The effect of surgery and metastatic risk prediction in patients with gastrointestinal tract signet-ring cell carcinoma.

PURPOSE: This study aimed to assess the efficacy of surgery as a treatment option for patients with signet-ring cell carcinoma (SRCC) in the gastrointestinal tract (GI-SRCC). METHODS: Using the Surveillance, Epidemiology, and End Results database, patients with GI-SRCC who underwent surgery or received nonsurgical treatment were included. Propensity score matching (PSM) analysis was used to balance baseline characteristics and reduce bias. Overall survival (OS) was calculated in matching cohorts to estimate prognosis for patients with GI-SRCC. Nomogram was established to predict metastasis for patients with GI-SRCC. RESULTS: The study enrolled a total of 9428 patients with GI-SRCC, with 1689 patients in the nonsurgery group and 7739 patients in the surgery group. After 1:1 PSM, we analyzed 743 patients from each group. Our survival analyses revealed that surgery independently correlated with improved OS for patients with GI-SRCC (hazard ratio, 0.37; 95% CI, 0.33-0.42; P < .001). Subgroup analysis further confirmed the positive impact of surgery on the prognosis of patients with nonmetastatic GI-SRCC. Notably, distinct subsets of patients with metastasis, particularly those originating from the upper GI (esophagus, proximal stomach, and distal stomach) and left colon, demonstrated a significant improvement in OS after surgery. However, no significant survival difference was observed for patients with metastatic right colon and rectum SRCC. Using nomogram, we quantitatively assessed the risk of metastasis in patients with right colon and rectum SRCC, which exhibited robust predictive accuracy, with area under the curve values of 0.829. CONCLUSION: Our study highlighted surgery's positive impact on prognosis for both patients with nonmetastatic and metastatic upper GI-SRCC and left colon SRCC. Hence, we recommend surgery as a treatment option for these groups. In addition, for patients with metastatic right colon and rectum SRCC ineligible for surgery, our predictive nomogram can offer a convenient tool to aid early intervention and improve prognosis.

LncRNA MEG3: Targeting the Molecular Mechanisms and Pathogenic causes of Metabolic Diseases.

BACKGROUND: Non-coding RNA is a type of RNA that does not encode proteins, distributed among rRNA, tRNA, snRNA, snoRNA, microRNA and other RNAs with identified functions, where the Long non-coding RNA (lncRNA) displays a nucleotide length over 200. LncRNAs enable multiple biological processes in the human body, including cancer cell invasion and metastasis, apoptosis, cell autophagy, inflammation, etc. Recently, a growing body of studies has demonstrated the association of lncRNAs with obesity and obesity-induced insulin resistance and NAFLD, where MEG3 is related to glucose metabolism, such as insulin resistance. In addition, MEG3 has been demonstrated in the pathological processes of various cancers, such as mediating inflammation, cardiovascular disease, liver disease and other metabolic diseases. OBJECTIVE: To explore the regulatory role of lncRNA MEG3 in metabolic diseases. It provides new ideas for clinical treatment or experimental research. METHODS: In this paper, in order to obtain enough data, we integrate and analyze the data in the PubMed database. RESULTS: LncRNA MEG3 can regulate many metabolic diseases, such as insulin resistance, NAFLD, inflammation and so on. CONCLUSION: LncRNA MEG3 has a regulatory role in a variety of metabolic diseases, which are currently difficult to be completely cured, and MEG3 is a potential target for the treatment of these diseases. Here, we review the role of lncRNA MEG3 in mechanisms of action and biological functions in human metabolic diseases.

Celastrol-loaded biomimetic nanodrug ameliorates APAP-induced liver injury through modulating macrophage polarization.

