bluuebunny/crossref_metadata_2025_split huggingface dataset:
CYP2D6 and CYP2C8 pharmacogenetics and pharmacological interactions to predict imatinib plasmatic exposure in GIST patients
Authors: Dalle Fratte Chiara , Gagno Sara , Roncato Rossana , Polesel Jerry , Zanchetta Martina , Buzzo Mauro , Posocco Bianca , De Mattia Elena , Borsatti Rachele , Puglisi Fabio , Foltran Luisa , Guardascione Michela , Buonadonna Angela , Cecchin Erika , Toffoli Giuseppe 
Published: September 2022

AimsPatients on treatment with oral fixed dose imatinib are frequently under‐ or overexposed to the drug. We investigated the association between the gene activity score (GAS) of imatinib‐metabolizing cytochromes (CYP3A4, CYP3A5, CYP2D6, CYP2C9, CYP2C19, CYP2C8) and imatinib and nor‐imatinib exposure. We also investigated the impact of concurrent drug–drug‐interactions (DDIs) on the association between GAS and imatinib exposure.MethodsSerial plasma samples were collected from 33 GIST patients treated with imatinib 400 mg daily within a prospective clinical trial. Imatinib and nor‐imatinib Ctrough were quantified by liquid chromatography with tandem mass spectrometry (LC‐MS/MS). Genetic polymorphisms with a functional impact on imatinib‐metabolizing cytochromes were identified and a GAS was calculated for each gene. A DDI‐adjusted GAS was also generated.ResultsImatinib and nor‐imatinib Ctrough were measured in 161 plasma samples. CYP2D6 GAS and metabolizer status based on genotype were associated with imatinib and (imatinib + nor‐imatinib) Ctrough. CYP2D6 poor and intermediate metabolizers were predicted to have a lower nor‐imatinib/imatinib metabolic ratio than normal metabolizers (0.197 and 0.193 vs. 0.247, P = .0205), whereas CYP2C8*3 carriers had a higher ratio than CYP2C8*1/*1 patients (0.263 vs. 0.201, P = .0220). CYP2C9 metabolizer status was inversely related to the metabolic ratio with an effect probably driven by the linkage disequilibrium between CYP2C9*2 and CYP2C8*3. The CYP2D6 DDI‐adjusted GAS was still predictive of imatinib exposure.ConclusionsThese findings highlight that CYP2D6 plays a major role in imatinib pharmacokinetics, but other players (i.e., CYP2C8) may influence imatinib exposure. These findings could drive the selection of patients more susceptible to imatinib under‐ or overexposure who could be candidates for personalized treatment and intensified monitoring strategies.
Oculocerebrorenal syndrome of Lowe protein controls cytoskeletal reorganisation during human platelet spreading
Authors: Bura Ana , de Matteis Maria Antonietta , Bender Markus , Swinkels Maurice , Versluis Jurjen , Jansen A. J. Gerard , Jurak Begonja Antonija 
Published: September 2022

SummaryLowe syndrome (LS) is a rare, X‐linked disorder characterised by numerous symptoms affecting the brain, the eyes, and the kidneys. It is caused by mutations in the oculocerebrorenal syndrome of Lowe (OCRL) protein, a 5‐phosphatase localised in different cellular compartments that dephosphorylates phosphatidylinositol‐4,5‐bisphosphate into phosphatidylinositol‐4‐monophosphate. Some patients with LS also have bleeding disorders, with normal to low platelet (PLT) count and impaired PLT function. However, the mechanism of PLT dysfunction in patients with LS is not completely understood. The main function of PLTs is to activate upon vessel wall injury and stop the bleeding by clot formation. PLT activation is accompanied by a shape change that is a result of massive cytoskeletal rearrangements. Here, we show that OCRL‐inhibited human PLTs do not fully spread, form mostly filopodia, and accumulate actin nodules. These nodules co‐localise with ARP2/3 subunit p34, vinculin, and sorting nexin 9. Furthermore, OCRL‐inhibited PLTs have a retained microtubular coil with high levels of acetylated tubulin. Also, myosin light chain phosphorylation is decreased upon OCRL inhibition, without impaired degranulation or integrin activation. Taken together, these results suggest that OCRL contributes to cytoskeletal rearrangements during PLT activation that could explain mild bleeding problems in patients with LS.
Trophic cascades in tropical rainforests: Effects of vertebrate predator exclusion on arthropods and plants in Papua New Guinea
Authors: Houska Tahadlova Marketa , Mottl Ondrej , Jorge Leonardo R. , Koane Bonny , Novotny Vojtech , Sam Katerina 
Published: September 2022

