Sub-lethal effects of a copper sulfate fungicide on development and reproduction in three coccinellid species.

Copper-based fungicides reliably control various foliar diseases in citrus production, although they are suspected to exacerbate mite problems through various mechanisms. Studies have shown negative effects of various copper formulations on entomopathogenic fungi, nematodes, and parasitoids, but few have sought to measure its impact on the biology of predatory insects. We exposed the larvae of three species of ladybeetle (Coleoptera: Coccinellidae) to field rates of copper sulfate in combination with petroleum oil, a formulation commonly applied in Florida citrus. First instar larvae of Curinus coeruleus Mulsant, Harmonia axyridis Pallas, and Olla v-nigrum Mulsant received a 24 h exposure to residues on Petri dishes, and another 24 h exposure in the third instar. Treated larvae of all three species survived to adulthood at the same rate as control larvae, but larvae of O. v-nigrum experienced a significant increase in developmental time. Female adults of C. coeruleus and H. axyridis receiving copper sulfate exposures as larvae did not differ from control adults in pre-reproductive period, fecundity or fertility over ten days of reproduction. Treated O. v-nigrum females had significantly longer pre-reproductive periods than control females and laid significantly fewer eggs, although egg fertility was equivalent. We conclude that copper-sulfate fungicides are unlikely to disrupt biological control processes in citrus groves that are mediated by these coccinellid beetles

The effect of stellar evolution on SiC dust grain sizes

Stars on the asymptotic giant branch (AGB) produce dust in their circumstellar shells. The nature of the dust-forming environment is influenced by the evolution of the stars, in terms of both chemistry and density, leading to an evolution in the nature of the dust that is produced. Carbon-rich AGB stars are known to produce silicon carbide (SiC). Furthermore, observations of the ~11um SiC feature show that the spectral features change in a sequence that correlates with stellar evolution. We present new infrared spectra of amorphous SiC and show that the ~9um feature seen in both emission and absorption, and correlated with trends in the ~11um feature, may be due to either amorphous SiC or to nano-crystalline diamond with a high proportion of Si substituting for C. Furthermore, we identify SiC absorption in three ISO spectra of extreme carbon stars, in addition to the four presented by Speck et al. (1997). An accurate description of the sequence in the IR spectra of carbon stars requires accounting for both SiC emission and absorption features. This level of detail is needed to infer the role of dust in evolution of carbon stars. Previous attempts to find a sequence in the infrared spectra of carbon stars considered SiC emission features, while neglecting SiC absorption features, leading to an interpretation of the sequence inadequately describes the role of dust. We show that the evolutionary sequence in carbon star spectra is consistent with a grain size evolution, such that dust grains get progressively smaller as the star evolves. The evolution of the grain sizes provides a natural explanation for the shift of the ~11um SiC feature in emission and in absorption. Further evidence for this scenario is seen in both post-AGB star spectra and in meteoritic studies of presolar grains.Comment: accepted by ApJ 8 figure

Silicon carbide absorption features: dust formation in the outflows of extreme carbon stars

Infrared carbon stars without visible counterparts are generally known as extreme carbon stars. We have selected a subset of these stars with absorption features in the 10-13 $\mu$m range, which has been tentatively attributed to silicon carbide (SiC). We add three new objects meeting these criterion to the seven previously known, bringing our total sample to ten sources. We also present the result of radiative transfer modeling for these stars, comparing these results to those of previous studies. In order to constrain model parameters, we use published mass-loss rates, expansion velocities and theoretical dust condensation models to determine the dust condensation temperature. These show that the inner dust temperatures of the dust shells for these sources are significantly higher than previously assumed. This also implies that the dominant dust species should be graphite instead of amorphous carbon. In combination with the higher condensation temperature we show that this results in a much higher acceleration of the dust grains than would be expected from previous work. Our model results suggest that the very optically thick stage of evolution does not coincide with the timescales for the superwind, but rather, that this is a very short-lived phase. Additionally, we compare model and observational parameters in an attempt to find any correlations. Finally, we show that the spectrum of one source, IRAS 17534$-$3030, strongly implies that the 10-13 $\mu$m feature is due to a solid state rather than a molecular species.Comment: 13 Figure

