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PDF file - 63K, Appendix containing detailed methods for measurement of EBV DNA load.

Background: We hypothesized that poor control of Epstein–Barr virus (EBV) infection, leading to reactivation of the virus, increases the risk of non-Hodgkin lymphoma (NHL) in the general population of primarily immunocompetent persons.Methods: We conducted a case–control study nested within the Women's Health Initiative Observational Study cohort in which we measured antibodies to EBV antigens [immunoglobulin G (IgG) to viral capsid antigen (VCA), nuclear antigen (EBNA1), and early antigen-diffuse (EA-D)] and EBV DNA load in prediagnostic samples of 491 B-cell NHL cases and 491 controls.Results: We found no association with established EBV infection, based on seropositivity for VCA. Seropositivity for EBNA1 was associated with decreased risk of B-cell NHL, overall [OR = 0.5; 95% confidence interval (CI), 0.3–0.8] and for each of the histologic subtypes examined. Increased risk of chronic lymphocytic leukemia (CLL) and related subtypes was observed with higher levels of EBV DNA and antibody to EA-D, both markers reflective of reactivation. These associations were strongest for cases with the shortest time interval between blood draw and diagnosis.Conclusions: In balance, these results do not provide strong evidence of EBV playing a causal role in B-cell NHL in general population women. The associations we observed may reflect increased risk of NHL with underlying immune impairment or could be due to reverse causation.Impact: Further characterization of the subtype-specific association with CLL is warranted. Exclusion of cases with preclinical disease markers (such as monoclonal B-lymphocytosis for CLL) may help rule out reverse causation in future studies. Cancer Epidemiol Biomarkers Prev; 22(10); 1747–55. ©2013 AACR.

Antibody-mediated rejection (AMR) following orthotopic heart transplant (OHT) causes significant morbidity and mortality. There are limited data on antibodies to the angiotensin II type 1 receptor antibody (AT1R-Ab) causing rejection following OHT.This is a retrospective, single-center study that presents our 2-y experience with a series of 11 patients with evidence of nonspecific graft dysfunction and pathologic levels of AT1R-Ab. The clinical outcomes and treatments were compared to a group of 10 patients, also with evidence of nonspecific graft dysfunction, but who had nonsignificant AT1R-Ab titers.The mean age of the AT1R-Ab cohort was 52% and 73% were bridged to transplant with an left ventricular assist device. The average left ventricular ejection fraction at presentation was 45%, and most were not on an angiotensin receptor blocker (ARB). Endomyocardial biopsies in those with elevated AT1R-Ab levels frequently showed reactive endothelium/endocardium without C4d or intravascular CD68 staining. Ten patients (91%) were started on an ARB. Other therapies included plasmapheresis and IVIg (64%), with 4 patients also receiving rituximab. Most patients had symptom improvement, but minimal change in graft function at an average 6 mo of follow-up.The role of AT1R-Ab-mediated rejection in OHT recipients remains poorly understood. More than half of patients at our center who presented with graft dysfunction in the absence of acute cellular rejection or AMR were found to have elevated AT1R-Ab titers. Empiric AMR treatment in conjunction with ARB therapy may improve patient outcomes. Future studies are needed to better define the optimal treatment modalities for ATR1-Ab-mediated AMR.

Recovery of cardiac function is the ultimate goal of heart failure therapy. Unfortunately, cardiac recovery remains a rare and poorly understood phemomenon. Herein, we performed single nucleus RNA-sequencing (snRNA-seq) from non-diseased donors and heart failure patients. By comparing patients who recovered LV systolic function following LV assist device implantation to those who did not recover and donors, we defined the cellular and transcriptional landscape and predictors of cardiac recovery. We sequenced 40 hearts and recovered 185,881 nuclei with 13 distinct cell types. Using pseudobulk differential expression analysis to explicate cell specific signatures of cardiac recovery, we observed that recovered cardiomyocytes do not revert to a normal state, and instead, retain transcriptional signatures observed in heart failure. Macrophages and fibroblasts displayed the strongest signatures of recovery. While some evidence of reversion to a normal state was observed, many heart failure associated genes remained elevated and recovery signatures were predominately indicative of a biological state that was unique from donor and heart failure conditions. Acquisition of recovery states was associated with improved LV systolic function. Pro-inflammatory macrophages and inflammatory signaling in fibroblasts were identified as negative predictors of recovery. We identified downregulation of RUNX1 transcriptional activity in macrophages and fibroblasts as a central event associated with and predictive of cardiac recovery. In silico perturbation of RUNX1 in macrophages and fibroblasts recapitulated the transcriptional state of cardiac recovery. This prediction was corroborated in a mouse model of cardiac recovery mediated by BRD4 inhibition where we observed a decrease in macrophage and fibroblast Runx1 expression, diminished chromatin accessibility within peaks linked to the Runx1 locus, and acquisition of recovery signatures. These findings suggest that cardiac recovery is a unique biological state and identify RUNX1 as a possible therapeutic target to facilitate cardiac recovery.

Background The recently updated European LeukemiaNet risk stratification guidelines combine cytogenetic abnormalities and genetic mutations to provide the means to triage patients with acute myeloid leukemia for optimal therapies. Despite the identification of many prognostic factors, relatively few have made their way into clinical practice. Methods In order to assess and improve the performance of the European LeukemiaNet guidelines, we developed novel prognostic models using the biomarkers from the guidelines, age, performance status and select transcript biomarkers. The models were developed separately for mononuclear cells and viable leukemic blasts from previously untreated acute myeloid leukemia patients (discovery cohort, N = 185) who received intensive chemotherapy. Models were validated in an independent set of similarly treated patients (validation cohort, N = 166). Results Models using European LeukemiaNet guidelines were significantly associated with clinical outcomes and, therefore, utilized as a baseline for comparisons. Models incorporating age and expression of select transcripts with biomarkers from European LeukemiaNet guidelines demonstrated higher area under the curve and C-statistics but did not show a substantial improvement in performance in the validation cohort. Subset analyses demonstrated that models using only the European LeukemiaNet guidelines were a better fit for younger patients (age ASXL1, CEBPA, RUNX1 and TP53, demonstrated that these mutations provide a limited overall contribution to risk stratification across the entire population, given the low frequency of mutations and confounding risk factors. Conclusions While European LeukemiaNet guidelines remain a critical tool for triaging patients with acute myeloid leukemia, the findings illustrate the need for additional prognostic factors, including age, to improve risk stratification.

