmitoylated peptide-upregulated Rab7 expression correlated with Ag presentation via the TLR2/MyD88 pathway. Both JNK and ERK signaling pathways are required for upregulation of Rab7. In summary, our data suggest that TLR2-mediated cross-presentation occurs through the upregulation of Rab7 and a TAP-independent pathway that prime CTL responses.

Pure, single crystal Ge nanodots formed using a sandwich structure via pulsed UV excimer laser annealing.

In this paper, a sandwich structure comprising a SiO2 capping layer, amorphous Germanium (a-Ge) nanodots (NDs), and a pit-patterned Silicon (Si) substrate is developed, which is then annealed by utilizing a pulsed ultraviolet excimer laser in order to fabricate an array of pure, single crystal Ge NDs at room temperature. A wide bandgap SiO2 capping layer is used as a transparent thermally isolated layer to prevent thermal loss and Si-Ge intermixing. The two-dimensional pit-patterned Si substrate is designed to confine the absorbed laser energy, reduce the melting point, and block the surface migration of the Ge. After optimizing the laser radiation parameters such that the laser energy density is 200 mJ cm(-2), the laser annealing period is 10 s, and the number of laser shots is 10, pure, single crystal Ge NDs that have both a regular arrangement and a uniform size distribution are obtained in the pits of the Si substrates. The Raman spectrum shows a highly symmetric Ge transversal optical peak with a full width at half maximum of 4.2 cm(-1) at 300.7 cm(-1), which is close to that of the original Ge wafer. In addition, the high-resolution transmission electron microscopy image for the Ge NDs and the corresponding selected area electron diffraction pattern shows a clear single crystalline structure without any impurities.

Electronic nicotine delivery systems: regulatory and safety challenges: Singapore perspective.

OBJECTIVE: Many electronic nicotine delivery systems (ENDS) are marketed as safer tobacco alternative products or effective cessation therapies. ENDS samples were evaluated for design features, including nicotine and glycols content. This could be useful in developing a legal framework to handle ENDS. METHODS: Identification of the nicotine, glycerol and propylene glycol (PPG) contents was conducted using gas chromatography mass spectrometry with quantification performed using flame ionisation techniques. RESULTS: Varying nicotine amounts were found in ENDS cartridges which were labelled with the same concentration. Chemicals such as PPG and glycerol were found to be present in the nicotine-containing liquid of the cartridges. ENDS varied in their contents and packaging information. Limited information was available on the contents of nicotine and other chemicals present in a variety of ENDS sampled. CONCLUSIONS: Based on samples tested in this study, many contain misleading information on product ingredients. The results show poor consistency between actual nicotine content analysed on ENDS cartridges and the amount labelled. These findings raise safety and efficacy concerns for current and would-be recreational users or those trying to quit smoking.

Hydrothermal Hydrolyzation-Driven Topological Transformation of Ni-Co Bimetallic Compounds with Hollow Nanoflower Structure for Optimizing Hydrogen Evolution Catalysis.

Composition screening and structure optimization are two critical factors in improving the electrocatalytic performance of hybrid materials. Herein, we present a straightforward hydrothermal hydrolyzation-topological transformation strategy for the synthesis of a range of Ni-Co bimetallic compounds with a hollow nanoflower structure. Among these Ni-Co compounds, Ni2P/Co2P hollow nanoflowers (HNFs) exhibit the most impressive electrocatalytic activity for the hydrogen evolution reaction (HER), necessitating only an 153 mV overpotential to achieve a current density of 10 mA cm-2 under alkaline conditions. Importantly, this performance remains stable for over 48 h, indicating exceptional durability. The exceptional catalytic performance of Ni2P/Co2P HNFs arises from the synergy between the hybrid Ni2P/Co2P components and the hollow nanoflower structure. The former provides abundant catalytic sites, while electron rearrangement at the heterointerfaces enhances the adsorption/desorption of active species and facilitates electron transfer. The latter contributes to the exposure of catalytic sites, shortening mass and charge transfer routes, and bolstering structural stability during prolonged electrocatalysis. This research offers valuable insights into the screening and optimization of advanced hybrid electrocatalysts, holding significant promise for applications in the emerging field of new energy technologies.

ADAM9 drives the immunosuppressive microenvironment by cholesterol biosynthesis-mediated activation of IL6-STAT3 signaling for lung tumor progression.

