Correlation of baseline biomarkers with clinical outcomes and response to fulvestrant with vandetanib or placebo in patients with bone predominant metastatic breast cancer: An OCOG ZAMBONEY sub-study

AbstractBackgroundBone metastases are common in women with breast cancer and often result in skeletal related events (SREs). As the angiogenic factor vascular endothelial growth factor (VEGF) regulates osteoclast activity and is associated with more extensive bone metastases and SRE risk in metastatic breast cancer, we hypothesized that blockade of VEGF signaling could be a therapeutic strategy for inhibiting bone metastases progression and possibly prolonging overall (OS) or progression-free survival (PFS). The Zamboney trial was a randomized placebo-controlled study designed to assess whether patients with bone predominant metastatic breast cancer benefited from addition of the VEGF receptor (VEGFR) targeting agent, vandetanib, to endocrine therapy with fulvestrant. As a companion study, evaluation of biomarkers and their potential association with response to vandetanib or SRE risk was performed.MethodsBaseline overnight fasted serum from enrolled patients was analyzed for levels of various putative biomarkers including; VEGF-A, soluble (s)VEGFR2, sVEGFR3, transforming growth factor (TGF)-β1 and activinA by ELISA. Spearman correlation coefficients and Wilcoxon rank sum tests were used to investigate potential relationships between biomarker values and baseline clinical parameters. Prognostic and predictive ability of each marker was investigated using Cox proportional hazards regression with adjustments for treatment and baseline strata of serum CTx (<400 versus ≥400ng/L).ResultsOf 129 enrolled patients, serum was available for analysis in 101; 51 in vandetanib and 50 in placebo arm. Mean age amongst consenting patients was 59.8 years. Clinical characteristics were not significantly different between patients with or without serum biomarker data and serum markers were similar for patients by treatment arm. Baseline sVEGFR2 was prognostic for OS (HR=0.77, 95% CI=0.61–0.96, p=0.020), and although a modest association was observed, it was not significant for PFS (HR=0.90, 95% CI=0.80–1.01, p=0.085) nor time to first SRE (HR=0.82, 95% CI=0.66–1.02, p=0.079). When interaction terms were evaluated, sVEGFR2 was not found to be predictive of response to vandetanib, although a modest association remained with respect to PFS (interaction p=0.085). No other marker showed any significant prognostic or predictive ability with any measured outcome.ConclusionsIn this clinical trial, sVEGFR2 appeared prognostic for OS, hence validation of sVEGFR2 should be conducted. Moreover, the role of sVEGFR2 in breast cancer bone metastasis progression should be elucidated

Shifts in the Fecal Microbiota Associated with Adenomatous Polyps

BACKGROUND: Adenomatous polyps are the most common precursor to colorectal cancer, the second leading cause of cancer-related death in the United States. We sought to learn more about early events of carcinogenesis by investigating shifts in the gut microbiota of patients with adenomas. METHODS: We analyzed 16S rRNA gene sequences from the fecal microbiota of patients with adenomas (n = 233) and without (n = 547). RESULTS: Multiple taxa were significantly more abundant in patients with adenomas, including Bilophila, Desulfovibrio, proinflammatory bacteria in the genus Mogibacterium, and multiple Bacteroidetes species. Patients without adenomas had greater abundances of Veillonella, Firmicutes (Order Clostridia), and Actinobacteria (family Bifidobacteriales). Our findings were consistent with previously reported shifts in the gut microbiota of colorectal cancer patients. Importantly, the altered adenoma profile is predicted to increase primary and secondary bile acid production, as well as starch, sucrose, lipid, and phenylpropanoid metabolism. CONCLUSIONS: These data hint that increased sugar, protein, and lipid metabolism along with increased bile acid production could promote a colonic environment that supports the growth of bile-tolerant microbes such as Bilophilia and Desulfovibrio In turn, these microbes may produce genotoxic or inflammatory metabolites such as H2S and secondary bile acids, which could play a role in catalyzing adenoma development and eventually colorectal cancer. IMPACT: This study suggests a plausible biological mechanism to explain the links between shifts in the microbiota and colorectal cancer. This represents a first step toward resolving the complex interactions that shape the adenoma-carcinoma sequence of colorectal cancer and may facilitate personalized therapeutics focused on the microbiota

