Competition between unrelated peptides recognized by H-2-Kd restricted T cells

P815 (H-2d) target cells incubated with synthetic peptides corresponding to region 170-182 of HLA or to region 141-161 of influenza nucleoprotein (NP) are lysed by DBA/2 derived cytolytic T cells (CTL) specific for HLA or by BALB/c derived CTL-specific for NP, respectively. Both peptide Ag are recognized in the context of Kd. We show herein that these unrelated, nonhomologous peptides clearly compete reciprocally for recognition by the appropriate Kd restricted CTL. In contrast, different NP peptides that are recognized by other CTL restricted by HLA-B37, H-2-Db or KK, either failed to compete or were much less efficient as competitors than NP peptides recognized in the context of Kd. The efficiency of a peptide as a competitor correlated with its potency as an Ag. The most efficient competitor was a variant peptide of NP 147-158 with R156 deleted, which had been previously shown to be 1,000 times more efficient as an Ag than its natural homolog. Our results suggest that peptides recognized by CTL in the context of the same MHC class I restriction element may bind to the same or interdependent site(s) on the restriction molecule.     

Multiple miscarriages are associated with the risk of ovarian cancer: results from the European Prospective Investigation into Cancer and Nutrition

While the risk of ovarian cancer clearly reduces with each full-term pregnancy, the effect of incomplete pregnancies is unclear. We investigated whether incomplete pregnancies (miscarriages and induced abortions) are associated with risk of epithelial ovarian cancer. This observational study was carried out in female participants of the European Prospective Investigation into Cancer and Nutrition (EPIC). A total of 274,442 women were followed from 1992 until 2010. The baseline questionnaire elicited information on miscarriages and induced abortions, reproductive history, and lifestyle-related factors. During a median follow-up of 11.5 years, 1,035 women were diagnosed with incident epithelial ovarian cancer. Despite the lack of an overall association (ever vs. never), risk of ovarian cancer was higher among women with multiple incomplete pregnancies (HR(≥4vs.0): 1.74, 95% CI: 1.20-2.70; number of cases in this category: n?=?23). This association was particularly evident for multiple miscarriages (HR(≥4vs.0): 1.99, 95% CI: 1.06-3.73; number of cases in this category: n?=?10), with no significant association for multiple induced abortions (HR(≥4vs.0): 1.46, 95% CI: 0.68-3.14; number of cases in this category: n?=?7). Our findings suggest that multiple miscarriages are associated with an increased risk of epithelial ovarian cancer, possibly through a shared cluster of etiological factors or a common underlying pathology. These findings should be interpreted with caution as this is the first study to show this association and given the small number of cases in the highest exposure categories.     

Mitochondrial DNA backgrounds might modulate diabetes complications rather than T2DM as a whole

Mitochondrial dysfunction has been implicated in rare and common forms of type 2 diabetes (T2DM). Additionally, rare mitochondrial DNA (mtDNA) mutations have been shown to be causal for T2DM pathogenesis. So far, many studies have investigated the possibility that mtDNA variation might affect the risk of T2DM, however, when found, haplogroup association has been rarely replicated, even in related populations, possibly due to an inadequate level of haplogroup resolution. Effects of mtDNA variation on diabetes complications have also been proposed. However, additional studies evaluating the mitochondrial role on both T2DM and related complications are badly needed. To test the hypothesis of a mitochondrial genome effect on diabetes and its complications, we genotyped the mtDNAs of 466 T2DM patients and 438 controls from a regional population of central Italy (Marche). Based on the most updated mtDNA phylogeny, all 904 samples were classified into 57 different mitochondrial sub-haplogroups, thus reaching an unprecedented level of resolution. We then evaluated whether the susceptibility of developing T2DM or its complications differed among the identified haplogroups, considering also the potential effects of phenotypical and clinical variables. MtDNA backgrounds, even when based on a refined haplogroup classification, do not appear to play a role in developing T2DM despite a possible protective effect for the common European haplogroup H1, which harbors the G3010A transition in the MTRNR2 gene. In contrast, our data indicate that different mitochondrial haplogroups are significantly associated with an increased risk of specific diabetes complications: H (the most frequent European haplogroup) with retinopathy, H3 with neuropathy, U3 with nephropathy, and V with renal failure.     