Chronic inflammation associated with lung cancers contributes to immunosuppressive tumor microenvironments, reducing CD8+ T-cell function and leading to poor patient outcomes. A disintegrin and metalloprotease domain 9 (ADAM9) promotes cancer progression. Here, we aim to elucidate the role of ADAM9 in the immunosuppressive tumor microenvironment. A bioinformatic analysis of TIMER2.0 was used to investigate the correlation of ADAM9 and to infiltrate immune cells in the human lung cancer database and mouse lung tumor samples. Flow cytometry, immunohistochemistry, and RNA sequencing (RNA-seq) were performed to investigate the ADAM9-mediated immunosuppressive microenvironment. The coculture system of lung cancer cells with immune cells, cytokine array assays, and proteomic approach was used to investigate the mechanism. By analyzing the human LUAD database and the mouse lung cancer models, we showed that ADAM9 was associated with the immunosuppressive microenvironment. Additionally, ADAM9 released IL6 protein from cancer cells to inhibit IL12p40 secretion from dendritic cells, therefore leading to dendritic cell dysfunction and further affecting T-cell functions. Proteomic analysis indicated that ADAM9 promoted cholesterol biosynthesis and increased IL6-STAT3 signaling. Mechanistically, ADAM9 reduced the protein stability of LDLR, resulting in reduced cholesterol uptake and induced cholesterol biosynthesis. Moreover, LDLR reduction enhanced IL6-STAT3 activation. We reveal that ADAM9 has a novel biological function that drives the immunosuppressive tumor microenvironment by linking lung cancer's metabolic and signaling axes. Thus, by targeting ADAM9 an innovative and promising therapeutic opportunity was indicated for regulating the immunosuppression of lung cancer.

Lipid nanoparticle-encapsulated DNA vaccine robustly induce superior immune responses to the mRNA vaccine in Syrian hamsters.

DNA vaccines for infectious diseases and cancer have been explored for years. To date, only one DNA vaccine (ZyCoV-D) has been authorized for emergency use in India. DNA vaccines are inexpensive and long-term thermostable, however, limited by the low efficiency of intracellular delivery. The recent success of mRNA/lipid nanoparticle (LNP) technology in the coronavirus disease 2019 (COVID-19) pandemic has opened a new application for nucleic acid-based vaccines. Here, we report that plasmid encoding a trimeric spike protein with LNP delivery (pTS/LNP), similar to those in Moderna's COVID-19 vaccine, induced more effective humoral responses than naked pTS or pTS delivered via electroporation. Compared with TSmRNA/LNP, pTS/LNP immunization induced a comparable level of neutralizing antibody titers and significant T helper 1-biased immunity in mice; it also prolonged the maintenance of higher antigen-specific IgG and neutralizing antibody titers in hamsters. Importantly, pTS/LNP immunization exhibits enhanced cross-neutralizing activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants and protects hamsters from the challenge of SARS-CoV-2 (Wuhan strain and the Omicron BA.1 variant). This study indicates that pDNA/LNPs as a promising platform could be a next-generation vaccine technology.

An experimental demonstration for carrier reused bidirectional PON system with adaptive modulation DDO-OFDM downstream and QPSK upstream signals.

A light source centralized bidirectional passive optical network (PON) system based on multiband direct-detection optical orthogonal frequency division multiplexing (DDO-OFDM) downstream and quadrature phase-shift keying (QPSK) upstream is experimentally demonstrated. By introducing a simple optical single-side band (SSB) filter at the optical network unit (ONU), all the desired signal bands will be immune from the deleterious signal-signal beating interference (SSBI) noise with only single-end direct-detection scheme. An adaptive modulation configuration is employed to enhance the entire downstream throughput which results in a 150-Gbps downstream data rate with a single optical carrier. In the upstream direction, by recycling the clean downstream optical carrier, a 12.5 Gb/s QPSK format with coherent receiving mechanism in central office is adopted for better receiving sensitivity and dispersion tolerance. With the power enhancement by the long-reach PON architecture, the downstream splitting ratio can achieve as high as 1:1024.

Prognostic Value of Tumor Size in Gastric Cancer: A Retrospective Cohort Study Based on SEER Database.