The clustering of galaxies in the SDSS-III Baryon Oscillation Spectroscopic Survey : measuring DA and H at z = 0.57 from the baryon acoustic peak in the Data Release 9 spectroscopic Galaxy sample

We present measurements of the angular diameter distance to and Hubble parameter at z = 0.57 from the measurement of the baryon acoustic peak in the correlation of galaxies from the Sloan Digital Sky Survey III Baryon Oscillation Spectroscopic Survey. Our analysis is based on a sample from Data Release 9 of 264 283 galaxies over 3275 square degrees in the redshift range 0.43 < z < 0.70. We use two different methods to provide robust measurement of the acoustic peak position across and along the line of sight in order to measure the cosmological distance scale. We find DA(0.57) = 1408 ± 45 Mpc and H(0.57) = 92.9 ± 7.8 km s−1 Mpc−1 for our fiducial value of the sound horizon. These results from the anisotropic fitting are fully consistent with the analysis of the spherically averaged acoustic peak position presented in Anderson et al. Our distance measurements are a close match to the predictions of the standard cosmological model featuring a cosmological constant and zero spatial curvature.Publisher PDFPeer reviewe

The clustering of galaxies in the SDSS-III Baryon Oscillation Spectroscopic Survey : baryon acoustic oscillations in the Data Releases 10 and 11 Galaxy samples

We present a one per cent measurement of the cosmic distance scale from the detections of the baryon acoustic oscillations (BAO) in the clustering of galaxies from the Baryon Oscillation Spectroscopic Survey, which is part of the Sloan Digital Sky Survey III. Our results come from the Data Release 11 (DR11) sample, containing nearly one million galaxies and covering approximately 8500 square degrees and the redshift range 0.2 < z < 0.7. We also compare these results with those from the publicly released DR9 and DR10 samples. Assuming a concordance Λ cold dark matter (ΛCDM) cosmological model, the DR11 sample covers a volume of 13 Gpc3 and is the largest region of the Universe ever surveyed at this density. We measure the correlation function and power spectrum, including density-field reconstruction of the BAO feature. The acoustic features are detected at a significance of over 7σ in both the correlation function and power spectrum. Fitting for the position of the acoustic features measures the distance relative to the sound horizon at the drag epoch, rd, which has a value of rd,fid = 149.28 Mpc in our fiducial cosmology. We find DV = (1264 ± 25 Mpc)(rd/rd,fid) at z = 0.32 and DV = (2056 ± 20 Mpc)(rd/rd,fid) at z = 0.57. At 1.0 per cent, this latter measure is the most precise distance constraint ever obtained from a galaxy survey. Separating the clustering along and transverse to the line of sight yields measurements at z = 0.57 of DA = (1421 ± 20 Mpc)(rd/rd,fid) and H = (96.8 ± 3.4 km s−1 Mpc−1)(rd,fid/rd). Our measurements of the distance scale are in good agreement with previous BAO measurements and with the predictions from cosmic microwave background data for a spatially flat CDM model with a cosmological constant.Publisher PDFPeer reviewe

Simplified Models for LHC New Physics Searches

This document proposes a collection of simplified models relevant to the design of new-physics searches at the LHC and the characterization of their results. Both ATLAS and CMS have already presented some results in terms of simplified models, and we encourage them to continue and expand this effort, which supplements both signature-based results and benchmark model interpretations. A simplified model is defined by an effective Lagrangian describing the interactions of a small number of new particles. Simplified models can equally well be described by a small number of masses and cross-sections. These parameters are directly related to collider physics observables, making simplified models a particularly effective framework for evaluating searches and a useful starting point for characterizing positive signals of new physics. This document serves as an official summary of the results from the "Topologies for Early LHC Searches" workshop, held at SLAC in September of 2010, the purpose of which was to develop a set of representative models that can be used to cover all relevant phase space in experimental searches. Particular emphasis is placed on searches relevant for the first ~50-500 pb-1 of data and those motivated by supersymmetric models. This note largely summarizes material posted at http://lhcnewphysics.org/, which includes simplified model definitions, Monte Carlo material, and supporting contacts within the theory community. We also comment on future developments that may be useful as more data is gathered and analyzed by the experiments.Comment: 40 pages, 2 figures. This document is the official summary of results from "Topologies for Early LHC Searches" workshop (SLAC, September 2010). Supplementary material can be found at http://lhcnewphysics.or