Photo-induced reaction cross section data are of importance for a variety of current or emerging applications, such as radiation shielding design and radiation transport analyses, calculations of absorbed dose in the human body during radiotherapy, physics and technology of fission reactors (influence of photo-reactions on neutron balance) and fusion reactors (plasma diagnostics and shielding), activation analyses, safeguards and inspection technologies, nuclear waste transmutation, medical isotope production and astrophysical applications. To address these data needs the IAEA Photonuclear Data library was produced in 1999, containing evaluated photo-induced cross sections and neutron spectra for 164 nuclides which were deemed relevant for the applications. Since the release of the IAEA Photonuclear Data Library however, new experimental data as well as new methods to assess the reliability of experimental cross sections have become available. Theoretical models and input parameters used to evaluate photo-induced reactions have improved significantly over the years. In addition, new measurements of partial photoneutron cross sections using mono-energetic photon beams and advanced neutron detection systems have been performed allowing for the validation of the evaluations and assessments of the experimental data. Furthermore, technological advances have led to the construction of new and more powerful gamma-beam facilities, therefore new data needs are emerging. We report our coordinated efforts to address these data needs and present the results of the new up-to-date evaluations included in the new updated IAEA Photonuclear Data Library consisting of 219 nuclides. The new library includes 188 new evaluations produced by the CRP evaluators, and one evaluation taken from the JENDL/PD-2016 library, while 20 evaluations were retained from the previous 1999 IAEA Photonuclear Data Library. In most of the cases, the photon energy goes up to 200 MeV. A total of 55 nuclides are new in this library reflecting the progress in measurements but also the developing data needs. In this paper we discuss the new assessment method and make recommendations to the user community in cases where the experimental data are discrepant and the assessments disagree. In addition, in the absence of experimental data, we present model predictions for photo-induced reaction cross section on nuclides of potential interest to medical radioisotope production.

Adipocytes transfer mitochondria to macrophages in white and brown adipose tissues to maintain metabolic homeostasis. In obesity, adipocyte-to-macrophage mitochondria transfer is impaired, and instead, adipocytes release mitochondria into the blood to induce a protective antioxidant response in the heart. We found that adipocyte-to-macrophage mitochondria transfer in white adipose tissue is inhibited in murine obesity elicited by a lard-based high-fat diet, but not a hydrogenated-coconut-oil-based high-fat diet, aging, or a corn-starch diet. The long-chain fatty acids enriched in lard suppress mitochondria capture by macrophages, diverting adipocyte-derived mitochondria into the blood for delivery to other organs, such as the heart. The depletion of macrophages rapidly increased the number of adipocyte-derived mitochondria in the blood. These findings suggest that dietary lipids regulate mitochondria uptake by macrophages locally in white adipose tissue to determine whether adipocyte-derived mitochondria are released into systemic circulation to support the metabolic adaptation of distant organs in response to nutrient stress.

Background Ionizing radiation is a known cause of female breast cancer, but there have been few studies of the risk after prolonged radiation exposure at low dose rates. Methods This population-based case-control study estimated breast cancer risk after ∼25 years’ exposure to radiation from the Chernobyl accident. Cases (n = 468) were women ≤55 years old when first diagnosed with invasive breast cancer during October 2008 through February 2013, who lived in Bryansk Oblast, Russia at the time of the accident and their diagnoses. Controls, individually matched to cases on birth year, administrative district of residence and urban vs non-urban settlement during the accident, were women without breast cancer who lived in Bryansk Oblast at the time of the accident and on their cases’ diagnosis dates (n = 468). Subjects were interviewed regarding residence, dietary and food source histories to support individualized estimation of their radiation doses to the breast, which ranged from 0.04 − 41 centigray (cGy) (mean 1.3 cGy). Results In multivariable analyses, the odds ratio for breast cancer risk was 3.0 [95% confidence interval (CI): 1.3, 7.0] and 2.7 (95% CI: 1.0, 7.3) in the seventh and eighth dose octiles, respectively, relative to the lowest octile. Analyses of dose effect modification suggested that radiation-related risk may have been higher in women who were younger at the time of the accident and/or at the time of diagnosis. Conclusions This study suggests that prolonged exposure to ionizing radiation at low dose rates can increase risk of breast cancer.

Current prognostic models for acute myeloid leukemia (AML) are inconsistent at predicting clinical outcomes for individual patients. Variability in the quality of specimens utilized for biomarker discovery and validation may contribute to this prognostic inconsistency.We evaluated the impact of sample heterogeneity on prognostic biomarkers and methods to mitigate any adverse effects of this heterogeneity in 240 cryopreserved bone marrow and peripheral blood specimens from AML patients enrolled on SWOG (Southwest Oncology Group) trials.Cryopreserved samples displayed a broad range in viability (37% with viabilities ≤60%) and nonleukemic cell contamination (13% with lymphocyte percentages20%). Specimen viability was impacted by transport time, AML immunophenotype, and, potentially, patients' age. The viability and cellular heterogeneity in unsorted samples significantly altered biomarker results. Enriching for viable AML blasts improved the RNA quality from specimens with poor viability and refined results for both DNA and RNA biomarkers. For example, FLT3-ITD allelic ratio, which is currently utilized to risk-stratify AML patients, was on average 1.49-fold higher in the viable AML blasts than in the unsorted specimens.To our knowledge, this is the first study to provide evidence that using cryopreserved specimens can introduce uncontrollable variables that may impact biomarker results and enrichment for viable AML blasts may mitigate this impact.

Futile substrate cycling based on lipolytic release of fatty acids (FA) from intracellular triacylglycerols (TAG) and their re-esterification (TAG/FA cycling), as well as de novo FA synthesis (de novo lipogenesis (DNL)), represent the core energy-consuming biochemical activities of white adipose tissue (WAT). We aimed to characterize their roles in cold-induced thermogenesis and energy homeostasis.Male obesity-resistant A/J and obesity-prone C57BL/6J mice maintained at 30 °C were exposed to 6 °C for 2 or 7 days. In epididymal WAT (eWAT), TAG synthesis and DNL were determined using in vivoThe mass of WAT depots declined during cold exposure (CE). Plasma levels of TAG and non-esterified FA were decreased by day 2 but tended to normalize by day 7 of CE. TAG synthesis (reflecting TAG/FA cycle activity) gradually increased during CE. DNL decreased by day 2 of CE but increased several fold over the control values by day 7. Expression of genes involved in lipolysis, glyceroneogenesis, FA re-esterification, FA oxidation and mitochondrial biogenesis in eWAT was induced during CE. All these changes were more pronounced in obesity-resistant A/J than in B6 mice and occurred in the absence of uncoupling protein 1 in eWAT. Expression of markers of glyceroneogenesis in eWAT correlated negatively with hepatic FA synthesis by day 7 in both strains. Leptin and fibroblast growth factor 21 plasma levels were differentially affected by CE in the two mouse strains.Our results indicate integrated involvement of (i) TAG/FA cycling and DNL in WAT, and (ii) hepatic very-low-density lipoprotein-TAG synthesis in the control of blood lipid levels and provision of FA fuels for thermogenesis in cold. They suggest that lipogenesis in WAT contributes to a lean phenotype.

