Salvage radiotherapy after radical prostatectomy: analysis of toxicity by dose-fractionation in the RADICALS-RT trial

ABSTRACT: Emerging data indicate comparable disease control and toxicity of postoperative normo-fractionation and moderate hypofractionation radiotherapy (RT) in prostate cancer. In RADICALS-RT, patients were planned for treatment with either 66Gy in 33 fractions over 6.5 weeks or 52.5Gy in 20 fractions over 4 weeks. In this non-randomized, exploratory analysis, we explore the toxicity of these two schedules in patients who had adjuvant RT. METHODS: Information on RT dose was collected in all patients. Radiation Therapy Oncology Group toxicity score was recorded every 4 months for 2 years, 6-monthly until 5 years, then annually until 15 years. Patient-reported data were collected at baseline, 1, 5, and 10 years with use of standard questionnaires including Vaizey (bowel) and International Continence Society Male Short-Form (urinary incontinence). The highest grade of event was recorded within the first 2 years, and beyond 2 years, and compared between treatment groups using the χ² test. RESULTS: 217/634 (34%) patients were planned for 52.5Gy/20f and 417/634 (66%) for 66Gy/33f. In the first two years, grade 1 - 2 cystitis was reported more frequently among the 66Gy/33f group (52.5Gy/20f: 20% vs 66Gy/33f: 30%, p=0.04). After two years, grade 1-2 cystitis was reported in 16% in the 66Gy group, and 9% in the 52.5Gy group (p=0.08). Other toxicities were similar in the two groups and very few patients had any grade 3 - 4 toxicity. Patients reported slightly higher urinary and faecal incontinence scores at one year than at baseline, but no clinically meaningful differences were reported between 52.5Gy/20f and 66Gy/33f groups. Patient reported health was similar at baseline and at one year, and similar between 52.5Gy/20f and 66Gy/33f groups. CONCLUSION: Severe toxicity is rare after prostate bed radiotherapy with either 52.5Gy/20f or 66Gy/33f. Only modest differences were recorded in toxicity or in patient reported outcomes between these two schedules

The influence of soil communities on the temperature sensitivity of soil respiration

Soil respiration represents a major carbon flux between terrestrial ecosystems and the atmosphere, and is expected to accelerate under climate warming. Despite its importance in climate change forecasts, however, our understanding of the effects of temperature on soil respiration (RS) is incomplete. Using a metabolic ecology approach we link soil biota metabolism, community composition and heterotrophic activity, to predict RS rates across five biomes. We find that accounting for the ecological mechanisms underpinning decomposition processes predicts climatological RS variations observed in an independent dataset (n = 312). The importance of community composition is evident because without it RS is substantially underestimated. With increasing temperature, we predict a latitudinal increase in RS temperature sensitivity, with Q10 values ranging between 2.33 ±0.01 in tropical forests to 2.72 ±0.03 in tundra. This global trend has been widely observed, but has not previously been linked to soil communities

Loss of interleukin-12 modifies the pro-inflammatory response but does not prevent duct obstruction in experimental biliary atresia

BACKGROUND: Livers of infants with biliary atresia and of neonatal mice infected with rotavirus (RRV) have increased expression of interferon-gamma (IFNγ) and interleukin (IL)-12. While the expression of IFNγ regulates the obstruction of extrahepatic bile ducts by lymphocytes, the role of IL-12 in the pathogenesis of biliary obstruction is unknown. Based on the role of IL-12 as a key proinflammatory cytokine, we hypothesized that loss of IL-12 prevents the obstruction of extrahepatic bile ducts. METHODS: IL12-knockout (IL-12KO) and wild type mice were injected with RRV or saline at day 1 of age and monitored for the development of symptoms. The cellular and molecular phenotypes were determined at days 3, 7, and 14 by real-time PCR and flow cytometry. RESULTS: RRV infection of IL-12KO mice resulted in growth failure, jaundice/acholic stools, and decreased survival similar to wild-type mice. IL-12KO mice had a remarkable neutrophil-rich portal inflammation and epithelial sloughing of extrahepatic bile ducts. Loss of IL-12 decreased but did not abolish the hepatic expression of IFNγ, displayed a remarkable increase in expression of TNFα, IFNα, IFNβ and decreased expression of IL-4 and IL-5. CONCLUSION: Loss of IL-12 did not modify the progression of bile duct obstruction in experimental biliary atresia. However, the inflammatory response was predominantly neutrophil-based and displayed a Th1 response in the absence of IL-12

Identification of Giardia lamblia DHHC Proteins and the Role of Protein S-palmitoylation in the Encystation Process

Protein S-palmitoylation, a hydrophobic post-translational modification, is performed by protein acyltransferases that have a common DHHC Cys-rich domain (DHHC proteins), and provides a regulatory switch for protein membrane association. In this work, we analyzed the presence of DHHC proteins in the protozoa parasite Giardia lamblia and the function of the reversible S-palmitoylation of proteins during parasite differentiation into cyst. Two specific events were observed: encysting cells displayed a larger amount of palmitoylated proteins, and parasites treated with palmitoylation inhibitors produced a reduced number of mature cysts. With bioinformatics tools, we found nine DHHC proteins, potential protein acyltransferases, in the Giardia proteome. These proteins displayed a conserved structure when compared to different organisms and are distributed in different monophyletic clades. Although all Giardia DHHC proteins were found to be present in trophozoites and encysting cells, these proteins showed a different intracellular localization in trophozoites and seemed to be differently involved in the encystation process when they were overexpressed. dhhc transgenic parasites showed a different pattern of cyst wall protein expression and yielded different amounts of mature cysts when they were induced to encyst. Our findings disclosed some important issues regarding the role of DHHC proteins and palmitoylation during Giardia encystation.Fil: Merino, Maria Cecilia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra. Universidad Nacional de Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra; ArgentinaFil: Zamponi, Nahuel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra. Universidad Nacional de Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra; ArgentinaFil: Vranych, Cecilia Verónica. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra. Universidad Nacional de Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra; ArgentinaFil: Touz, Maria Carolina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra. Universidad Nacional de Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra; ArgentinaFil: Ropolo, Andrea Silvana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra. Universidad Nacional de Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra; Argentin

