がんの科学と治療

MGMT promoter methylation is currently considered the main prognostic biomarker in glioblastoma, yet some concerns remain about its actual impact on outcome. The aim of the present study was to analyze literature data on this topic. Therefore, a systematic review and analysis of recently published glioblastoma cohorts examining the relationship between MGMT methylation and prognosis was performed. We found that only 19/28 studies (68%) confirmed the prognostic value of MGMT methylation and/or its role in predicting response to temozolomide. In these studies, however, the population showed significantly lower rates of unfavorable prognosticators as compared with studies where MGMT methylation was not prognostic/predictive. Moreover, studies demonstrating a better prognosis for MGMT methylated cases had significantly lower rates of deaths at 3 and 6 months. Multivariate analysis showed that the 3-month and 6-month deaths are significantly associated with the prognostic/predictive value of MGMT methylation, and that the percent of MGMT methylated tumors and of patients treated with alkylating drugs trend towards statistical significance if modeled with the 6-month but not with the 3-month mortality rate. These results suggest that the paucity of short-term survivors may represent a bias in studies focusing on MGMT methylation and prognosis, and that a temporal threshold may be necessary in order to demonstrate the clinical benefit of MGMT promoter methylation.

Cancer is one of the most prevalent diseases that affect the major population with each year the frequency is increasing exponentially. Patients with diagnosed cancer are generally treated with the conventional therapies like radiation therapy, chemotherapy. However the survival rate and the life span are known to prolonged, these therapies are quite problematic let alone their detrimental side effects. Gene therapy on the other hand is quite promising since the body’s immune response is not compromised while targeting the cancerous cell. While getting further insights into the complex pathways and mechanisms associated with the development of malignant cells has led to the identification more sophisticated and specified cancer therapies, it nevertheless remains imperative to execute the conventional therapies and the associated anticancer drug molecules. Various characteristic features like less toxicity and ability to induce an immune response make the therapy quite probable for various cancers like pancreatic, ovarian and Glioblastoma. Based on the results obtained from pre-clinical studies in model animals, it has set stage for the commercialization of the human trials. The advantages associated with this therapy for the treatment has started attracting focus to further modify and optimize the procedures for better results.

Objective: To determine the role of c-Cbl in the apoptotic process, using several means, stressing the role of oxidative stress in cancer cells.

Methods: Prostatic epithelial cell apopotosis of c-Cbl-/-mice were compared to wildtype mice (n: 6 per condition), upon testosterone-antagonist flutamide. c-Cbl-deficient mouse embryonic fibroblasts (MEFs) were compared to wild type MEFs under etoposide or hydrogen peroxide treatments. The use of c-Cbl RNA silencing in the human prostate adenocarcinoma cell line LNCaP allowed to reveal c-Cbl’s role in LNCaPs’ apoptosis. The role of the p38-MAPK stress pathway in the LNCAP c-Cbl anti-apoptotic effect as well as its relationship with the well-documented Grb2-associated Tyrosine-Kinase-Receptor (TKR) down-regulation were investigated, using c-Cbl and/or Grb2 RNA silencing. Human c-Cbl protein expression was analysed by Western blotting and immunostaining, comparing prostatic adenocarcinoma (x22) to benign prostatic hypertrophia (x6). In situ tissue microarrays were used to assess several human malignancies (x17 and x6 spots/tissue) and to compare the magnitude of c-Cbl and oxidative stress expression.

Results: The cellular apoptotic threshold decreased in Mouse c-Cbl-/-prostatic cells and c-Cbl-/- MEFs. Only hydrogen peroxide in c-Cbl-/-MEFs induced apoptosis up to six times more than controls. Similar results were found in LNCaPs. c-Cbl down-regulates the activation of the apoptotic ASK1-p38MAPK stress pathway. c-Cbl is overexpressed in prostate, ovary, uterus, brain, lung, colon, rectum adenocarcinoma and in rhabdomyosarcoma. We found a correlation between malignant oxidative stress and c-Cbl over-expression.

Conclusions: c-Cbl increases the cellular apoptotic threshold of wild type MEFs and mouse prostate cells. c-Cbl behaves as a strong cellular protector against oxidative stress in MEFs and LNCaPs. The p38-MAPK pathway is down-regulated by c-Cbl, possibly independently of the Grb2-associated TKR down-regulation. A high c-Cbl expression in several cancers often associated with high oxidative stress expression has been found, suggesting that c-Cbl could thereby promote their survival.

