922017 research outputs found
Sort by
Randomized, Phase II Study of Selumetinib, an oral inhibitor of MEK, in combination with cisplatin and gemcitabine chemotherapy for patients with advanced biliary tract cancer.
No full textIntroductionCisplatin and gemcitabine (CisGem) is standard chemotherapy for advanced biliary tract cancer (BTC). The MEK inhibitor selumetinib showed synergy with gemcitabine when administered sequentially in BTC. This randomized phase 2 trial aimed to assess the efficacy of sequential or continuous selumetinib with CisGem.MethodsPatients with advanced BTC received CisGem; arm A included selumetinib every day, arm B: selumetinib, days 1-5, 8-19 each cycle. Arm C received CisGem alone. Selumetinib was dosed at 75mg BID but amended to 50mg BID due to toxicity. Results51 participants were evaluable for response. No significant difference was seen in mean change in tumor size at 10 weeks between Arm A and C (-7.8% vs -12.8%, p=0.54) or arm B and C (-15% vs -12.8%, p=0.78). There was no difference in median progression-free survival (6.0, 7.0, 6.3 months, p>0.95) or overall survival (11.7, 11.7, 12.8 months, p=0.70) for arms A, B and C, respectively. More participants experienced grade 3-4 toxicities in selumetinib-containing arms. More participants in arm A required chemotherapy dose reductions (p=0.01) with lower chemotherapy dose intensity during the first 10 weeks.ConclusionAdding sequential or continuous selumetinib to CisGem failed to improve efficacy and increased toxicity in patients with advanced BTC
Caries risk assessment related knowledge, attitude, and behaviors among Chinese dentists: A crosssectional survey
No full textObjectivesTo investigate caries risk assessment (CRA)-related knowledge, attitudes, and practices among dentists in China, to describe their subjective ratings of the significance of specific caries risk factors and to identify factors associated with the level of knowledge, attitudes, and use of CRA in routine clinical practice.Materials and MethodsA cross-sectional anonymous online questionnaire survey was performed. The questionnaire was distributed via WeChat (Tencent, Shenzhen, China) to practicing dentists between November 25 and December 25, 2021. For participant recruitment, we employed purposive and snowball sampling techniques. Data were collected using a specialized web-based survey tool (www.wjx.cn) and analyzed with descriptive statistics and regression analyses.ResultsA total of 826 valid questionnaires were collected. Only 292 (35.4%) respondents used CRA in routine practice, among whom a majority (243, 83.2%) did not use a specific CRA tool. The routine use of CRA was associated with the type of practicing office, attendance of caries-related lectures, the habit of reading caries-related literature, geographic location and the total knowledge score. The mean total knowledge score was 3.13 (score range: 0 to 6). Knowledge levels were related to several sociodemographic characteristics, including geographic location, the type of practicing office, attendance of caries-related lectures and the habit of reading caries-related literature. The risk factor deemed most important was “current oral hygiene”.ConclusionsCaries risk assessment has not widely entered clinical practice in China. The level of CRA-related knowledge among dentists was generally suboptimal
Effect of Temperature on the Preferential Intergranular Oxidation Susceptibility of Thermally-Treated Alloy 600
No full textThermally-treated Alloy 600 coupons were tested in pressurized water reactor simulated primary water at 320 °C and in high-pressure superheated steam at 400 °C to study the effect of a “semi-continuous” network of intergranular carbides on the stress corrosion cracking “precursors events”: preferential intergranular oxidation (PIO) and diffusion-induced grain boundary migration (DIGM). The intergranular carbides were partially consumed due to the environmental exposure, whereby the Cr released from the carbides contributed to the formation of the external oxide layer that limited both PIO and DIGM. The results were compared with previous studies in which similar coupons were exposed to H2-steam
Prognostic and predictive factors for locoregional and systemic therapies in hepatocellular carcinoma
No full textHepatocellular carcinoma (HCC) is a growing health concern, with an estimated global incidence of over 1 million by 2025. In its intermediate and advanced stages, HCC remains a challenging condition to treat, despite a recently expanded array of systemic therapies, which continues to grow. Extensive efforts have accordingly been made to identify predictive factors to guide treatment decisions. However, currently only one predictive biomarker is in widespread clinical use, namely elevated alpha-fetoprotein for second-line systemic therapy with ramucirumab. This article reviews known prognostic and predictive biomarkers for patients with HCC who are treated with locoregional and systemic therapies, including recent controversies around the potential impact of HCC aetiology on the efficacy of systemic therapies
Translating CPS with Shared-Variable Concurrency in SpaceEx
No full textCyber-physical systems (CPS), combining continuous physical behavior and discrete control behavior, have been widely utilized in recent years. However, the traditional modeling languages used to specify discrete systems are no longer applicable to CPS, since CPS subsume the combination of the cyber and the physical. To address this, a modeling language for CPS based on shared variables is proposed. In this paper, we present an implementation of this language in SpaceEx. Thus, a bridge between our language and hybrid automata is established.<br/
The Cold Futures of Mouse Genetics: Modes of Strain Cryopreservation since the 1970s
No full textCryopreservation, or the freezing of embryos or sperm, has become a routine part of many research projects involving laboratory mice. In this article, we combine historical and sociological methods to produce a cryopolitical analysis of this less explored aspect of animal research. We provide a longitudinal account of mouse embryo and semen storage and uses in the UK and show that cryopreservation enabled researchers to overcome particular challenges—fears of strain loss, societal disapproval, and genetic drift—in ways which enabled the continued existence of strains and contributed to the scaling up of mouse research since World War II. We use the theoretical lens of cryopolitics to explore three different, yet overlapping, cryopolitical strategies that we identify. All share the ability to ensure the continued maintenance of genetically-defined strains without the need for continually breeding colonies of mice. We argue that, in contrast to more common imaginaries of species conservation, the cryopolitical rationale can best be understood as purposefully not letting the strain die without requiring animals to live. The ability to freeze mice, then, had the potential to unsettle who the objects of care are in mouse research, from individual animals to the concept of the strain itself
