Final analysis from RESONATE: Up to six years of follow‐up on ibrutinib in patients with previously treated chronic lymphocytic leukemia or small lymphocytic lymphoma

Ibrutinib, a once‐daily oral inhibitor of Bruton's tyrosine kinase, is approved in the United States and Europe for treatment of patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). The phase 3 RESONATE study showed improved efficacy of single‐agent ibrutinib over ofatumumab in patients with relapsed/refractory CLL/SLL, including those with high‐risk features. Here we report the final analysis from RESONATE with median follow‐up on study of 65.3 months (range, 0.3‐71.6) in the ibrutinib arm. Median progression‐free survival (PFS) remained significantly longer for patients randomized to ibrutinib vs ofatumumab (44.1 vs 8.1 months; hazard ratio [HR]: 0.148; 95% confidence interval [CI]: 0.113‐0.196; P˂.001). The PFS benefit with ibrutinib vs ofatumumab was preserved in the genomic high‐risk population with del(17p), TP53 mutation, del(11q), and/or unmutated IGHV status (median PFS 44.1 vs 8.0 months; HR: 0.110; 95% CI: 0.080‐0.152), which represented 82% of patients. Overall response rate with ibrutinib was 91% (complete response/complete response with incomplete bone marrow recovery, 11%). Overall survival, censored for crossover, was better with ibrutinib than ofatumumab (HR: 0.639; 95% CI: 0.418‐0.975). With up to 71 months (median 41 months) of ibrutinib therapy, the safety profile remained consistent with prior reports; cumulatively, all‐grade (grade ≥3) hypertension and atrial fibrillation occurred in 21% (9%) and 12% (6%) of patients, respectively. Only 16% discontinued ibrutinib because of adverse events (AEs). These long‐term results confirm the robust efficacy of ibrutinib in relapsed/refractory CLL/SLL irrespective of high‐risk clinical or genomic features, with no unexpected AEs. This trial is registered at www.clinicaltrials.gov (NCT01578707)

Grass burning under our feet: Indigenous enterprise development in a political economy of whiteness

In this article we discuss some of our findings from two research projects that explore opportunities for Indigenous enterprise development in remote locations in Northern and Central Australia. Based on a series of focus groups and in-depth interviews with Indigenous community leaders, Traditional Owners, government officials, Land Council officials and other stakeholders, we discuss barriers to economic development faced by Indigenous communities in remote regions. We argue that many of these barriers are the material effects of discursive practices of ‘whiteness’ in the political economy. We discuss the relationships between institutions and Indigenous communities that constitute the Indigenous political economy and argue that these relationships are informed by discursive practices of whiteness and colonial-capitalist relations of power. We conclude by discussing the implications of our findings for management learning and public policy

Influence of silver content on the tribomechanical behavior on Ag-TiCN bioactive coatings

Surface modification of bulk materials used in biomedical applications has become an important prerequisite for better biocompatibility. In particular, to overcome the particle generation, low-wear coatings based on carbon (nitrogen) and containing antimicrobial elements such as silver are promising candidates. Thus, the present work explores the potentialities of silver-containing carbonitride-based (Ag-TiCN) thin films prepared by direct current unbalanced reactive magnetron sputtering. The silver content in the coatings was varied from 0 to 26.7 at.% by changing the targets and the fraction of C2H2 and N2 in the gas mixture with Ar. The obtained Ag-TiCN based coatings were characterized in terms of composition and microstructure. Mechanical and tribological properties of the films were studied by nanoindentation and reciprocating pin-on disk testing in a fetal bovine serum solution, respectively. Raman, scanning electron microscope and energy dispersive X-ray analysis was carried out in the contact region after tribological tests to obtain information about the friction mechanism. The cytotoxicity of the coatings was assessed by in vitro tests using fibroblast cells. The coatings comprised a mixture of TiCxN1−x, Ag and a-C(N)x phases whose relative proportion varied depending on the Ag/Ti ratio. The mechanical, tribological and cytotoxicity properties were correlated with the chemical and phase composition. When the Ag/Ti ratios were below 0.20 (Ag contents b6.3 at.%) the films resulted harder (~18 GPa) with higher wear resistance (~10−6 mm3/Nm), showing similar friction coefficient (~0.3) and good biocompatibility.The authors are grateful to the financial support of the CRUP Institution by the project "Accao No E-1007/08", the Spanish Ministry of Science and Innovation (projects FUNCOAT CSD2008-00023 and HP2007-0116), Junta de Andalucia (project TEP 06782) and CSIC-FCT institutions (2007PT0043). The work was financially supported by Portuguese national funds through the FCT-Fundacao para a Ciencia e a Tecnologia, (project PTDC/CTM/102853/2008) and partially sponsored by FEDER funds through the program COMPETE - Programa Operacional Factores de Competitividade

Retardadores de crescimento no desenvolvimento e na qualidade ornamental de Zinnia elegans Jacq. 'Lilliput' envasada

