Health-related quality of life in patients with a germline BRCA mutation and metastatic pancreatic cancer receiving maintenance olaparib

BACKGROUND: Patients with metastatic pancreatic cancer (mPC) often have a detriment in health-related quality of life (HRQoL). In the randomized, double-blind, Phase III POLO trial progression-free survival was significantly longer with maintenance olaparib, a poly(ADP-ribose) polymerase inhibitor, than placebo in patients with a germline BRCA1 and/or BRCA2 mutation (gBRCAm) and mPC whose disease had not progressed during first-line platinum-based chemotherapy. The prespecified HRQoL evaluation is reported here. PATIENTS AND METHODS: Patients were randomized to receive maintenance olaparib (300 mg bid; tablets) or placebo. HRQoL was assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30-item module at baseline, every 4 weeks until disease progression, at discontinuation, and 30 days after last dose. Scores ranged from 0 to 100; a ≥ 10-point change or difference between arms was considered clinically meaningful. Adjusted mean change from baseline was analysed using a mixed model for repeated measures. Time to sustained clinically meaningful deterioration (TSCMD) was analysed using a log-rank test. RESULTS: Of 154 randomized patients, 89 of 92 olaparib-arm and 58 of 62 placebo-arm patients were included in HRQoL analyses. The adjusted mean change in Global Health Status (GHS) score from baseline was less than 10 points in both arms and there was no significant between-group difference (-2.47; 95% CI - 7.27, 2.33; P=0.31). Analysis of physical functioning scores showed a significant between-group difference (-4.45 points; 95% CI - 8.75, -0.16; P=0.04). There was no difference in TSCMD for olaparib versus placebo for GHS (P=0.25; HR 0.72; 95% CI 0.41, 1.27) or physical functioning (P=0.32; HR 1.38; 95%CI 0.73, 2.63). CONCLUSIONS: HRQoL was preserved with maintenance olaparib treatment with no clinically meaningful difference compared with placebo. These results support the observed efficacy benefit of maintenance olaparib in patients with a gBRCAm and mPC. CLINCALTRIALS.GOV NUMBER: NCT02184195

Measurement of cosmic-ray muons and muon-induced neutrons in the Aberdeen Tunnel Underground Laboratory

postprin

Mammalian adaptation markers in avian-origin H7N9 virus, a comprehensive investigation in isolates and clinical specimens from the H7N9 influenza affected area

Oral PresentationsBackground: An avian-origin H7N9 virus emerged in eastern China in February 2013 and has since caused 133 confirmed human infections (Gao R, et al. N Engl J Med. 2013;368:1888-1897). We have compared human isolates and avian viruses isolated from epidemiologically linked poultry markets and confirmed that the human infections were caused by direct transmission from a poultry source (Chen Y, et al. Lancet. 2013;381:1916-1985). In addition to the Q226L substitution in the HA, which may provide virus with some ability to bind to human-type receptors, what other adaptations has this virus gained to make it different from other avian influenza viruses? Materials and Methods: We characterized H7N9 and other related H7 and N9 subtype viruses isolated in April 2013 from local poultry markets that were associated with human infections. Genetic mutations, polymerases activity, growth kinetic in mammalian and avian cells and replication ability in mice were determined using reverse genetic versions of H7N9 virus. Results: Replication ability and growth kinetics of the avian H7 subtype influenza viruses were compared in avian and mammalian cell lines. Our data suggest that the reassortant H7N9 virus has adapted to, and may have become established in, land-based poultry. It is currently not clear if this virus may still be circulating in some poultry populations, continuing to evolve and posing a threat for further human infections. We studied the virus genome for mammalian adaptation markers by performing sequence analysis on virus isolates and RT-PCR products derived from samples obtained from 46 patients hospitalized in the First Affiliated Hospital of Zhejiang University Medical School, Hangzhou, China. Virus adaptation markers in the HA, NA and PB2 genes were analyzed in sequential samples. Multiple adaptation markers were identified in these genes of clinical isolates and serial respiratory samples. Our data showed that the avian-origin H7N9 has attempted to adapt to replicate in human cells using various mechanisms already displayed by other viruses. An in vitro assay showed that viruses with substitutions at these positions exhibit enhanced RNP polymerase activity, and a study of growth kinetics demonstrated that isolates carrying these adaptation markers replicate to a higher titer in mammalian cells. Replication efficiency of these clinical variants was also evaluated in mice. As neuraminidase inhibitors are used as the first line of antiviral drugs for the treatment of H7N9 infection, we also analyzed oseltamivir resistance-associated mutations in the NA genes of viruses shed in either serial nasal swab or sputum specimens obtained from 40 of the hospitalized patients. Conclusions: This study provides a comprehensive analysis of avian-origin H7N9 virus from poultry and in human infections. The novel H7N9 virus attempted multiple adaptive strategies for efficient replication in humans. Further characterization of this H7N9 avian influenza virus for understanding the mechanism of replication adaptation and the role in efficient human transmission is necessary.published_or_final_versio