To face the challenges in hyperthermic oncology we have made research on nano-heating the malignant and healthy cells and this review paper shows our results which were presented at the largest OMICS Group Conference in the United States in 2013. We introduced nano-heating technology which means selecting and heating the membrane of the malignant cells purely by the electromagnetic effects without any extra nano-particle applications. The technology (called modulated electrothermia or oncothermia) is impedance controlled capacitive coupling; no plane-wave radiation is dominating as in other capacitive (radiative) solutions. The nano-selection is based on the metabolic, on the adherent and on the organizing deviations of the malignant cells from their healthy hosts. The cell-killing mechanism is connected to the intensive, but very local, nano-range heating. These effects are proven in silico, in vitro and in vivo experiments, as well as in pre-clinical and veterinarian applications. Based on the controllable and safe methodology the treatment is applied in human clinical practice. My objective is to summarize the results which are connected with oncothermia method.

Helicobacter pylori is gram-negative bacterial pathogen, associated with chronic gastritis and other severe gastro duodenal diseases such as peptic and gastric ulcers, gastric cancer, and mucosa-associated lymphoid tissue (MALT) lymphoma. One of the intriguing virulence factors of H. pylori is cag Pathogenicity Island (cagPAI) which codes for Type IV secreting system. Type IV secreting system is found in many strains of H. pylori. Present work focuses on protein interaction studies to clarify and confirm the interactions and assembly of proteins present in outer membrane and pilus structure of t4ss. During the interaction studies of t4ss we have focused on only CagC, Cag3 and CagM interactions based on steriochemical properties. It is found that the pattern of pilus formation follows the specific order of assembly and the order of assembly is CagC-C dimer formation followed by tetramer formation to form stable pilus assembly of t4ss. The order of interaction at the outer membrane is CagM interacts with CagC-C dimer and then with Cag3 to form sub-assembly of t4ss.This findings of structural interaction can be used to prevent onset of diseases caused by H. pylori by preventing the formation of t4ss, pilus assembly and ultimately the translocation of onco protein CagA in host organism.

Breast cancer is one of the leading causes of deaths worldwide in women with hormone therapy, chemotherapy, targeted therapies, or their combinations being the current options for treating the disease at the different stages (stages I-III) with associated side-effects or increasing life-span at the advanced stage (stage IV). Small interfering RNA (siRNA) as an effective tool to selectively knockdown of a particular gene could be harnessed in combination with plasmid DNA (carrying a gene of interest) and conventional anti-cancer drugs for precisely treating breast cancer with minimal side effects. However the limitation of the naked siRNA and DNA in penetrating the plasma membrane and their sensitiveness to nuclease-mediated cleavage render the technology rather complex in therapeutic intervention. Recently, we have developed pH-sensitive carbonate apatite as a potential nano-carrier to efficiently deliver siRNA or DNA across the cell membrane and facilitate them to escape endosomal acidic compartment resulting in specific cleavage of a particular mRNA transcript or expression of a desirable protein, respectively. Moreover, we demonstrated nanoparticle-assisted delivery of the siRNAs targeting cyclin B1, PLCgamma- 2/calmodulin1, NFκB1/NFκB2, ABCG2/ABCB1 and cROS1 mRNAs sensitizes cervical adenocarcinoma and breast cancer cells towards traditional anti-cancer drugs. Here, we report that co-delivery of the siRNA targeting HER2/ErbB2 gene transcript and p53 gene with the help of carbonate apatite nanoparticles synergistically induces inhibition of growth/proliferation of breast cancer cell lines as well as regression of the breast tumor induced in Balb/c mice. Additionally, combined delivery of nanoparticle-associated HER2/ErbB2 siRNA and p53 gene apparently slows down the growth of the established tumor in presence of doxorubicin or paclitaxel compared with the individual free drugs. Thus, the combination of HER2/ErbB2 knockdown and restoring of normal p53 function could be a highly promising approach necessitating further studies through pre-clinical trials with different models of breast cancer to establish the therapeutic role of this combination therapy prior to conducting clinical trials in breast cancer patients.