Energy Distribution in f(R) Gravity

The well-known energy problem is discussed in f(R) theory of gravity. We use the generalized Landau-Lifshitz energy-momentum complex in the framework of metric f(R) gravity to evaluate the energy density of plane symmetric solutions for some general f(R) models. In particular, this quantity is found for some popular choices of f(R) models. The constant scalar curvature condition and the stability condition for these models are also discussed. Further, we investigate the energy distribution of cosmic string spacetime.Comment: 15 pages, accepted for publication in Gen. Relativ. & Gra

A phase I open-label, dose-escalation study of NUC-3373, a targeted thymidylate synthase inhibitor, in patients with advanced cancer (NuTide:301)

The study was funded and the investigational drug NUC-3373 was supplied by NuCana plc. The centres that conducted this study are National Institute for Health and Care Research (NIHR) Biomedical Research Centres that also receive institutional funding as Cancer Research UK (CRUK) and Experimental Cancer Medicine Centres (ECMC). The Glasgow Experimental Cancer Medicine Centre (ECMC) is funded by Cancer Research UK and The Chief Scientist’s Office, Scotland (grant award A25174).Purpose 5-fluorouracil (5-FU) is inefficiently converted to the active anti-cancer metabolite, fluorodeoxyuridine-monophosphate (FUDR-MP), is associated with dose-limiting toxicities and challenging administration schedules. NUC-3373 is a phosphoramidate nucleotide analog of fluorodeoxyuridine (FUDR) designed to overcome these limitations and replace fluoropyrimidines such as 5-FU. Patients and methods NUC-3373 was administered as monotherapy to patients with advanced solid tumors refractory to standard therapy via intravenous infusion either on Days 1, 8, 15 and 22 (Part 1) or on Days 1 and 15 (Part 2) of 28-day cycles until disease progression or unacceptable toxicity. Primary objectives were maximum tolerated dose (MTD) and recommended Phase II dose (RP2D) and schedule of NUC-3373. Secondary objectives included pharmacokinetics (PK), and anti-tumor activity. Results Fifty-nine patients received weekly NUC-3373 in 9 cohorts in Part 1 (n = 43) and 3 alternate-weekly dosing cohorts in Part 2 (n = 16). They had received a median of 3 prior lines of treatment (range: 0–11) and 74% were exposed to prior fluoropyrimidines. Four experienced dose-limiting toxicities: two Grade (G) 3 transaminitis; one G2 headache; and one G3 transient hypotension. Commonest treatment-related G3 adverse event of raised transaminases occurred in < 10% of patients. NUC-3373 showed a favorable PK profile, with dose-proportionality and a prolonged half-life compared to 5-FU. A best overall response of stable disease was observed, with prolonged progression-free survival. Conclusion NUC-3373 was well-tolerated in a heavily pre-treated solid tumor patient population, including those who had relapsed on prior 5-FU. The MTD and RP2D was defined as 2500 mg/m2 NUC-3373 weekly. NUC-3373 is currently in combination treatment studies. Trial registration Clinicaltrials.gov registry number NCT02723240. Trial registered on 8th December 2015. https://clinicaltrials.gov/study/NCT02723240.Peer reviewe

A Phase 2a cohort expansion study to assess the safety, tolerability, and preliminary efficacy of CXD101 in patients with advanced solid-organ cancer expressing HR23B or lymphoma.

BACKGROUND: This Phase 2a dose expansion study was performed to assess the safety, tolerability and preliminary efficacy of the maximum tolerated dose of the oral histone de-acetylase (HDAC) inhibitor CXD101 in patients with relapsed / refractory lymphoma or advanced solid organ cancers and to assess HR23B protein expression by immunohistochemistry as a biomarker of HDAC inhibitor sensitivity. METHODS: Patients with advanced solid-organ cancers with high HR23B expression or lymphomas received CXD101 at the recommended phase 2 dose (RP2D). Key exclusions: corrected QT > 450 ms, neutrophils  1. Baseline HR23B expression was assessed by immunohistochemistry. RESULTS: Fifty-one patients enrolled between March 2014 and September 2019, 47 received CXD101 (19 solid-organ cancer, 28 lymphoma). Thirty-four patients received ≥80% RP2D. Baseline characteristics: median age 57.4 years, median prior lines 3, male sex 57%. The most common grade 3-4 adverse events were neutropenia (32%), thrombocytopenia (17%), anaemia (13%), and fatigue (9%) with no deaths on CXD101. No responses were seen in solid-organ cancers, with disease stabilisation in 36% or patients; the overall response rate in lymphoma was 17% with disease stabilisation in 52% of patients. Median progression-free survival was 1.2 months (95% confidence interval (CI) 1.2-5.4) in solid-organ cancers and 2.6 months (95%CI 1.2-5.6) in lymphomas. HR23B status did not predict response. CONCLUSIONS: CXD101 showed acceptable tolerability with efficacy seen in Hodgkin lymphoma, T-cell lymphoma and follicular lymphoma. Further studies assessing combination approaches are warranted. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT01977638 . Registered 07 November 2013

Conceptual Framework on Workplace Deviance Behavior: A Review

This article aims to highlight the importance of organizational climate with both destructive and constructive deviance behaviour in different cultural setting with workplace as a common ground. First, we discuss the need for research in workplace deviance especially destructive and constructive deviance behaviour with the review of previous studies from deviance literature. Next, we present the importance of climate and culture with both destructive and constructive deviance by proposing relationship among them with the help of a framework. The presented theoretical framework can be useful for conducting future empirical research. Finally, we present the conclusion and future research in conducting cross-national research with respect to deviance

