151398 research outputs found
Sort by
A phase Ia study of the MEK1/2 inhibitor PD-0325901 with the c-MET inhibitor crizotinib in patients with advanced solid cancers
No full textBackground: Single-agent MEK1/2 inhibition has been disappointing in clinical trials targeting RAS mutant (MT) cancers, probably due to upstream receptor activation, resulting in resistance. We previously found that dual c-MET/MEK1/2 inhibition attenuated RASMT colorectal cancer (CRC) xenograft growth. In this study, we assessed safety of MEK1/2 inhibitor PD-0325901 with c-MET inhibitor crizotinib and determined the optimal biological doses for subsequent clinical trials.Methods:In this dose-escalation phase I trial, patients with advanced solid tumours received PD-0325901 with crizotinib, using a rolling-6 design to determine the maximum tolerable dose (MTD) and safety/tolerability. Blood samples for pharmacokinetics and skin biopsies were collected. Results:Twenty-five patients were recruited in 4 cohorts up to doses of crizotinib 200mg B.D continuously with PD-0325901 8mg B.D, days 1-21 every 28 days. One in six patients exhibited a dose-limiting toxicity at this dose level. Drug-related adverse events were in keeping with single-agent toxicity profiles. The best clinical response was stable disease in seven patients (29%).Conclusions:PD-0325901/crizotinib can be given together at pharmacologically-active doses. The MTD for PD-0325901/crizotinib was 8mg B.D (days 1-21) and 200mg B.D continuously in a 28-days cycle. The combination was further explored with an alternate MEK1/2 inhibitor in RASMT CRC patients. EudraCT-Number: 2014-000463-40 <br/
Towards efficient coordination of power distribution network and electric vehicles: deep reinforcement learning with robust reward function
No full textThe rapid increase in electric vehicle (EV) usage has led to an urgent need for coordinating EV charging activities with power distribution networks (PDNs) to accommodate the resulting redistributed electrical demand and implement greater operational flexibility for PDNs. However, current efforts relying on the implementation of EV charging price strategies to influence the decision-making activities of EV users at charging stations face challenges arising from the uncertainty of EV charging behavior and data privacy concerns. The present work addresses these issues by developing a robust reinforcement learning approach that requires no personal EV user information to determine charging schedules and pricing strategies at charging stations, while the uncertainty in EV behavior is addressed by applying a robust reward function. The loss function is relaxed using Holder's and Cauchy-Schwarz inequalities, which yields an upper bound for the loss caused by the worst-case scenario and thereby enhances the computational efficiency of the solution process. Numerical results demonstrate that the proposed method contributes to balancing the PDN load and improving the utilization of fast charging stations (FCSs). Compared to deterministic and traditional robust methods, the proposed method reduces computation time in uncertain environments while ensuring moderate revenue of FCSs
Peptide hydrogels as a long-acting multipurpose drug delivery platform for combined contraception and HIV prevention
No full textRemarkable concordance in associations between epigenetic clocks and health behaviors across three countries
No full textResearch utilizing epigenetic clocks has accelerated in recent years, but it is largely unknown how consistently these measures perform across country and cultural contexts, and thus, how useful they are for understanding the large differences in health outcomes across countries. We assess epigenetic aging in three countries (the US, Ireland, and Northern Ireland) utilizing nationally representative survey data from each country and evaluated how these measures are associated with three well-studied health behaviors (heavy alcohol use, smoking, and BMI). In general, we found remarkable consistency across these studies, suggesting epigenetic clocks are potentially highly useful for monitoring health and aging processes in different contexts. More research is needed on other health risks and in non-Western and low- and middle-income countries
Duplicate bug report retrieval for new bug reports
No full textIssue tracking systems are used to manage and track software requirements and bug reports. In an issue tracking system, two bug reports created by two persons may be duplicate as they may refer to the same bug in a software system. Previous research shows that an estimated 35.8% to 41.6% of bug reports are duplicate, and this causes significant inefficiencies in software development and maintenance as developers have to waste time to identify if a bug report has duplicate reports prior to fixing the bug. Therefore, retrieving duplicate bug reports is important to improve productivity in software development. This paper proposes to use pre-trained language models (e.g., BERT and RoBERTa) to embed bug reports and to compute probability scores for retrieving duplicate bug reports. The proposed approach is evaluated with four common real datasets (i.e., Eclipse, Mozilla, NetBeans and Open Office) for the duplicate bug report retrieval task. The experimental results show that the proposed models are very effective for new duplicate bug report retrieval.<br/
Movable-element STARS-assisted near-field wideband communications
No full textA novel movable-element simultaneously transmitting and reflecting surface (ME-STARS)-assisted near-field wideband communication framework is proposed. In particular, the position of each STARS element can be adjusted to combat the significant wideband beam squint issue in the near field instead of using costly true-time delay components. Four practical ME-STARS element movement modes are proposed, namely region-based (RB), horizontal-based (HB), vertical-based (VB), and diagonal-based (DB) modes. Based on this, a near-field wideband multi-user downlink communication scenario is considered, where a sum rate maximization problem is formulated by jointly optimizing the base station (BS) precoding, ME-STARS beamforming, and element positions. To solve this intractable problem, a two-layer algorithm is developed. For the inner layer, the block coordinate descent optimization framework is utilized to solve the BS precoding and ME-STARS beamforming in an iterative manner. For the outer layer, the particle swarm optimization-based heuristic search method is employed to determine the desired element positions. Numerical results show that: 1) the ME-STARSs can effectively address the beam squint for near-field wideband communications compared to conventional STARSs with fixed element positions; 2) the RB mode achieves the most efficient beam squint effect mitigation, while the DB mode achieves the best trade-off between performance gain and hardware overhead; and 3) an increase in the number of ME-STARS elements or BS subcarriers substantially improves the system performance