Acquired Resistance to BRAF Inhibitors Mediated by a RAF Kinase Switch in Melanoma Can Be Overcome by Cotargeting MEK and IGF-1R/PI3K

SummaryBRAF is an attractive target for melanoma drug development. However, resistance to BRAF inhibitors is a significant clinical challenge. We describe a model of resistance to BRAF inhibitors developed by chronic treatment of BRAFV600E melanoma cells with the BRAF inhibitor SB-590885; these cells are cross-resistant to other BRAF-selective inhibitors. Resistance involves flexible switching among the three RAF isoforms, underscoring the ability of melanoma cells to adapt to pharmacological challenges. IGF-1R/PI3K signaling was enhanced in resistant melanomas, and combined treatment with IGF-1R/PI3K and MEK inhibitors induced death of BRAF inhibitor-resistant cells. Increased IGF-1R and pAKT levels in a post-relapse human tumor sample are consistent with a role for IGF-1R/PI3K-dependent survival in the development of resistance to BRAF inhibitors

Fine-mapping of the HNF1B multicancer locus identifies candidate variants that mediate endometrial cancer risk.

Common variants in the hepatocyte nuclear factor 1 homeobox B (HNF1B) gene are associated with the risk of Type II diabetes and multiple cancers. Evidence to date indicates that cancer risk may be mediated via genetic or epigenetic effects on HNF1B gene expression. We previously found single-nucleotide polymorphisms (SNPs) at the HNF1B locus to be associated with endometrial cancer, and now report extensive fine-mapping and in silico and laboratory analyses of this locus. Analysis of 1184 genotyped and imputed SNPs in 6608 Caucasian cases and 37 925 controls, and 895 Asian cases and 1968 controls, revealed the best signal of association for SNP rs11263763 (P = 8.4 × 10(-14), odds ratio = 0.86, 95% confidence interval = 0.82-0.89), located within HNF1B intron 1. Haplotype analysis and conditional analyses provide no evidence of further independent endometrial cancer risk variants at this locus. SNP rs11263763 genotype was associated with HNF1B mRNA expression but not with HNF1B methylation in endometrial tumor samples from The Cancer Genome Atlas. Genetic analyses prioritized rs11263763 and four other SNPs in high-to-moderate linkage disequilibrium as the most likely causal SNPs. Three of these SNPs map to the extended HNF1B promoter based on chromatin marks extending from the minimal promoter region. Reporter assays demonstrated that this extended region reduces activity in combination with the minimal HNF1B promoter, and that the minor alleles of rs11263763 or rs8064454 are associated with decreased HNF1B promoter activity. Our findings provide evidence for a single signal associated with endometrial cancer risk at the HNF1B locus, and that risk is likely mediated via altered HNF1B gene expression

Assessment of function and clinical utility of alcohol and other drug web sites: An observational, qualitative study

Background The increasing popularity and use of the internet makes it an attractive option for providing health information and treatment, including alcohol/other drug use. There is limited research examining how people identify and access information about alcohol or other drug (AOD) use online, or how they assess the usefulness of the information presented. This study examined the strategies that individuals used to identify and navigate a range of AOD websites, along with the attitudes concerning presentation and content. Methods Members of the general community in Brisbane and Roma (Queensland, Australia) were invited to participate in a 30-minute search of the internet for sites related to AOD use, followed by a focus group discussion. Fifty one subjects participated in the study across nine focus groups. Results Participants spent a maximum of 6.5 minutes on any one website, and less if the user was under 25 years of age. Time spent was as little as 2 minutes if the website was not the first accessed. Participants recommended that AOD-related websites should have an engaging home or index page, which quickly and accurately portrayed the site’s objectives, and provided clear site navigation options. Website content should clearly match the title and description of the site that is used by internet search engines. Participants supported the development of a portal for AOD websites, suggesting that it would greatly facilitate access and navigation. Treatment programs delivered online were initially viewed with caution. This appeared to be due to limited understanding of what constituted online treatment, including its potential efficacy. Conclusions A range of recommendations arise from this study regarding the design and development of websites, particularly those related to AOD use. These include prudent use of text and information on any one webpage, the use of graphics and colours, and clear, uncluttered navigation options. Implications for future website development are discussed

