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Identification of anticancer drugs to radiosensitise BRAF-wild-type and mutant colorectal cancer

Cancer Biology & Medicine 2019年第2期16卷 234-246页

作者： Rebecca Carter Azadeh Cheraghchi-Bashi Adam Westhorpe Sheng Yu Yasmin Shanneik Elena Seraia Dj.mila Ouaret Yasuhiro Inoue Catherine Koch j.nny Wilding Daniel Ebner anderson j. ryan Francesca M. Buffa Ricky A. Sharma NIHR University College London Hospitals Biomedical Research Centre/ UCL Cancer Institute University College London London WC1E 6DD UK NIHR Oxford Biomedical Research Centre Department of Oncology University of Oxford Oxford 0X1 2JD UK Computational Biology and Integrative Genomics University of Oxford Oxford 0X1 2JD UK NDM Research Building Nuffield Department of Medicine University of Oxford Oxford 0X1 2JD UK Weatherall Institute of Molecular Medicine John Radcliffe Hospital University of Oxford Oxford 0X1 2JD UK Mie University Graduate School of Medicine Department of Gastrointestinal and Pediatric Surgery Division of Reparative Medicine Institute of Life Sciences Edobashi 2-174 Tsu Japan Departme nt of Biology Massachusetts In stitute of Tech no logy Cambridge Massachusetts 02142 USA Target Discovery Institute National Phenotypic Screening Centre Nuffield Department of Medicine University of OxfordOxford 0X1 2JD UK CRUK & MRC Oxford Institute for Radiation Oncology University of Oxford Oxford 0X1 2JD UK

Obj.ctive: Patients with BRAF-mutant colorectal cancer(CRC) have a poor prognosis. Molecular status is not currently used to select which drug to use in combination with radiotherapy. Our aim was to identify drugs that radiosensitise CRC cells with known BRAF ***: We screened 298 oncological drugs with and without ionising radiation in colorectal cancer cells isogenic for BRAF. Hits from rank product analysis were validated in a 16-cell line panel of human CRC cell lines, using clonogenic survival assays and xenograft models in ***: Most consistently identified hits were drugs targeting cell growth/proliferation or DNA damage repair. The most effective class of drugs that radiosensitised wild-type and mutant cell lines was PARP inhibitors. In clonogenic survival assays, talazoparib produced a radiation enhancement ratio of 1.9 in DLD1(BRAF-wildtype) cells and 1.8 in RKO(BRAF V600 E) cells. In DLD1 xenografts, talazoparib significantly increased the inhibitory effect of radiation on tumour growth(P ≤ 0.01).Conclusions: Our method for screening large drug libraries for radiosensitisation has identified PARP inhibitors as promising radiosensitisers of colorectal cancer cells with wild-type and mutant BRAF backgrounds.

关键词： Radiosensitizer colorectal cancer PARP inhibitor radiotherapy

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Management of gestational diabetes mellitus via nutritional interventions:The relevance of gastric emptying

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World j.urnal of Diabetes 2024年第7期15卷 1394-1397页

作者： Wei-Kun Huang ryan j.j.lleh Christopher K Rayner Tong-Zhi Wu Adelaide Medical School and Centre of Research Excellence in Translating Nutritional Science to Good Health The University of AdelaideAdelaide 5000Australia Adelaide Medical School and Centre of Research Excellence in Translating Nutritional Science to Good Health The University of Adelaide and Department of Gastroenterology and HepatologyRoyal Adelaide HospitalAdelaide 5000Australia