As zínias têm grande potencial como plantas floríferas envasadas e representam rápida fonte de novidade para a floricultura com o auxílio de retardadores de crescimento. Avaliaram-se os efeitos de retardadores de crescimento no desenvolvimento e na produção de plantas envasadas de porte baixo, compactas e atrativas de 'Lilliput' Zinnia elegans, cultivar altamente ornamental, com sementes de baixo custo. O delineamento experimental foi em blocos casualizados, com dez tratamentos (controle e três concentrações de cada retardador: daminozide, paclobutrazol e chlormequat) e quatro repetições (dois vasos por unidade experimental, com uma planta por vaso de 0,6 L). Paclobutrazol (0,5; 0,75 e 1,0 mg i.a. por vaso) e chlormequat (1,0; 2,0 e 3,0 g L-1) foram aplicados ao substrato (40 mL por vaso), enquanto o daminozide (2,5; 3,75 e 5,0 g L-1) foi aplicado através de pulverização foliar (10 mL por vaso), no estádio de gema floral apical visível. Daminozide (2,5 e 3,75 g L-1), paclobutrazol (0,5; 0,75 e 1,0 mg i.a. por vaso) e 1,0 g L-1 de chlormequat reduziram significativamente a altura das plantas e o comprimento dos ramos laterais, sem afetar o diâmetro dos capítulos, atrasar o ciclo de produção e causar fitotoxicidade. Entretanto, as plantas não se apresentaram suficientemente baixas e compactas para atender às exigências de qualidade do mercado. Chlormequat (2,0 e 3,0 g L-1) causou fitotoxicidade e daminozide (5,0 g L-1) aumentou o ciclo de produção.Zinnias have good potential to be used as flowering, potted plants, being a quick source of novelty for the floriculture industry with the aid of growth retardants. This study evaluated the effect of growth retardants on development and production of short, compact and attractive plants of potted 'Lilliput' Zinnia elegans, a highly ornamental zinnia with low cost seeds. Trials were set up in randomized blocks, with ten treatments (control and three treatments of each retardant: daminozide, paclobutrazol and chlormequat) and four replications (two pots per experimental unit, with one plant per 0.6-L pot). Paclobutrazol (0.5, 0.75 and 1.0 mg a.i. per pot) and chlormequat (1.0, 2.0 and 3.0 g L-1) were applied as a single drench (40 mL per pot), and daminozide (2.5, 3.75 and 5.0 g L-1) as a single foliar spray to runoff (10 mL per pot), at apical flower bud stage. Daminozide (2.5 and 3.75 g L-1), paclobutrazol (0.5, 0.75 and 1.0 mg a.i. per pot) and chlormequat at 1.0 g L-1 significantly reduced plant height and side branches length, without affecting flower diameter, delaying production cycle and causing phytotoxicity symptoms. However, plants were not short and compact enough to meet market quality demand. Chlormequat (2.0 and 3.0 g L-1) caused phytotoxicity symptoms and daminozide (5.0 g L-1) delayed production cycle

Identification of independent association signals and putative functional variants for breast cancer risk through fine-scale mapping of the 12p11 locus.

BACKGROUND: Multiple recent genome-wide association studies (GWAS) have identified a single nucleotide polymorphism (SNP), rs10771399, at 12p11 that is associated with breast cancer risk. METHOD: We performed a fine-scale mapping study of a 700 kb region including 441 genotyped and more than 1300 imputed genetic variants in 48,155 cases and 43,612 controls of European descent, 6269 cases and 6624 controls of East Asian descent and 1116 cases and 932 controls of African descent in the Breast Cancer Association Consortium (BCAC; http://bcac.ccge.medschl.cam.ac.uk/ ), and in 15,252 BRCA1 mutation carriers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Stepwise regression analyses were performed to identify independent association signals. Data from the Encyclopedia of DNA Elements project (ENCODE) and the Cancer Genome Atlas (TCGA) were used for functional annotation. RESULTS: Analysis of data from European descendants found evidence for four independent association signals at 12p11, represented by rs7297051 (odds ratio (OR) = 1.09, 95 % confidence interval (CI) = 1.06-1.12; P = 3 × 10(-9)), rs805510 (OR = 1.08, 95 % CI = 1.04-1.12, P = 2 × 10(-5)), and rs1871152 (OR = 1.04, 95 % CI = 1.02-1.06; P = 2 × 10(-4)) identified in the general populations, and rs113824616 (P = 7 × 10(-5)) identified in the meta-analysis of BCAC ER-negative cases and BRCA1 mutation carriers. SNPs rs7297051, rs805510 and rs113824616 were also associated with breast cancer risk at P < 0.05 in East Asians, but none of the associations were statistically significant in African descendants. Multiple candidate functional variants are located in putative enhancer sequences. Chromatin interaction data suggested that PTHLH was the likely target gene of these enhancers. Of the six variants with the strongest evidence of potential functionality, rs11049453 was statistically significantly associated with the expression of PTHLH and its nearby gene CCDC91 at P < 0.05. CONCLUSION: This study identified four independent association signals at 12p11 and revealed potentially functional variants, providing additional insights into the underlying biological mechanism(s) for the association observed between variants at 12p11 and breast cancer risk.UK funding includes Cancer Research UK and NIH.This is the final version of the article. It first appeared from BioMed Central via http://dx.doi.org/10.1186/s13058-016-0718-

The upgrade of the ALICE TPC with GEMs and continuous readout

The upgrade of the ALICE TPC will allow the experiment to cope with the high interaction rates foreseen for the forthcoming Run 3 and Run 4 at the CERN LHC. In this article, we describe the design of new readout chambers and front-end electronics, which are driven by the goals of the experiment. Gas Electron Multiplier (GEM) detectors arranged in stacks containing four GEMs each, and continuous readout electronics based on the SAMPA chip, an ALICE development, are replacing the previous elements. The construction of these new elements, together with their associated quality control procedures, is explained in detail. Finally, the readout chamber and front-end electronics cards replacement, together with the commissioning of the detector prior to installation in the experimental cavern, are presented. After a nine-year period of R&D, construction, and assembly, the upgrade of the TPC was completed in 2020.publishedVersio

Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus

A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10-20), ER-negative BC (P=1.1 × 10-13), BRCA1-associated BC (P=7.7 × 10-16) and triple negative BC (P-diff=2 × 10-5). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10-3) and ABHD8 (P<2 × 10-3). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3′-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk