Characterization of immunogenic cell death regulators predicts survival and immunotherapy response in lung adenocarcinoma.

Lung adenocarcinoma (LUAD) is highly lethal tumor; understanding immune response is crucial for current effective treatment. Research investigated immunogenic cell death (ICD) impact on LUAD through 75 ICD-related genes which encompass cell damage, endoplasmic reticulum stress, microenvironment, and immunity. Transcriptome data and clinical info were analyzed, revealing two ICD-related clusters: B, an immune osmotic subgroup, had better prognosis, stronger immune signaling, and higher infiltration, while A represented an immune-deficient subgroup. Univariate Cox analysis identified six prognostic genes (AGER, CD69, CD83, CLEC9A, CTLA4, and NT5E), forming a validated risk score model. It was validated across datasets, showing predictive performance. High-risk group had unfavorable prognosis, lower immune infiltration, and higher chemotherapy sensitivity. Conversely, low-risk group had better prognosis, higher immune infiltration, and favorable immunotherapy response. The key gene NT5E was examined via immunohistochemistry, with higher expression linked to poorer prognosis. NT5E was predominantly expressed in B cells, fibroblasts, and endothelial cells, correlated with immune checkpoints. These outcomes suggest that NT5E can serve as a LUAD therapeutic target. The study highlights gene predictive value, offers an efficient tumor assessment tool, guides clinical treatment strategies, and identifies NT5E as therapeutic target for LUAD.

[Retracted] MTSS1 inhibits colorectal cancer metastasis by regulating the CXCR4/CXCL12 signaling axis.

Following the publication of the above paper, it was drawn to the Editors' attention by a concerned reader that certain of the Transwell migration assay data shown in Fig. 1B were strikingly similar to data that had appeared in different form in another article by different authors at a different research institution. Furthermore, a number of overlapping data panels were observed comparing among migration assay data shown in Fig. 1B and C and Fig. 7B, such that these data, which were purported to show the results from differently performed experiments, may have been derived from the same original source(s). Owing to the fact that the contentious data in the above article had already been published elsewhere prior to its submission to International Journal of Molecular Medicine, the Editor has decided that this paper should be retracted from the Journal. After having been in contact with the authors, they agreed with the decision to retract the paper. The Editor apologizes to the readership for any inconvenience caused. [International Journal of Molecular Medicine 47: 65, 2021; DOI: 10.3892/ijmm.2021.4898].

Chitinase-3 like-protein-1 promotes glioma progression via the NF-κB signaling pathway and tumor microenvironment reprogramming.

Background: Chitinase-3-like protein 1 (CHI3L1) is overexpressed in various types of tumors, especially in glioma, and contributes to tumor progression. However, the definite role of CHI3L1 and involved pathway in glioma progression are not completely understood. Methods: CHI3L1 expression in human gliomas and its association with patient survival was determined using enzyme-linked immunosorbent assay, western blot, immunohistochemistry, and public databases. Single-cell RNA-seq was used to characterize the landscape of tumor and myeloid cells. Human proteome microarray assay was applied to identify the binding partners of CHI3L1. Protein-protein interactions were analyzed by co-immunoprecipitation and cellular co-localization. The roles of CHI3L1 in glioma proliferation and invasion were investigated in tumor cell lines by gain- and loss- of function, as well as in vivo animal experiments. Results: CHI3L1 was up-regulated in all disease stages of glioma, which was closely related with tumor survival, growth, and invasion. CHI3L1 was primarily expressed in glioma cells, followed by neutrophils. Moreover, glioma cells with high expression of CHI3L1 were significantly enriched in NF-κB pathway. Pseudo-time trajectory analysis revealed a gradual transition from CHI3L1low to CHI3L1high glioma cells, along with the NF-κB pathway gradually reversed from inhibition to activation. Intriguingly, CHI3L1 binds to actinin alpha 4 (ACTN4) and NFKB1, and enhances the NF-κB signaling pathway by promoting the NF-κB subunit nuclear translocation in glioma cells. Further, CHI3L1 were released into the tumor microenvironment (TME) and interacted with CD44 expressed on tumor-associated macrophages to activate AKT pathway, thereby contributing to M2 macrophage polarization. In addition, CHI3L1 positively correlated to the expression of immune checkpoints, such as CD274 (PD-L1) and HAVCR2 (LAG3), which then remodeled the TME to an immunosuppressive phenotype. Conclusion: Our research revealed that CHI3L1 facilitated NF-κB pathway activation within glioma cells and reprogramed the TME, thereby serving as a promising therapeutic target for glioma.

