RESUMO
BACKGROUND: Arachidonic acid (AA) pathway has been shown to play a role in the development and progression of prostate cancer (PCa). In this study we aimed to assess the changes in concentrations of hydroxyeicosatetraenoic acids (HETEs) in serum samples from patients diagnosed with PCa compared to controls. METHODS: HETEs were determined using ultrahigh pressure liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). RESULTS: Elevated concentrations of 5-HETE, 8-HETE, 11-HETE and 15-HETE were observed in 6 out of 20 patients diagnosed with PCa; no statistical differences with controls were observed for 12-HETE and AA in the discovery set. An independent validation set composed of 222 samples divided in five groups ranging from subjects with low PSA and no PCa, to patients with advanced PCa was included. In 30% of the patients in the advanced PCa group, up to ten times higher concentrations of the same set of HETEs were observed with a significant concomitant decrease of the concentration of AA. Logistic regression and Kaplan-Meier curves illustrate that a decreased concentration of AA is a predictor of PCa biochemical recurrence after radical prostatectomy (RP). CONCLUSIONS: From the present study we conclude that a significant association between AA and AA metabolites in serum and PCa progression exists, although serum concentrations of HETEs exhibited low sensitivity toward the diagnosis of PCa.
Assuntos
Ácidos Hidroxieicosatetraenoicos/sangue , Neoplasias da Próstata/sangue , Idoso , Ácido Araquidônico/metabolismo , Cromatografia Líquida de Alta Pressão , Progressão da Doença , Humanos , Masculino , Pessoa de Meia-Idade , Próstata/metabolismo , Neoplasias da Próstata/patologia , Espectrometria de Massas em TandemRESUMO
Viruses are the most commonly used vectors for clinical gene therapy. The risk of dissemination of a viral vector into the environment via excreta from the treated patient, a phenomenon called shedding, is a major safety concern for the environment. Despite the significant number of clinical gene therapy trials that have been conducted worldwide, there is currently no overview of actual shedding data available. In this article, an inventory of shedding data obtained from a total of 100 publications on clinical gene therapy trials using retroviral, adenoviral, adeno-associated viral and pox viral vectors is presented. In addition, the experimental set-up for shedding analysis including the assays used and biological materials tested is summarized. The collected data based on the analysis of 1619 patients in total demonstrate that shedding of these vectors occurs in practice, mainly determined by the type of vector and the route of vector administration. Due to the use of non-quantitative assays, the lack of information on assay sensitivity in most publications, and the fact that assay sensitivity is expressed in various ways, general conclusions cannot be made as to the level of vector shedding. The evaluation of the potential impact and consequences of the observations is complicated by the high degree of variety in the experimental design of shedding analysis between trials. This inventory can be supportive to clinical gene therapy investigators for the establishment of an evidence-based risk assessment to be included in a clinical protocol application, as well as to national regulatory authorities for the ongoing development of regulatory guidelines regarding gene therapy.
Assuntos
Terapia Genética , Eliminação de Partículas Virais , Animais , Ensaios Clínicos como Assunto , Vetores Genéticos/administração & dosagem , Vetores Genéticos/metabolismo , Humanos , Disseminação de Informação , Neoplasias/genética , Neoplasias/terapia , Fatores de TempoRESUMO
Gene therapy is an active research area in The Netherlands and Dutch scientists involved in fundamental and clinical gene therapy research significantly contribute to the progresses made in this field. This ranges from the establishment of the 293, 911 and PER.C6 cell lines, which are used worldwide for the production of replication-defective adenoviral vectors, to the development of targeted viral vectors and T lymphocytes as well as of non-viral vectors. Several milestones have been achieved in Dutch clinical gene therapy trials, including the first treatment worldwide of patients with adenosine deaminase deficiency with genetically corrected hematopoietic stem cells in collaboration with French and British scientists. Until now, about 230 patients with various diseases have been treated with viral and non-viral gene therapy in this country. Ongoing and upcoming Dutch clinical trials focus on the translation of new developments in gene therapy research, including the restoration of genetic defects other than SCID, and the use of oncolytic adenoviruses and targeted T cells for the treatment of cancer. The growing commercial interest in Dutch clinical gene therapy is reflected by the involvement of two Dutch companies in ongoing trials as well as the participation of Dutch clinical centres in large phase III international multicenter immuno-gene therapy trials on prostate cancer sponsored by an American company. Translational gene therapy research in The Netherlands is boosted at a governmental level by the Dutch Ministry of Health via a dedicated funding programme. This paper presents an overview on milestones in Dutch basic gene therapy research as well as on past, present and future clinical gene therapy trials in The Netherlands.
Assuntos
Técnicas de Transferência de Genes , Terapia Genética , Adenoviridae/genética , Animais , Ensaios Clínicos como Assunto , Vetores Genéticos/metabolismo , Humanos , Países BaixosRESUMO
The treatment of superficial bladder cancer requires adjuvant therapies besides transurethral resection because of a high recurrence rate after this standard treatment alone. Current adjuvant therapies involve intravesical chemotherapy for patients at low and intermediate risk for recurrence and progression, and intravesical bacillus Calmette-Guérin for patients at intermediate and high risk. However, these adjuvant therapies fail in a significant number of patients, dictating the need for new and improved adjuvant treatment modalities for superficial bladder cancer. Immunotherapy aiming at the modulation of the immune system of the patient is a promising alternative adjuvant. This review discusses the current status of the clinical development of various immunotherapy approaches for superficial bladder cancer, including passive immunotherapy, immune stimulants, immunogene therapy and cancer vaccination.