Meta-analysis of five genome-wide association studies identifies multiple new loci associated with testicular germ cell tumor

The international Testicular Cancer Consortium (TECAC) combined five published genome-wide association studies of testicular germ cell tumor (TGCT; 3,558 cases and 13,970 controls) to identify new susceptibility loci. We conducted a fixed-effects meta-analysis, including, to our knowledge, the first analysis of the X chromosome. Eight new loci mapping to 2q14.2, 3q26.2, 4q35.2, 7q36.3, 10q26.13, 15q21.3, 15q22.31, and Xq28 achieved genome-wide significance (P < 5 × 10−8). Most loci harbor biologically plausible candidate genes. We refined previously reported associations at 9p24.3 and 19p12 by identifying one and three additional independent SNPs, respectively. In aggregate, the 39 independent markers identified to date explain 37% of father-to-son familial risk, 8% of which can be attributed to the 12 new signals reported here. Our findings substantially increase the number of known TGCT susceptibility alleles, move the field closer to a comprehensive understanding of the underlying genetic architecture of TGCT, and provide further clues to the etiology of TGCT

Control of Transcription by Cell Size

Cell size increases significantly with increasing ploidy. Differences in cell size and ploidy are associated with alterations in gene expression, although no direct connection has been made between cell size and transcription. Here we show that ploidy-associated changes in gene expression reflect transcriptional adjustment to a larger cell size, implicating cellular geometry as a key parameter in gene regulation. Using RNA-seq, we identified genes whose expression was altered in a tetraploid as compared with the isogenic haploid. A significant fraction of these genes encode cell surface proteins, suggesting an effect of the enlarged cell size on the differential regulation of these genes. To test this hypothesis, we examined expression of these genes in haploid mutants that also produce enlarged size. Surprisingly, many genes differentially regulated in the tetraploid are identically regulated in the enlarged haploids, and the magnitude of change in gene expression correlates with the degree of size enlargement. These results indicate a causal relationship between cell size and transcription, with a size-sensing mechanism that alters transcription in response to size. The genes responding to cell size are enriched for those regulated by two mitogen-activated protein kinase pathways, and components in those pathways were found to mediate size-dependent gene regulation. Transcriptional adjustment to enlarged cell size could underlie other cellular changes associated with polyploidy. The causal relationship between cell size and transcription suggests that cell size homeostasis serves a regulatory role in transcriptome maintenance.National Institutes of Health (U.S.) (grant GM035010)National Institutes of Health (U.S.) (grant GM040266

The prolyl hydroxylase enzymes are positively associated with hypoxia-inducible factor-1α and vascular endothelial growth factor in human breast cancer and alter in response to primary systemic treatment with epirubicin and tamoxifen