Trans-membrane cationic flow and hemodialysis]

Abnormalities of intracellular ion concentrations and transmembrane fluxes were reported in uremia. In RBC from 12 chronically hemodialyzed patients (age 41 + 12, 7 men, 5 women; mean dialysis duration 31 + 24 months), we evaluated the acute effects of hemodialysis on intracellular Na and K concentrations, ouabain sensitive Na/K pump, furosemide sensitive Na/K cotransport, Na/Li countertransport, and passive permeability to Na. Six patients were normotensive and 6 were taking antihypertensive drugs which were withdrawn before the study. When compared to our normal reference group, uremic patients showed a significant increase in intracellular K concentration and a significant decrease in ouabain-sensitive Na/K pump. Intracellular sodium was not increased. No correlation was found between the activity of sodium-potassium pump and the duration of hemodialysis. The other transport systems were comparable to normal. No significant change was observed between the values measured before and after dialysis. Ouabain sensitive Na/K pump was lower in hypertensive as compared to normotensive patients, but this difference was not significant. Our data support the existence of ion transport derangements in uremia, which are not acutely affected by hemodialysis.     

Effect of menstrual cycle hormones on cation transport in the red-cell membrane

Erythrocyte cation transport, plasma prorenin and renin and sexual hormones were sequentially evaluated in 12 normal volunteers over the menstrual cycle. Na-K cotransport and Na-Li countertransport raised in 6 out of 12 subjects in synchronization with the ovulatory phase. When the maximal % variation (ovulatory phase) versus baseline (follicular phase) of the Na-K cotransport was plotted versus the maximal % increment of oestrogens. A direct, highly significant inverse correlation was observed (r = 0.904, p less than 0.001). Moreover, a highly significant inverse correlation between plasma prorenin and intraerythrocyte Na (r = -0.857, p less than 0.001) in the follicular phase was found. Our data suggest that erythrocyte cation transport can be influenced by sexual hormones in human.     

Effects of thymoquinone on liver miRNAs and oxidative stress in Ehrlich acid mouse solid tumor model

We investigated the effects of thymoquinone (TQ) on the expression of liver microRNAs (miRNAs), liver histopathology and oxidative stress in Ehrlich acid solid tumor model induced mice. We used 24 male BALB/c mice divided randomly into three groups. Control (C) group mice were injected intraperitoneally (i.p.) with 0.5 ml saline for four weeks. Tumor (T) group mice were injected i.p. with 0.5 ml saline for four weeks, then Ehrlich acid tumor cells were injected subcutaneously into the neck to induce solid tumor formation. TQ (T + Tq) group mice injected i.p. with 10 mg/kg TQ for four weeks, then Ehrlich acid tumor cells were injected subcutaneously into the neck of the mice in this group to induce solid tumor formation. At the end of the study, liver from all groups were removed for histopathological and miRNAs analysis, and oxidative stress measurement. We found that the expression of miR-206b-3p was up-regulated and the oxidative stress and necrosis increased in the liver tissue of mice with Ehrlich acid solid tumor. TQ application decreased the oxidative stress, prevented necrosis, increased regeneration and down-regulated the expression of miR-206b-3p in the liver tissue.     

Chromosome bands in freshwater triclads

Four species of Triclads belonging to three families, Dugesia polychroa and Dugesia mediterranea (Dugesiidae), Planaria torva (Planariidae) and Dendrocoelum lacteum (Dendrocoelidae) were studied for chromosome banding: C-banding for all the species, ASG banding for Dugesia polychroa and G-banding for Dugesia polychroa and Dugesia mediterranea. C-banding results for Dugesia lugubris-polychroa group suggest a high level of heterochromatin evolution in the group. Small bands strictly limited to the centromeric region were seen in Dugusia lugubris and this pattern is similar to the patterns of some species belonging to other families, notably Planaria torva and Dendrocoelum lacteum. This could be considered a primitive character. In contrast numerous heterochromatin bands which are useful to characterize the different karyotypes were seen in Dugesia polychroa and Dugesia mediterranea. Our data suggest that heterochromatin is important in freshwater triclad speciation.