AbstractInsect herbivores have the potential to consume large amounts of plant tissue in tropical forests, but insectivorous vertebrates effectively control their abundances, indirectly increasing plant fitness accordingly. Despite several studies already sought understanding of the top‐down effects on arthropod community structure and herbivory, such studies of trophic cascades in old tropics are underrepresented, and little attention was paid to top‐down forces in various habitats. Therefore, we examine how flying insectivorous vertebrates (birds and bats) impact arthropods and, consequently, affect herbivore damage of leaves in forest habitats in Papua New Guinea. In a 3‐month long predator exclosure experiment conducted at four study sites across varying elevation and successional stage, we found that vertebrate predators reduced arthropod density by ∼52%. In addition, vertebrate predators decreased the mean body size of arthropods by 26% in leaf chewers and 47% in non‐herbivorous arthropods but had only a small effect on mesopredators and sap suckers. Overall, the exclusion of vertebrate predators resulted in a ~ 41% increase in leaf damage. Our results, across different types of tropical forests in Papua New Guinea, demonstrate that flying vertebrate insectivores have a crucial impact on plant biomass, create a selective pressure on larger and non‐predatory prey individuals and they prey partition with mesopredators.
Efficacy of created and restored nesting sites for the conservation of colonial Laridae in the South of France
Authors: Schwartz Timothée , Besnard Aurélien , Pin Christophe , Scher Olivier , Blanchon Thomas , Béchet Arnaud , Sadoul Nicolas 
Published: September 2022

AbstractBy rapidly modifying key habitat components, habitat restoration is at risk of producing attractive cues for animals without providing habitats of sufficient quality. As such, individual fitness components, such as reproduction, could be reduced and restored habitats could become ecological traps. This risk notably appears by using artificial constructions in restoration projects, yet few studies have evaluated their efficacy in a robust way. We investigated this by analyzing 154 islets that were created or restored to improve the conservation status of 7 colonial Laridae species in the South of France. From 2007 to 2016, we compared occupancy dynamics and breeding parameters of these species between the restored sites and 846 unmanaged nesting sites. We also explored species’ preference for different nesting site characteristics and their respective effect on breeding parameters. Restored nesting sites were 2–9 times as attractive as unmanaged sites for all species except the Black‐headed Gull (Chroicocephalus ridibundus). Colonization probability was up to 100 times higher in sites already used by other species the previous year and increased with distance to the shore until >0.2 when distance was over 250 m. Abandonment probability was 29–70% lower when breeding was successful the previous year in all species except the Sandwich Tern (Thalasseus sandvicensis). Productivity and breeding success probability were 2 times higher on managed sites. Distance from the shore was an important attractive characteristic of artificial nesting sites in all species. Other nesting site characteristics had species‐specific effects on colonization, abandonment, and breeding success. Our results indicate that managed nesting sites are successful conservation tools for colonial Laridae in the Mediterranean and do not act as ecological traps. Our study showed that testing the ecological trap hypothesis is a robust way to evaluate the success of restoration projects of breeding habitats.
Improvement of the splanchnic blood flow and hepatic vein oxygenation following revascularization in patients with chronic mesenteric ischaemia
Authors: Høyer Christian , Zacho Helle D. , Stefanov Viktor , Abrahamsen Jan 
Published: September 2022

