There is no significant association between death receptor 4 (DR4) gene polymorphisms and lung cancer in Turkish population.

Death receptor 4 (DR4) gene is a candidate tumor suppressor gene that has a role in apoptotic pathway. It was reported in literature that polymorphisms in DR4 gene lead to susceptibility to many cancers. In accordance with this information, we aimed to investigate the association between G422A, C626G, A683C and A1322G polymorphisms in DR4 gene and lung cancer. We selected 60 patients with lung cancer (LC) and 30 healthy, sex and age matched volunteers randomly. Four polymorhisms, G422A, C626G, A683C and A1322G, in DR4 gene were analyzed with Polymerase Change Reaction (PCR)--Restriction Fragment Lenght Polymorphism (RFLP) and Amplification Refractory Mutation System (ARMS) techniques in both groups. Our results showed that there are no statistically significances between the patients and controls in terms of the G422A, C626G, A683C and A1322G polymorphisms in DR4 gene (p > 0,05). Our findings showed no role of DR4 gene polymorphisms in susceptibility to LC and provide a plausible explanation for DR4 genetic heterogeneity in LC susceptibility.

Targeting multidrug-resistant tuberculosis (MDR-TB) by therapeutic vaccines.

Tuberculosis (TB) has scourged humankind for millennia, and latent infection affects nearly one-third of today's world population. The emergence of multidrug-resistant (MDR)-TB is a major global threat and reflects treatment failure of drug-sensitive disease. MDR-TB management is a burden for patients and society; success rates are unacceptably low with prolonged treatment duration. Mycobacterium tuberculosis (Mtb) possesses the ability to transform into a dormant state in which it can persist in the face of antimicrobial treatment and host defense. This sub-population of persisters is largely responsible for lengthy and difficult treatment. Targeting persistent bacilli could eventually improve the treatment success rate (currently 50-65 %) and shorten duration of treatment. A subset of therapies in the pipeline, termed therapeutic vaccines, use the host immune response to attack Mtb. The historical occurrence of an exacerbated host response has resulted in a negative perception of therapeutic vaccines. Thus, a renewed concept of immunotherapy is needed. We review current perspectives of immunotherapy in MDR-TB based on the knowledge of TB immunology and briefly discuss the profiles of several therapeutic vaccine products.

Alterations in p16 and p53 genes and chromosomal findings in patients with lung cancer: fluorescence in situ hybridization and cytogenetic studies.

BACKGROUND: Chromosomal aberrations and instability of gene(s) are two factors related to the genetic instability of cancer cells. A loss of the tumor-suppressor function of the genes p16 and p53 is the most common event leading to the development of human cancers. Carcinoma of the lung is the leading cause of cancer deaths in the world. Chromosomal abnormalities in lung cancer may provide a valuable clue to the identification of target loci and culminate in a successful search for the major genes. The aim of this study was to investigate (i) alterations of the p16 and p53 genes and (ii) chromosomal aberrations in patients with small cell and non-small cell lung cancer by fluorescence in situ hybridization (FISH) and cytogenetic studies. We carried out cytogenetic analysis by Giemsa-banding in 18 cases. FISH probes for the p16 and p53 genes were also used on interphase nuclei to screen the alterations in these genes in lung cancer (LC). RESULTS: We observed a high frequency of losses of the p16 - in 8/18 (44%) - and p53 - in 7/18 (39%) - genes in the cases with LC. A total of 18 patients showed predominantly numerical and structural aberrations. Among these two types, structural aberrations predominated and usually consisted of deletions, breaks, and fragilities in various chromosomes. Both structural and numerical changes were observed in almost all patients. Chromosomes 3 and 1 were found to be most frequently involved in structural abnormalities, followed by chromosomes 6, 9, and 8. Autosomal aneuploidies were also observed to be the most frequent (chromosomes 22, 19, 18, 20, 9, and 17), followed by those of the X and Y chromosomes. The expression of fragile sites was also found to be significantly higher in seven chromosomal regions: 3p14, 1q21, 1q12, 6q26, 9q13, 8q22, and 8q24. CONCLUSION: Our data confirmed that DNA damage and genomic instability may be factors contributing to the mutation profile and development of lung cancer. The patients who developed lung cancer showed a high frequency of loss of both p16 and p53, in addition to chromosomal aberrations. Tobacco could be a major carcinogenic factor in lung-cancer progression. The loss of p16 and p53, and increased incidence of autosomal aneuploidy and chromatid breaks, along with other chromosomal alterations, can contribute to the progression of the disease.

