Vitamin D3 replacement enhances antigen-specific immunity in older adults

This article has been accepted for publication in Immunotherapy Advances Published by Oxford University Press

Beta-catenin/TCF4 transactivates miR-30e during intestinal cell differentiation

The Wnt/beta-catenin/TCF4 pathway plays critical roles in the maintenance of small intestinal epithelium; however, downstream targets of the beta-catenin/TCF4 complex are not extensively characterized. We identified miR-30e as an immediate target activated by the beta-catenin/TCF4 complex. miR-30e was detected in the peri-nuclear region of the intestinal crypt IEC-6 cells. Bioinformatics analysis revealed clustered beta-catenin/TCF4 binding sites within the miR-30e promoter region. This promoter region was cloned into pGL3-control luciferase reporter vector, with the enhancer region removed. Transfection of pCMV-SPORT6-beta-catenin expression vector dose-dependently increased luciferase activity, and co-transfection of pCMV-SPORT6-TCF4 expression vector further enhanced the promoter activity. Dexamethasone-induced IEC-6 cells differentiation caused a 2.5-fold increase in miR-30e expression, and upon beta-catenin siRNA transfection, miR-30e increased 1.3-fold. Electrophoretic mobility shift assay and chromatin immunoprecipitation assay confirmed the binding between beta-catenin/TCF4 complexes from IEC-6 nuclear extracts and the putative sequences in the miR-30e promoter. These results demonstrate that beta-catenin/TCF4 transactivates miR-30e during intestinal cell differentiation

SIRT1 Promotes N-Myc Oncogenesis through a Positive Feedback Loop Involving the Effects of MKP3 and ERK on N-Myc Protein Stability

The N-Myc oncoprotein is a critical factor in neuroblastoma tumorigenesis which requires additional mechanisms converting a low-level to a high-level N-Myc expression. N-Myc protein is stabilized when phosphorylated at Serine 62 by phosphorylated ERK protein. Here we describe a novel positive feedback loop whereby N-Myc directly induced the transcription of the class III histone deacetylase SIRT1, which in turn increased N-Myc protein stability. SIRT1 binds to Myc Box I domain of N-Myc protein to form a novel transcriptional repressor complex at gene promoter of mitogen-activated protein kinase phosphatase 3 (MKP3), leading to transcriptional repression of MKP3, ERK protein phosphorylation, N-Myc protein phosphorylation at Serine 62, and N-Myc protein stabilization. Importantly, SIRT1 was up-regulated, MKP3 down-regulated, in pre-cancerous cells, and preventative treatment with the SIRT1 inhibitor Cambinol reduced tumorigenesis in TH-MYCN transgenic mice. Our data demonstrate the important roles of SIRT1 in N-Myc oncogenesis and SIRT1 inhibitors in the prevention and therapy of N-Myc–induced neuroblastoma

Elastic lateral buckling of cantilever litesteel beams under transverse loading

The LiteSteel Beam (LSB) is a new hollow flange channel section developed by OneSteel Australian Tube Mills using its patented dual electric resistance welding and automated continuous roll-forming technologies. The LSB has a unique geometry consisting of torsionally rigid rectangular hollow flanges and a relatively slender web. Its flexural strength for intermediate spans is governed by lateral distortional buckling characterised by simultaneous lateral deflection, twist and web distortion. Recent research on LSBs has mainly focussed on their lateral distortional buckling behaviour under uniform moment conditions. However, in practice, LSB flexural members are subjected to non-uniform moment distributions and load height effects as they are often under transverse loads applied above or below their shear centre. These loading conditions are known to have significant effects on the lateral buckling strength of beams. Many steel design codes have adopted equivalent uniform moment distribution and load height factors based on data for conventional hot-rolled, doubly symmetric I-beams subject to lateral torsional buckling. The non-uniform moment distribution and load height effects of transverse loading on cantilever LSBs, and the suitability of the current design modification factors to include such effects are not known. This paper presents a numerical study based on finite element analyses of the elastic lateral buckling strength of cantilever LSBs subject to transverse loading, and the results. The applicability of the design modification factors from various steel design codes was reviewed, and suitable recommendations are presented for cantilever LSBs subject to transverse loading

Rituximab for lymphoproliferative disease prior to haematopoietic stem cell transplantation for X-linked severe combined immunodeficiency

Copyright © 2008 Wiley-Liss, Inc., A Wiley CompanyLymphoproliferative disease (LPD) is a complication of congenital and acquired immunodeficiency states. There are a number of treatment options for LPD arising after haematopoietic stem cell or solid organ transplantation including reduction of immunosuppression, targeted therapies, such as the anti-CD20 monoclonal antibody, rituximab, and EBV specific cytotoxic lymphocytes. Treatment of LPD in children with congenital immunodeficiency syndromes remains unsatisfactory and is associated with a high mortality rate. We recently managed an infant found to have polymorphic LPD concurrent with X-linked severe combined immunodeficiency (SCID). Haematopoietic stem cell transplantation (HSCT) had to be deferred because of progressive LPD. Treatment with rituximab resulted in regression of the LPD following which the patient received a 5/6 HLA matched umbilical cord blood (UCB) transplant. The patient remains well 20 months following transplantation. Rituximab treatment may have a useful role in the control of LPD associated with congenital immunodeficiency prior to HSCT.Toby N. Trahair, Brynn Wainstein, Nicholas Manton, Anthony J. Bourne, John B. Ziegler, Michael Rice and Susan J. Russel

