Breast cancer (BC) is the most diagnosed cancer in women. Cuproptosis is new regulated cell death, distinct from known death mechanisms and dependent on copper and mitochondrial respiration. However, the comprehensive relationship between cuproptosis and BC is still blank until now. In the present study, we acquired 13 cuproptosis-related regulators (CRRs) from the previous research and downloaded the RNA sequencing data of TCGA-BRCA from the UCSC XENA database. The 13 CRRs were all differently expressed between BC and normal samples. Using consensus clustering based on the five prognostic CRRs, BC patients were classified into two cuproptosis-clusters (C1 and C2). C2 had a significant survival advantage and higher immune infiltration levels than C1. According to the Cox and LASSO regression analyses, a novel cuproptosis-related prognostic signature was developed to predict the prognosis of BC effectively. The high- and low-risk groups were divided based on the risk scores. Kaplan-Meier survival analysis indicated that the high-risk group had shorter overall survival (OS) than the low-risk group in the training, test and entire cohorts. GSEA indicated that the immune-related pathways were significantly enriched in the low-risk group. According to the CIBERSORT and ESTIMATE analyses, patients in the high-risk group had higher infiltrating levels of antitumor lymphocyte cell subpopulations and higher immune score than the low-risk group. The typical immune checkpoints were all elevated in the high-risk group. Furthermore, the high-risk group showed a better immunotherapy response than the low-risk group based on the Tumor Immune Dysfunction and Exclusion (TIDE) and Immunophenoscore (IPS). In conclusion, we identified two cuproptosis-clusters with different prognoses using consensus clustering in BC. We also developed a cuproptosis-related prognostic signature and nomogram, which could indicate the outcome, the tumor immune microenvironment, as well as the response to immunotherapy.
Esophageal-gastric junction adenocarcinoma (AEG) is an aggressive tumor with high incidence and dismal prognosis worldwide. Despite significant advances in therapeutic strategies, the 5-year survival rate still remains low. Diallyl disulfide (DADS), which is one of the major volatile components isolated from garlic, has been shown to have multi-targeted antitumor activities in a variety of cancer cells. However, the exact anti-metastatic effects and underlying molecular mechanisms of DADS in AEG have not been elucidated. The present study demonstrated that DADS inhibited cell viability of OE19 cells with low cytotoxicity to healthy hepatocytes, L02 cells, in vitro. Non-toxic doses of DADS were ≤10 µg/ml for a 24-h treatment. Our data showed that these non-toxic doses of DADS were found to block the metastasis of OE19 cells by suppressing MMPs, increasing u-PA and TIMPs, as well as altering the balance of MMPs/TIMPs, which at least in part resulted from the suppression of NF-κB and PI3K/AKT signaling pathways. The present study provides a previously neglected insight into the investigation of DADS in suppressing tumor metastasis and its underlying molecular mechanisms in vitro. Hence, DADS could be a promising anticancer agent for anti-metastatic treatment of AEG in the future.
Gene therapy shows promising application in cancer therapy, but the lack of an ideal gene delivery system is still a tough challenge for cancer gene therapy. Previously, we prepared a novel cationic nanogel, heparin-polyethylenimine (HPEI), which had potential application in gene delivery. In the present study, we constructed a plasmid with high expression efficiency of interleukin-15 (IL15) and investigated the effects HPEI-plasmid IL15 (HPEI-pIL15) complexes on the distribution level of the lung. We then evaluated the anticancer effect of HPEI-pIL15 complexes on lung metastases of B16-F10 melanoma and CT26 colon carcinoma. These results demonstrated that intravenous injection of the HPEI-pIL15 complex exhibited the highest plasmid distribution level in the lung compared with that of PEI2K-pIL15 and PEI25K-pIL15, and mice treated with HPEI-pIL15 had a lower tumor metastasis index compared with other treatment groups. Moreover, the number of natural killer cells, which were intermingled among the tumor cells, and the level of tumor necrosis factor-a and interferon-c in the serum also increased in the pIL15-treated mice. Furthermore, the cytotoxic activity of spleen cells also increased significantly in the HPEI-pIL15 group. In addition, induction of apoptosis and inhibition of cell proliferation in lung tumor foci in the HPEI-pIL15 group was observed. Taken together, treating lung metastasis cancer with the HPEI nanogels delivered by plasmid IL15 might be a new and interesting cancer gene therapy protocol. (Cancer Sci 2011; 102: 1403-1409 L ung metastasis is the most common cause of cancer death in both men and women. Investigators have done a lot to improve its prognosis and the development of new modalities of treatment. Gene therapy is a promising and powerful method; currently, its potential in cancer treatment is widely recognized. However, the major limitation of gene therapy of the lung is the low efficiency of gene transfer and the technical difficulties of regimen delivery.(1) Delivery vectors play an important role in gene therapy because the plasmid DNA must be protected from damage and its entry into the cell must be facilitated. Some polymers and cationic lipids have shown high gene transfection efficiency in the lung for DNA encapsulated.(2) The cationic polymer polyethylenimine (PEI) has the ability to protect DNA from undesirable degradation during the transfection process and is one of the most effective non-viral gene vectors. (3)(4)(5) However, PEI also has a shortcoming: the increase in transfection efficiency is accompanied by an increase in cytotoxicity, and both efficiency and cytotoxicity increase as its molecular weight increases. To address this challenge, we used heparin to couple PEI together, forming HPEI nanogels; these nanogels had high transfection efficiency and low toxicity, showing promising application as a non-viral gene delivery system. (6) Interleukin-15 (IL15) is a cytokine first identified in the supernatant of the monkey epithelial cell line CV-1 ⁄ EBNA and has a simila...
Background: The current National Comprehensive Cancer Network (NCCN) guidelines for non-small cell lung cancer (NSCLC) recommend that surgeons sample is not clear. We aimed to define a minimal number of examined lymph nodes for removal or sampling for optimized nodal staging recommendation, with a focus on T 1-3 N 0 M 0 patients. Methods: A total of 55,101 consecutive patients were selected, including 52,099 patients with US Surveillance, Epidemiology, and End Results (SEER) data and 3,002 patients in a Chinese multicenter database from 11 thoracic referral centers, who underwent complete resection plus lymph node dissection or sampling for stage T 1-3 N 0 M 0 NSCLC. Propensity score-matching analysis was performed with R software, and a cut-off value was calculated using X-tile software. Survival was evaluated using the Kaplan-Meier method and Cox proportional hazard models.Results: Five-year survival rates with respect to total examined lymph nodes numbers (examined lymph nodes <10 vs. examined lymph nodes ≥10) were 69% and 64% (group A), 66% and 63% (group B), 62% and 58% (group C), 81% and 75% (group D). There were significant differences between examined lymph nodes <10 and examined lymph nodes >10 in each group (P<0.001).Conclusions: A minimum of 10 examined lymph nodes would significantly improve T 1-3 N 0 M 0 NSCLC prognosis and patients' survival rates if implemented as a minimum standard for lymphadenectomy.Therefore, we recommended a minimum of 10 examined lymph nodes for T 1-3 N 0 M 0 patients.
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