The role of the IGF axis in IGFBP-1 and IGF-I induced renal enlargement in Snell dwarf mice

Insulin-like growth factor (IGF) binding protein-1 (IGFBP-1) is generally believed to inhibit IGF action in the circulation. In contrast, IGFBP-1 has been reported to interact with cell surfaces and enhance IGF-I action locally in some tissues. Renal IGFBP-1 levels are found elevated in various conditions characterized by renal growth (e.g. diabetes mellitus, hypokalemia). To test whether IGFBP-1 is a renotropic factor, IGFBP-1 was administered alone or in combination with IGF-I to Snell dwarf mice, an in vivo model without compensatory feedback effects on growth hormone (GH) secretion. In three control groups of Snell dwarf mice, placebo, GH or IGF-I was administered. Compared with placebo, kidney weight increased in all treated groups, however, with different effects on kidney morphology. Administration of IGF-I, alone or in combination with IGFBP-1, tended to increase glomerular volume, while no changes were seen in the other groups. Administration of IGFBP-1 or IGFBP-1+IGF-I both caused dilatation of the thin limbs of Henle's loop, while GH or IGF-I administration had no visible effect. Furthermore, IGF-I administration resulted in an increased mean number of nuclei per cortical area and renal weight, whereas GH, IGF-I+IGFBP-1 or IGFBP-1 caused a decreased renal nuclei number. In situ hybridization and immunohistochemistry showed specific changes of the renal IGF system expression patterns in the different groups. Particularly, IGFBP-1 administration resulted in extensive changes in the mRNA expression of the renal IGF system, whereas the other administration regimen resulted in less prominent modifications. In contrast, administration of IGFBP-1 and IGFBP-1+IGF-I resulted in identical changes in the protein expression of the renal IGF system. Our results indicate that IGFBP-1, alone or in combination with IGF-I, demonstrated effects on the renal tubular system that differ from the effects of IGF-I

Measurement of Bottom versus Charm as a Function of Transverse Momentum with Electron-Hadron Correlations in p+p Collisions at sqrt(s)=200 GeV

The momentum distribution of electrons from semi-leptonic decays of charm and bottom for mid-rapidity |y|<0.35 in p+p collisions at sqrt(s)=200 GeV is measured by the PHENIX experiment at the Relativistic Heavy Ion Collider (RHIC) over the transverse momentum range 2 < p_T < 7 GeV/c. The ratio of the yield of electrons from bottom to that from charm is presented. The ratio is determined using partial D/D^bar --> e^{+/-} K^{-/+} X (K unidentified) reconstruction. It is found that the yield of electrons from bottom becomes significant above 4 GeV/c in p_T. A fixed-order-plus-next-to-leading-log (FONLL) perturbative quantum chromodynamics (pQCD) calculation agrees with the data within the theoretical and experimental uncertainties. The extracted total bottom production cross section at this energy is \sigma_{b\b^bar}= 3.2 ^{+1.2}_{-1.1}(stat) ^{+1.4}_{-1.3}(syst) micro b.Comment: 432 authors, 6 pages text, 3 figures. Submitted to Phys. Rev. Lett. Plain text data tables for the points plotted in figures for this and previous PHENIX publications are (or will be) publicly available at http://www.phenix.bnl.gov/papers.htm

A screening-based approach identifies cell cycle regulators AURKA, CHK1 and PLK1 as targetable regulators of chondrosarcoma cell survival

Chondrosarcomas are malignant cartilage tumors that are relatively resistant towards conventional therapeuticapproaches. Kinase inhibitors have been investigated and shown successful for several different cancer types. Inthis study we aimed at identifying kinase inhibitors that inhibit the survival of chondrosarcoma cells and therebyserve as new potential therapeutic strategies to treat chondrosarcoma patients.An siRNA screen targeting 779 different kinases was conducted in JJ012 chondrosarcoma cells in parallelwith a compound screen consisting of 273 kinase inhibitors in JJ012, SW1353 and CH2879 chondrosarcoma celllines. AURKA, CHK1 and PLK1 were identified as most promising targets and validated further in a morecomprehensive panel of chondrosarcoma cell lines. Dose response curves were performed using tyrosine kinaseinhibitors: MK-5108 (AURKA), LY2603618 (CHK1) and Volasertib (PLK1) using viability assays and cell cycleanalysis. Apoptosis was measured at 24 h after treatment using a caspase 3/7 assay. Finally, chondrosarcomapatient samples (N = =34) were used to examine the correlation between AURKA, CHK1 and PLK1 RNAexpression and documented patient survival.Dose dependent decreases in viability were observed in chondrosarcoma cell lines after treatment with MK-5108, LY2603618 and volasertib, with cell lines showing highest sensitivity to PLK1 inhibition. In additionincreased sensitivity to conventional chemotherapy was observed after CHK1 inhibition in a subset of the celllines. Interestingly, whereas AURKA and CHK1 were both expressed in chondrosarcoma patient samples, PLK1expression was found to be low compared to normal cartilage. Analysis of patient samples revealed that highCHK1 RNA expression correlated with a worse overall survival.AURKA, CHK1 and PLK1 are identified as important survival genes in chondrosarcoma cell lines. Althoughfurther research is needed to validate these findings, inhibiting CHK1 seems to be the most promising potentialtherapeutic target for patients with chondrosarcoma.Toxicolog

A new variant of red blood cell pyruvate kinase deficiency

A new mutant pyruvate kinase (ATP: pyruvate phosphotransferase, EC 2.7.1.40) from human erythrocytes is described. The mutant enzyme shows an increased thermolability, a decreased Km value for the substrate phosphoenolpyruvate and a loss of allosteric properties during the lifespan of the erythrocytes. By comparing the previous obtained data from other patients it seems that there can be distinguished at least three types of pyruvate kinase deficiencies

Normalisation of red blood cell pyruvate kinase in pyruvate kinase deficiency by riboflavin treatment

A patient with an erythrocyte glutathione reductase activity of 50% of the normal value and an abnormal pyruvate kinase (PK) was given 36 mg riboflavin daily for 6 months. The glutathione reductase activity was restored and the abnormal pyruvate kinase was converted to normal. The clinical state of the patient improved. It can be concluded that the abnormality of PK, at least with this patient, is a secondary effect. Therefore, it is suggested that other abnormalities be searched for when an altered PK is detected. Treatment of this abnormality will help the patients more efficiently