Long-course temozolomide in aggressive pituitary adenoma: real-life experience in two tertiary care centers and review of the literature

Pituitary - Aggressive pituitary adenomas (APAs) and pituitary carcinomas (PCs) are challenging for their invasive nature, resistance to treatment and recurrences. Temozolomide (TMZ) is...     

Indoor exposure to environmental tobacco smoke and dampness: respiratory symptoms in Sardinian children--DRIAS study

Indoor exposures at home, environmental tobacco smoke (ETS) and mould/dampness adversely affect respiratory health of children. Disturbi Respiratori nell’Infanzia e Ambiente in Sardegna (DRIAS) (Respiratory Symptoms in children and the Environment in Sardegna, Italy) aims at relating the prevalence of respiratory and allergic symptoms to indoor exposures in Sardinian children.DRIAS, a cross-sectional investigation of respiratory symptoms/diseases, used a modified version of ISAAC questionnaire, included 4122 children attending 29 primary schools in the school year 2004-2005.If both parents smoke the prevalence for current wheeze and current asthma is almost doubled in comparison with never smokers, for persistent cough and phlegm a role is suggested when only mother smokes. Among mothers smoking in pregnancy, the prevalence of current wheeze and current asthma is increased. Exposure to ETS and family atopy have a joint effect resulting in an almost tripling of prevalence for current wheeze and more than four times for current asthma. Exposure to “dampness” (mould or dampness) both during the first year of life and currently is associated with increased prevalence of current wheeze, persistent cough or phlegm and current rhino-conjunctivitis; if exposure is only during the first year of life a doubling or more of prevalence is observed for current wheeze, current asthma, and persistent cough or phlegm.DRIAS results add evidence to the causal role of childhood exposure to ETS in the development of respiratory symptoms (cough, phlegm, and wheezing) and asthma. The joint effect of ETS and family atopy is corroborated. The results strengthen the evidence for a causal association between “dampness” and respiratory health, pointing to its possible independent role in causing asthma, a long-lasting exposure entails a doubled prevalence for both asthmatic and bronchitis symptoms.     

Adenovirus-mediated gene transfer of placental growth factor to perivascular tissue induces angiogenesis via upregulation of the expression of endogenous vascular endothelial growth factor-A

Placental growth factor (PlGF) is a member of the vascular endothelial growth factor (VEGF) family that binds specifically to VEGF receptor (VEGFR)-1. However, the mechanism of PlGF- and VEGFR-1-mediated angiogenesis has remained unclear and some in vitro studies suggest that VEGF-A/VEGFR-2 signaling may also play a role in PlGF-mediated angiogenesis. To clarify these issues we evaluated angiogenic responses in a well-characterized periadventitial angiogenesis model using adenovirus-mediated PlGF-2 (AdvPlGF-2) gene transfer. We also investigated the roles of VEGFR-1 and VEGFR-2 in PlGF-2-mediated angiogenesis. Using a periadventitial collar technique, AdvPlGF-2 (1 x 10(9) plaque-forming units/ml) was transferred to the adventitia of New Zealand White rabbits alone or together with adenoviruses encoding soluble VEGFR-1 (sVEGFR-1) or soluble VEGFR-2 (sVEGFR-2). Adenoviruses encoding LacZ were used as controls. All animals were killed 7 days after gene transfer. Increased neo-vessel formation, upregulation of endogenous VEGF-A expression, and a significant inflammatory response were seen in AdvPlGF-2-transduced arteries. The neo-vessels were large and well perfused. sVEGFR-1 and sVEGFR-2 suppressed the angiogenic response of PlGF-2 by 80 and 71.7%, respectively. We conclude that adenovirus-mediated PlGF-2 gene transfer to vascular tissue increases endogenous VEGF-A expression and produces significant angiogenesis. Both sVEGFR-1 and sVEGFR-2 can inhibit PlGF-2-mediated angiogenesis. PlGF-2 is a potentially useful candidate for the induction of therapeutic angiogenesis in vivo.     

A Pichia pastoris VPS15 homologue is required in selective peroxisome autophagy

Methylotrophic yeasts contain large peroxisomes during growth on methanol. Upon exposure to excess glucose or ethanol these organelles are selectively degraded by autophagy. Here we describe the cloning of a Pichia pastoris gene (PpVPS15) involved in peroxisome degradation, which is homologous to Saccharomyces cerevisiae VPS15. In methanol-grown cells of a P. pastoris VPS15 deletion strain, the levels of peroxisomal marker enzymes remained high after addition of excess glucose or ethanol. Electron microscopic studies revealed that the organelles were not taken up by vacuoles, suggesting that PpVPS15 is required at an early stage in peroxisome degradation. Received: 25 January / 4 June 1999     

Diagnostic Value of Plasma and Urinary 2‐Hydroxyglutarate to Identify Patients With Isocitrate Dehydrogenase‐Mutated Glioma

Background.

Mutant isocitrate dehydrogenase (IDH) 1/2 enzymes can convert α-ketoglutarate into 2-hydroxyglutarate (2HG). The aim of the present study was to explore whether 2HG in plasma and urine could predict the presence of IDH1/2 mutations in patients with glioma.

Materials and Methods.

All patients had histological confirmation of glioma and a recent brain magnetic resonance imaging scan showing the neoplastic lesion. Plasma and urine samples were taken from all patients, and the 2HG concentrations were determined using liquid chromatography tandem mass spectrometry.

Results.