An alternative simulation approach for surface flashover in a vacuum using a 1D2V continuum and kinetic model

Surface flashover across an insulator in a vacuum is a destructive plasma discharge which undermines the behaviors of a range of applications in electrical engineering, particle physics and space engineering, etc. This phenomenon is widely modeled by the particle-in-cell (PIC) simulation, here the continuum and kinetic simulation method is first proposed and implemented as an alternative solution for flashover modeling, aiming for the prevention of unfavorable particle noises in PIC models. A one dimension in space, two dimensions in velocity kinetic simulation model is constructed. Modeling setup, physical assumptions, and simulation algorithm are presented in detail, and a comparison with the well-known secondary electron (SE) emission avalanche analytical expression and existing PIC simulation are made. The obtained kinetic simulation results are consistent with the analytical prediction, and feature noise-free data of surface charge density as well as fluxes of primary and SEs. Discrepancies between the two simulation models and analytical predictions are explained. The code is convenient for updating and to include additional physical processes. The possible implementations of outgassing and plasma species for the final breakdown stage are discussed. The proposed continuum and kinetic approach are expected to inspire future modeling studies for the flashover mechanism and mitigation

A phase I open-label, dose-escalation study of NUC-3373, a targeted thymidylate synthase inhibitor, in patients with advanced cancer (NuTide:301)

Purpose: 5-fluorouracil (5-FU) is inefficiently converted to the active anti-cancer metabolite, fluorodeoxyuridine-monophosphate (FUDR-MP), is associated with dose-limiting toxicities and challenging administration schedules. NUC-3373 is a phosphoramidate nucleotide analog of fluorodeoxyuridine (FUDR) designed to overcome these limitations and replace fluoropyrimidines such as 5-FU. Patients and methods: NUC-3373 was administered as monotherapy to patients with advanced solid tumors refractory to standard therapy via intravenous infusion either on Days 1, 8, 15 and 22 (Part 1) or on Days 1 and 15 (Part 2) of 28-day cycles until disease progression or unacceptable toxicity. Primary objectives were maximum tolerated dose (MTD) and recommended Phase II dose (RP2D) and schedule of NUC-3373. Secondary objectives included pharmacokinetics (PK), and anti-tumor activity. Results: Fifty-nine patients received weekly NUC-3373 in 9 cohorts in Part 1 (n = 43) and 3 alternate-weekly dosing cohorts in Part 2 (n = 16). They had received a median of 3 prior lines of treatment (range: 0–11) and 74% were exposed to prior fluoropyrimidines. Four experienced dose-limiting toxicities: two Grade (G) 3 transaminitis; one G2 headache; and one G3 transient hypotension. Commonest treatment-related G3 adverse event of raised transaminases occurred in &lt; 10% of patients. NUC-3373 showed a favorable PK profile, with dose-proportionality and a prolonged half-life compared to 5-FU. A best overall response of stable disease was observed, with prolonged progression-free survival. Conclusion: NUC-3373 was well-tolerated in a heavily pre-treated solid tumor patient population, including those who had relapsed on prior 5-FU. The MTD and RP2D was defined as 2500 mg/m2 NUC-3373 weekly. NUC-3373 is currently in combination treatment studies

Burden-driven feedback control of gene expression

Cells use feedback regulation to ensure robust growth despite fluctuating demands for resources and differing environmental conditions. However, the expression of foreign proteins from engineered constructs is an unnatural burden that cells are not adapted for. Here we combined RNA-seq with an in vivo assay to identify the major transcriptional changes that occur in Escherichia coli when inducible synthetic constructs are expressed. We observed that native promoters related to the heat-shock response activated expression rapidly in response to synthetic expression, regardless of the construct. Using these promoters, we built a dCas9-based feedback-regulation system that automatically adjusts the expression of a synthetic construct in response to burden. Cells equipped with this general-use controller maintained their capacity for native gene expression to ensure robust growth and thus outperformed unregulated cells in terms of protein yield in batch production. This engineered feedback is to our knowledge the first example of a universal, burden-based biomolecular control system and is modular, tunable and portable

Genome-wide joint SNP and CNV analysis of aortic root diameter in African Americans: the HyperGEN study

<p>Abstract</p> <p>Background</p> <p>Aortic root diameter is a clinically relevant trait due to its known relationship with the pathogenesis of aortic regurgitation and risk for aortic dissection. African Americans are an understudied population despite a particularly high burden of cardiovascular diseases. We report a genome-wide association study on aortic root diameter among African Americans enrolled in the HyperGEN study. We invoked a two-stage, mixed model procedure to jointly identify SNP allele and copy number variation effects.</p> <p>Results</p> <p>Results suggest novel genetic contributors along a large region between the <it>CRCP </it>and <it>KCTD7 </it>genes on chromosome 7 (p = 4.26 × 10^<b>-7</b>); and the <it>SIRPA </it>and <it>PDYN </it>genes on chromosome 20 (p = 3.28 × 10^<b>-8</b>).</p> <p>Conclusions</p> <p>The regions we discovered are candidates for future studies on cardiovascular outcomes, particularly in African Americans. The methods we employed can also provide an outline for genetic researchers interested in jointly testing SNP and CNV effects and/or applying mixed model procedures on a genome-wide scale.</p