Polychlorinated biphenyls, cytochrome P450 1A1 (CYP1A1) polymorphisms, and breast cancer risk among African American women and white women in North Carolina: a population-based case-control study

INTRODUCTION: Epidemiologic studies have not shown a strong relationship between blood levels of polychlorinated biphenyls (PCBs) and breast cancer risk. However, two recent studies showed a stronger association among postmenopausal white women with the inducible M2 polymorphism in the cytochrome P450 1A1 (CYP1A1) gene. METHODS: In a population-based case-control study, we evaluated breast cancer risk in relation to PCBs and the CYP1A1 polymorphisms M1 (also known as CYP1A1*2A), M2 (CYP1A1*2C), M3 (CYP1A1*3), and M4 (CYP1A1*4). The study population consisted of 612 patients (242 African American, 370 white) and 599 controls (242 African American, 357 white). RESULTS: There was no evidence of strong joint effects between CYP1A1 M1-containing genotypes and total PCBs in African American or white women. Statistically significant multiplicative interactions were observed between CYP1A1 M2-containing genotypes and elevated plasma total PCBs among white women (P value for likelihood ratio test = 0.02). Multiplicative interactions were also observed between CYP1A1 M3-containing genotypes and elevated total PCBs among African American women (P value for likelihood ratio test = 0.10). CONCLUSIONS: Our results confirm previous reports that CYP1A1 M2-containing genotypes modify the association between PCB exposure and risk of breast cancer. We present additional evidence suggesting that CYP1A1 M3-containing genotypes modify the effects of PCB exposure among African American women. Additional studies are warranted, and meta-analyses combining results across studies will be needed to generate more precise estimates of the joint effects of PCBs and CYP1A1 genotypes

The future of pediatric dentistry education and curricula : A Chilean perspective

Publisher Copyright: © 2016 The Author(s). Copyright: Copyright 2016 Elsevier B.V., All rights reserved.Background: A meeting was organised to consolidate a network of researchers and academics from Australia, Brazil, Chile, the UK and the USA, relating to Early Childhood Caries (ECC) and Dental Trauma (DT). As part of this meeting, a dedicated session was held on the future of paediatric dental education and curricula. Twenty-four paediatric dentistry (PD) academics, representing eight Chilean dental schools, and three international specialists (from Brazil and Latvia) participated in group discussions facilitated by five members of the ECC/DT International Collaborative Network. Data were collected from group discussions which followed themes developed as guides to identify key issues associated with paediatric dentistry education, training and research. Discussion: Participants discussed current PD dental curricula in Chile, experiences in educating new cohorts of oral health care providers, and the outcomes of existing efforts in education and research in PD. They also, identified challenges, opportunities and areas in need of further development. Summary: This paper provides an introspective analysis of the education and training of PD in Chile; describes the input provided by participants into pediatric dentistry education and curricula; and sets out some key priorities for action with suggested directions to best prepare the future dental workforce to maximise oral health outcomes for children. Immediate priorities for action in paediatric dentistry in Chile were proposed.publishersversionPeer reviewe

The natural history and management of hamstring injuries

Hamstring injuries in sport can be debilitating. The anatomical complexity of this muscle makes uniform assessment of injury epidemiology difficult and insures that post-injury management strategies must be individually focused. This article reviews the anatomy of the hamstring, its role in athletic movement, common mechanisms of injury, and management guidelines with the goal of return into sporting activity in mind

Inhibition of N1-Src kinase by a specific SH3 peptide ligand reveals a role for N1-Src in neurite elongation by L1-CAM

In the mammalian brain the ubiquitous tyrosine kinase, C-Src, undergoes splicing to insert short sequences in the SH3 domain to yield N1- and N2-Src. We and others have previously shown that the N-Srcs have altered substrate specificity and kinase activity compared to C-Src. However, the exact functions of the N-Srcs are unknown and it is likely that N-Src signalling events have been misattributed to C-Src because they cannot be distinguished by conventional Src inhibitors that target the kinase domain. By screening a peptide phage display library, we discovered a novel ligand (PDN1) that targets the unique SH3 domain of N1-Src and inhibits N1-Src in cells. In cultured neurons, PDN1 fused to a fluorescent protein inhibited neurite outgrowth, an effect that was mimicked by shRNA targeting the N1-Src microexon. PDN1 also inhibited L1-CAM-dependent neurite elongation in cerebellar granule neurons, a pathway previously shown to be disrupted in Src(−/−) mice. PDN1 therefore represents a novel tool for distinguishing the functions of N1-Src and C-Src in neurons and is a starting point for the development of a small molecule inhibitor of N1-Src