Overexpression of Cdc25C predicts response to radiotherapy and survival in esophageal squamous cell carcinoma patients treated with radiotherapy followed by surgery

Biomarker identification is crucial for the selection of patients who might benefit from radiotherapy.To explore potential markers for response and prognosis in patients with locally advanced esophageal carcinoma treated with radiotherapy followed by surgery,we evaluated the expression of cell cycle checkpoint-related proteins Chk2,Cdc25C,and Cyclin D1.A total of 56 patients with locally advanced esophageal squamous cell carcinoma were treated with radiotherapy followed by surgery.Pretreatment tumor biopsy specimens were analyzed for Chk2,Cdc25C,and Cyclin D1 expression by immunohistochemistry.High expression of Chk2,Cyclin D1,and Cdc25C was observed in 44(78.6%),15(26.8%),and 27(48.2%) patients,respectively.The median survival was 16 months(range,3-154 months),with a 5-year overall survival rate of 19.6%.Overexpression of Chk2 was associated with smoking(P = 0.021),overexpression of Cdc25C was associated with patient age(P = 0.033) and tumor length(P = 0.001),and overexpression of Cdc25C was associated with pathologic complete response(P = 0.038).Univariate analysis demonstrated that overexpression of Cdc25C and pathologic complete response was associated with better survival.In multivariate analysis,Cdc25C was the most significant independent predictor of better survival(P = 0.014) for patients treated with radiotherapy followed by surgery.Overexpression of Cdc25C was significantly associated with pathologic complete response and better survival of patients with locally advanced esophageal cancer treated with radiotherapy followed by surgery.These results suggest that Cdc25C may be a biomarker of treatment response and good prognosis for esophageal carcinoma patients.Thus,immunohistochemical staining of Cdc25C in a pretreatment specimen may be a useful method of identifying optimal treatment for patients with esophageal carcinoma.

Expression and unique functions of four nuclear factor of activated T cells isoforms in non-small cell lung cancer

Nuclear factor of activated T cells (NFAT) is an important family of transcription factors that can be activated by calmodulin and calcineurin in human cells. To investigate the expression and clinical significance of NFAT isoforms and calcineurin in non-small cell lung cancer (NSCLC), we collected tumor and adjacent normal tissues from 159 NSCLC patients and assembled them in a tissue microarray. Protein levels of NFAT1, NFAT2, NFAT3, NFAT4, and calcineurin were determined using immunohistochemistry. Correlations between NFAT and calcineurin expression and clinicopathologic characteristics were analyzed. We found that the positive rates of NFAT1 (52.8%, 84/159), NFAT2 (11.3%, 18/159), NFAT3 (28.3%, 45/ 159), NFAT4 (47.2%, 75/159), and calcineurin (47.8%, 76/159) expression were significantly higher in tumor tissues than in adjacent normal lung tissues (P < 0.001), respectively. The positive rate of NFAT1 expression was significantly higher in patients with adenocarcinoma (63.5% , 47/74) than in those with squamous cell carcinoma (43.5%, 37/85) (χ2 = 6.340, P = 0.012); with lymph node metastasis (61.6%, 53/ 86) than without lymph node metastasis (42.5%, 31/73) (χ2 = 5.818, P = 0.016); and with stage-II and -III diseases (61.8%, 55/89) than with stage-I disease (41.4%, 29/70) (χ2 = 6.524, P = 0.011). Moreover, the overexpression of NFAT1 was associated with poor survival of NSCLC patients (χ2 = 5.006, P = 0.025). The positive rate of NFAT4 was significantly higher in patients with squamous carcinoma (57.6%, 49/85) than in those with adenocarcinoma (35.1%, 26/74) (χ2 = 8.045, P = 0.005) and with high and moderate differentiation (54.9% , 61/111) than with low differentiation (29.2% , 14/48) (χ2 = 8.943, P = 0.003). Calcineurin overexpression was significantly associated with histologic type (higher in squamous carcinoma than in adenocarcinoma, χ2 = 8.897, P = 0.003), differentiation grade (higher in high-moderation grade than in low grade, χ2 = 9.566, P = 0.002) and gender (higher in male than in female, χ2 = 5.766, P = 0.016). Furthermore, calcineurin expression was significantly correlated with NFAT4 level (r = 0.429, P < 0.001). These results suggest that NFAT1 expression is associated with lung adenocarcinoma progression, and NFAT4 expression, which was higher in squamous lung cancer, is associated with calcineurin expression and differentiation grade.

