Retroviral expression of a kinase-defective IGF-I receptor suppresses growth and causes apoptosis of CHO and U87 cells in-vivo

BACKGROUND: Phosphatidylinositol-3,4,5-triphosphate (PtdInsP3) signaling is elevated in many tumors due to loss of the tumor suppressor PTEN, and leads to constitutive activation of Akt, a kinase involved in cell survival. Reintroduction of PTEN in cells suppresses transformation and tumorigenicity. While this approach works in-vitro, it may prove difficult to achieve in-vivo. In this study, we investigated whether inhibition of growth factor signaling would have the same effect as re-expression of PTEN. METHODS: Dominant negative IGF-I receptors were expressed in CHO and U87 cells by retroviral infection. Cell proliferation, transformation and tumor formation in athymic nude mice were assessed. RESULTS: Inhibition of IGF-IR signaling in a CHO cell model system by expression of a kinase-defective IGF-IR impairs proliferation, transformation and tumor growth. Reduction in tumor growth is associated with an increase in apoptosis in-vivo. The dominant-negative IGF-IRs also prevented growth of U87 PTEN-negative glioblastoma cells when injected into nude mice. Injection of an IGF-IR blocking antibody αIR3 into mice harboring parental U87 tumors inhibits tumor growth and increases apoptosis. CONCLUSION: Inhibition of an upstream growth factor signal prevents tumor growth of the U87 PTEN-deficient glioma to the same extent as re-introduction of PTEN. This result suggests that growth factor receptor inhibition may be an effective alternative therapy for PTEN-deficient tumors

Glycine propionyl-L-carnitine increases plasma nitrate/nitrite in resistance trained men

We have recently demonstrated that oral intake of glycine propionyl-L-carnitine (GPLC) increases plasma nitrate/nitrite (NOx), a surrogate measure of nitric oxide production. However, these findings were observed at rest, and in previously sedentary subjects

Effect of histamine on lung contractile elements in growing cattle

peer reviewedaudience: researcher, professionalOBJECTIVE: To determine the effect of histamine on the contractile elements of the respiratory tract in neonatal calves and young adult cattle. SAMPLE POPULATION: Samples of trachealis muscle, bronchi, and intrapulmonary arteries and veins dissected from the respiratory tracts of healthy bovids (2 to 8 days and 16 to 20 months old). PROCEDURE: Histamine cumulative concentration-effect curves (10(-6) to 10(-3) M) were constructed in duplicate smooth muscle samples mounted in organ baths. Contractile responses to histamine were compared with reference contractions elicited by methacholine (10(-5) M) for airways or KCl (127 mM) for vessels. RESULTS: In young adult cattle, trachealis muscle had a substantial contractile response to histamine (84% of methacholine-induced contraction), whereas bronchi reacted slightly (15 and 20% for large and small bronchi, respectively). Although contractile responses to KCl were comparable in arteries and veins, histamine-induced contractions were greater for intrapulmonary veins than for arteries (202 vs 48% of KCl-induced contraction). In neonatal calves, histamine-induced contraction of veins also exceeded that of arteries (230 vs 54% of KCl-induced contraction); however, unlike in young adult cattle, histamine produced notable contraction of large and small bronchi (48 and 60% of methacholine-induced contraction, respectively). CONCLUSIONS AND CLINICAL RELEVANCE: Compared with intrapulmonary arteries, intrapulmonary veins have greater contractile responses to histamine in neonatal and young adult cattle. Data suggest loss of histamine responsiveness in bronchial smooth muscle as neonatal calves grow to young adults. Venodilation may be useful in treatment of lung edema in cattle