Photon strength functions describing the average response of the nucleus to an electromagnetic probe are key input information in the theoretical modelling of nuclear reactions. Consequently they are important for a wide range of fields such as nuclear structure, nuclear astrophysics, medical isotope production, fission and fusion reactor technologies. They are also sources of information for widely used reaction libraries such as the IAEA Reference Input Parameter Library and evaluated data files such as EGAF. In the past two decades, the amount of reaction gamma-ray data measured to determine photon strength functions has grown rapidly. Different experimental techniques have led to discrepant results and users are faced with the dilemma of which (if any) of the divergent data to adopt. We report on a coordinated effort to compile and assess the existing experimental data on photon strength functions from the giant dipole resonance region to energies below the neutron separation energy. The assessment of the discrepant data at energies around or below the neutron separation energy has been possible only in a few cases where adequate information on the model-dependent analysis and estimation of uncertainties was available. In the giant dipole resonance region, we adopt the recommendations of the new IAEA photonuclear data library. We also present global empirical and semi-microscopic models that describe the photon strength functions in the entire energy region and reproduce reasonably well most of the experimental data. The compiled experimental photon strengths and recommended model calculations are available from the PSF database hosted at the IAEA (http://www-nds.iaea.org/PSFdatabase)., SCOPUS: re.j, info:eu-repo/semantics/published

Modigliani and Miller present an equity-quantity shifting equilibrating process to achieve an optimal firm value in the presence of corporate taxes. However, in the era in which they derived their various propositions regarding the relation between a firm’s value and its capital structure, well-capitalized takeover specialists including private equity firms and sovereign funds did not exist, at least by today’s standards. In this paper we develop a simple arbitrage strategy, made viable by the presence of takeover firms, which presents an alternative equilibrating process to achieve the same optimal firm value. This alternative process is markedly different from that of the Modigliani and Miller theorem in terms of its predictions for debt use and restores the prospect of capital structure irrelevancy despite the existence of corporate taxes.

Purpose Younger patients with acute myeloid leukemia (AML) harboring NPM1 mutations without FLT3–internal tandem duplications (ITDs; NPM1-positive/FLT3-ITD–negative genotype) are classified as better risk; however, it remains uncertain whether this favorable classification can be applied to older patients with AML with this genotype. Therefore, we examined the impact of age on the prognostic significance of NPM1-positive/FLT3-ITD–negative status in older patients with AML. Patients and Methods Patients with AML age ≥ 55 years treated with intensive chemotherapy as part of Southwest Oncology Gorup (SWOG) and UK National Cancer Research Institute/Medical Research Council (NCRI/MRC) trials were evaluated. A comprehensive analysis first examined 156 patients treated in SWOG trials. Validation analyses then examined 1,258 patients treated in MRC/NCRI trials. Univariable and multivariable analyses were used to determine the impact of age on the prognostic significance of NPM1 mutations, FLT3-ITDs, and the NPM1-positive/FLT3-ITD–negative genotype. Results Patients with AML age 55 to 65 years with NPM1-positive/FLT3-ITD–negative genotype treated in SWOG trials had a significantly improved 2-year overall survival (OS) as compared with those without this genotype (70% v 32%; P < .001). Moreover, patients age 55 to 65 years with NPM1-positive/FLT3-ITD–negative genotype had a significantly improved 2-year OS as compared with those age > 65 years with this genotype (70% v 27%; P < .001); any potential survival benefit of this genotype in patients age > 65 years was marginal (27% v 16%; P = .33). In multivariable analysis, NPM1-positive/FLT3-ITD–negative genotype remained independently associated with an improved OS in patients age 55 to 65 years (P = .002) but not in those age > 65 years (P = .82). These results were confirmed in validation analyses examining the NCRI/MRC patients. Conclusion NPM1-positive/FLT3-ITD–negative genotype remains a relatively favorable prognostic factor for patients with AML age 55 to 65 years but not in those age > 65 years.

The aim of this study was to describe the fate of patients with newly diagnosed acute myeloid leukemia (AML) who did not achieve an initial remission while being treated on a contemporary cooperative group trial. We analyzed the outcome of patients entered into S0106, a recently reported cooperative group trial for patients with newly diagnosed AML. A total of 589 eligible patients was treated, of whom 150 (25%) did not achieve a remission while on study and were available for further analysis. The 4-year survival rate for the entire cohort of 150 patients was 23%. Among the 64 patients who received an allogeneic hematopoietic cell transplant, the 4-year survival rate was 48% compared with 4% for the 86 patients who did not undergo transplantation. Among those transplanted, we could not detect a difference in outcome according to remission status, donor source, type of preparative regimen, or cytogenetic risk category. More than 20% of patients with newly diagnosed AML who fail induction therapy can still be cured, particularly if they are able to receive an allogeneic hematopoietic cell transplant. These results suggest that early HLA typing and donor identification are important components of the initial therapy of AML.

Die stetig ansteigende Inzidenz der chronischen Nierenerkrankung (CKD) stellt - nicht zuletzt aufgrund der dialyseassoziierten Kosten - eine medizinische und gesundheitspolitische Herausforderung dar. Digitale Strategien können Lösungsansätze bieten, um in Zukunft durch die Kombination einer Vielzahl technischer Parameter mit den Patientendaten die anspruchsvolle Therapie zeitgemäß, ressourcenschonend und effizienter zu gestalten als es bei handschriftlicher Dokumentation möglich ist. Die Arbeit stellt dialyserelevante Kommunikationsabläufe dar, Einsatzmöglichkeiten digitaler Lösungen sowie technische und datenschutzrechtliche Aspekte. Erläutert werden beispielhaft Planung und Datenaustausch, Dokumentations- und Organisationsstruktur, aber auch die Einbindung des Patienten in die Dialysebehandlung.