Mammalian adaptation markers in avian-origin H7N9 virus, a comprehensive investigation in isolates and clinical specimens from the H7N9 influenza affected area

Oral PresentationsBackground: An avian-origin H7N9 virus emerged in eastern China in February 2013 and has since caused 133 confirmed human infections (Gao R, et al. N Engl J Med. 2013;368:1888-1897). We have compared human isolates and avian viruses isolated from epidemiologically linked poultry markets and confirmed that the human infections were caused by direct transmission from a poultry source (Chen Y, et al. Lancet. 2013;381:1916-1985). In addition to the Q226L substitution in the HA, which may provide virus with some ability to bind to human-type receptors, what other adaptations has this virus gained to make it different from other avian influenza viruses? Materials and Methods: We characterized H7N9 and other related H7 and N9 subtype viruses isolated in April 2013 from local poultry markets that were associated with human infections. Genetic mutations, polymerases activity, growth kinetic in mammalian and avian cells and replication ability in mice were determined using reverse genetic versions of H7N9 virus. Results: Replication ability and growth kinetics of the avian H7 subtype influenza viruses were compared in avian and mammalian cell lines. Our data suggest that the reassortant H7N9 virus has adapted to, and may have become established in, land-based poultry. It is currently not clear if this virus may still be circulating in some poultry populations, continuing to evolve and posing a threat for further human infections. We studied the virus genome for mammalian adaptation markers by performing sequence analysis on virus isolates and RT-PCR products derived from samples obtained from 46 patients hospitalized in the First Affiliated Hospital of Zhejiang University Medical School, Hangzhou, China. Virus adaptation markers in the HA, NA and PB2 genes were analyzed in sequential samples. Multiple adaptation markers were identified in these genes of clinical isolates and serial respiratory samples. Our data showed that the avian-origin H7N9 has attempted to adapt to replicate in human cells using various mechanisms already displayed by other viruses. An in vitro assay showed that viruses with substitutions at these positions exhibit enhanced RNP polymerase activity, and a study of growth kinetics demonstrated that isolates carrying these adaptation markers replicate to a higher titer in mammalian cells. Replication efficiency of these clinical variants was also evaluated in mice. As neuraminidase inhibitors are used as the first line of antiviral drugs for the treatment of H7N9 infection, we also analyzed oseltamivir resistance-associated mutations in the NA genes of viruses shed in either serial nasal swab or sputum specimens obtained from 40 of the hospitalized patients. Conclusions: This study provides a comprehensive analysis of avian-origin H7N9 virus from poultry and in human infections. The novel H7N9 virus attempted multiple adaptive strategies for efficient replication in humans. Further characterization of this H7N9 avian influenza virus for understanding the mechanism of replication adaptation and the role in efficient human transmission is necessary.published_or_final_versio

A Computational Investigation on the Connection between Dynamics Properties of Ribosomal Proteins and Ribosome Assembly

Assembly of the ribosome from its protein and RNA constituents has been studied extensively over the past 50 years, and experimental evidence suggests that prokaryotic ribosomal proteins undergo conformational changes during assembly. However, to date, no studies have attempted to elucidate these conformational changes. The present work utilizes computational methods to analyze protein dynamics and to investigate the linkage between dynamics and binding of these proteins during the assembly of the ribosome. Ribosomal proteins are known to be positively charged and we find the percentage of positive residues in r-proteins to be about twice that of the average protein: Lys+Arg is 18.7% for E. coli and 21.2% for T. thermophilus. Also, positive residues constitute a large proportion of RNA contacting residues: 39% for E. coli and 46% for T. thermophilus. This affirms the known importance of charge-charge interactions in the assembly of the ribosome. We studied the dynamics of three primary proteins from E. coli and T. thermophilus 30S subunits that bind early in the assembly (S15, S17, and S20) with atomic molecular dynamic simulations, followed by a study of all r-proteins using elastic network models. Molecular dynamics simulations show that solvent-exposed proteins (S15 and S17) tend to adopt more stable solution conformations than an RNA-embedded protein (S20). We also find protein residues that contact the 16S rRNA are generally more mobile in comparison with the other residues. This is because there is a larger proportion of contacting residues located in flexible loop regions. By the use of elastic network models, which are computationally more efficient, we show that this trend holds for most of the 30S r-proteins

