Pembrolizumab plus Olaparib in Patients with Metastatic Castration-resistant Prostate Cancer: Long-term Results from the Phase 1b/2 KEYNOTE-365 Cohort A Study

Metastatic castration-resistant prostate cancer; Olaparib; PembrolizumabCáncer de próstata metastásico resistente a la castración; Olaparib; PembrolizumabCàncer de pròstata metastàtic resistent a la castració; Olaparib; PembrolizumabBackground Pembrolizumab and olaparib have shown single-agent activity in patients with previously treated metastatic castration-resistant prostate cancer (mCRPC). Objective To evaluate the efficacy and safety of pembrolizumab plus olaparib in mCRPC. Design, setting, and participants Cohort A of the phase 1b/2 KEYNOTE-365 study enrolled patients with molecularly unselected, docetaxel-pretreated mCRPC whose disease progressed within 6 mo of screening. Intervention Pembrolizumab 200 mg intravenously every 3 wk plus olaparib 400-mg capsule or 300-mg tablet orally twice daily. Outcome measurements and statistical analysis The primary endpoints were safety, confirmed prostate-specific antigen (PSA) response rate, and objective response rate (ORR) as per Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, by blinded independent central review. The secondary endpoints included radiographic progression-free survival (rPFS) and overall survival (OS). Results and limitations Of 104 enrolled patients, 102 were treated. The median age was 70 yr (interquartile range [IQR], 65–76), and 59 patients (58%) had measurable disease as per RECIST v1.1. The median time from the first dose to database cutoff was 24 mo (IQR, 22–47). The confirmed PSA response rate was 15%. The confirmed ORR was 8.5% (five partial responses) for patients with measurable disease. The median rPFS was 4.5 mo (95% confidence interval [CI], 4.0–6.5) and median OS was 14 mo (95% CI, 10.4–18.2). Clinical activity was consistent across the programmed death ligand 1 (PD-L1)-positive and homologous recombination repair mutation subgroups. Treatment-related adverse events (TRAEs) occurred in 93 patients (91%). Grade 3–5 TRAEs occurred in 49 patients (48%). Six deaths (5.9%) were due to adverse events; two (myocardial infarction and unknown cause) were attributed to treatment. Limitations of the study include the single-arm design. Conclusions Pembrolizumab plus olaparib had a safety profile consistent with the profiles of the individual agents and demonstrated antitumor activity in previously treated patients with molecularly unselected, docetaxel-pretreated mCRPC

The integral equation approach to kinematic dynamo theory and its application to dynamo experiments in cylindrical geometry

The conventional magnetic induction equation that governs hydromagnetic dynamo action is transformed into an equivalent integral equation system. An advantage of this approach is that the computational domain is restricted to the region occupied by the electrically conducting fluid and to its boundary. This integral equation approach is first employed to simulate kinematic dynamos excited by Beltrami-like flows in a finite cylinder. The impact of externally added layers around the cylinder on the onset of dynamo actions is investigated. Then it is applied to simulate dynamo experiments within cylindrical geometry including the von Karman sodium (VKS) experiment and the Riga dynamo experiment. A modified version of this approach is utilized to investigate magnetic induction effects under the influence of externally applied magnetic fields which is also important to measure the proximity of a given dynamo facility to the self-excitation threshold.Comment: 22 pages, 14 figure

Prédiction des transferts et de la croissance microbienne lors du transport de carcasses de porcs

26eme congrès français de thermique, Pau, FRA, 29-/05/2018 - 01/06/2018National audienceLors du transport de carcasses de porcs, plusieurs facteurs influencent l'évolution de la charge microbienne notamment la température et l'activité de l'eau qui dépendent des transferts dechaleur et d'eau au sein et autour des carcasses. Une expérimentation a été réalisée sur une maquette à l'échelle ~1/3 d'un camion frigorifique chargé de carcasses pour déterminer l'hétérogénéité des coefficients de transfert. Un modèle a ensuite été développé pour simuler les transferts de chaleur et dematière au niveau du jambon de la carcasse. Enfin, ce modèle de transfert a été couplé à un modèle de microbiologie prédictive

Euler configurations and quasi-polynomial systems

In the Newtonian 3-body problem, for any choice of the three masses, there are exactly three Euler configurations (also known as the three Euler points). In Helmholtz' problem of 3 point vortices in the plane, there are at most three collinear relative equilibria. The "at most three" part is common to both statements, but the respective arguments for it are usually so different that one could think of a casual coincidence. By proving a statement on a quasi-polynomial system, we show that the "at most three" holds in a general context which includes both cases. We indicate some hard conjectures about the configurations of relative equilibrium and suggest they could be attacked within the quasi-polynomial framework.Comment: 21 pages, 6 figure

Metastatic Renal Cell Carcinoma Rapidly Progressive to Sunitinib: What to Do Next?