Gemcitabine, vinorelbine, and Cisplatin in the treatment of advanced nonsmall cell lung cancer.

OBJECTIVES: Currently, cisplatin-based doublet combinations are accepted to be the first-line chemotherapy for advanced nonsmall cell lung cancer (NSCLC). Although triplet chemotherapeutics have been shown to be more effective and active than doublets, their toxicity was higher as expected. Therefore, we conducted this phase II trial using the combination of gemcitabine-cisplatin-vinorelbine with lower than usual but acceptable doses of gemcitabine and cisplatin to obtain higher response rate than doublet but less toxicity than triplet combinations. METHODS: In this trial, stage IIIB and IV chemotherapy naive NSCLC patients with measurable disease and performance status of 0 to 2 were included. Gemcitabine and vinorelbine at the doses of 900 mg/m and 25 mg/m, respectively were administered on days 1 and 8, and cisplatin at a dose of 50 mg/m on day 1, every 21 days. RESULTS: Three of the 39 patients included in the trial were complete responders (7.7%). The overall response rate was 56.4%, median time to the progression was 6 months, median overall survival time was 12 months, and 1-year survival rate was 49.6%. Grade II to III neutropenia and thrombocytopenia occurred in 24% and 30% of the patients, respectively. Febrile neutropenia was observed in 13.5% of the patients and only these patients received G-CSF. Platelet and erythrocyte transfusions were required in 12 (32.4%) patients. No toxic or early death was observed. CONCLUSIONS: This combination of gemcitabine-cisplatin-vinorelbine with lower doses of cisplatin and gemcitabine was effective and active in advanced NSCLC. The overall response rate, 1-year survival and median survival time were nearly similar to previous trials in which higher doses of these 3 drugs were used. The toxicities were more acceptable and manageable than the regimes with higher doses; therefore, we may suggest a treatment option for advanced stage NSCLC.

Expression of cyclooxygenase-1 and cyclooxygenase-2 in bronchial epithelium and nonsmall cell lung carcinoma.

BACKGROUND: Cyclooxygenase (Cox) is the main target enzyme for the nonsteroidal antiinflammatory drugs that have been shown to suppress carcinogenesis in both experimental models and epidemiologic studies. METHODS: To evaluate its utility as an intermediate biomarker in bronchial chemoprevention trials, the authors examined Cox 1 and Cox 2 expression in normal and premalignant bronchial epithelial cells and nonsmall cell lung carcinoma (NSCLC) samples using an immunohistochemical staining technique. Included in the current study were 101 NSCLC samples and 77 bronchial biopsy samples obtained from 15 healthy smokers. RESULTS: In the normal bronchial epithelium, Cox 2 expression was found to be completely negative whereas Cox 1 expression was noted in a few scattered cells. The areas of basal cell hyperplasia and squamous metaplasia demonstrated the same pattern. There were relatively more Cox 2-positive tumors, as defined by positive staining in > 10% of tumor cells, than Cox 1-positive tumors (30 of 101 tumors [30%] vs. 14 of 101 tumors [14%]; P = 0.01). When tumor types were considered, there were more Cox 2-positive adenocarcinomas compared with squamous cell carcinomas (21 of 51 adenocarcinomas [41%] vs. 9 of 46 squamous cell carcinomas [20%]; P = 0.03). In contrast, fewer adenocarcinomas tended to show Cox 1 expression compared with squamous cell carcinomas (4 of 51 adenocarcinomas [8%] vs. 9 of 46 squamous cell carcinomas [20%]; P = 0.14). Although smokers tended to have more Cox 2-positive tumors than nonsmokers (29 of 91 tumors in the smokers [32%] vs. 1 of 10 tumors in the nonsmokers [10%]; P = 0.15), there was no statistically significant relation found between Cox 1 or Cox 2 expression and smoking status or prognostically significant clinicopathologic features. CONCLUSIONS: The results of the current study suggest that Cox 1 and Cox 2 expression may not be a useful intermediate biomarker in bronchial chemoprevention trials. Nevertheless, considering the patterns of Cox 1 and Cox 2 expression in tumor cells, Cox expression status may be a useful parameter when designing treatment strategies for a subset of NSCLC patients.