AbstractObjectivesChronic mesenteric ischaemia (CMI) is an underdiagnosed but severe condition. Access to functional testing is often limited and the diagnosis is usually based primarily on symptoms and imaging. One of the functional tests available is measurement of the splanchnic blood flow (SBF). The purpose of the present investigation was to evaluate if changes in the splanchnic perfusion after revascularization can be detected by measuring the SBF and hepatic vein oxygenation.Materials and MethodsThe SBF was measured in 10 patients before and after revascularization of the mesenteric arteries by either percutaneous transluminal angioplasty (n = 9) or open revascularization (n = 1). The SBF was measured indirectly using Fick's principle and using the tracer Tc‐99m Mebrofenin along with assessment of hepatic blood oxygenation, before and after a standard meal, following catheterization of a hepatic vein and the femoral artery.ResultsNine of 10 patients (90%) achieved a profound increase in SBF after revascularization (mean increase in postprandial response to meal stimulation from 71 ± 95 to 531 ± 295 ml/min, p = 0.001), and an increase in postprandial hepatic vein oxygen saturation (from 52 ± 14% to 59 ± 13%, p = 0.006). The symptoms of the patients diminished accordingly. One patient had no symptom relief, and no increase in postprandial SBF, but an angiographic result with no significant stenosis postrevascularization.ConclusionsRevascularization increased the SBF and hepatic vein oxygen saturation significantly concurrent with symptom relief and according with the angiographic successful result in the vast majority of patients. A satisfying angiographic result post vascular intervention does not rule out CMI.
Safety, tolerability, pharmacokinetic, and pharmacodynamic characteristics of vutiglabridin: A first‐in‐class, first‐in‐human study
Authors: Na Joo Young , Yoon Deok Yong , Yoo Hyounggyoon , Lee SeungHwan , Yu Kyung‐Sang , Jang In‐Jin , Yoo Sang‐Ku , Kim Youngah , Oh Jaeseong 
Published: September 2022

AbstractThis study aimed to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of vutiglabridin, a potential anti‐obesity treatment under development, for the first time in humans. A randomized, placebo‐controlled, single‐ and multiple‐ascending dose study (SAD and MAD, respectively) was performed in healthy Koreans and Whites. Subjects randomly received a single oral dose of 30–720 mg vutiglabridin or placebo at a ratio of 8:2 in the SAD study or 240–480 mg vutiglabridin or placebo once daily for 14 days in the MAD study. Food effect was also evaluated in 240 mg single dose group. Pharmacokinetics were evaluated through plasma concentrations, and pharmacodynamic biomarkers related to obesity or inflammation were analyzed. Safety and tolerability were assessed throughout the study. Single and multiple doses of vutiglabridin were generally well‐tolerated. The pharmacokinetic parameters show less than dose‐proportionality increase, and plasma concentrations increased more than two‐fold after multiple administrations. The mean half‐life of Koreans and Whites in the MAD study was 110 and 73 h, respectively. The systemic exposure of vutiglabridin was significantly increased when taken with a high‐fat meal, and the systemic exposure was lower in Whites than in Koreans. Vutiglabridin was well‐tolerated in healthy Koreans and Whites. The plasma concentration increased less than the dose‐proportionality manner. These results justify further investigation of vutiglabridin in patients with obesity.
Design and conduct considerations for studies in patients with hepatic impairment
Authors: Ravenstijn Paulien , Chetty Manoranjenni , Manchandani Pooja , Elmeliegy Mohamed , Qosa Hisham , Younis Islam 
Published: September 2022

