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Abstract: In recent years, the application of molecular biological techniques to the diagnosis and treatment of cancer has proved successful. In this kind of pathologies, molecular diagnosis is of fundamental importance as it allows identification at a pre-symptomatic stage, and then in the early phase, of the subjects in which cancer disease is developing. Molecular diagnosis of tumors by deoxy-ribonucleic acid (DNA) analysis is conducted on biological samples such as urine, feces, sputum, vaginal swab, and blood, searching and identifying in the various samples for the presence of cell carriers of an altered genetic information. The sensitivity of this kind of analysis is so high as to be very reliable even in the presence in the sample of a few tumor cells, level not reachable through the traditional “tumor markers”. The achievement of a facilitated early diagnosis of the tumor and, consequently, through the organization of specific therapeutic interventions, the prevention of the invasiveness of the pathology, allow to insert this kind of analysis among the most important investigations in the field of cancer prevention. Molecular oncology examinations have targeted the mutational study of the most involved genes in the onset of hereditary and/or family cancers such as breast, ovary, colon, melanoma, stomach, thyroid, etc. In addition, given the growing focus on the molecular mechanisms underlying the individual response to conventional chemotherapeutic drugs and molecular targeted agents responsible for drug resistance, pharmacogenetics exams have been added to those of molecular oncology. Some genes, when altered and/or mutated, can cause the development of tumors. In some types of cancer, the mutation may affect only somatic cells: in this case, the development will manifest itself only in the subject carrier of the mutation. Otherwise, if the mutation affects germ cells genes, it may occur the possibility to convey to children a susceptibility to the development of tumors. In fact, a significant proportion of cancers are hereditary. For example, it is estimated that about 7% of breast cancers, 10% of ovarian cancers, and about 5-10% of colorectal cancers, are caused by recurrent mutations at specific genes level. The early detection of cancer, with the ability to identify individuals at risk of developing the disease, is now the best way to reduce mortality from it. Determining whether a person has a mutation in a gene involved in neoplastic transformation that predisposes to the development of cancer (susceptibility or genetic predisposition) can significantly decrease its incidence and mortality. For example, as a result of in-depth studies of families at risk, it has been estimated that women who have inherited mutations in breast cancer genes (BRCA1 or BRCA2) are likely to develop breast cancer in 87% of cases, compared with 10% of non-bearers. This probability falls to 44-60% in the case of ovarian cancer, compared with 1% probability of not carriers. In this area, basic research has been developed with the aim of contributing to the study of the molecular mechanisms of oncogenesis, which generally has multistage character, with an initial immortalization and cell transformation and subsequent tumor progression. In this regard, studies at the molecular and functional level have been focused on models of different types of cancer, e.g. melanoma. In parallel, it has been studied the possible oncogenetic role of certain families of genes that have a functional role in embryogenesis, and in general in cell proliferation/differentiation, e.g. homeotic (HOX) genes. The gene expression profiles of purified cancer cells can be evaluated by microarray technique, comparing them with those of normal cells: comparative analysis, based on specific software, allows the identification of genes selectively modulated in the genetic program of tumor cells, in particular of genes specifically involved in the onset and progression of tumors. The modern goal of cancer therapy is to eliminate the disease by minimizing trauma and paying attention to the quality of life (QOL). With the passing of time, there has been a change of therapeutic paradigms and we have gone from the objective of maximum tolerable treatment to that of minimum effective treatment. This clinical imperative has its foundation in the quick transfer of biological knowledges to the care, integrating molecular informations with the development of new treatment methods. Especially for a delicate operation, even psychologically, such as that for breast cancer. In this setting, we have focused particularly on the technique of sentinel lymph node, demonstrating the possibility to avoid the treatment of the axilla in patients at low risk of recurrence. The term “molecular targeted therapy” is used to refer to agents that target specific pathways activated in the processes of growth, survival, invasion, and metastasis of cancer cells and in tumor neo-angiogenesis. The large and perhaps excessive optimism, caused by the gradual deepening of the knowledges of these mechanisms, has received a further boost by the arrival on the therapeutic scene of imatinib and other drugs belonging to the class of targeted biomolecular agents, including some monoclonal antibodies (McAb) such as trastuzumab, rituximab, cetuximab, and bevacizumab, and some small molecules, already entered clinical practice. But the question we must ask is whether that enthusiasm is justified and supported by scientifically strong and clinically proven data. The difficulties encountered in the research and development of new truly effective molecules and the disappointing results obtained in the early life of some of these agents and, not least, the high costs of treatments must lead to greater caution. The medical oncologist has the inescapable duty to possess sufficient culture to be able to properly use these new therapies in his diagnosis and treatment decision-making. Keywords: Gynecologic malignancies, diagnosis, treatment, prevention, molecular biology, genetics.Download Full Article |
