Abstract CAMSAP2 has been reported to act as an oncogene in hepatocellular carcinoma. However, the expression CAMSAP2 and its potential roles in colorectal cancer remain unclear. In this study, qRT-PCR and immunoblotting analysis were used to detect the mRNA and protein levels of CAMSAP2 in colorectal cancer tissues and cell lines. Wound-healing, transwell migration and invasion assay were performed to determine whether CAMSAP2 promotes the capabilities of migration and invasion of colorectal cancer cells. The results showed that CAMSAP2 was highly elevated in colorectal cancer tissues and cell lines. Moreover, the high CAMSAP2 expression was positively correlated with tumor invasion depth, lymph node metastasis, distant metastasis, and the poor prognosis of colorectal cancer. Additionally, ectopic expression of CAMSAP2 in colorectal cancer cells promoted the migration and invasion in vitro and enhanced the lung metastasis in nude mice. Conversely, silencing CAMSAP2 resulted in an opposite phenomenon. By gain- and loss-of function experiments, we demonstrated that MMP-1 was a substantial downstream target of CAMSAP2, and it played a crucial role in regulating the migration and invasion induced by CAMSAP2 in colorectal cancer cells. Mechanistically, CAMSAP2 promoted the activation of JNK/c-Jun signaling pathway and subsequently upregulated the transcription activity of MMP-1. Taken together, our findings demonstrated that CAMSAP2 promoted colorectal cancer cell migration, invasion and metastasis through activation of JNK/c-Jun/MMP-1 signaling pathway, indicating CAMSAP2 is a promising therapeutic target for the treatment of metastatic colorectal cancer patients.
Centrosome-associated protein E (CENPE) is a plus end-directed kinetochore motor protein, which plays a critical role in mitosis. In this in silico study, using data from the Cancer Genome Atlas-Esophageal Carcinoma (TCGA-ESCA), we analyzed the expression profile of CENPE mRNA in esophageal squamous cell carcinoma (ESCC) and adenocarcinoma (EA), its independent prognostic value and the potential mechanisms of its dysregulation in EA. Results showed that both ESCC and EA tissues had significantly elevated CENPE expression compared with their respective adjacent normal tissues. However, Kaplan-Meier survival curves showed that high CENPE was associated with unfavorable OS in EA. Univariate and multivariate analysis confirmed that CENPE expression was an independent indicator of unfavorable OS in EA patients, as a continuous variable (HR: 1.861, 95%CI: 1.235–2.806, p = 0.003) or as categorical variables (HR: 2.550, 95%CI: 1.294–5.025, p = 0.007). However, CENPE expression had no prognostic value in ESCC. Compared with the methylation status in normal samples, 3 CpG sites were hypomethylated (cg27388036, cg27443373, and cg24651824) in EA, among which two sites (cg27443373 and cg24651824) showed moderately negative correlation with CENPE expression. In addition, we also found that although heterozygous loss (-1) was frequent in EA (50/88, 56.8%), it was not necessarily associated with decreased CENPE expression compared with the copy neutral (0) cases. The methylation of the -1 group was significantly lower than that of the +1/0 group (p = 0.04). Based on these findings, we infer that CENPE upregulation in EA might serve as a valuable indicator of unfavorable OS. The methylation status of cg27443373 and cg24651824 might play a critical role in modulating CENPE expression.
Objective:To investigate the effect of TNF-α in diabetes mellitus patients on microangiophathy.Methods:The expression of tumor necrosis factor-alpha in 67 patients with type 2 diabetes mellitus (35 cases with microangiopathy, 32 case without microangio-pathy and 25 cases healthy) were measured by immunoradio-metric The concentration of TG, TC, FPG, HbA1c, FIB was determined.Results:The expression of tumor necrosis factor-alpha of the patients with diabetes mellitus were significantly higher than that in controls (P0.01).The expression of tumor necrosis factor-alpha in diabetes mellitus with microanglopathy increased significantly compared with diabetes mellitus without microangiopathy(P0.01).Conclusions:TNF-α has relationship with the development of diabetic microangiopathy.
The objective of this study is to investigate the clinical significance of folate-receptor-positive circulating tumor cells (FR+CTC) for the diagnosis of lung cancer, especially in early-stage patients.A total of 72 lung cancer patients, including 31 with stage I diseases and two with stage 0 diseases, were enrolled in this study. Twenty-four patients with benign lung diseases and two healthy volunteers served as the control group. Three milliliters of peripheral blood were collected from each participant for FR+CTC analysis on enrollment. FR+CTC enumeration was performed using immunomagnetic leukocyte depletion and ligand-targeted polymerase chain reaction techniques.The study results revealed that using a cutoff value of 8.7 CTC Units/3 mL, the sensitivity, and specificity of FR+CTC for diagnosis of lung cancer were 81.94% and 73.08%, respectively. Such high sensitivity (74.19%) and specificity (73.08%) persisted even if only stage I lung cancer patients were retained in the analysis. In receiver operating characteristic analysis, the performance of FR+CTC (area under the curve = 0.8153) was superior to other clinical biomarkers such as carcinoembryonic antigen, neuron-specific enolase, and cytokeratin 19 fragments. In a subgroup analysis, patients with nodule size of >3 cm showed an improved sensitivity (88.46%); although, the specificity appeared to decrease (40%). All five patients with benign diseases in this subgroup had inflammatory diseases, indicating that large inflammatory nodules may also release FR -expressing cells into the circulatory system.FR+CTC is a reliable biomarker for the early diagnosis of small-sized lung cancer. Further study with larger sample size is required to assess the diagnostic efficiency of FR+CTC in patients with large nodule sizes.