Exploring facilitators and disruptors of polarization during adolescence within contested settings: a case study of Catholic and Protestant youth in Northern Ireland
No full textToday’s adolescents must find ways to engage in a shared reality, especially in settings marked by intergroup conflict, as a prerequisite for reducing conflict and building collective solutions to societal problems. Polarization processes (epistemic) have been notably overlooked within this critical developmental period. This qualitative case study addresses this gap by identifying key socializing actors and settings within established theoretical frameworks (Ecological Systems Theory, Social Identity, and Intergroup Contact) using in-depth interview data from 45 Catholic and Protestant adolescents living in post-conflict Northern Ireland. Inductive analysis was conducted with the interview data. Findings reveal the importance of family, friends, school, and media as intersecting socializing actors for adolescents. Intergroup contact among peers from different ethno-religious backgrounds disrupted adolescents’ engagement in polarizing and divisive rhetoric. Lastly, adolescents perceived educational actors and settings as less influential than their personal connections to peers and family. Directions for future research leveraging intergroup contact to enhance adolescents’ information networks and educational interventions are discussed
Initial radiographic outcomes of titanium cage implants in anterior cervical discectomy and fusion: a retrospective review
No full textIntroductionAnterior cervical discectomy and fusion (ACDF) is a common surgical treatment for degenerative diseases and trauma in the cervical spine. The procedure aims to restore and maintain lordosis in the cervical spine and increase intervertebral disc height; ultimately leading to vertebral body fusion and spinal stabilisation. Polyetheretherketone cages are commonly utilised; however, new implant technologies such as 3D-printed titanium cages have emerged. There are few published reports regarding titanium cages, and therefore, this study evaluated the initial radiological outcomes of the CONDUITTM EIT Cellular Titanium Cervical Cage (DePuy Synthes, Wurmlingen, Germany). The aim is to contribute to the existing literature and establish the non-inferiority of this implant type compared to other common implants.MethodsThis study reviewed 29 patients retrospectively, who underwent 36 ACDF procedures in the Regional Spinal Unit in Northern Ireland. Radiological images were assessed at three time points: pre-operative, one-day post-operative, and follow-up (on average 6.19 months later). At each time point, intervertebral disc height, segmental Cobb angle of the operated segment, and the overall C2-C7 Cobb angle of the cervical spine were measured. To ensure the accuracy of the assessed data, all images were independently reviewed by both the author and an external observer, allowing for the calculation of the intraclass correlation coefficient for each measurement. The Wilcoxon signed rank test was used to assess the significance of changes in each radiographic variable between different time points. Spearman’s rank correlation was used to identify any relationships between the radiographic variables.ResultsIntervertebral disc height increased from an average pre-operative value of 3.79 ±1.38 mm to an average follow-up value of 5.94 ± 1.41 mm, significantly increasing by an average of 2.14 ± 1.98mm (p<0.001). Segmental Cobb Angle increased from an average pre-operative kyphotic value of -1.14 ± 8.42° to an average follow-up lordotic reading of 1.71 ± 6.28°, significantly increasing by an average of 2.86 ± 7.60° (p=0.045). Overall, the C2-C7 Cobb angle increased from an average pre-operative lordotic value of 7.36 ± 8.46° to an average follow-up lordotic value of 10.34± 12.09°, significantly increasing by an average of 2.98 ± 9.94° (p=0.021). Interestingly, all variables were the highest immediately post-operatively and then declined over the follow-up period (intervertebral disc height declined by 0.62 ± 0.98mm (<0.001), segmental Cobb angle by 0.96 ± 1.39° (p<0.007) and overall Cobb angle by 0.29 ± 8.46° (p=0.422). There was a moderate positive Spearman’s correlation coefficient of 0.498 (p=0.002) between the change in intervertebral disc height and overall C2-C7 Cobb angle. Additionally, the correlation coefficient between change in intervertebral disc height and segmental Cobb angle was 0.238 (p=0.162), indicating a non-significant weak positive relationship. The correlation coefficient between overall Cobb angle and segmental Cobb angle was -0.17 (p=0.92), indicating a very weak negative relationship, although not significant.ConclusionsTitanium cages demonstrated effectiveness in this study, showing favourable initial radiological outcomes and proving non-inferior to other cage types in this regard. Further research is needed to evaluate titanium cages, including their associated clinical outcomes, comprehensively
Recent developments and workflows of non-targeted LC-HRMS screening in the detection of veterinary drug residues in foods
No full textMonitoring veterinary drug residues in food is one key link to ensuring food safety. In recent years, non-targeted screening technology based on liquid chromatography-high resolution mass spectrometry (LC-HRMS) has attracted widespread attention. However, the development and application of non-targeted screening methods still face many challenges due to the constantly updated variety of veterinary drugs, the complexity of sample matrices, the large amount of data, and the cumbersome data identification process. To address the above challenges, this review systematically proposes a workflow for non-targeted screening, focusing on the research progress in sample preparation, instrument analysis, data preprocessing, and recognition strategy. In addition, it summarizes molecular formula prediction models, chemical structure prediction models, and retention time validation models, discusses the latest application of this technique in detecting veterinary drug residues in food, providing new insights to meet the challenges of non-targeted screening.</p