B-blockers increase response to chemotherapy via direct antitumour and anti-angiogenic mechanisms in neuroblastoma

Background: The use of b-blockers for the management of hypertension has been recently associated with significant clinical benefits in cancer patients. Herein, we investigated whether b-blockers could be used in combination with chemotherapy for the treatment of neuroblastoma. Methods: Seven b-blockers were tested for their antiproliferative and anti-angiogenic properties alone, and in combination with chemotherapy in vitro; the most potent drug combinations were evaluated in vivo in the TH-MYCN mouse model of neuroblastoma. Results: Three b-blockers (i.e., carvedilol, nebivolol and propranolol) exhibited potent anticancer properties in vitro and interacted synergistically with vincristine, independently of P-glycoprotein expression. b-blockers potentiated the anti-angiogenic, antimitochondrial, antimitotic and ultimately pro-apoptotic effects of vincristine. In vivo, b-blockers alone transiently slowed tumour growth as compared with vehicle only (P<0.01). More importantly, when used in combination, b-blockers significantly increased the tumour regression induced by vincristine (P<0.05). This effect was associated with an increase in tumour angiogenesis inhibition (P<0.001) and ultimately resulted in a four-fold increase in median survival, as compared with vincristine alone (P<0.01). Conclusion: b-blockers can increase treatment efficacy against neuroblastoma, and their combination with chemotherapy may prove beneficial for the treatment of this disease and other drug-refractory cancers. © 2013 Cancer Research UK. All rights reserved

Effects of randomized whey-protein loads on energy intake, appetite, gastric emptying, and plasma gut-hormone concentrations in older men and women

Background: Protein- and energy-rich supplements are used widely for the management of malnutrition in the elderly. Information about the effects of protein on energy intake and related gastrointestinal mechanisms and whether these differ between men and women is limited. Objective: We determined the effects of whey protein on energy intake, appetite, gastric emptying, and gut hormones in healthy older men and women. Design: Eight older women and 8 older men [mean ± SEM age: 72 ± 1 y; body mass index (in kg/m2): 25 ± 1] were studied on 3 occasions in which they received protein loads of 30 g (120 kcal) or 70 g (280 kcal) or a flavored water control drink (0 kcal). At regular intervals over 180 min, appetite (visual analog scales), gastric emptying (3-dimensional ultrasonography), and blood glucose and plasma gut-hormone concentrations [insulin, glucagon, ghrelin, cholecystokinin, gastric inhibitory polypeptide (GIP), glucagon-like peptide 1 (GLP-1), and peptide tyrosine tyrosine (PYY)] were measured, and ad libitum energy intake was quantified from a buffet meal (180-210 min; energy intake, appetite, and gastric emptying in the men have been published previously). Results: Energy intake at the buffet meal was ∼80% higher in older men than in older women (P 0.05). There was no effect of sex on gastric emptying, appetite, gastrointestinal symptoms, glucose, or gut hormones (P > 0.05). There was a protein load-dependent slowing of gastric emptying, an increase in concentrations of insulin, glucagon, cholecystokinin, GIP, GLP-1, and PYY, and an increase in total energy intake (drink plus meal: 12% increase with 30 g and 32% increase with 70 g; P < 0.001). Energy intake at the buffet meal was inversely related to the stomach volume and area under the curve of hormone concentrations (P < 0.05). Conclusion: In older men and women, whey-protein drinks load-dependently slow gastric emptying and alter gut hormone secretion compared with a control but have no suppressive effect on subsequent ad libitum energy intake. This trial was registered at www.anzctr.org.au as ACTRN12612000941864.Caroline Giezenaar, Laurence G Trahair, Natalie D Luscombe-Marsh, Trygve Hausken, Scott Standfield, Karen L Jones, Kylie Lange, Michael Horowitz, Ian Chapman, and Stijn Soene

Persistent MRD before and after allogeneic BMT predicts relapse in children with acute lymphoblastic leukaemia

Minimal residual disease (MRD) during early chemotherapy is a powerful predictor of relapse in acute lymphoblastic leukaemia (ALL) and is used in children to determine eligibility for allogeneic haematopoietic stem cell transplantation (HSCT) in first (CR1) or later complete remission (CR2/CR3). Variables affecting HSCT outcome were analysed in 81 children from the ANZCHOG ALL8 trial. The major cause of treatment failure was relapse, with a cumulative incidence of relapse at 5 years (CIR) of 32% and treatment-related mortality of 8%. Leukaemia-free survival (LFS) and overall survival (OS) were similar for HSCT in CR1 (LFS 62%, OS 83%, n = 41) or CR2/CR3 (LFS 60%, OS 72%, n = 40). Patients achieving bone marrow MRD negativity pre-HSCT had better outcomes (LFS 83%, OS 92%) than those with persistent MRD pre-HSCT (LFS 41%, OS 64%, P 50. A Cox multivariate regression model for LFS retained both B-other ALL subtype (hazard ratio 4·1, P = 0·0062) and MRD persistence post-HSCT (hazard ratio 3·9, P = 0·0070) as independent adverse prognostic variables. Persistent MRD could be used to direct post-HSCT therapy.Rosemary Sutton, Peter J. Shaw, Nicola C. Venn, Tamara Law, Anuruddhika Dissanayake, Tatjana Kilo, Michelle Haber, Murray D. Norris, Chris Fraser, Frank Alvaro, Tamas Revesz, Toby N. Trahair, Luciano Dalla-Pozza, Glenn M. Marshall, and Tracey A. O’Brie