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Abstract: Radiotherapy-induced fibrosis (RTIF)presents a challenge in radiotherapy for cancer patients. Although numerous studies have attempted to elucidate the mechanisms leading to RTIF, the pathogenesis of RTIF at the cellular and molecular level is still incompletely described. One key component involved in the post-radiation injury is the pleuripotent cytokine transforming growth factor (TGF)-β. TGF-β signaling pathway has been under intensive investigation about its critical role in radiation-induced fibroproliferative disease. Connective tissue growth factor (CTGF), also known as insulin-like growth factor binding protein-related protein 2 (IGFBP-rP2) is a potent regulator of fibroblast proliferation, cell adhesion, andstimulation of extracellular matrix production. CTGF is known as a major downstream mediator of the chronic fibrotic effects of TGF-β. Here we have demonstrated that irradiation and TGF-β induced CTGF, subsequently upregulates fibrotic factors such as fibronectin and type IV collagen. Furthermore, as HMG-CoA reductase inhibitors, statins inhibit expressions of CTGF and downstream fibrotic proteins in both normal human fetal fibroblasts (HFL-1) and human dermal fibroblasts (HDF) on TGF-β treatment or irradiation. Our study also demonstrates that simvastatin not only suppressed TGF-β-induced fibrosis through inhibition of CTGF production but also CTGF-induced fibrosis. We further show that simvastatin may act in a TGF-β-independent manner by inhibiting Rho kinase pathway. Taken together, these data suggest that radiotherapy may upregulate CTGF expression in a TGF-β-dependent and -independent manner, thereby enhancing expression of profibrotic factors and inducing lung fibrosis. Keywords: CTGF, Statins, Fibrosis, TGF-β, Radiation, Rho/ROCK pathway.Download Full Article |
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Abstract: Over the last ten years rapid progress is being made regarding the incorporation of nanoparticles in cancer diagnosis and treatment. Besides the limitations that have to be addressed, there are various research studies suggesting some promising nanodiagnostic and nanotherapeutic platforms for cancer managment. Nanotherapeutic platforms are based on the localized application of nanoparticles using targeting moieties, most usually antibodies, in order to in vivo direct nanoparticles to cancer cells. Thereafter, either nanoparticles react to external stimulus, for example under radiofrequency waves nanoparticles generate thermal energy, or they are used for targeted drug-delivery platforms, which allows the augmentation of drug concentration in the cancerous site of the body and thus minimizing side effects and increasing the efficacy of the drug. Regarding nanodiagnostics, particular focus is paid on nanoparticles that can act as contrast agents in cancer imaging for in vivo nanodiagnostics and on nanobiochips and nanobiosensor, devices that incorporate the “lab on a chip” notion for in vitro nanodiagnostics. In this review, several advanced nanodiagnostic and nanotherapeutic platforms are discussed, on the development of more effective and targeted molecular techniques in the diagnosis and treatment of cancer. Keywords: Nanotechnology, cancer, nanodiagnostics, nanotherapeutics. Download Full Article |
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Abstract: We found depletion of NACA in two kinds of B lymphoma cell lines, Raji and Kapas, were able to induce apoptosis in this study. We also explored whether depletion of β subunit had the same effect, and we were interested in which domain of NACA was potentially responsible to this anti-apoptosis function. Lentivirus-based shRNA was used to deplete endogenous NACA or NACB. Those cells’ viabilities were measured by Alamar-blueTM assay. Cell apoptosis was identified by molecular markers caspase9 and PARP, as well as cellular markers Annexin V and propidium iodide (PI) staining. NACA mutants were constructed by PCR site-directed mutagenesis and delivered into cells by Lentivirus. Immunofluoresce was used to investigate cellular distribution in 293FT cells. Our results demonstrated that the depletion of NACA, but not NACB, was able to induce apoptosis. Deletion of middle or C-term rather than N-term induced obvious apoptosis. The middle part of NACA was response to bind NACB and form a complex. Without middle part, NACA redistributed into nuclei. We conclude NACA against apoptosis is independent of β subunit. C-term of NACA, which is identified as ubiquitin binding domain, and may take important role in anti-apoptosis function. Keywords: NACA, B-cell lymphoma, anti-apoptosis, depletion mutant.Download Full Article |
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Abstract: Pancreatic neuroendocrine tumors (PNETs) are a heterogeneous group of neoplasms that are the second most common among pancreatic neoplasms. Treatment of PNETs appears to be quite difficult because diagnosis in many patients occurs only at the latest stage when distant metastases are recognized. Therefore, treatment with drugs targeting PNET oncogenesis is a promising strategy in such patients. In this work, we review the present knowledge on the molecular nature of PNETs, and the genetic basis of PNET-associated hereditary syndromes, including multiple endocrine neoplasia type I, von Hippel–Lindau disease, neurofibromatosis type I, and tuberous sclerosis. In addition, the results of phase III, randomized, placebo-controlled trials of the efficacy of everolimus and sunitinib for treatment of extensive non-resectable PNETs are reviewed. Keywords: Neuroendocrine tumor, multiple endocrine neoplasia type I, von Hippel–Lindau disease, neurofibromatosis type I, tuberous sclerosis, targeted therapy, everolimus, sunitinib.Download Full Article |