Drug-induced liver injury (DILI) is a major concern in clinical treatment as well as postmarketing surveillance, showing an urgent requirement for the development of protective medications. Celastrol (Cel), a highly active natural product extracted from the roots of Tripterygium wilfordii, has a potential liver protective activity due to its antioxidant and anti-inflammatory effects. However, the further application of Cel to DILI remains a challenge because of its short half-life, low solubility, and toxic side effects. Herein, we developed a Cel-loaded biomimetic nanodrug based on erythrocyte membrane vesicles (EMV) for protecting the liver from acetaminophen (APAP)-induced liver injury. The Cel-loaded EMV (C-EMV) with lower cytotoxicity had a well-sustained release effect and exhibited excellent ability for liver accumulation under physiological and pathological conditions. By suppressing the inflammatory response of pro-inflammatory macrophage M1 polarization while stimulating anti-inflammatory macrophage M2 polarization, C-EMV could significantly alleviate the primary pathological manifestations related to liver injury, including aberrant elevation of biochemical indicators, histopathological alterations, neutrophil infiltration as well as hepatocyte DNA fragmentation. The macrophage depletion experiment further demonstrated that the protective effect of C-EMV on APAP-induced liver injury appeared to be dependent on hepatic macrophages. Therefore, C-EMV as a biomimetic nanodrug exhibits great potential for attenuating the progress of DILI, providing a new approach to protecting the liver from DILI as well as other liver inflammatory diseases through a targeted nanodelivery system. KEY MESSAGES: EMV biomimetic nanocarrier has good monodispersity and sustained-release property. EMV biomimetic nanocarrier displays excellent liver-targeting capability under physiological and pathological conditions. C-EMV biomimetic nanodrug with lower cytotoxicity regulates macrophage polarization in vitro and in vivo. C-EMV biomimetic nanodrug can significantly alleviate APAP-induced liver injury. The protective effect of C-EMV on APAP-induced liver injury is dependent on hepatic macrophages.

Nomogram predicting the cancer-specific survival of early-onset colorectal cancer patients with synchronous liver metastasis: a population-based study.

PURPOSE: This research aimed to explore prognostic factors for early-onset colorectal cancer (EO-CRC) patients with liver metastasis (LM) and develop nomogram for predicting cancer-specific survival (CSS) probability quantitatively. METHODS: Our study included 4368 EO-CRC patients with LM registered in the Surveillance, Epidemiology, and End Results (SEER) database between 2010 and 2017. Potential prognostic factors for EO-CRC patients with LM were identified by multivariable Cox regression analysis. Prognostic nomogram was subsequently constructed based on these prognostic factors. The discriminative ability, calibration, and clinical usefulness of the nomogram were assessed by the area under the receiver operating characteristic (ROC) curves (AUC), calibration curves, and decision curve analysis (DCA). RESULTS: In the training cohort, marital status, primary tumor location, histopathological grade, T stage, number of metastatic organs, carcinoembryonic antigen (CEA), perineural invasion (PI), surgery of primary site, chemotherapy, radiation therapy, and metastatic lymph nodes ratio (LNR) were prognostic factors for cancer-specific mortality of EO-CRC patients with LM. The 1-, 2-, and 3-year AUC values of the prognostic nomogram were 0.777, 0.781, and 0.788, respectively. Calibration curves indicated acceptable agreement between nomogram-predicted survival and actual observed survival at 1, 2, and 3 years. DCA curves exhibited good positive net benefits in the prognostic model in most threshold probabilities at different time points. All of these results were reproducible in the validation cohort. CONCLUSIONS: This study identified prognostic factors for EO-CRC patients with LM and developed a prognostic nomogram with good performance and clinical usability, which may help clinicians make better treatment decisions.

Numerical Simulation of Impregnation Process of Reactive Injection Pultrusion for Glass Fiber/PA6 Composites.

Pultrusion of thermoplastic composites has been the hotspot of manufacturing high-performance thermoplastic composites in recent years. The optimization of process parameters in the pultrusion usually needed repeated attempts, which wasted lots of manpower and material resources. A numerical simulation method can accelerate the optimization of process parameters. In this work, the impregnation process of reactive injection pultrusion for glass fiber reinforced nylon 6 (GF/PA6) composites was modeled and numerically simulated by a finite element/controlled volume (Fe/CV) method. Based on Darcy's law, the impregnation process can be regarded as the two-phase flow (liquid resin and air) in porous media (undirectional glass fibers). The distribution of resin flow during the impregnation was explored. The effects of pulling rate and injection pressure on the impregnation time and resin reflux distance were analyzed, and the appropriate range of relevant process parameters was determined. The results showed that increasing the pulling rate can significantly control the reflux distance of resin in the impregnation mold and shorten the impregnation time, but too high a pulling rate would increase the impregnation time. Increasing the injection pressure can greatly shorten the resin impregnation time, but it would significantly increase the resin reflux distance. This work can effectively guide the subsequent optimization of process parameters of reactive injection pultrusion for GF/PA6 composites.

Tumour-associated neutrophils secrete AGR2 to promote colorectal cancer metastasis via its receptor CD98hc-xCT.

