MART-1(27-35)-peptide-pulsed immature dendritic cells (DCs) resulted in immunologic and clinical activity in a prior phase 1 trial. A phase 2 cohort expansion was initiated to further characterize the phenotype and cytokine milieu of the DC vaccines and their immunologic activity in vitro and to further examine a possible link between clinical activity and determinant spreading. In an open-label phase 2 trial, 10(7) autologous ex vivo generated DCs pulsed with the HLA-A*0201 immunodominant peptide MART-1(27-35) were administered to 10 subjects with stage II-IV melanoma. The experimental vaccines were administered intradermally in a biweekly schedule for a total of three injections, and blood for immunologic assays was obtained before each administration and at three time points after. DC vaccine preparations had wide intra- and interpatient variability in terms of cell surface markers and preferential cytokine milieu, but they did not correlate with the levels of antigen-specific T cells after vaccination. Of four patients with measurable disease, one had stable disease for 6 months and another has a continued complete response for over 2 years, which is confounded by receiving a closely sequenced CTLA4 blocking antibody. The DC vaccines induced determinant spreading in this subject, and CTLA4 blockade reactivated T cells with prior antigen exposure. The DC phenotype and cytokine profile do not correlate with the ability to induce antigen-specific T cells, while determinant spreading after DC immunization may be a marker of an efficient antitumor response. Sequential CTLA4 blockade may enhance the immune activity of DC-based immunotherapy.

The murine melanoma B16 expresses the murine counterpart of the human MART-1/Melan-A (MART-1) antigen, sharing a 68.6% amino acid sequence identity. In this study, mice were vaccinated with bone marrow-derived murine dendritic cells genetically modified with a replication-incompetent adenoviral vector to express the human MART-1 gene (AdVMART1). This treatment generated a protective response to a lethal tumor challenge of unmodified murine B16 melanoma cells. The response was mediated by major histocompatibility complex class I-restricted cytotoxic T lymphocytes specific for MART-1 antigen, which produced high levels of interferon-gamma when reexposed to MART-1 in vitro and lysed targets in a calcium-dependent mechanism suggestive of perforin/granzyme B lysis. MART-1 was presented by the dendritic cells used for vaccination and not by epitopes cross-presented by host antigen-presenting cells. In conclusion, dendritic cells genetically modified to express the human MART-1 antigen generate potent murine MART-1-specific protective responses to B16 melanoma.

Gastric cancer (GC) is one of the leading causes of cancer death in the world. Numerous efforts are being made to find chemoprotective agents able to reduce its risk. Amongst these, green tea has been reported to have a protective effect against stomach cancer. This article aims to critically evaluate all epidemiological studies reporting an association between green tea consumption and GC risk. MEDLINE, EBSCOHOST and Google Scholar were used to search for clinical trials of green tea and its correlation to stomach cancer. Studies include cohort and case-control studies. Outcome of interests are inverse association, no association, and positive association. Seventeen epidemiologic studies were reviewed. Eleven studies were conducted in Japan, five in China, and one with Japanese descendent in Hawaii. Ten case-control studies and seven cohort studies were included. The relative risks or odds ratio of GC for the highest level of green tea consumption was compared. Seven studies suggested no association, eight an inverse association, and one a positive association. One study had shown a significantly lowered GC risk when tea was served warm to cold. Another study also showed a significantly risk with lukewarm tea. All studies that analyzed men and women separately have suggested a reduced risk in women than in men, albeit no significant difference. This review demonstrates that there is insufficient information to support green tea consumption reduces the risk of GC. More studies on the subject matter are warranted.

Genetic immunotherapy with tumor antigen gene -modified dendritic cells ( DC ) generates robust immunity, although antitumor protection is not complete in all models. Previous experience in a model in which C57BL / 6 mice immunized with DC transduced with adenoviral vectors expressing MART -1 demonstrated a 20 -40% complete protection to a tumor challenge with B16 melanoma cells. Tumors that did develop in immunized mice had slower growth kinetics compared to tumors implanted in naïve mice. In the present study, we wished to determine if the supraphysiological production of the Th1 -skewing cytokine interleukin -12 ( IL -12 ) could enhance immune activation and antitumor protection in this model. In a series of experiments immunizing mice with DC cotransduced with MART -1 and IL -12, antitumor protection and antigen -specific splenocyte cytotoxicity and interferon g production inversely correlated with the amount of IL -12 produced by DC. This adverse effect of IL -12 could not be explained by a direct cytotoxic effect of natural killer cells directed towards DC, nor the production of nitric oxide leading to down -regulation of the immune response -the two mechanisms previously recognized to explain immune -suppressive effects of IL -12 -based vaccine therapy. In conclusion, in this animal model, IL -12 production by gene -modified DC leads to a cytokine -induced dose -dependent inhibition of antigen -specific antitumor protection.

The endothelium-dependent vasodilators ACh, histamine, and bradykinin were studied in the isolated, perfused human placental cotyledon. Histamine caused a decrease in perfusion pressure that was attenuated by cimetidine. Bradykinin, at lower concentrations (10−20 to 10−14 M), produced a concentration-dependent decrease in perfusion pressure, whereas at higher concentrations it produced an increase in perfusion pressure. ACh was without any effect. The decrease in perfusion pressure observed with bradykinin was potentiated by captopril and was significantly attenuated in the presence of HOE-140, the B2-receptor antagonist, or by pretreatment with an inhibitor of nitric oxide synthase, but not by an inhibitor of cyclooxygenase. The decrease in perfusion pressure observed with bradykinin was potentiated by ANG I but not by ANG II. It is concluded that endothelium-dependent vasodilation can be demonstrated with histamine and bradykinin in the fetoplacental vessels, and at least for bradykinin, this is partly mediated by release of nitric oxide. The potentiation of the bradykinin response in the presence of ANG I may serve to buffer the vasoconstriction produced by ANG II in the fetoplacental circulation.