Regulatory T cells (Treg) play important roles in preventing autoimmunity, graft-versus host disease and transplant rejection. In rodent transplant models, tolerance induction strategies can induce graft protective CD25CD4 Treg in vivo but therapeutic exploitation of active regulation will more likely depend on protocols that allow generation or selection of regulatory cells ex vivo for use as a cellular therapy. We have used adoptive transfer skin and islet allograft models to identify, develop and evaluate ex vivo protocols that generate donor-reactive, adaptive Treg.Naïve CDA CD4 T cells were stimulated with allogeneic antigen-presenting cell under neutral conditions or with cytokine modification, restimulated under identical conditions and subsequently analyzed for cytokine profile, phenotypic markers characteristic of Treg and in vivo regulatory function.Without modification, CD4 T cells default to a Th2 phenotype characterized by a dominant interleukin-4 response which is profoundly detrimental to allograft survival. However, addition of exogenous interferon-gamma suppresses interleukin-4 production without priming for effector function, induces suppressor of cytokine signaling-1 and results in up-regulation of Foxp3 and CD62L. The generation of these populations is enhanced by, but is independent of, the presence of naturally occurring endogenous Treg. Most importantly, when tested for regulatory function in vivo, these cells prevent rejection of both skin and islet allografts mediated by effector T cells.These data reveal an unexpected role for interferon-gamma in the generation of Treg ex vivo and suggest a possible route for the generation of regulatory cells for therapeutic use.
Ultra-high dose rate radiotherapy (FLASH radiation) can naturally render normal tissues around the tumor tissue resistant to radiotherapy. In contrast, the tumor tissue remains sensitive to radiation under the same conditions. However, the effects of different fractions and dose rates on FLASH radiation remain unclear. This study aimed to determine the optimal dose rate and fraction of FLASH radiation for thoracic radiotherapy. Female Balb/c mice aged 6-8 weeks were irradiated with different dose rates (100 Gy/s or 250 Gy/s) and fractions (1, 2, or 4). Survival was observed in mice receiving 30Gy, with lung tissue examined for acute radiation damage 48 h post-radiation. Late radiation pneumonia and survival rates were monitored in mice irradiated with 20 Gy. The median overall survival (OS) was not reached on the 95th day for mice irradiated with 250 Gy/s FLASH radiation, while it was 89.5 days for those irradiated with 100 Gy/s (P = 0.0436). Mice irradiated with 30 Gy/2 Fr and 250 Gy/s FLASH had shorter median OS than those with 30 Gy/1F (P = 0.0132). However, there was no significant difference in OS between mice irradiated with 30 Gy/2 F and 30 Gy/4 F. Survival curves for mice receiving 20 Gy showed no significant difference in toxicity between different dose rates and fractions. FLASH radiation at 250 Gy/s reduced the incidence of acute radiation pneumonitis in mice compared to 100 Gy/s. Different fractions of irradiation influenced survival in mice, but they were only observed in acute radiation reactions and not chronic radiation reactions. Among the tested fraction methods, fraction 2 had the worst impact on the survival of mice, while fractions 1 and 4 showed similar effects and improved survival compared to fraction 2.
We explored the clinical usefulness of serum carbonic anhydrase 9 as a potential biomarker for conventional renal cell cancer.This study included 91 patients with conventional renal cell cancer and 32 healthy individuals. Enzyme linked immunosorbent assay was used to measure the carbonic anhydrase 9 level. A followup (median 38 months) was performed to track early recurrence after surgery for patients with localized disease. Recurrence-free survival curves were calculated by the Kaplan-Meier method and compared using the log rank test.The mean serum carbonic anhydrase 9 level in patients with metastatic conventional renal cell cancer (216.68 +/- 67.02 pg/ml) or localized conventional renal cell cancer (91.65 +/- 13.29 pg/ml) was significantly higher than in healthy individuals (14.59 +/- 6.22 pg/ml, p <0.001 and p = 0.001, respectively). The mean serum carbonic anhydrase 9 level in patients with metastatic conventional renal cell cancer was significantly higher than in those with localized disease (p = 0.004). Of patients with localized disease those with recurrence had a significantly higher serum carbonic anhydrase 9 than those without recurrence (p = 0.001). On univariate analysis serum carbonic anhydrase 9, tumor stage, tumor grade and tumor size were associated with recurrence. The recurrence-free survival curve indicates that patients with a high serum carbonic anhydrase 9 level had a significantly higher recurrence rate than those with a low serum carbonic anhydrase 9 (p = 0.001).Our data suggest that serum carbonic anhydrase 9 is increased as the tumor progression occurs. A high carbonic anhydrase 9 level is associated with postoperative recurrence.
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