Gestational diabetes mellitus(GDM)represents one of the most common medical complications of pregnancy and is important to the well-being of both mothers and offspring in the short and long *** intervention remains the mainstay for the management of *** efficacy of nutritional approaches(*** restriction and small frequent meals)to improving the maternal-neonatal outcomes of GDM was attested to by Chinese population data,discussed in two articles in recent issues of this ***,a specific focus on the relevance of postprandial glycaemic control was *** rather than fasting hyperglycaemia often represents the predominant manifestation of disordered glucose homeostasis in Chinese women with *** is now increasing appreciation that the rate of gastric emptying,which controls the delivery of nutrients for digestion and absorption in the small intestine,is a key determinant of postprandial glycaemia in both health,type 1 and 2 *** remains to be established whether gastric emptying is abnormally rapid in GDM,particularly among Chinese women,thus contributing to a predisposition to postprandial hyperglycaemia,and if so,how this influences the therapeutic response to nutritional *** is essential that we understand the role of gastric emptying in the regulation of postprandial glycaemia during pregnancy and the potential for its modulation by nutritional strategies in order to improve postprandial glycaemic control in GDM.

关键词： Gastric emptying Postprandial glycaemia Diet Nutritional interventions Gestational diabetes mellitus

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Machine learning-guided accelerated discovery of structure-property correlations in lean magnesium alloys for biomedical applications

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j.urnal of Magnesium and Alloys 2024年第6期12卷 2267-2283页

作者： Sreenivas Raguraman Maitreyee Sharma Priyadarshini Tram Nguyen ryan McGovern Andrew Kim Adam j.Griebel Paulette Clancy Timothy P.Weihs Department of Materials Science and Engineering Johns Hopkins University3400 N Charles StBaltimore21218MDU.S.A Hopkins Extreme Materials Institute Johns Hopkins University3400 N Charles StBaltimore21218MDU.S.A Department of Chemical and Biomolecular Engineering Johns Hopkins University3400 N Charles StBaltimore21218MDU.S.A Translational Tissue Engineering Center Johns Hopkins School of Medicine400 N BroadwayBaltimore21231MDU.S.A Department of Biomedical Engineering Johns Hopkins University3400 N Charles StBaltimore21218MDU.S.A Research and Development Fort Wayne Metals Research ProductsLLC9609 Ardmore AveFort Wayne46809INU.S.A Department of Mechanical Engineering Johns Hopkins University3400 N Charles StBaltimore21218MDU.S.A

Magnesium alloys are emerging as promising alternatives to traditional orthopedic implant materials thanks to their biodegradability,biocompatibility,and impressive mechanical ***,their rapid in-vivo degradation presents challenges,notably in upholding mechanical integrity over *** study investigates the impact of high-temperature thermal processing on the mechanical and degradation attributes of a lean Mg-Zn-Ca-Mn alloy,*** rapid,cost-efficient characterization methods like X-ray diffraction and optical microscopy,we swiftly examine microstructural changes post-thermal *** Pearson correlation coefficient analysis,we unveil the relationship between microstructural properties and critical targets(properties):hardness and corrosion ***,leveraging the least absolute shrinkage and selection operator(LASSO),we pinpoint the dominant microstructural factors among closely correlated *** findings underscore the significant role of grain size refinement in strengthening and the predominance of the ternary Ca_(2)Mg_(6)Zn_(3)phase in corrosion *** suggests that achieving an optimal blend of strength and corrosion resistance is attainable through fine grains and reduced concentration of ternary *** thorough investigation furnishes valuable insights into the intricate interplay of processing,structure,and properties in magnesium alloys,thereby advancing the development of superior biodegradable implant materials.

关键词： Magnesium alloys Machine learning Corrosion Mechanical properties Rapid characterization

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Opposite latitudinal gradients for species richness and phylogenetic diversity of endemic snakes in the Atlantic Forest

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Current Zoology 2024年第4期70卷 522-530页