A total of 84 patients were enrolled: 38 with R132H-IDH1 mutated and 46 with wild type. Among the 38 patients with mutant IDH1, 21 had high-grade glioma and 17 had low-grade glioma. Among the 46 patients with IDH1 wild-type glioma, 35 and 11 had high- and low-grade glioma, respectively. In all patients, we analyzed the mean 2HG concentration in the plasma, urine, and plasma/urine ratio (Ratio_2HG). We found a significant difference in the Ratio_2HG between patients with and without an IDH1 mutation (22.2 ± 8.7 vs. 15.6 ± 6.8; p < .0001). The optimal cutoff value for Ratio_2HG to identify IDH1 mutation was 19 (sensitivity, 63%; specificity, 76%; accuracy, 70%). In the patients with high-grade glioma only, the optimal cutoff value was 20 (sensitivity, 76%; specificity, 89%; accuracy, 84%; positive predictive value, 80%; negative predictive value, 86%). In 7 of 7 patients with high-grade glioma, we found a correlation between the Ratio_2HG value and the response to treatment.

Conclusion.

Ratio_2HG might be a predictor of the presence of IDH1 mutation. The measurement of 2HG could be useful for disease monitoring and also to assess the treatment effects in these patients.     

Developmental quotient at 24 months and fatty acid composition of diet in early infancy: a follow up study

Accepted 11 December 1996
AIM—A follow up study of developmental quotient (DQ) at 24 months of toddlers whose diets in early infancy differed in fatty acid composition, and in whom an association between diet and DQ was observed at 4months.
METHODS—81 toddlers were distributed among three groups according to early type of diet: standard infant formula (SFo, n = 30); long chain polyunsaturated fatty acid (LC-PUFA) enriched formula (LCPFo, n = 26); human milk (HM, n = 25). DQ at 24 months was assessed by Brunet-Lézine''s psychomotor developmental test. A subgroup (n = 20; SFo 8; LCPFo 6; HM 6) was tested for erythrocyte phosphatidylcholine and phosphatidylethanolamine.
RESULTS—No DQ differences were found by analysis of variance. Neither DQ nor erythrocyte docosahexaenoic acid at 4 months were predictors of DQ scores at 24 months. Phosphatidylcholine arachidonic and docosahexaenoic acid correlated positively, and phosphatidylcholine linoleic acid and phosphatidylethanolamine eicosapentaenoic acid negatively, with DQ. Multiple regression analysis including these variables explained 52% of interindividual DQ variance. A strong association was found between the erythrocyte phosphatidylcholine arachidonic/linoleic acid ratio and DQ (r = 0.75; p = 0.0001).
CONCLUSIONS—The diet/DQ association found at 4 months was not predictive of DQ scores at 24 months. Irrespective of dietary or genetic factors, there appears to be a strong correlation between the LC-PUFA composition of the red cell membrane and higher neurodevelopmental performance.

     

Pharmacological interventions for improving adenovirus usage in gene therapy

Gene therapy may be an innovative and promising new treatment strategy for cancer but is limited due to a low efficiency and specificity of gene delivery to the target cells. Adenovirus is the preferred gene therapy vector for systemic delivery because of its unparalleled in vivo transduction efficiency. Intravenous administration of low doses of adenovirus results in adenovirus sequestration in the liver due to binding to the scavenger receptor present on Kupffer cells. When the amount of adenovirus surpasses the binding capacity of Kupffer cells, hepatocytes absorb adenovirus particles in a blood factor-dependent manner. Increasing the Ad dose even more will saturate both the Kupffer cells and hepatocytes. Then sinusoid endothelial cells bind adenovirus particles in an RGD motif-dependent manner. Strategies to eradicate the binding to liver cells include drugs to interfere or eliminate binding to specific cell types, adenovirus capsid protein mutations and chemical modifications of adenovirus to shield the capsid proteins from cellular receptors. The combined use of these approaches should ultimately lead to successful systemic application of adenovirus in humans.     

Epicardium-derived cells enhance proliferation, cellular maturation and alignment of cardiomyocytes

During heart development, cells from the proepicardial organ spread over the naked heart tube to form the epicardium. From here, epicardium-derived cells (EPDCs) migrate into the myocardium. EPDCs proved to be indispensable for the formation of the ventricular compact zone and myocardial maturation, by largely unknown mechanisms. In this study we investigated in vitro how EPDCs affect cardiomyocyte proliferation, cellular alignment and contraction, as well as the expression and cellular distribution of proteins involved in myocardial maturation. Embryonic quail EPDCs induced proliferation of neonatal mouse cardiomyocytes. This required cell-cell interactions, as proliferation was not observed in transwell cocultures. Western blot analysis showed elevated levels of electrical and mechanical junctions (connexin43, N-cadherin), sarcomeric proteins (Troponin-I, α-actinin), extracellular matrix (collagen I and periostin) in cocultures of EPDCs and cardiomyocytes. Immunohistochemistry indicated more membrane-bound expression of Cx43, N-cadherin, the mechanotransduction molecule focal adhesion kinase, and higher expression of the sarcoplasmic reticulum Ca²⁺ ATPase (SERCA2a). Newly developed software for analysis of directionality in immunofluorescent stainings showed a quantitatively determined enhanced cellular alignment of cardiomyocytes. This was functionally related to increased contraction. The in vitro effects of EPDCs on cardiomyocytes were confirmed in three reciprocal in vivo models for EPDC-depletion (chicken and mice) in which downregulation of myocardial N-cadherin, Cx43, and FAK were observed. In conclusion, direct interaction of EPDCs with cardiomyocytes induced proliferation, correct mechanical and electrical coupling of cardiomyocytes, ECM-deposition and concurrent establishment of cellular array. These findings implicate that EPDCs are ideal candidates as adjuvant cells for cardiomyocyte integration during cardiac (stem) cell therapy.