Specific associations for lymphoma in the general population suggest that chronic immune dysfunction/dysregulation may be associated with the development of B-cell non-Hodgkin lymphoma (NHL). Furthermore, polymorphisms in several cytokine genes have been associated with increased lymphoma risk, most consistently with genes for TNF and IL10. To evaluate the hypothesis that prediagnostic circulating cytokine levels would be associated with increased B-cell lymphoma risk, we conducted a nested case-control study within the Women's Health Initiative Observational Study cohort involving 491 B-cell NHL cases and 491 controls. Levels of eleven cytokines, including IL1β, IL2, IL4, IL5, IL6, IL10, IL12, IL13, TNF, IFNγ and GM-CSF, were measured using a Luminex suspension bead-based multiplexed array in prediagnostic serum samples collected a median of 6 years prior to the lymphoma diagnosis. We observed a modestly increased risk of all B-cell NHL in women with increased levels of the cytokines TNF and IL10 (OR1.22, CI 1.07-1.38 and OR 1.09, CI 1.04-1.15, respectively, per doubling in the serum cytokine concentration) and this association showed some variation according to histologic subtype. The increased risk was strongest for those neoplasms diagnosed in close proximity to the blood draw for some histologic subtypes but not others, suggesting a component of reverse causation. Further study will be required to better understand how genetic polymorphisms in TNF and IL10 genes may interact with circulating cytokine levels and states of chronic immune dysfunction/stimulation to contribute to the risk of B-cell NHL.

INTRODUCTION: ELN-2017 guideline is the gold standard for risk stratifying AML patients. However, clinical prognostic factors such as age are not incorporated into the guideline. Therefore, we examined if novel prognostic models incorporating clinical factors and expression of select transcripts can improve the current guideline. The prognostic models were developed utilizing molecular data from unsorted mononuclear cells (MNCs) and viable leukemic blasts (VLBs). METHODS: Specimens were obtained from untreated AML patients (N=383) who received intensive chemotherapy on SWOG trials S9031, S9333, S0106 and S0112. Patients were randomly separated into discovery (N=190) and validation (N=193) cohorts. Participants provided informed consent in compliance with the Declaration of Helsinki, SWOG, NCI, and Fred Hutch regulations. VLBs were isolated using fluorescence-activated cell sorting (FACS, Pogosova et al., 2018, Biopreserv Biobank 16;42-52). RNA and DNA were extracted from MNCs and VLBs. FLT3-ITD, NPM1, CEBPA, ASXL1, RUNX1 and TP53 mutations were identified using fragment analyses and NGS. Transcript expression for BAALC, CEBPA, CCNA1, CD34, ERG1, EVI1, FLT3, GATA2, IL3RA, JAG1, KIT, MN1, RUNX1, and WT1 was quantified using Q-RT/PCR assays. Specimen attributes across paired samples were compared using McNemar's test and the Wilcoxon signed rank test. Associations with overall survival (OS), relapse-free survival (RFS), and complete remission (CR) were assessed using the Kaplan-Meier method, Cox proportional hazards regression, and logistic regression. Models were built in the discovery cohort using a pre-defined 3-step process of variable selection and 5-fold cross validation of this process; final model performance was evaluated in the validation cohort. RESULTS: Mutations, transcripts and clinical variables . Mutation frequencies, FLT3-ITD AR, and clinical outcomes were not significantly different between discovery and validation cohorts. The percentage of patients with high FLT3-ITD AR (per ELN-2017 definition) was increased in the VLBs compared to MNCs (77% vs 66%, respectively); FLT3-ITD AR was reclassified for 19 patients. Transcript expression was significantly increased in VLBs relative to MNCs for 8 transcripts (P Model Development and Performance. Multivariable models for CR, OS, and RFS were fit using age, ELN-2017 risk group, PS, AML onset, immunophenotype, clinical trial, and combinations of these baseline variables as covariates. In the discovery cohort, the models with the best performance were obtained when clinical variables and transcript expression were integrated; however, these integrated models were not superior to AGE+ELN2017 models in the validation cohort (Table 1), whether utilizing molecular data from MNCs or VLBs. Quartile risk groups from the AGE+ELN2017 model displayed increased discrimination with respect to OS than the ELN risk groups (Figure 1A,B). The discriminative performances of the ELN2017 and AGE+ELN2017 models for OS were also examined in older adults (age ≥55). Given the small numbers of patients, risk scores for the AGE+ELN2017 model were divided into tertiles to identify 3 risk groups. The three risk groups derived from the AGE+ELN2017 scores showed increased ability to discriminate for projected OS relative to ELN2017 risk groups (Figure 1C, D). DISCUSSION: ELN2017 models were significantly associated with clinical outcomes, but AGE+ELN2017 models may perform slightly better than ELN2017 models. Models incorporating selected transcript expression did not improve the ELN2017 models, whether transcripts were examined in MNCs or VLBs. While ELN-2017 prognostic guideline remains a critical tool for risk stratifying AML patients, the findings highlight the need for additional prognostic factors, including age, to improve the accuracy of risk stratification. Disclosures Othus: Celgene: Other: Data Safety and Monitoring Committee; Glycomimetics: Other: Data Safety and Monitoring Committee. Erba:Agios, Amgen, Astellas Pharma, Daiichi Sankyo, ImmunoGen, Janssen, Jazz Pharmaceuticals, Juno, Millennium, Seattle Genetics: Research Funding; Celgene, Incyte, Novartis: Speakers Bureau; Amgen, Celgene, Daiichi Sankyo, ImmunoGen, Incyte, Jazz Pharmaceuticals, Millennium, Novartis, Ono, Pfizer, Seattle Genetics, Sunesis: Consultancy. List:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Radich:Novartis: Other: RNA Sequencing; TwinStrand Biosciences: Research Funding. Willman:to come: Patents & Royalties; to come: Membership on an entity's Board of Directors or advisory committees; to come: Research Funding.

