Improved overall survival in dendritic cell vaccination-induced immunoreactive subgroup of advanced melanoma patients

Background  

We present our experience of therapeutic vaccination using dendritic cells (DC) pulsed with autologous tumor antigens in patients with advanced melanoma.     

Foxl2 disruption causes mouse ovarian failure by pervasive blockage of follicle development

FOXL2 mutations cause gonadal dysgenesis or premature ovarian failure (POF) in women, as well as eyelid/forehead dysmorphology in both sexes (the 'blepharophimosis-ptosis-epicanthus inversus syndrome', BPES). Here we report that mice lacking Foxl2 recapitulate relevant features of human BPES: males and females are small and show distinctive craniofacial morphology with upper eyelids absent. Furthermore, in mice as in humans, sterility is confined to females. Features of Foxl2 null animals point toward a new mechanism of POF, with all major somatic cell lineages failing to develop around growing oocytes from the time of primordial follicle formation. Foxl2 disruption thus provides a model for histogenesis and reproductive competence of the ovary.     

TCV-309, a novel platelet activating factor antagonist,inhibits leukocyte accumulation and protects against splanchnic artery occlusion shock

The aim of this study was to evaluate: (1) the accumulation of leukocytes in the ileum and the lung during splanchnic artery occlusion (SAO) shock; (2) the role of platelet-activating factor (PAF) and tumor necrosis factor (TNF-) in this phenomenon. Untreated anesthetized rats subjected to total occlusion of the celiac, superior and inferior mesenteric arteries for 45 min, followed by reperfusion, uniformly died within 90 min after reperfusion. The mean survival time was 93±7 min. The neutrophilic infiltrate was quantitated in the ileum and in the lung using a myeloperoxidase (MPO) assay. MPO activity in the ileum and in the lung averaged 0.05±0.03 and 0.4±0.02 U×10^–3/g protein in animals killed before occlusion. MPO activity did not change in rats killed immediately before reperfusion and was significantly elevated (0.11±0.02 and 1.7±0.6 U×10^–3/g protein in the ileum and the lung, respectively) in those killed 80 min after the beginning of the reperfusion. The histological examination confirmed the accumulation of leukocytes in the mucosa of the ileum and the lung over the 80 min. SAO shocked rats exhibited leukopenia and increased serum levels of TNF-. In order to evaluate the role of PAF and TNF- in SAO shock, a powerful PAF receptor antagonist, TCV-309 (5 g/kg i.v.), was injected 5 min after reperfusion. TCV-309 increased survival time, lowered serum TNF-, reduced MPO activity in both the ileum and the lung and ameliorated leukopenia induced by SAO shock. In addition, the drug significantly reduced ileal necrosis and pulmonary morphological alterations induced by shock. These results suggest an important role for PAF in the adhesion of leukocytes in SAO shock.     

Circulating E-Selectin Levels in Chronic Hepatitis C Patients with Normal or Elevated Transaminase Before and After Alpha-Interferon Treatment

E-selectin, an adhesion molecule of the selectin family, is involved in leukocyte adhesion to the endothelium and in the cellular immunological reactions. Expression of this molecule, in fact, is physiologically absent, but it becomes evident on sinusoidal lining cells during inflammatory liver disease. The aim of this study was to evaluate the behavior of E-selectin in chronic hepatitis C (CH-C) patients with persistently normal transaminase in comparison to patients with CH-C and elevated transaminase, and its changes during alpha-interferon therapy. Immunohistochemical localization of E-selectin was also performed on liver tissue specimens of both groups. Fifty-eight subjects were divided into 3 groups: group A included 18 patients with CH-C and persistently normal transaminase; group B 20 patients with CH-C and persistently elevated transaminase levels and group C included 20 healthy subjects, representing the control group. The first two groups were treated with r-IFN at a dose of 6 MU 3 times a week for 3 months and followed-up with 3 MU 3 times a week for another 3 months. Serum baseline values of E-selectin in groups A and B were significantly higher than those in group C (P < 0.04), but there was no difference between groups A and B. Furthermore, there was a trend toward higher E-selectin values as histological severity increased (r = 0.69; P < 0.0001). Post-treatment E-selectin serum values showed a moderate decrease in both groups, but only among responder patients; while E-selectin levels were unchanged in non responders. Immunohistochemical localization showed no staining for E-selectin in normal liver specimens, while there was a quite similar staining for E-selectin in the two groups of patients. In conclusion, this study shows that serum E-selectin levels in patients with CH-C and persistently normal transaminase are higher than in controls and they are associated with severity of liver disease. Liver of these patients express E-selectin molecules, suggesting an activation of the immune system almost identical to that of patients with CH-C and elevated transaminase. In both groups only responder patients showed a moderate decrease below baseline serum values.     