Introduction: The purpose of the present study was to investigate the relationship of expression of hypoxia inducible factor (HIF)-1α-modifying enzymes prolyl hydroxylase (PHD)1, PHD2 and PHD3 to response of tumours and survival in breast cancer patients enrolled in a phase II trial of neoadjuvant anthracycline and tamoxifen therapy.Methods: The expression of PHD1, PHD2 and PHD3 together with HIF-1α and the HIF-inducible genes vascular endothelial cell growth factor (VEGF) and carbonic anhydrase IX were assessed by immunohistochemistry using a tissue microarray approach in 211 patients with T2-4 N0-1 breast cancer enrolled in a randomised trial comparing single-agent epirubicin versus epirubicin and tamoxifen as the primary systemic treatment.Results: PHD1, PHD2 and PHD3 were detected in 47/179 (26.7%), 85/163 (52.2%) and 69/177 (39%) of tumours at baseline. PHD2 and PHD3 expression was moderate/strong whereas PHD1 expression was generally weak. There was a significant positive correlation between HIF-1α and PHD1 (P = 0.002) and PHD3 (P &lt; 0.05) but not PHD2 (P = 0.41). There was a significant positive relationship between VEGF and PHD1 (P &lt; 0.008) and PHD3 (P = 0.001) but not PHD2 (P = 0.09). PHD1, PHD2 and PHD3 expression was significantly increased after epirubicin therapy (all P &lt; 0.000) with no significant difference in PHD changes between the treatment arms. There was no significant difference in response in tumours that expressed PHDs and PHD expression was not associated with survival.Conclusions: Although expression of the PHDs was not related to response or survival in patients receiving neoadjuvant epirubicin, our data provide the first evidence that these enzymes are upregulated on therapy in breast cancer and that the biological effects independent of HIF make them therapeutic targets. © 2011 Fox et al.; licensee BioMed Central Ltd

Antimicrobial resistance among migrants in Europe: a systematic review and meta-analysis

BACKGROUND: Rates of antimicrobial resistance (AMR) are rising globally and there is concern that increased migration is contributing to the burden of antibiotic resistance in Europe. However, the effect of migration on the burden of AMR in Europe has not yet been comprehensively examined. Therefore, we did a systematic review and meta-analysis to identify and synthesise data for AMR carriage or infection in migrants to Europe to examine differences in patterns of AMR across migrant groups and in different settings. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, PubMed, and Scopus with no language restrictions from Jan 1, 2000, to Jan 18, 2017, for primary data from observational studies reporting antibacterial resistance in common bacterial pathogens among migrants to 21 European Union-15 and European Economic Area countries. To be eligible for inclusion, studies had to report data on carriage or infection with laboratory-confirmed antibiotic-resistant organisms in migrant populations. We extracted data from eligible studies and assessed quality using piloted, standardised forms. We did not examine drug resistance in tuberculosis and excluded articles solely reporting on this parameter. We also excluded articles in which migrant status was determined by ethnicity, country of birth of participants' parents, or was not defined, and articles in which data were not disaggregated by migrant status. Outcomes were carriage of or infection with antibiotic-resistant organisms. We used random-effects models to calculate the pooled prevalence of each outcome. The study protocol is registered with PROSPERO, number CRD42016043681. FINDINGS: We identified 2274 articles, of which 23 observational studies reporting on antibiotic resistance in 2319 migrants were included. The pooled prevalence of any AMR carriage or AMR infection in migrants was 25·4% (95% CI 19·1-31·8; I2 =98%), including meticillin-resistant Staphylococcus aureus (7·8%, 4·8-10·7; I2 =92%) and antibiotic-resistant Gram-negative bacteria (27·2%, 17·6-36·8; I2 =94%). The pooled prevalence of any AMR carriage or infection was higher in refugees and asylum seekers (33·0%, 18·3-47·6; I2 =98%) than in other migrant groups (6·6%, 1·8-11·3; I2 =92%). The pooled prevalence of antibiotic-resistant organisms was slightly higher in high-migrant community settings (33·1%, 11·1-55·1; I2 =96%) than in migrants in hospitals (24·3%, 16·1-32·6; I2 =98%). We did not find evidence of high rates of transmission of AMR from migrant to host populations. INTERPRETATION: Migrants are exposed to conditions favouring the emergence of drug resistance during transit and in host countries in Europe. Increased antibiotic resistance among refugees and asylum seekers and in high-migrant community settings (such as refugee camps and detention facilities) highlights the need for improved living conditions, access to health care, and initiatives to facilitate detection of and appropriate high-quality treatment for antibiotic-resistant infections during transit and in host countries. Protocols for the prevention and control of infection and for antibiotic surveillance need to be integrated in all aspects of health care, which should be accessible for all migrant groups, and should target determinants of AMR before, during, and after migration. FUNDING: UK National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare Charity, the Wellcome Trust, and UK National Institute for Health Research Health Protection Research Unit in Healthcare-associated Infections and Antimictobial Resistance at Imperial College London