Dalteparin and Rivaroxaban Sequential Use in Cancer Patients with Venous Thromboembolism.

OBJECTIVE: To determine the effect and safety of sequential treatment with the low-molecular-weight heparin dalteparin and the direct oral anticoagulants rivaroxaban in patients with cancer- associated venous thromboembolism (VTE). STUDY DESIGN: Observational study. PLACE AND DURATION OF STUDY: Department of Oncology, the Second Affiliated Hospital of Soochow University, between January 2017 and September 2019. METHODOLOGY: Patients with active cancer, diagnosed with VTE and who received sequential treatment with dalteparin and rivaroxaban, were retrospectively reviewed. Logistic regression analysis was used to identify risk factors associated with VTE recurrence. RESULTS: Ninety-nine patients with active cancer were enrolled in the study. The median delteparin treatment time was nine days (5-20 days), and 2.8 months (1-6 months) for rivaroxaban. Sixty (60.6%) patients had eliminated VTE, and 39 (39.4%) had persistent VTE, but with relieved symptoms. No major bleeding was observed. Eleven (11.1%) patients had minor bleeding, including melena (5.1%), hematuria (3.0%), vaginal bleeding (1.0%), gingival bleeding (1.0%), and subcutaneous hemorrhage (1.0%). During the 6 months follow-up period, one (1.0%) developed pulmonary embolism, and seven (7.1%) experienced recurrent VTE. Univariate logistic regression analysis showed that bleeding occurrence and anticoagulant treatment duration were the two significant factors affecting VTE recurrence (p<0.05). CONCLUSION: Maintenance of rivaroxaban after initial dalteparin treatment could effectively reduce the risk of VTE recurrence and was well tolerated by patients with cancer-associated VTE. However, in the clinical practice, the treatment duration is often insufficient, so it is essential to follow-up these patients to ensure sufficient treatment time. Key Words: Venous thromboembolism, Low-molecular-weight heparins, Directly oral anticoagulants, Cancer.

MTSS1 inhibits colorectal cancer metastasis by regulating the CXCR4/CXCL12 signaling axis.

The liver is the most common site of metastasis for colorectal cancer (CRC). Metastasis suppressor 1 (MTSS1), a potential tumor suppressor gene associated with tumor metastasis, has been reported to play an important role in cancer development. The present study aimed to investigate the effects and underlying mechanisms of MTSS1 on the biological behavior of CRC cells both in vitro and in vivo. A CRC mouse model with a high liver metastatic potential was established by injecting mice with SW1116 cells, and the association between MTSS1 expression levels and the metastatic potential of forming liver metastasis lesions was subsequently analyzed. MTSS1 gain­ and loss­of­function experiments were performed by transfecting the CRC cell lines, SW1116 and DLD­1, with Plvx­IRES­ZsGreen1­MTSS1 plasmid and short hairpin RNA, respectively. Cell proliferation, migration, invasion and cell cycle distribution were analyzed by MTT, Transwell and flow cytometric assays, respectively. To further determine the underlying mechanisms of MTSS1 in CRC, the expression levels of cell surface chemokine C­X­C receptor 4 (CXCR4) and its downstream signaling factors, Rac and cell division cycle 42 (CDC42), were analyzed with or without C­X­C motif chemokine ligand 12 (CXCL12) stimulation. The results revealed that as the CRC metastatic potential increased, the expression levels of MTSS1 decreased. The overexpression of MTSS1 exerted an inhibitory effect on cell proliferation, migration and invasion, while the knockdown of MTSS1 exerted the opposite effects in vitro. Flow cytometric analysis and western blot analysis demonstrated that MTSS1 negatively regulated the expression levels of cell surface CXCR4 and its downstream signaling pathway activation. On the whole, the results of the present study indicate that MTSS1 may play an important negative role in CRC metastasis and the underlying mechanisms may involve the downregulation of the CXCR4/CXCL12 signaling axis.