Supervised group Lasso with applications to microarray data analysis

BACKGROUND: A tremendous amount of efforts have been devoted to identifying genes for diagnosis and prognosis of diseases using microarray gene expression data. It has been demonstrated that gene expression data have cluster structure, where the clusters consist of co-regulated genes which tend to have coordinated functions. However, most available statistical methods for gene selection do not take into consideration the cluster structure. RESULTS: We propose a supervised group Lasso approach that takes into account the cluster structure in gene expression data for gene selection and predictive model building. For gene expression data without biological cluster information, we first divide genes into clusters using the K-means approach and determine the optimal number of clusters using the Gap method. The supervised group Lasso consists of two steps. In the first step, we identify important genes within each cluster using the Lasso method. In the second step, we select important clusters using the group Lasso. Tuning parameters are determined using V-fold cross validation at both steps to allow for further flexibility. Prediction performance is evaluated using leave-one-out cross validation. We apply the proposed method to disease classification and survival analysis with microarray data. CONCLUSION: We analyze four microarray data sets using the proposed approach: two cancer data sets with binary cancer occurrence as outcomes and two lymphoma data sets with survival outcomes. The results show that the proposed approach is capable of identifying a small number of influential gene clusters and important genes within those clusters, and has better prediction performance than existing methods

Study of the reaction e^{+}e^{-} -->J/psi\pi^{+}\pi^{-} via initial-state radiation at BaBar

We study the process $e^+e^-\to J/\psi\pi^{+}\pi^{-}$ with initial-state-radiation events produced at the PEP-II asymmetric-energy collider. The data were recorded with the BaBar detector at center-of-mass energies 10.58 and 10.54 GeV, and correspond to an integrated luminosity of 454 $\mathrm{fb^{-1}}$. We investigate the $J/\psi \pi^{+}\pi^{-}$ mass distribution in the region from 3.5 to 5.5 $\mathrm{GeV/c^{2}}$. Below 3.7 $\mathrm{GeV/c^{2}}$ the $\psi(2S)$ signal dominates, and above 4 $\mathrm{GeV/c^{2}}$ there is a significant peak due to the Y(4260). A fit to the data in the range 3.74 -- 5.50 $\mathrm{GeV/c^{2}}$ yields a mass value $4244 \pm 5$ (stat) $\pm 4$ (syst)$\mathrm{MeV/c^{2}}$ and a width value $114 ^{+16}_{-15}$ (stat)$\pm 7$(syst)$\mathrm{MeV}$ for this state. We do not confirm the report from the Belle collaboration of a broad structure at 4.01 $\mathrm{GeV/c^{2}}$. In addition, we investigate the $\pi^{+}\pi^{-}$ system which results from Y(4260) decay

Patient Retention and Adherence to Antiretrovirals in a Large Antiretroviral Therapy Program in Nigeria: A Longitudinal Analysis for Risk Factors

Substantial resources and patient commitment are required to successfully scale-up antiretroviral therapy (ART) and provide appropriate HIV management in resource-limited settings. We used pharmacy refill records to evaluate risk factors for loss to follow-up (LTFU) and non-adherence to ART in a large treatment cohort in Nigeria.We reviewed clinic records of adult patients initiating ART between March 2005 and July 2006 at five health facilities. Patients were classified as LTFU if they did not return >60 days from their expected visit. Pharmacy refill rates were calculated and used to assess non-adherence. We identified risk factors associated with LTFU and non-adherence using Cox and Generalized Estimating Equation (GEE) regressions, respectively. Of 5,760 patients initiating ART, 26% were LTFU. Female gender (p < 0.001), post-secondary education (p = 0.03), and initiating treatment with zidovudine-containing (p = 0.004) or tenofovir-containing (p = 0.05) regimens were associated with decreased risk of LTFU, while patients with only primary education (p = 0.02) and those with baseline CD4 counts (cell/ml(3)) >350 and <100 were at a higher risk of LTFU compared to patients with baseline CD4 counts of 100-200. The adjusted GEE analysis showed that patients aged <35 years (p = 0.005), who traveled for >2 hours to the clinic (p = 0.03), had total ART duration of >6 months (p<0.001), and CD4 counts >200 at ART initiation were at a higher risk of non-adherence. Patients who disclosed their HIV status to spouse/family (p = 0.01) and were treated with tenofovir-containing regimens (p < or = 0.001) were more likely to be adherent.These findings formed the basis for implementing multiple pre-treatment visit preparation that promote disclosure and active community outreaching to support retention and adherence. Expansion of treatment access points of care to communities to diminish travel time may have a positive impact on adherence