OBJECTIVE: Reciprocal cellular crosstalk within the tumour microenvironment (TME) actively participates in tumour progression. The anterior gradient-2 (AGR2) can be secreted to extracellular compartments and contribute to colorectal cancer (CRC) metastasis. We investigated the cellular source for secreted AGR2 in the TME and underlying mechanisms mediating secreted AGR2's effects. DESIGN: Tissue microarray, tumour tissues, blood samples and tumour-associated neutrophils (TANs) from patients with CRC were isolated for phenotypical and functional analyses. The role of TAN-secreted AGR2 was determined in neutrophil-specific Agr2 knockout (Agr2f/f;Mrp-Cre) mice. The biological roles and mechanisms of secreted AGR2 in CRC metastasis were determined in vitro and in vivo. RESULTS: TANs were a predominant cell type for secreting AGR2 in the TME of CRC. TANs-secreted AGR2 promoted CRC cells' migration. Neutrophils-specific ablation of Agr2 in mice ameliorated CRC liver metastases. The heavy chain of CD98 (CD98hc) served as the functional receptor for secreted AGR2. Mechanistically, secreted AGR2 increased xCT activity in a CD98hc-dependent manner, subsequently activating Ras homologue family member A/Rho-associated protein kinase 2 cascade. CRC cells actively recruited TANs through the C-X-C motif chemokine 2. Moreover, CRC-derived transforming growth factor beta 1 (TGF-ß1) educated peripheral blood neutrophils to become AGR2+ TANs that secrete AGR2. Abundant infiltration of AGR2+ TANs and high expression of TGF-ß1 and CD98hc-xCT were correlated with poor prognosis of patients with CRC. CONCLUSIONS: Our study unveils a novel crosstalk between TANs and CRC cells involving the secreted AGR2-CD98hc-xCT axis that promotes metastasis and impacts the outcomes of patients with CRC.

Risk and prognostic nomograms for colorectal neuroendocrine neoplasm with liver metastasis: a population-based study.

PURPOSE: Liver metastasis (LM) significantly shortens the survival time of colorectal neuroendocrine neoplasms (NENs) patients. This research aimed to explore risk and prognostic factors in colorectal NENs patients with LM and develop nomograms for predicting the risk of LM and survival probability quantitatively. METHODS: A total of 9926 colorectal NENs patients registered in the Surveillance, Epidemiology, and End Results (SEER) database between 2010 and 2017 were included. Risk factors for LM in colorectal NENs patients were identified by multivariate logistic regression analysis. Potential prognostic factors for colorectal NENs patients with LM were identified by multivariable Cox regression analysis. Nomograms were constructed for quantifying the probability of LM occurrence and survival. RESULTS: At diagnosis, 8.7% of colorectal NENs patients suffered LM, with 1-, 3-, and 5-year cancer-specific survival (CSS) rates of 44.3%, 26.5%, and 18.0%, respectively. Factors associated with LM occurrence included gender, age at diagnosis, primary tumor location, carcinoembryonic antigen (CEA), histological differentiation, T stage, and N stage. Age at diagnosis, race, histological differentiation, N stage, tumor size, primary tumor location, primary site surgery, and extraliver metastasis were prognostic factors of cancer-specific mortality. The area under the receiver operating characteristics (ROC) curve of the nomogram for predicting LM was 0.888 (95% CI: 0.877-0.898), and the C-index of the nomogram for estimating CSS probability was 0.705 (95% CI: 0.682-0.729). CONCLUSIONS: This research identified the risk and prognostic factors in colorectal NENs patients with LM. The nomograms constructed by this study can be convenient tools for facilitating clinical decision-making.

TRIM39 deficiency inhibits tumor progression and autophagic flux in colorectal cancer via suppressing the activity of Rab7.

The biological function of TRIM39, a member of TRIM family, remains largely unexplored in cancer, especially in colorectal cancer (CRC). In this study, we show that TRIM39 is upregulated in tumor tissues compared to adjacent normal tissues and associated with poor prognosis in CRC. Functional studies demonstrate that TRIM39 deficiency restrains CRC progression in vitro and in vivo. Our results further find that TRIM39 is a positive regulator of autophagosome-lysosome fusion. Mechanistically, TRIM39 interacts with Rab7 and promotes its activity via inhibiting its ubiquitination at lysine 191 residue. Depletion of TRIM39 inhibits CRC progression and autophagic flux in a Rab7 activity-dependent manner. Moreover, TRIM39 deficiency suppresses CRC progression through inhibiting autophagic degradation of p53. Thus, our findings uncover the roles as well as the relevant mechanisms of TRIM39 in CRC and establish a functional relationship between autophagy and CRC progression, which may provide promising approaches for the treatment of CRC.

Secreted AGR2 promotes invasion of colorectal cancer cells via Wnt11-mediated non-canonical Wnt signaling.