Background. Although tumor size is regarded as the "T" stage of the tumor-node-metastasis (TNM) staging system for many solid tumors, its prognostic impact in gastric cancer remains uncertain and conflicting. Methods. We enrolled 6960 eligible patients from the Surveillance, Epidemiology, and End Results (SEER) database. The X-tile program was used to select the best cut-off value of tumor size. Then, the Kaplan-Meier method and the Cox proportional hazards model were applied to examine the efficacy of tumor size on prognostic prediction for overall survival (OS) and gastric cancer-specific survival (GCSS). The presence of nonlinear association was determined by the restricted cubic spline (RCS) model. Results. Tumor size was divided into 3 groups: small size (≤2.5 cm), medium size (2.6-5.2 cm), and large size (≥5.3 cm). After adjusting by covariates such as depth of tumor infiltration, the large and medium groups showed a worse prognosis than the small group; however, no survival difference in OS was suggested between the medium and large groups. Similarly, although there was a nonlinear relationship between tumor size and survival, increasing tumor size did not show an independent negative effect on prognosis in the RCS analysis. However, the stratified analyses proposed this 3-way cut of tumor size in prognostic prediction for patients with both inadequate lymphadenectomy and negative nodal metastasis. Conclusions. Tumor size as a prognostic predictor may not have good clinical applicability in gastric cancer. Otherwise, it was recommended for patients with both insufficient examinations of lymph nodes and stage N0 disease.

A thirty-three gene-based signature predicts lymph node metastasis and prognosis in patients with gastric cancer.

Recently, several studies have indicated the great potential of gene expression signature of the primary tumor in predicting lymph node metastasis; however, few current gene biomarkers can predict lymph node status and prognosis in gastric cancer (GC). Thus, we used the RNA-seq data from The Cancer Genome Atlas (TCGA) to identify differentially expressed genes between pathological lymph node-negative (pN0) and positive (pN+) patients and to establish a gene signature that could predict lymph node metastasis. Meanwhile, the robustness of identified gene signatures was validated in an independent dataset Asian Cancer Research Group (n = 300). In this study, our thirty-three gene-based signature was highly correlated with lymph node metastasis and could successfully discriminate pN + patients in the training set (Area under the receiver operating characteristic curve = 0.951). Moreover, Disease-free survival (P = 0.0029) and overall survival (P = 0.026) were significantly worse in high-risk compared with low-risk patients overall and when confined to pN0 patients only (P < 0.0001). Of note, this gene signature also proved useful in predicting lymph node status and survival in the validation cohort. The present study suggests a thirty-three gene-based signature that could effectively predict lymph node metastasis and prognosis in GC.

SEC23A confers ER stress resistance in gastric cancer by forming the ER stress-SEC23A-autophagy negative feedback loop.

BACKGROUND: Sec23 homolog A (SEC23A), a core component of coat protein complex II (COPII), has been reported to be involved in several cancers. However, the role of SEC23A in gastric cancer remains unclear. METHODS: The expression of SEC23A in gastric cancer was analyzed by using qRT-PCR, western blotting and IHC staining. The role of SEC23A in ER stress resistance was explored by functional experiments in vitro and vivo. The occupation of STAT3 on the SEC23A promoter region was verified by luciferase reporter plasmids and CHIP assay. The interaction between SEC23A and ANXA2 was identified by Co-IP and mass spectrometry analysis. RESULTS: We demonstrated that SEC23A was upregulated in gastric cancer and predicted poor prognosis in patients with gastric cancer. Mechanistically, SEC23A was transcriptional upregulated by ER stress-induced pY705-STAT3. Highly expressed SEC23A promoted autophagy by regulating the cellular localization of ANXA2. The SEC23A-ANXA2-autophay axis, in turn, protected gastric cancer cells from ER stress-induced apoptosis. Furthermore, we identified SEC23A attenuated 5-FU therapeutic effectiveness in gastric cancer cells through autophagy-mediated ER stress relief. CONCLUSION: We reveal an ER stress-SEC23A-autophagy negative feedback loop that enhances the ability of gastric cancer cells to resist the adverse survival environments. These results identify SEC23A as a promising molecular target for potential therapeutic intervention and prognostic prediction in patients with gastric cancer.

Correction: DNA vaccination induced protective immunity against SARS CoV-2 infection in hamsterss.

[This corrects the article DOI: 10.1371/journal.pntd.0009374.].