Background: From 10% to 26% of patients with metastatic renal cell carcinoma (mRCC) experience rapidly progressive disease (PD) on treatment with sunitinib. Objective: To investigate the benefit of subsequent treatment with another tyrosine kinase inhibitor (TKI) or a mammalian target of rapamycin (mTOR) inhibitor in such primary refractory patients. Design, setting, and participants: A total of 150 mRCC patients with rapidly PD on first- line sunitinib (within two cycles, n = 93, or four cycles, n = 57) were identified: median age 59 yr; nephrectomy 86%; histological subtypes: clear cell (77.8%), papillary (14%), and sarco- matoid features (18%); according to the Memorial Sloan-Kettering Cancer Center and French classifications: good risk (11% and 7%, respectively), intermediate (68% and 63%, respectively), and poor (21% and 29%, respectively). Outcome measurements and statistical analysis: Data were retrospectively collected by a questionnaire from 19 European oncology centers between March 2005 and March 2011. Pro- gression-free survival (PFS) and overall survival (OS) were calculated (Kaplan-Meier method). Results and limitations: Median OS from the start of first-line treatment was 7.4 mo. Second-line treatment was administered to 86 (57%) patients (44 mTOR inhibitors: 23 ever- olimus and 21 temsirolimus; 39 TKIs alone or in combination; three chemotherapy). Second- line PFS was not significantly different between TKIs and mTOR inhibitors (2.0 vs 0.9 mo; p = 0.536). Median OS from the start of second-line treatment was 5.0 mo for mTOR inhibitors and 6.6 mo for TKIs (p = 0.15). Conclusions: Treatment with further TKIs or mTOR inhibitors for mRCC patients primarily refractory to first-line sunitinib in the observed time period achieved very minimal benefit, suggesting avoiding TKI rechallenge and possibly preferring alternative strategies, such as immune checkpoint inhibitors, after PD to a treatment line including a TKI in this setting. Patient summary: The present work collected data about 150 patients affected by meta- static renal cell carcinoma, who received one of the current standard of care as first-line treatment, namely, the antiangiogenic drug sunitinib, and experienced rapid worsening of the disease. We investigated and described the subsequent outcome of such patients treated with two different types of drug, administered as second-line therapy, to better understand the best strategy to adopt for patients who got no benefit from sunitinib and to describe the current therapeutic approach in such cases

A comment on Scott's “Black Polygamous Family Formation”

This brief article takes a critical look at Joseph W. Scott's article “Black Polygamous Family Formation.” While Scott's research is seen as helpful, several problems in his treatment of plural mating and marriage arrangements among Black Americans are discussed. Major conceptual problems are created by Scott's use (or misuse) of the concept “polygyny.” Significant methodological problems are also posed by his sampling approach, operationalization of concepts, and analytic strategies. Studies such as Scott's are of optimal value when their exploratory nature, and consequent limitation, are clearly acknowledged.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/44661/1/10834_2005_Article_BF01082935.pd

The nuclear receptors of Biomphalaria glabrata and Lottia gigantea: Implications for developing new model organisms

© 2015 Kaur et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are creditedNuclear receptors (NRs) are transcription regulators involved in an array of diverse physiological functions including key roles in endocrine and metabolic function. The aim of this study was to identify nuclear receptors in the fully sequenced genome of the gastropod snail, Biomphalaria glabrata, intermediate host for Schistosoma mansoni and compare these to known vertebrate NRs, with a view to assessing the snail's potential as a invertebrate model organism for endocrine function, both as a prospective new test organism and to elucidate the fundamental genetic and mechanistic causes of disease. For comparative purposes, the genome of a second gastropod, the owl limpet, Lottia gigantea was also investigated for nuclear receptors. Thirty-nine and thirty-three putative NRs were identified from the B. glabrata and L. gigantea genomes respectively, based on the presence of a conserved DNA-binding domain and/or ligand-binding domain. Nuclear receptor transcript expression was confirmed and sequences were subjected to a comparative phylogenetic analysis, which demonstrated that these molluscs have representatives of all the major NR subfamilies (1-6). Many of the identified NRs are conserved between vertebrates and invertebrates, however differences exist, most notably, the absence of receptors of Group 3C, which includes some of the vertebrate endocrine hormone targets. The mollusc genomes also contain NR homologues that are present in insects and nematodes but not in vertebrates, such as Group 1J (HR48/DAF12/HR96). The identification of many shared receptors between humans and molluscs indicates the potential for molluscs as model organisms; however the absence of several steroid hormone receptors indicates snail endocrine systems are fundamentally different.The National Centre for the Replacement, Refinement and Reduction of Animals in Research, Grant Ref:G0900802 to CSJ, LRN, SJ & EJR [www.nc3rs.org.uk]

Antioxidant activity relationship of phenolic compounds in Hypericum perforatum L.

<p>Abstract</p> <p>Background</p> <p>The St John's Wort (<it>Hypericum perforatum</it>; Clusiaceae) has been used in traditional and modern medicine for a long time due to its high content of biologically active phenolics. The purpose of this work was to develop a method for their fractionation and identification, and to determine the most active antioxidant compounds in plant extract.</p> <p>Results</p> <p>An LC-MS method which enables fast qualitative and semiquantitative analysis was developed. The composition determined is in agreement with the previous results, where 6 flavonoids, 4 naphthodianthrones and 4 phloroglucinols have been identified. Significant antioxidant activity was determined for most of the fractions by DPPH assay (the lowest IC₅₀of 0.52 μg/ml), NO scavenging (6.11 μg/ml), superoxide scavenging (1.86 μg/ml), lipid peroxidation (0.0079 μg/ml) and FRAP (the highest reduction capacity of 104 mg Fe equivalents/g) assays.</p> <p>Conclusion</p> <p>LC-MS technique has been successfully applied for a quick separation and identification of the major components of <it>H. perforatum </it>fractions. Majority of the fractions analyzed have expressed a very high antioxidative activity when compared to synthetic antioxidants. The antioxidant activity could be attributed to flavonoids and phenolic acids, while phloroglucinols and naphthodianthrones showed no significant activity. It is demonstrated that it is possible to obtain, by fractionation, <it>H. perforatum </it>preparations with significantly increased phloroglucinols-to-naphthodianthrones ratio (up to 95:5).</p