Human anterior gradient-2 (AGR2), a member of protein disulfide isomerase (PDI) family, is present in both intracellular and extracellular compartments. Although AGR2 is overexpressed in various human cancers and reported to promote aggressive tumor features, little is known regarding AGR2's extracellular functions during tumorigenesis. Here, we demonstrate that secreted AGR2 promotes cell migration and metastasis of colorectal cancer (CRC) in vitro and in vivo. Mechanistically, secreted AGR2 elevated Wnt11 expression, triggering non-canonical Wnt signaling: the Ca2+/Calmodulin-dependent protein kinase II (CaMKII) and c-jun amino-terminal kinase (JNK) pathways. Knockdown of Wnt11 or pretreatment with CaMKII and JNK inhibitors reversed the secreted AGR2's migration-promoting effect. Further studies revealed that AGR2 antagonized canonical Wnt/ß-catenin signaling via activating CaMKII. Collectively, our study uncovers a critical role of Wnt11-mediated non-canonical Wnt signaling (CaMKII and JNK pathways) in secreted AGR2's promoted migration of CRC cells. These results raise the possibility that secreted AGR2 may be a potential therapeutic target towards inhibiting CRC metastasis.

The prognostic value of AGR2 expression in solid tumours: a systematic review and meta-analysis.

The prognostic value of anterior gradient-2 (AGR2) in tumours remains inconclusive. Here, we systematically reviewed the literature evidence and assessed the association between AGR2 expression and prognosis in solid tumours. The primary outcomes were overall survival (OS), disease-specific survival (DSS), and disease-free survival (DFS)/recurrence-free survival (RFS)/progression-free survival (PFS). All analyses were performed by STATA 12.0, with the hazard ratio (HR) or odds ratios (OR), and 95% confidence interval (CI) as the effect size estimate. A total of 20 studies containing 3285 cases were included. Pooled analyses revealed that AGR2 overexpression had an unfavourable impact on OS (HR 1.93, 95% CI 1.32-2.81) and time to tumour progression (TTP) (DFS/RFS/PFS) (HR 1.60 95% CI 1.06-2.40) in solid tumour patients. Subgroup analyses indicated that AGR2 overexpression in breast cancer patients was significantly associated with poor OS (HR 3.02, 95% CI 1.03-8.81) and TTP (HR 1.93, 95% CI 1.17-3.20). Excluding breast cancer, AGR2 overexpression was also found to have a significant correlation with poor OS in the remaining solid tumour patients (HR 1.51, 95% CI 1.04-2.19). Overall, AGR2 might be a potential biomarker to predict prognosis in solid tumour patients.

Knockdown of dishevelled-1 attenuates cyclosporine A-induced apoptosis in H9c2 cardiomyoblast cells.

Cyclosporine (CsA) has become a mainstay for immune suppression of organ transplants. It is known that patients receiving CsA manifest increased growth of aggressive cardiotoxicity. We have demonstrated that CsA induces myocardium cell apoptosis in vivo and vitro. Recently, dishevelled-1 (Dvl-1) protein, which is a cytoplasmic mediator of Wnt/ß-catenin signaling, was explored in cardiac diseases. However, whether Dvl-1 is involved in CsA-induced apoptosis remains to be determined. The aim of this study was to explore the role of Dvl-1 in CsA-induced apoptosis in H9c2 cardiomyoblast cells and to investigate the role of the Wnt/ß-catenin signaling cascade in this progress. H9c2 cells were treated with CsA in dose and time-dependent manners. We found that the appropriate concentrations and time-points of CsA-induced the expression of Dvl-1 and subsequent up-regulation of ß-catenin and c-Myc, which is consistent with previously demonstrated concentrations and time-points when H9c2 cells apoptosis occurred. Then, cells were transfected with small interfering RNA (siRNA) against Dvl-1 and stimulated with previously demonstrated concentration of CsA. Dvl-1 down-regulation decreased the apoptotic rate, caspase-3 activity, and the Bax/Bcl-2 ratio in H9c2 cells treated with CsA. Furthermore, knocking down the expression of Dvl-1 partially suppressed the activity of the Wnt/ß-catenin pathway. Moreover, we further deleted the downstream member ß-catenin by specific siRNA, and found that CsA-induced the Bax/Bcl-2 ratio and the expression of c-Myc, which were attenuated. Our results are the first to unveil this novel aspect of Dvl-1 signaling. In addition, these data provide insight into the pathogenesis and the therapeutic strategies of CsA-induced myocardial injury.