Brief Communication: Role of Nuclear Background and in vivo Environment in Variable Segregation Behavior of the Aging-Dependent T414G Mutation at Critical Control Site for Human Fibroblast mtDNA Replication

Previous work had shown a large accumulation (up to 50% of mtDNA) of a noninherited T414G transversion at a critical control site for mtDNA replication in skin fibroblasts from the majority of human subjects above 65 years old, and its absence in younger individuals. In the present studies, long-term in vitro culture of several fibroblasts populations carrying the heteroplasmic T414G mutation revealed an outgrowth of the mutant cells by wild-type cells. This observation supported the previous conclusion that the mutation accumulation is an in vivo phenomenon, while, at the same time, indicating intrinsic physiological differences between mutant and wild-type cells. Furthermore, subcloning experiments revealed a striking mosaic distribution of the mutation in the original fibroblasts populations, as shown by its presence, in heteroplasmic or homoplasmic form, in a fraction (18–32%) of the fibroblasts, and its absence in the others. In other investigations, transfer of mitochondria from mutation-carrying fibroblasts into mtDNA-less 143B.TK^–0 206 cells revealed the persistence of the mosaic distribution of the mutation, however, with a near-complete shift to homoplasmy. The generality of the latter phenomenon would exclude a founder effect by one or few mitochondria in the transformation experiments, and would rather point to the important role of the nuclear background in the in vitro behavior of the T414G mutation. The stability of the homoplasmic mutation in ⁰ cell transformants provides a powerful tool for analyzing its biochemical effects.     

Trisomy 8 in myelodysplasia and acute leukemia is constitutional in 15-20% of cases.

The trisomy 8 found in malignancies may derive from a constitutional trisomy 8 mosaicism (CT8M), and in these cases the trisomy itself may be regarded as the first mutation in a multistep carcinogenetic process. To assess the frequency of CT8M in hematological dysplastic and neoplastic disorders with trisomy 8, an informative sample of 14 patients was collected. The data ascertained included chromosome analyses of fibroblast cultures and of PHA-stimulated blood cultures in patients with normal blood differential count, as well as possible CT8M clinical signs. One patient showed trisomy 8 in all cell types analyzed and undoubtedly has a CT8M; a second patient consistently showed trisomy 8 in PHA-stimulated blood cultures when no immature myeloid cells were present in blood and should be considered as having CT8M; a third patient, with Philadelphia-positive chronic myelocytic leukemia, was more difficult to interpret, but the possibility that she had CT8M is likely. A few clinical signs of CT8M were also present in these three patients. Our data indicate that the frequency of CT8M in hematological dysplastic and neoplastic disorders with trisomy 8 is approximately 15-20%.     

Pathogenesis of human cytomegalovirus infection and cellular targets

In acquired immunodeficiency syndrome patients with human cytomegalovirus (HCMV), disseminated infection, and end-organ disease, autopsy findings show a generalized HCMV infection of endothelial cells. On the other hand, immunocompromised transplanted patients show presence of virus and virus products in peripheral blood leukocytes (PBL), when affected by a disseminated HCMV infection. All diagnostic assays are based on the detection of virus and viral components in PBL or whole blood, including polymorphonuclear leukocytes and monocytes. The interplay between endothelial cells and leukocytes represents the pathogenetic basis for all clinical syndromes originating during disseminated HCMV infections and is the trigger for the transmission of HCMV from mother to fetus during primary infections of pregnant women. The two biologic properties of endothelial cell tropism and leukocyte (polymorphonuclear- and monocyte-) tropism are shared by all recent clinical HCMV isolates, whereas they are missing in laboratory-adapted strains. The potential role of HCMV in the pathogenesis of atherosclerosis both in the immunocompetent (after angioplasty) and the heart transplant patient is receiving support from seroepidemiologic findings, in vivo animal models, in vitro data, and also some clinical observations. The interaction of endothelial cells and leukocytes with subsequent spreading of infection to smooth muscle cells may be a major pathogenetic mechanism at the basis of this important vascular disease.