Background Data on the efficacy and safety of all targeted therapies for metastatic renal cell carcinoma (mRCC) including sunitinib are collected in the Czech RENIS patient registry. RENIS thus provides a uniquely large sample of long-term effectiveness and prognostic data of sunitinib according to adverse/risk factors measured by the Memorial Sloan Kettering Cancer Center (MSKCC) score. The aim of this study was to analyze the long-term overall (OS) and progression-free survival (PFS) of sunitinib, when used as 1st line treatment, based on MSKCC risk group scores including MSKCC scores for two intermediate subgroups. Methods Data from mRCC patients treated using sunitinib in the 1st line were collected in RENIS between 06/2007 and 02/2018. OS/PFS were then stratified based on MSKCC scores: a) favorable risk (0 adverse factors (AF)), b) intermediate risk (pooled 1–2 AFs), and c) poor risk (3+ AFs). The OS/PFS of the intermediate risk group was further stratified into two subgroups: i) 1 AF and ii) 2 AFs. All OS/PFS data were analyzed using Kaplan-Meier estimates. Differences in OS/PFS between risk groups were assessed using median survival, 95% confidence intervals (CI), and the log-rank test. Then we assessed the OS/PFS for 1-, 3-, and 5-year survival. Results Over the 11-year follow-up, 2390 patients were treated using sunitinib with 806, 1450, and 134 patients in the favorable, intermediate, and poor MSKCC risk groups. The more favorable MSKCC risk group was accompanied by an improved OS and PFS (p Table . 957P OS and PFS results for sunitinib treatment based on MSKCC risk groups MSKCC favorable MSKCC intermediate MSKCC poor MSKCC intermediate All patients 1 AF 2 AFs Overall survival Median survival (95% CI) 44.7months (40.9-50.5) 24.1months (21.9-26.0) 9.5months (7.2-14.1) 28.2months (25.9-30.7) 16.2months (14.5-20.2) 28.5months (26.3-30.5) 1-year survival (95% CI) 85.0% (82.4-87.6) 69.1% (66.6-71.7) 44.3% (35.0-53.7) 74.3% (71.4-77.2) 58.0% (53.1-62.9) 73.3% (71.4-75.2) 3-year survival (95 %CI) 57.3% (53.4-61.3) 37.1% (34.1-40.1) 9.6% (3.1-16.2) 42.0% (38.3-45.7) 26.3% (21.4-31.2) 42.9% (40.5-45.2) 5-year survival (95% CI) 35.6% (31.2-40.1) 23.4% (20.4-26.4) 3.2% (0.0-8.8) 26.5% (22.7-30.3) 16.5% (11.8-21.2) 26.8% (24.3-29.2) n 806 1450 134 969 481 2390 Log-rank p-value - Progression-free survival Median survival (95% CI) 17.0months (15.4-18.8) 9.0months (8.3-9.5) 4.5months (3.9-6.1) 10.1months (9.4-11.4) 6.2months (5.5-7.5) 10.6months (9.9-11.5) 1-year survival (95% CI) 61.8% (58.3-65.3) 40.7% (38.0-43.4) 20.8% (13.1-28.5) 45.1% (41.8-48.4) 31.6% (27.1-36.1) 46.9% (44.7-49.0) 3-year survival (95 %CI) 25.1% (21.7-28.5) 13.0% (11.0-15.1) 1.8% (0.0-5.1) 15.9% (13.2-18.6) 7.0% (4.2-9.7) 16.6% (14.9-18.4) 5-year survival (95% CI) 10.4% (7.7-13.2) 8.0% (6.2-9.8) 1.8% (0.0-5.1) 9.7 (7.3-12.0) 4.5% (2.1-6.9) 8.4% (7.0-9.9) n 806 1450 134 969 481 2390 Log-rank p-value - Conclusions Better MSKCC risk scores were associated with significantly longer OS and PFS. To our knowledge, this is the largest published sunitinib mRCC cohort described relative to MSKCC risk groups. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure J. Finek: Honoraria (self): Amgen; Honoraria (self): BMS; Honoraria (self): Roche; Honoraria (self): Bayer; Honoraria (self): Teva; Honoraria (self): MSD; Honoraria (self): Merck; Honoraria (self): Sanofi; Honoraria (self): Pierre Fabre. A. Poprach: Honoraria (self): Pfizer; Honoraria (self): Roche; Honoraria (self): Ipsen; Honoraria (self): Novartis; Honoraria (self): BMS; Honoraria (self): Bayer. B. Melichar: Honoraria (self): BMS; Honoraria (self): Merck; Honoraria (self): MSD; Honoraria (self): Roche; Honoraria (self): Novartis; Honoraria (self): Astellas Pharma; Honoraria (self): Pfizer; Honoraria (self): Bayer. J. Kopecky: Honoraria (self): BMS; Honoraria (self): Novartis; Honoraria (self): Pfizer. M. Zemanova: Advisory / Consultancy: Novartis; Honoraria (self): Eli Lilly; Travel / Accommodation / Expenses: MSD; Travel / Accommodation / Expenses: Boehringer Ingelheim. T. Buchler: Honoraria (self): Amgen; Honoraria (self): Roche; Honoraria (self): Novartis; Honoraria (self): Pfizer; Advisory / Consultancy: Roche; Advisory / Consultancy: BMS; Advisory / Consultancy: Pfizer; Travel / Accommodation / Expenses: Janssen. K. Kopeckova: Honoraria (self): Novartis; Travel / Accommodation / Expenses: Bayer; Travel / Accommodation / Expenses: Pfizer. T. Mlcoch: Full / Part-time employment: Value Outcomes. T. Dolezal: Full / Part-time employment: Value Outcomes. All other authors have declared no conflicts of interest.

The standard dose of imatinib for newly diagnosed patients with chronic phase chronic myeloid leukaemia (CP-CML) is 400 mg daily (IM400), but the optimal dose is unknown. This randomized phase II study compared the rates of molecular, haematological and cytogenetic response to IM400 vs. imatinib 400 mg twice daily (IM800) in 153 adult patients with CP-CML. Dose adjustments for toxicity were flexible to maximize retention on study. Molecular response (MR) at 12 months was deeper in the IM800 arm (4-log reduction of BCR-ABL1 mRNA: 25% vs. 10% of patients, P = 0·038; 3-log reduction: 53% vs. 35%, P = 0·049). During the first 12 months BCR-ABL1 levels in the IM800 arm were an average 2·9-fold lower than in the IM400 arm (P = 0·010). Complete haematological response was similar, but complete cytogenetic response was higher with IM800 (85% vs. 67%, P = 0·040). Grade 3-4 toxicities were more common for IM800 (58% vs. 31%, P = 0·0007), and were most commonly haematological. Few patients have relapsed, progressed or died, but both progression-free (P = 0·048) and relapse-free (P = 0·031) survival were superior for IM800. In newly diagnosed CP-CML patients, IM800 induced deeper MRs than IM400, with a trend for improved progression-free and overall survival, but was associated with more severe toxicity.