AbstractDespite the liver being the primary site for clearance of xenobiotics utilizing a myriad of mechanisms ranging from cytochrome P450 enzyme pathways, glucuronidation, and biliary excretion, there is a dearth of information available as to how the severity of hepatic impairment (HI) can alter drug absorption and disposition (i.e., pharmacokinetics [PK]) as well as their efficacy and safety or pharmacodynamics (PD). In general, regulatory agencies recommend conducting PK studies in subjects with HI when hepatic metabolism/excretion accounts for more than 20% of drug elimination or if the drug has a narrow therapeutic range. In this tutorial, we provide an overview of the global regulatory landscape, clinical measures for hepatic function assessment, methods to stage HI severity, and consequently the impact on labeling. In addition, we provide an in‐depth practical guidance for designing and conducting clinical trials for patients with HI and on the application of modeling and simulation strategies in lieu of dedicated trials for dosing recommendations in patients with HI.
Neurofeminism: Feminist critiques of research on sex/gender differences in the neurosciences
Authors: Friedrichs Kassandra , Kellmeyer Philipp 
Published: September 2022

AbstractOver the last three decades, the human brain and its role in determining behavior have been receiving a growing amount of attention in academia as well as in society more generally. Neuroscientific explanations of human behavior or other phenomena are often especially appealing to lay people. Therefore, neuroscientific explanations that can affect individuals, groups, or social relations in general should be formulated in a careful and responsible way. One field in which especially feminist scholars request more caution is the neuroscientific examination of sex/gender differences. Feminist scholars have described various ways in which sexist bias might be present in neuroscientific research on sex/gender differences. In this context, they coined the term “neurosexism” to describe the entanglement between neuroscientific work and sexist ideology, and “neurofeminism” as a response to that. Here, we aim to give an overview over the contemporary neurofeminist literature. In the first part, common levels of analysis in the neurofeminist literature are presented and the research level is explored in more detail. In the second part, some common developments in more recent neurofeminist scholarship are discussed. For this, we review recent publications with the aim to provide neuroscientists with a solid understanding of neurofeminist criticism so that they may evaluate neuroscientific claims about on sex/gender differences from this critical perspective.
THE DYNAMIC EFFECTS OF MULTILATERAL TRADE POLICY WITH EXPORT CHURNING
Authors: Mix Carter 
Published: September 2022

AbstractThis article examines the relationship between export churning and the aggregate response to trade policy. I show that export churning—the share of bilateral exports by new or exiting exporters—varies systematically across export destinations and build a multicountry model with destination‐specific investments in exporting capacity that is consistent with churning patterns. The model then predicts that trade liberalizations with minor export destinations deliver higher bilateral export growth than liberalizations with major export destinations, and the data support this prediction. Furthermore, the aggregate effects of trade policy depend critically on the pattern of export churning in the model.
Women's behaviours towards cervical cancer screening in the COVID‐19 pandemic: A moderated‐mediation‐model based on Information‐Motivation‐Behavioural Skills
Authors: Taştekin Ouyaba Ayşe , İnfal Kesim Selma 
Published: September 2022

AbstractAims(1) To establish a predictive model based on the Information‐Motivation‐Behavioural Skills model, which can analyse the factors affecting the behaviours of women towards cervical cancer screening in the COVID‐19 pandemic, and (2) to test the mediating effects of behavioural skills in the model, and (3) to test the moderated mediation effect of age.DesignA cross‐sectional study was conducted among 354 women aged 30–65 between May and August 2021 in Turkey.MethodsData were collected by using an online survey. The direct and indirect effects were tested in the structural equation model and the moderated‐mediation effect was tested in the PROCESS macro.ResultsBehavioural skills mediate the effect of motivation on cervical cancer screening behaviours. In addition, age has a moderated mediation effect on this mediation effect.ConclusionOur study revealed that as women's motivation for cervical cancer screening increased, their behavioural skills also increased. It can be stated that middle‐aged and older women with higher behavioural skills are more likely to have screening during the pandemic and to comply with national recommendations.ImpactThis study is the first quantitative study to test the impact of the components of the Information‐Motivation‐Behavioural Skills model on cervical cancer screening during the COVID‐19 pandemic. In addition, the results reveal the mediating effect of behavioural skills in the relationship between motivation and cervical cancer scanning behaviour and the moderated mediation effect of age. Our results can provide insight for nurses into how to triage women with delayed cervical cancer screening, how to build screening capacity, and how intervention strategies should be developed to improve compliance with cervical cancer screening and follow‐up recommendations in women at risk during and after the pandemic.
The guideline for therapeutic drug monitoring guidelines development
Authors: Zeng Linan , Yi Qiusha , Huang Liang , Chen Wenqian , Men Peng , Zhang Jingjing , Jiang Zhimei , Miao Liyan , Zhao Rongsheng , Zhang Xianglin , Zhang Lingli 
Published: September 2022