Characterization of m6A RNA Methylation Regulators Predicts Survival and Immunotherapy in Lung Adenocarcinoma.

N6-methyladenosine (m6A) RNA modification is a reversible mechanism that regulates eukaryotic gene expression. Growing evidence has demonstrated an association between m6A modification and tumorigenesis and response to immunotherapy. However, the overall influence of m6A regulators on the tumor microenvironment and their effect on the response to immunotherapy in lung adenocarcinoma remains to be explored. Here, we comprehensively analyzed the m6A modification patterns of 936 lung adenocarcinoma samples based on 24 m6A regulators. First, we described the features of genetic variation in these m6A regulators. Many m6A regulators were aberrantly expressed in tumors and negatively correlated with most tumor-infiltrating immune cell types. Furthermore, we identified three m6A modification patterns using a consensus clustering method. m6A cluster B was preferentially associated with a favorable prognosis and enriched in metabolism-associated pathways. In contrast, m6A cluster A was associated with the worst prognosis and was enriched in the process of DNA repair. m6A cluster C was characterized by activation of the immune system and a higher stromal cell score. Surprisingly, patients who received radiotherapy had a better prognosis than patients without radiotherapy only in the m6A cluster C group. Subsequently, we constructed an m6A score model that qualified the m6A modification level of individual samples by using principal component analysis algorithms. Patients with high m6A score were characterized by enhanced immune cell infiltration and prolonged survival time and were associated with lower tumor mutation burden and PD-1/CTLA4 expression. The combination of the m6A score and tumor mutation burden could accurately predict the prognosis of patients with lung adenocarcinoma. Furthermore, patients with high m6A score exhibited greater prognostic benefits from radiotherapy and immunotherapy. This study demonstrates that m6A modification is significantly associated with tumor microenvironment diversity and prognosis. A comprehensive evaluation of m6A modification patterns in single tumors will expand our understanding of the tumor immune landscape. In addition, our m6A score model demonstrated that the level of immune cell infiltration plays a significant role in cancer immunotherapy and provides a basis to increase the efficiency of current immune therapies and promote the clinical success of immunotherapy.

Effect of the weekly administration of liposome-Paclitaxel combined with s-1 on advanced gastric cancer.

OBJECTIVE: This study is aimed to assess the efficacy and toxicity of weekly liposome-paclitaxel and S-1 combination therapy as first-line treatment for advanced gastric cancer. METHODS: The chemotherapy regime was 80 mg/m(2) liposome-paclitaxel given on days 1, 8, 15 and 22, combined with S-1 60 mg (body surface area > 1.5) or 50 mg (1.25 < body surface area < 1.5) twice a day on days 1-28, 6 weeks as one cycle. The patients continued to be treated until they received four cycles or until they developed either progressive disease or untolerated toxicity. The response rate, progression-free survival, overall survival and toxicity were evaluated. RESULTS: A total of 56 patients were enrolled, and the median age was 60 years (range = 38-70 years; 39 males and 17 females). The response rate and disease control rate were 25% (14/56) and 87.5% (49/56), respectively. The median progression-free survival was 6.1 months (95% confidence interval: 5.0-7.2), and the median overall survival was 10.6 months (95% confidence interval: 7.2-14.0). The most frequent hematological toxicities were neutropenia and anemia, which occurred in 22 (48.9%) and 11 (19.6%) patients, respectively. CONCLUSIONS: The weekly administration of a combined regimen of liposome-paclitaxel plus S-1 is effective and has a favorable toxicity profile for advanced gastric cancer.