The reporting and methodological quality of split-mouth trials in oral implantology: A methodological study
No full textObjectives: To assess the reporting and methodological quality of split-mouth trials (SMTs) in oral implantology published during the past ten years, and to investigate whether there was any improvement over time.Materials and Methods: We searched PubMed for SMTs in oral implantology published during 2011-20. We used CONSORT 2010, its extension for within-person trial (WPT), and an SMT-specific methodological checklist to assess trial reporting quality (TRQ), WPT-specific reporting quality (WRQ), and SMT-specific methodological quality (SMQ), respectively. Binary scores were given to each item, and total scores of TRQ (range 0-32), WRQ (0-15), and SMQ (0-3) were calculated for each study. Multivariable regression analyses were performed to compare the quality of SMTs published before (2011-17) and after (2018-20) the release of CONSORT for WPT.Results: Seventy-nine SMTs were included. The mean TRQ, WRQ, and SMQ were 16.4, 6.7, and 1.3, respectively. Less than one-third (n=25, 31.6%) reported the rationale for using splitmouth designs. Only 4 (5.1%) trials adequately conducted sample size calculation, and 40 (50.6%) used appropriate statistical methods that considered dependency and clustering of data. In multivariable analyses, compared with 2011-17, studies published in 2018-20 had significantly higher TRQ (P = 0.044), while WRQ and SMQ did not show improvement.Conclusions: The reporting and methodological quality of SMTs in oral implantology need to be improved. Joint efforts are needed to improve the reporting and methodology of SMTs in this field
Mechanism of melatonin metabolism by CYP1A1. What determines the bifurcation pathways of hydroxylation versus deformylation?
No full textMelatonin, a widely consumed cosmetic active ingredient, has a variety of uses as skin protector through antioxidant and anti-inflammatory functions as well as giving the body UV-induced defenses and immune system support. In the body, melatonin is synthesized from a tryptophan amino acid in a cascade of reactions, but as melatonin is toxic at high concentrations it is metabolized in the human skin by the cytochrome P450 enzymes. The P450s are diverse heme based monooxygenases that catalyze oxygen atom transfer processes that trigger metabolism and detoxification in the body. In the cata-lytic cycle of the P450s, a short-lived high-valent iron(IV)-oxo heme cation radical is formed that has been proposed to be the active oxidant. How and why it activates melatonin in the human body and what the origin of the product distributions is, are unknown. This encouraged us to do a detailed computational study on a typical human P450 isozyme, namely CYP1A1. We initially did a series of molecular dynamics simulations with substrate docked into several orientations. These simulations reveal several stable substrate-bound orientations in the active site, which may lead to differences in substrate activation channels. Using tunneling analysis on the full protein structures, we show that two of the four binding conformations lead to open substrate binding pockets. As a result, in these open pockets the substrate is not tightly bound and can escape back into the solution. In the closed conformations, by contrast, the substrate is mainly oriented with the methoxy group pointing toward the heme, although under a different angle. We then created large quantum cluster models of the enzyme and focused on the chemical reaction mechanisms for melatonin activation leading to competitive O-demethylation and C6-aromatic hydroxylation pathways. The calculations show that active site positioning determines the product distributions, but the bond that is activated is not necessarily closest to the heme in the enzyme-substrate complex. As such, the docking and molecular dynamics positioning of substrate versus oxidant gives misleading predictions on product distributions. In particular, in QM cluster model I we observe that through a tight hydrogen bonding network a preferential 6-hydroxylation of melatonin is obtained. However, O-demethylation becomes possible in alternative substrate-binding orientations that have the C6-aro-matic ring position shielded. Finally, we investigated enzymatic and non-enzymatic O-demethylation processes and show that the hydrogen bonding network in the substrate binding pocket can assist and perform this step prior to product release from the enzyme
Current and Future Perspectives on the Utility of Provocative Tests of Anal Sphincter Function: a state-of-the-art summary
No full textBackgroundThe maintenance of fecal continence depends upon coordinated interactions between the pelvic floor, anorectum, and anal sphincter complex orchestrated by central and peripheral neural activities. The current techniques to objectively measure anorectal function rely on fixed diameter catheters placed inside the anal canal with a rectal balloon to obtain measurements of anal resting and squeeze function, and rectal compliance. Until recently it had not been possible to measure the distensibility of the anal canal, or in other words its ability to resist opening against an increasing pressure, which has been proposed as the main determinant of a biological sphincter’s function. Anal acoustic reflectometry (AAR) and the functional lumen imaging probe (FLIP) are two novel, provocative techniques that dynamically assess the anal sphincter complex under volume-controlled distension. In doing so, both provide information on the viscoelastic properties of the anal canal and offer new insights into its function. PurposeThis review details the current and potential future applications of AAR and FLIP and highlights the unanswered questions relevant to these new technologies. <br/