RasGTPase-activating protein is a target of caspases in spontaneous apoptosis of lung carcinoma cells and in response to etoposide

p120 RasGTPase-activating protein (RasGAP), the main regulator of Ras GTPase family members, is cleaved at low caspase activity into an N-terminal fragment that triggers potent anti-apoptotic signals via activation of the Ras/PI-3 kinase/Akt pathway. When caspase activity is increased, RasGAP fragment N is further processed into two fragments that effectively potentiate apoptosis. Expression of RasGAP protein and its cleavage was assessed in human lung cancer cells with different histology and responsiveness to anticancer drug-induced apoptosis. Here we show that therapy-sensitive small lung carcinoma cell (SCLC) lines have lower RasGAP expression levels and higher spontaneous cleavage with formation of fragment N compared to therapy-resistant non-small cell lung carcinoma cell (NSCLC) lines. The first RasGAP cleavage event strongly correlated with the increased level of spontaneous apoptosis in SCLC. However, generation of protective RasGAP fragment N also related to the potency of SCLC to develop secondary therapy-resistance. In response to etoposide (ET), RasGAP fragment N was further cleaved in direct dependence on caspase-3 activity, which was more pronounced in NSCLC cells. Caspase inhibition, while effectively preventing the second cleavage of RasGAP, barely affected the first cleavage of RasGAP into fragment N that was always detectable in NSCLC and SCLC cells. These findings suggest that different levels of RasGAP and fragment N might play a significant role in the biology and different clinical course of both subtypes of lung neoplasms. Furthermore, constitutive formation of RasGAP fragment N can potentially contribute to primary resistance of NSCLC to anticancer therapy by ET but also to secondary therapy-resistance in SCLC

Expression of DNA damage response proteins and complete remission after radiotherapy of stage IB–IIA of cervical cancer

The primary aim of this study was to investigate if the expression of the DNA damage identifying protein DNA-PKcs known to be involved in DNA repair after treatment with ionising radiation can be used as a predictive marker for radiotherapy (RT) response in cervical cancer. Formalin-fixed primary tumour biopsies from 109 patients with cervical cancer, FIGO-stage IB–IIA, treated with preoperative brachytherapy followed by radical surgery were analysed by immunohistochemistry. In addition, correlation studies between early pathological tumour response to radiation and expression of Ku86, Ku70, Mdm-2, p53 and p21 in primary tumours were also performed. We found that tumour-transformed tissue shows positive immunostaining of DNA-PKcs, Ku86 and Ku70, while non-neoplastic squamous epithelium and tumour-free cervix glands show negative immunoreactivity. Expression of DNA-PKcs positively correlated with both Ku86 and Ku70, and a statistically significant correlation between the Ku subunits was also found. After RT, 85 patients demonstrated pathologic complete remission (pCR), whereas 24 patients had residual tumour in the surgical specimen (non-pCR). The main finding of our study is that there was no correlation between the outcome of RT and the expression of DNA-PK subunits. Positive p53 tumours were significantly more common among non-pCR cases than in patients with pCR (P=0.031). Expression of p21 and Mdm-2 did not correlate with the outcome of RT

Analysis of resilience and sexual behavior in persons with HIV infection

Abstract The main objective of this study was to evaluate ex post facto resilience in persons with HIV infection and its relationship to socio-demographic and sexual behavior variables. Participants included 159 persons with HIV infection, of both sexes, aged between 19 and 55 years. Fifty-one percent of patients were infected through homosexual means. Sixty-seven percent were in the asymptomatic phase of infection. Assessment instruments used were the following: a questionnaire on socio-demographic data and sexual behavior and the Connor-Davidson Resilience Scale. The evaluation was individual, voluntary, and anonymous. The results showed that 49.05% of patients had average resilience, 27.68% had high resilience, and 23.37% had low resilience. They found that heterosexual patients infected with HIV, diagnosed between 1985 and 1990 (23 and 28 years of diagnosis) and those who had disclosed their HIV status to more than 30 people, had greater resilience than homosexual patients, diagnosed between 1996 and 2000 (13 and 17 years of diagnosis) and those who had disclosed their HIV status to 1–5 people. Finally, resilience was not a predictor of sexual risk factor. It is suggested that health interventions take into account the resilience and psychological variables that may be beneficial to improve coping with the disease

Induction of unscheduled DNA synthesis in human bone marrow cells by bifunctional alkylating agents

Abstract A technique has been developed for handling human bone marrow cells intended for the examination of DNA repair synthesis. DNA-repair synthesis, induced by melphalan and nitrogen mustard, was measured as the incorporation of 3H-thymidine, registered by autoradiography as unscheduled DNA synthesis (UDS). Comparison of various cell populations disclosed considerable differences in their UDS level, this generally being greatest for the blast populations. During maturation of both myelopoietic and erythropoietic cells, there was a decrease in the UDS level, which was lowest for the end-cell stage. The lymphocytes and monocytes differed considerably in their capacity for UDS. The developed technique would appear to offer an opportunity for determining the capacity for DNA-repair synthesis in malignant bone marrow cells, a factor that has been linked to sensitivity to alkylating agents.</jats:p

[Radioimmunotherapy is rapidly developing to clinically efficient therapy]

The use of monoclonal antibodies (mabs) in cancer therapy has gained renewed interest, due to recent reports of remarkable clinical response, particularly in patients with low-grade non-Hodgkin lymphoma. Better defined and more appropriate target antigens and "humanized" mabs, reducing the risk of inducing neutralising human anti-mouse antibodies, have contributed to the improvement in results. Conjugation of mabs with various radionuclides is now being explored as a means of further enhancing clinical efficacy, the idea being to allow systemic delivery of targeted radiation to areas of disease while sparing normal tissue. Radioimmunotherapy may be administered as a single large dose of radiolabelled mabs, usually requiring haematological stem cell support, or as multiple, smaller fractions. The criteria for the selection of mabs and radionuclides are discussed in the article, as are recent clinical data and the problems and prospects of future developments in radioimmunotherapy