AbstractAimThe guideline is meant to standardize the principles, procedures, and methods for developing therapeutic drug monitoring (TDM) guidelines and promoting open, transparent, scientific, and credible TDM guidelines.MethodsDivision of Therapeutic Drug Monitoring, Chinese Pharmacological Society established guideline working groups, declared and managed conflicts of interest. The guideline working groups used the Delphi method to formulate the purpose and scope of the guidelines and questions in the PICO format, searched and synthesized evidence, and integrated with the current situation in China and TDM characteristics to preliminarily develop recommendations for the guideline for TDM guideline development in China. Through internal discussions of the guideline working groups and external peer review, the content was improved, and we eventually formulated a guideline suitable for guiding TDM‐related guidelines.ResultsThe guideline provides suggestions for problems to be identified and solved in the planning, development, publishing, and updating stages of TDM guidelines, including forming guideline working groups, planning guidelines, declaration and management of interests, formulating questions and selecting outcomes, preparing the planning proposal, evidence retrieval and synthesis, evidence assessment, developing recommendations, drafting guidelines, external review guidelines, publishing and disseminating guidelines, postevaluation of guidelines, and updating guidelines.ConclusionsThis guideline can provide methodological guidance and reference for the development of TDM guidelines.
Thermodynamic properties and bioactive compounds of mandacaru dried waste
Authors: Gondim Carolina de Miranda , de Figueirêdo Rossana Maria Feitosa , Queiroz Alexandre José de Melo , Esmero Janaína Almeida Dantas , Moura Henrique Valentim , Moreira Inacia dos Santos 
Published: September 2022

AbstractMandacaru is a cactus native to the semiarid region of Brazil, of which the fruits are edible, highly perishable and rich in bioactive compounds, present mainly in the peel. The aim of this study was to determine the drying kinetics of the processed peels of the mandacaru fruit at three different temperatures, fit mathematical models to the experimental data, determine the effective diffusivity and the thermodynamic properties and evaluate the influence of the drying conditions on the bioactive compound concentrations. The residues from the mandacaru fruits, composed of the peels, were ground with a 3% ascorbic acid solution to transform them into a homogeneous paste. The peel paste was placed in stainless steel trays, spread out to give an approximately 0.5 cm layer and dried in a convective drying oven with forced air circulation at a velocity of 1.0 m/s at temperatures of 50, 60 and 70°C. Mathematical models found in the literature were fitted to the drying kinetics of the mandacaru fruit peel paste, and of these the Midilli model fitted the experimental data best. The effective diffusivity of the water increased with drying temperature, as also the Gibbs free energy. The activation energy was to the order of 39.15 kJ/mol. The enthalpy presented positive values, decreasing with increase in drying temperature, but the entropy presented negative values, progressively lower with increase in temperature. Important betalain concentrations were determined in the mandacaru fruit peels, especially betaxanthins, an active principal of interest to the food industry as a natural pigment. Despite the decrease in concentration of the bioactive compounds with convective drying, the powders still presented significant amounts, the temperature of 70°C resulting in the highest bioactive compound concentrations in the powder samples.Practical applicationsThe use of the data presented here for the thermodynamic properties and bioactive compounds provides support for the use of the dried Mandacaru residues (previously discarded) in the production of new foods, due to knowledge of the processing time and composition of the sample. The Mandacaru peel powder, rich in bioactive compounds, could be incorporated into various food formulations in the bakery and yogurt segments, amongst others.