A rat model of high altitude polycythemia rapidly established by hypobaric hypoxia exposure

Objective To investigate the effects of simple hypobaric hypoxia on parameters of hematology and blood rheology in order to establish a rat model of simulated high altitude polycythemia(HAPC) for the study of pathophysiologic mechanisms and medical prevention and treatment of HAPC.Methods Fortyeight male Wistar rats were randomly divided into three normal control groups and three hypoxia model groups.Normal control group rats were bred in normoxia conditions,and hypoxia group rats were subjected to hypoxic exposure for 8 hours per day at simulated 5 500 m high altitude in a hypobaric chamber.After hypoxic exposure for 2,4,12 weeks,one group of normal control and hypoxia model rats were killed and blood was collected,respectively.Then parameters of erythrocyte and blood rheology were examined.Results Mucous membrane of hypoxia model rats showed obviously cyanosis after 2 weeks hypoxic exposure.Hemoglobin concentration of hypoxia model rats were beyond 210 g/L after 2 weeks,4 weeks and 12 weeks hypoxia exposure and significantly increased than that of normal control rats respectively.Besides,RBC counts,hematocrit,whole blood viscosity,erythrocyte aggregation index of hypoxia model rats were all notably higher than those of normal control rats respectively.Conclusion A rat model of high altitude polycythemia can be rapidly established by hypobaric hypoxia exposure at simulated 5 500 m high altitude for 8 hours daily.

The physiological effects of resveratrol and its potential application in high altitude medicine

Resveratrol, as a natural polyphenolic compound, has a wide range of beneficial effects, which includes anti-tumor, cardiovascular protection, anti-oxidant and estrogen-like effects, and so on. Its various physiological properties are closely related to the therapeutic principle for prevention and treatment of high altitude hypoxia injury. Resveratrol may play an important role in relieving or curing high altitude diseases, especially high altitude polycythemia(HAPC). However, the literature about study and application of resveratrol in plateau medicine field is rarely reported up to now. In this review, we summarized the physiological effects of resveratrol, discussed the possible main principle of resveratrol for HAPC therapy, and looked forward to resveratrol's perspective or potential application in high altitude medicine.

Expression of Coxsackievirus and Adenovirus Receptor in Human Lung Cancer： Possible Clinical Significance

OBJECTIVE To explore the relationship between CAR and the development of human lung cancer, as well as to provide the basis for the clinical treatment of lung cancer using an adenovirus vector-based gene therapy. METHODS CAR expression was assessed immunohisto- chemically in tumoral, paraneoplastic and normal samples from 112 lung cancer patients. At the same time, the mRNA and protein expression of CAR in 32 cases were determined by RT-PCR and Western blot. The relationship between CAR expression and clinicopathologic parameters was statistically analyzed. RESULTS There was no expression of CAR in normal lung tissue but a little in paraneoplastic tissue. The positive rate was 43% in squamous cell carcinoma, and 70% in adenocarcinoma. Both were much significantly higher than that in paraneoplastic tissue. The CAR expression level in adenocarcinoma was higher than that in squamous cell cancer, mRNA expression by RT-PCR and protein expression by Western blot were consistent with immunohistochemistry results. CONCLUSION CAR is overexpressed in human lung cancer, especially in adenocarcinoma. This data offer the reliable basis for adenovirus-mediated gene therapy of lung cancer; more important, CAR may take part in the formation or development of lung cancer; this may be exploitable for the development of antibody-directed therapy in human lung cancer.

A human-specific insertion promotes cell proliferation and migration by enhancing TBC1D8B expression

Human-specific insertions play important roles in human phenotypes and diseases.Here we reported a 446-bp insertion(Insert-446)in intron 11 of the TBC1D8B gene,located on chromosome X,and traced its origin to a portion of intron 6 of the EBF1 gene on chromosome 5.Interestingly,Insert-446 was present in the human Neanderthal and Denisovans genomes,and was fixed in humans after human-chimpanzee divergence.We have demonstrated that Insert-446 acts as an enhancer through binding transcript factors that promotes a higher expression of human TBC1D8B gene as compared with orthologs in macaques.In addition,over-expression TBC1D8B promoted cell proliferation and migration through“a dual finger”catalytic mechanism(Arg538 and Gln573)in the TBC domain in vitro and knockdown of TBC1D8B attenuated tumorigenesis in vivo.Knockout of Insert-446 prevented cell proliferation and migration in cancer and normal cells.Our results reveal that the human-specific Insert-446 promotes cell proliferation and migration by upregulating the expression of TBC1D8B gene.These findings provide a significant insight into the effects of human-specific insertions on evolution.