RAMPART : a model for a regulatory-ready academic-led phase III trial in the adjuvant renal cell carcinoma setting

AstraZeneca LP have provided an educational grant for the trial and free of charge durvalumab and tremelimumab. A small grant is also provided by Kidney Cancer UK. MRC CTU at UCL provides funding for staff working on the trial.The development of therapeutics in oncology is a highly active research area for the pharmaceutical and biotechnology industries, but also has a strong academic base. Many new agents have been developed in recent years, most with specific biological targets. This has mandated the need to look at different ways to streamline the evaluation of new agents. One solution has been the development of adaptive trial designs that allow the evaluation of multiple agents, concentrating on the most promising agents while screening out those which are unlikely to benefit patients. Another way forward has been the growth of partnerships between academia and industry with the shared goal of designing and conducting high quality clinical trials which answer important clinical questions as efficiently as possible. The RAMPART trial (NCT03288532) brings together both of these processes in an attempt to improve outcomes for patients with locally advanced renal cell carcinoma (RCC), where no globally acceptable adjuvant strategy after nephrectomy currently exist. RAMPART is led by the MRC CTU at University College London (UCL), in collaboration with other international academic groups and industry. We aim to facilitate the use of data from RAMPART, (dependent on outcomes), for a future regulatory submission that will extend the license of the agents being investigated. We share our experience in order to lay the foundations for an effective trial design and conduct framework and to guide others who may be considering similar collaborations.Publisher PDFPeer reviewe

RAMPART : a phase III multi-arm multi-stage trial of adjuvant checkpoint inhibitors in patients with resected primary renal cell carcinoma (RCC) at high or intermediate risk of relapse

AstraZeneca LP have provided an educational grant for the trial and free of charge durvalumab and tremelimumab. A small grant is also provided by Kidney Cancer UK. MRC CTU at UCL also provides funding for staff working on the trial. The TransRAMPART sample collection is being funded by a Prospective Sample Collection award from Cancer Research UK.Background 20–60% of patients with initially locally advanced Renal Cell Carcinoma (RCC) develop metastatic disease despite optimal surgical excision. Adjuvant strategies have been tested in RCC including cytokines, radiotherapy, hormones and oral tyrosine-kinase inhibitors (TKIs), with limited success. The predominant global standard-of-care after nephrectomy remains active monitoring. Immune checkpoint inhibitors (ICIs) are effective in the treatment of metastatic RCC; RAMPART will investigate these agents in the adjuvant setting. Methods/design RAMPART is an international, UK-led trial investigating the addition of ICIs after nephrectomy in patients with resected locally advanced RCC. RAMPART is a multi-arm multi-stage (MAMS) platform trial, upon which additional research questions may be addressed over time. The target population is patients with histologically proven resected locally advanced RCC (clear cell and non-clear cell histological subtypes), with no residual macroscopic disease, who are at high or intermediate risk of relapse (Leibovich score 3–11). Patients with fully resected synchronous ipsilateral adrenal metastases are included. Participants are randomly assigned (3,2:2) to Arm A - active monitoring (no placebo) for one year, Arm B - durvalumab (PD-L1 inhibitor) 4-weekly for one year; or Arm C - combination therapy with durvalumab 4-weekly for one year plus two doses of tremelimumab (CTLA-4 inhibitor) at day 1 of the first two 4-weekly cycles. The co-primary outcomes are disease-free-survival (DFS) and overall survival (OS). Secondary outcomes include safety, metastasis-free survival, RCC specific survival, quality of life, and patient and clinician preferences. Tumour tissue, plasma and urine are collected for molecular analysis (TransRAMPART).Publisher PDFPeer reviewe

Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche.

Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-cause mortality. Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation, but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (P < 5 × 10(-8)) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with three loci (DLK1-WDR25, MKRN3-MAGEL2 and KCNK9) demonstrating parent-of-origin-specific associations concordant with known parental expression patterns. Pathway analyses implicated nuclear hormone receptors, particularly retinoic acid and γ-aminobutyric acid-B2 receptor signalling, among novel mechanisms that regulate pubertal timing in humans. Our findings suggest a genetic architecture involving at least hundreds of common variants in the coordinated timing of the pubertal transition