Background: We hypothesized that poor control of Epstein–Barr virus (EBV) infection, leading to reactivation of the virus, increases the risk of non-Hodgkin lymphoma (NHL) in the general population of primarily immunocompetent persons. Methods: We conducted a case–control study nested within the Women's Health Initiative Observational Study cohort in which we measured antibodies to EBV antigens [immunoglobulin G (IgG) to viral capsid antigen (VCA), nuclear antigen (EBNA1), and early antigen-diffuse (EA-D)] and EBV DNA load in prediagnostic samples of 491 B-cell NHL cases and 491 controls. Results: We found no association with established EBV infection, based on seropositivity for VCA. Seropositivity for EBNA1 was associated with decreased risk of B-cell NHL, overall [OR = 0.5; 95% confidence interval (CI), 0.3–0.8] and for each of the histologic subtypes examined. Increased risk of chronic lymphocytic leukemia (CLL) and related subtypes was observed with higher levels of EBV DNA and antibody to EA-D, both markers reflective of reactivation. These associations were strongest for cases with the shortest time interval between blood draw and diagnosis. Conclusions: In balance, these results do not provide strong evidence of EBV playing a causal role in B-cell NHL in general population women. The associations we observed may reflect increased risk of NHL with underlying immune impairment or could be due to reverse causation. Impact: Further characterization of the subtype-specific association with CLL is warranted. Exclusion of cases with preclinical disease markers (such as monoclonal B-lymphocytosis for CLL) may help rule out reverse causation in future studies. Cancer Epidemiol Biomarkers Prev; 22(10); 1747–55. ©2013 AACR.

This randomized phase 3 clinical trial evaluated the potential benefit of the addition of gemtuzumab ozogamicin (GO) to standard induction and postconsolidation therapy in patients with acute myeloid leukemia. Patients were randomly assigned to receive daunorubicin (45 mg/m2 per day on days 1, 2, and 3), cytarabine (100 mg/m2 per day by continuous infusion on days 1–7), and GO (6 mg/m2 on day 4; DA+GO) vs standard induction therapy with daunorubicin (60 mg/m2 per day on days 1, 2, and 3) and cytarabine alone (DA). Patients who achieved complete remission (CR) received 3 courses of high-dose cytarabine. Those remaining in CR after consolidation were randomly assigned to receive either no additional therapy or 3 doses of GO (5 mg/m2 every 28 days). From August 2004 until August 2009, 637 patients were registered for induction. The CR rate was 69% for DA+GO and 70% for DA (P = .59). Among those who achieved a CR, the 5-year relapse-free survival rate was 43% in the DA+GO group and 42% in the DA group (P = .40). The 5-year overall survival rate was 46% in the DA+GO group and 50% in the DA group (P = .85). One hundred seventy-four patients in CR after consolidation underwent the postconsolidation randomization. Disease-free survival was not improved with postconsolidation GO (HR, 1.48; P = .97). In this study, the addition of GO to induction or postconsolidation therapy failed to show improvement in CR rate, disease-free survival, or overall survival. This trial is registered with www.clinicaltrials.gov as #NCT00085709.

This paper presents the approach of a combined use of resonance integrals and average Maxwellian cross sections (MACS) at kT = 30 keV to test and validate the resolved resonance range or its reconstructed cross section curve. Based on these two integral measurements a sensitive and energy dependent test can be provided. These two integral quantities cover with their neutron spectra the energy region between En = 0.5 eV up to several hundred keV, respectively, with different weighting. Our principal motivation is to produce a validation tool, sensitive to the lower and upper parts of the resonance region through the difference in the applied 1/E and kT = 30 keV Maxwell–Boltzmann spectra of the resonance integral and MACS data.

This paper presents a novel approach using average parameters from statistical models in the continuum to produce statistical resolved resonances in the resonance range. Based on unresolved resonance parameters and the random ladder method, average parameters such as the scattering radius, level spacing, reduced neutron width and the radiative width are used to create resolved resonances from thermal energy up to the first excited level. Using the TALYS reaction code and the CALENDF processing code, the method is tested on ≃2400 isotopes and will be used to produce resolved resonance ranges in the TENDL libraries for reactions missing experimental resolved and unresolved parameters. Additionally, the R-matrix code AVEFIT is used to approximate the resonance structure effects above the first excited level of selected isotopes.

This paper develops a framework for analyzing socially and privately optimal bank loan-monitoring decisions, with and without capital regulation. In contrast to the monitoring decision of a social planner who seeks to maximize the utility of aggregate consumption, banks choose to monitor only if doing so is consistent with maximizing the market value of equity. As a consequence, socially and privately optimal monitoring choices can diverge. Under some circumstances, appropriately configured capital regulation can bring private loan-monitoring decisions into line with those of the social planner. Nevertheless, the capital ratio required to attain this outcome hinges on a number of factors that are likely to be economy-specific, including the banking system's monitoring technology and its exposure to default. Thus, it is unlikely that a unique capital ratio will be able to induce socially optimal monitoring in all economies.

The present report describes our efforts to convert an existing LXR agonist into an LXR antagonist using a structure-based approach. A series of benzenesulfonamides was synthesized based on structural modification of a known LXR agonist and was determined to be potent dual liver X receptor (LXR α/β) ligands. Herein we report the identification of compound 54 as the first reported LXR antagonist that is suitable for pharmacological in vivo evaluation in rodents.

This paper examines determinants of pass through from the market interest rate to bank retail deposit and loan rates. A dynamic adjustment cost model with imperfect competition implies that these rates depend on own lagged values and on lagged, current, and expected future values of the security rate. Greater competition in retail markets reduces the impact of lagged and expected rates on current retail rates while raising the effect of the current security rate, yielding greater pass through. These results have important implications for both the specifications used in empirical work and biases introduced into estimates of pass-through effects.

Dendritic cells are a sentinel in defending against pathogens and tick saliva facilitates transmission of tick-borne pathogens by modulating the host immune response. The maturation of dendritic cells is inhibited by tick saliva. To elucidate the mechanism of this inhibition, we tested the impact of Ixodes ricinus tick saliva on signalling pathways activated by Toll-like receptor (TLR-2) ligand and Borrelia afzelii in spleen dendritic cells. The activation of nuclear factor-κB (NF-κB) p65 and phosphatidylinositol-3 kinase (PI3K)/Akt pathways was decreased by tick saliva upon both TLR-2 and Borrelia stimulation. Among the mitogen-activated protein kinases (MAPK), the activation of extracellular matrix-regulated kinase (Erk1/2) was suppressed by tick saliva, but not p38. In response to spirochaetes, the amount of TNF-α decreased in the presence of tick saliva which was mediated by selective suppression of Erk1/2, NF-κB and Akt as tick saliva mimicked the effect of their specific inhibitors, UO126, IKK-IV and LY294002, respectively. Saliva-induced enhancement of IL-10 was not observed in the presence of specific inhibitor of Protein Kinase A (PKA), H-89, suggesting the involvement of PKA pathway in IL-10 production. Our cumulative data show that tick saliva interferes with several signalling pathways, thus modulating the immune functions of dendritic cells.

Among the Life Span Study (LSS) of Atomic-bomb survivors, recent estimates showed that unspecified bladder cancer had high radiation sensitivity with a notably high female-to-male excess relative risk (ERR) per radiation dose ratio and were the only sites for which the ERR did not decrease with attained age. These findings, however, did not consider lifestyle factors, which could potentially confound or modify the risk estimates. This study estimated the radiation risks of the most prevalent subtype of urinary tract cancer, urothelial carcinoma, while accounting for smoking, consumption of fruit, vegetables, alcohol and level of education (a surrogate for socioeconomic status). Eligible study subjects included 105,402 (males = 42,890) LSS members who were cancer-free in 1958 and had estimated radiation doses. Members were censored due to loss of follow-up, incident cancer of another type, death, or the end of calendar year 2001. Surveys (by mail or clinical interview) gathered lifestyle data periodically for 1963-1991. There were 63,827 participants in one or more survey. Five hundred seventy-three incident urothelial carcinoma cases occurred, of which 364 occurred after lifestyle information was available. Analyses were performed using Poisson regression methods. The excess relative risk per weighted gray unit (the gamma component plus 10 times the neutron component, Gy(w)) was 1.00 (95% CI: 0.43-1.78) but the risks were not dependent upon age at exposure or attained age. Lifestyle factors other than smoking were not associated with urothelial carcinoma risk. Neither the magnitude of the radiation ERR estimate (1.00 compared to 0.96), nor the female-to-male (F:M) ERR/Gy(w) ratio (3.2 compared to 3.4) were greatly changed after accounting for all lifestyle factors. A multiplicative model of gender-specific radiation and smoking effects was the most revealing though there was no evidence of significant departures from either the additive or multiplicative joint effect models. Among the LSS cohort members with doses greater than 0.005 Gy(w) (average dose 0.21 Gy(w)), the attributable fraction of urothelial carcinoma due to radiation was 7.1% in males and 19.7% in females. Among current smokers, the attributable fraction of urothelial carcinoma due to smoking was 61% in males and 52% in females. Relative risk estimates of smoking risk were approximately two for smokers compared to nonsmokers. After adjustment for lifestyle factors, gender-specific radiation risks and the F:M ERR/Gy(w), the ratios of excess urothelial carcinoma risk were similar to the estimates without adjusting for lifestyle factors. Smoking was the primary factor responsible for excess urothelial carcinoma in this cohort. These findings led us to conclude that the radiation risk estimates of urothelial carcinoma do not appear to be strongly confounded or modified by smoking, consumption of alcohol, fruits, or vegetables, or level of education.

The eukaryotic initiation factor 4E (eIF4E) plays a central role in the initiation of gene translation and subsequent protein synthesis by binding the 5' terminal mRNA cap structure. We designed and synthesized a series of novel compounds that display potent binding affinity against eIF4E despite their lack of a ribose moiety, phosphate, and positive charge as present in m7-GMP. The biochemical activity of compound 33 is 95 nM for eIF4E in an SPA binding assay. More importantly, the compound has an IC(50) of 2.5 μM for inhibiting cap-dependent mRNA translation in a rabbit reticular cell extract assay (RRL-IVT). This series of potent, truncated analogues could serve as a promising new starting point toward the design of neutral eIF4E inhibitors with physicochemical properties suitable for cellular activity assessment.

Structural modification of a series of dual LXRα/β agonists led to the identification of a new class of LXRβ partial agonists. An X-ray co-crystal structure shows that a representative member of this series, pyrrole 5, binds to LXRβ with a reversed orientation compared to 1.

Myelodysplastic syndromes (MDS) incidence is unclear because of historical lack of population-based registration and possibly because of underdiagnosis. We conducted a study to evaluate completeness of MDS registration in the Seattle-Puget Sound region of the Surveillance, Epidemiology, and End Results (SEER) program—which has reported the highest rates among the SEER registries since mandatory reporting of MDS began in 2001. We identified incident MDS cases of any age that occurred within a nonprofit healthcare system in western Washington State in 2005 or 2006 through the local SEER registry or by relevant diagnostic code followed by medical chart review to classify these patients as unlikely, possible, or definite/probable MDS. We calculated age-standardized incidence rates for all identified MDS cases and for case groups based on identification method, and we summarized medical histories of the MDS patients. MDS incidence in our study population was estimated as 7.0 per 100,000 person-years in 2005–2006 when combining MDS cases identified by SEER and definite/probable cases identified by chart review, which was similar to the rate of 6.9 reported by our local SEER registry. The addition of possible MDS cases identified from chart review increased the rate to 10.2 per 100,000. MDS patients frequently had previous cancer diagnoses (25%) and comorbidities such as high blood pressure and diabetes. Our investigation suggests that although reporting of confirmed MDS diagnoses in our region appears complete, MDS incidence is likely underestimated because of omission of cases who are symptomatic but do not receive definitive diagnoses. Am. J. Hematol., 2010. © 2010 Wiley-Liss, Inc.

Background: The length of the interval between age at menarche and age at first birth is positively associated with breast cancer risk. We examined the risk of breast cancer in atomic bomb survivors to investigate whether women exposed to radiation between menarche and first birth had a higher risk of radiogenic breast cancer than women exposed at the same age but outside this interval. Methods: Women (n = 30,113) were classified into three reproductive status at the time of the bombings (ATB) categories (premenarche, between menarche and first birth, or after first birth). Poisson regression was used to test the primary hypothesis. Results: When the background rate of breast cancer was taken to depend on city, age ATB, and attained age only, the radiation-related excess relative risk (ERR) varied significantly among the three categories (P = 0.049). However, after controlling for significant heterogeneity in the baseline risk of breast cancer between reproductive status ATB groups (P < 0.001), no significant heterogeneity (P = 0.88) was observed in the ERR, with an ERR per Gy of 1.36 [95% confidence interval (CI), 0.54-2.75] for women exposed between menarche and first birth ATB, and 1.07 (95% CI, 0.22-3.62) and 1.53 (95% CI, 0.63-2.90) for those exposed premenarche or after first birth, respectively. Conclusions: The radiation-associated risk of breast cancer does not vary significantly by reproductive status ATB. Impact: It is possible that radiation exerts similar carcinogenic effects on the breast regardless of its stage of differentiation, or that the differences in radiosensitivity are too small to be detected in this cohort. Cancer Epidemiol Biomarkers Prev; 19(7); 1746–54. ©2010 AACR.

The nematode Caenorhabditis elegans's (CE) successful use in studies of aging is well documented. Cold temperature stress of mixed populations of CE provides a rapid inexpensive means of obtaining three life stage-specific cohorts. Cohorts are obtained in quantities that allow acquisition of replicate metabolite profiles of changes associated with development, aging, and senescence. The fractionation technique is effective with monoxenic and axenic CE cultures. Cohort Y contains 100% young worms, and Cohort A contains 75% adult worms. Cohort M, prereproductive and reproductive, contains some A and Y due to continuous egg laying and hatch. Principal component analysis of normalized data from metabolite profiles obtained using high-performance liquid chromatography electrochemical analysis clearly separates Cohort Y from Cohort A and monoxenic from axenic cultured worms. Access to replicate quantities of age-defined worms will aid studies of alterations in homeostatic controls associated with aging and senescence.

We report on efforts to develop reliable photonuclear cross section and photon strength function data by measuring, compiling, assessing, evaluating the available data, and producing tables of Giant Dipole Resonance parameters and global models for use in basic sciences and applications., SCOPUS: cp.p, info:eu-repo/semantics/published

Summary Attempts to overcome multi-drug resistance in acute myeloid leukaemia (AML) have been limited by toxicities. To investigate the effect of reducing peak drug levels, we performed sequential phase II studies using continuous infusion daunorubicin and cytarabine without (AD) and then with ciclosporin (ADC) in older patients with AML. Untreated patients (age 56+ years) received daunorubicin (45 mg/m2 per day for 3 d) and cytarabine (200 mg/m2 per day for 7 d), both by continuous infusion, without (S0112, 60 patients) and then with (S0301, 50 patients) the addition of ciclosporin. Complete response (CR) rates were 38% on S0112 and 44% on S0301. Fatal induction toxicities occurred in 17% and 12% respectively, arising primarily from infection and haemorrhage. Median overall and relapse-free survival was 7 and 8 months for AD respectively, and 6 and 14 months for ADC. Patients with phenotypic or functional P-glycoprotein had somewhat higher CR rates with ADC than AD, although confidence intervals overlapped. In these sequential trials, continuous infusion AD produced CR rates comparable to those with bolus daunorubicin. The addition of ciclosporin did not cause undue toxicities, produced a similar CR rate, and possibly improved relapse-free survival. Further correlate analyses did not identify a subpopulation specifically benefitting from the addition of ciclosporin.

We describe the physics and data included in the Reference Input Parameter Library, which is devoted to input parameters needed in calculations of nuclear reactions and nuclear data evaluations. Advanced modelling codes require substantial numerical input, therefore the International Atomic Energy Agency (IAEA) has worked extensively since 1993 on a library of validated nuclear-model input parameters, referred to as the Reference Input Parameter Library (RIPL). A final RIPL coordinated research project (RIPL-3) was brought to a successful conclusion in December 2008, after 15 years of challenging work carried out through three consecutive IAEA projects. The RIPL-3 library was released in January 2009, and is available on the Web through (http://www-nds.iaea.org/RIPL-3/). This work and the resulting database are extremely important to theoreticians involved in the development and use of nuclear reaction modelling (ALICE, EMPIRE, GNASH, UNF, TALYS) both for theoretical research and nuclear data evaluations. The numerical data and computer codes included in RIPL-3 are arranged in seven segments: MASSES contains ground-state properties of nuclei for about 9000 nuclei, including three theoretical predictions of masses and the evaluated experimental masses of Audi et al. (2003). DISCRETE LEVELS contains 117 datasets (one for each element) with all known level schemes, electromagnetic andmore » {gamma}-ray decay probabilities available from ENSDF in October 2007. NEUTRON RESONANCES contains average resonance parameters prepared on the basis of the evaluations performed by Ignatyuk and Mughabghab. OPTICAL MODEL contains 495 sets of phenomenological optical model parameters defined in a wide energy range. When there are insufficient experimental data, the evaluator has to resort to either global parameterizations or microscopic approaches. Radial density distributions to be used as input for microscopic calculations are stored in the MASSES segment. LEVEL DENSITIES contains phenomenological parameterizations based on the modified Fermi gas and superfluid models and microscopic calculations which are based on a realistic microscopic single-particle level scheme. Partial level densities formulae are also recommended. All tabulated total level densities are consistent with both the recommended average neutron resonance parameters and discrete levels. GAMMA contains parameters that quantify giant resonances, experimental gamma-ray strength functions and methods for calculating gamma emission in statistical model codes. The experimental GDR parameters are represented by Lorentzian fits to the photo-absorption cross sections for 102 nuclides ranging from {sup 51}V to {sup 239}Pu. FISSION includes global prescriptions for fission barriers and nuclear level densities at fission saddle points based on microscopic HFB calculations constrained by experimental fission cross sections.« less

The European Activation System, EASY, includes as the source of nuclear data the European Activation File (EAF). A new version of EAF, EAF-2007, has been developed that contains cross-section data for deuteron-and proton-induced reactions in addition to the traditional neutron-induced data. The main reason for the addition of these data to EAF is to enable activation calculations to be performed for the International Fusion Materials Irradiation Facility, which is a planned materials test facility, and for other accelerator-driven devices with an incident upper energy limit of 60 MeV EAF-2007 has benefited from the generation and maintenance of comprehensive activation files and the development of the processing code SAFEPAQ-II. Cross-section validation exercises against both experimental data and systematics, which were started on the EAF-4 file (1995), enable a comprehensive assessment of the data. Although EAF-2007 is the best-validated activation neutron cross-section library in the world, currently