作者： j.séThales da Motta Portillo j.suéanderson Rēgo Azevedo Fausto Erritto Barbo Ricardo j.Sawaya Programa de Pos-Graduacao em Biologia Animal Instituto de BiocienciasLetras e Ciencias ExatasUniversidade Estadual Paulista"Julio de Mesquita Filho"Rua Cristovao Colombo2265Sao Josédo Rio PretoSao Paulo 15054-000Brazil Programa de Colecoes Cientificas Biologicas Coordenagao de BiodiversidadeInstituto Nacional de Pesquisas da AmazoniaAvenida AndréAraujo2936ManausAmazonas 69067-375Brazil Gothenburg Global Biodiversity Centre University of GothenburgBox 461GothenburgVastra Gotaland SE-40530Sweden Instituto Federal de Educacao Ciencia e Tecnologia de Minas GeraisRodovia Machado-Paraguacukm 3MachadoMinas Gerais 37750-000Rraizil Centro de Ciencias Naturais e Humanas UniversidadeFederaldo ABCRua Arcturus03Sao Bernardo do CampoSao Paulo09606-070Brazil

The decrease in species richness toward higher latitudes is an expected biogeographical *** pattern could be related to particular envi-ronmental constraints and the evolutionary history of ***,species richness does not fully represent the evolutionary history of the clades behind their *** diversity better clarifies the role of historical factors in biogeographical *** analyzed envi-ronmental and historical drivers related to latitudinal variation in species richness and phylogenetic diversity of Atlantic Forest endemic *** implemented species distribution models,from voucherbased locality points,to map the snake ranges and *** used generalized additive mixed models to evaluate the relationships among the diversity metrics and area,topographical roughness,and past climate change velocity since the Last Maximum Glacial in the Atlantic Forest latitudinal *** to the expected general pattern,species richness was higher toward higher latitudes,being positively related to past climatic *** richness also increased with total area and higher topographical *** diversity,on the other hand,showed opposite relationships related to the same *** diversity increased with lower climatic stability in lower ***,dimensions of diversity were affected in different ways by historical and environmental constraints in this unique and threatened biodiversity hotspot.

关键词： biodiversity latitudinal gradient neotropical region phylogenetic diversity serpents species richness.

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Exploring a targeted approach for public health capacity restrictions during COVID-19 using a new computational model

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Infectious Disease Modelling 2024年第1期9卷 234-244页

作者： Ashley N.Micuda Mark R.anderson Irina Babayan Erin Bolger Logan Cantin Gillian Groth Ry Pressman-Cyna Charlotte Z.Reed Noah j.Rowe Mehdi Shafiee Benj.min Tam Marie C.Vidal Tianai Ye ryan D.Martin Department of Physics Engineering Physics&AstronomyQueen's UniversityKingstonONCanada Department of Medical Biophysics Western UniversityLondonONCanada Department of Mathematics and Statistics Queen's UniversityKingstonONCanada Department of Biology Queen's UniversityKingstonONCanada Department of Electrical and Computer Engineering Nazarbayev UniversityNur-SultanKazakhstan Energetic Cosmos Laboratory Nazarbayev UniversityNur-SultanKazakhstan School of Computing Queen's UniversityKingstonONCanada Department of Biomedical and Molecular Sciences Queen's UniversityKingstonONCanada Department of Physics University of OxfordOxfordUnited Kingdom Department of Physics Stanford UniversityStanfordCAUnited States

This work introduces the Queen's University Agent-Based Outbreak Outcome Model(QUABOOM).This tool is an agent-based Monte Carlo simulation for modelling epidemics and informing public health *** illustrate the use of the model by examining capacity restrictions during a *** find that public health measures should focus on the few locations where many people interact,such as grocery stores,rather than the many locations where few people interact,such as small *** also discuss a case where the results of the simulation can be scaled to larger population sizes,thereby improving computational efficiency.

关键词： Monte-carlo Agent-based epidemic modelling COVID-19 Small business capacity restrictions Public health Basic reproductive number

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Characterizing obj.ctive and self-report habitual physical activity and sedentary time in outpatients with an acquired brain inj.ry

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Sports Medicine and Health Science 2024年第4期6卷 338-343页

作者： Liam P.Pellerine Katerina Miller ryan j.Frayne Myles W.O'Brien Division of Kinesiology School of Health and Human PerformanceFaculty of HealthDalhousie UniversityHalifaxNova ScotiaCanada Acquired Brain Inj.ry NeuroCommons Nova Scotia Health AuthorityHalifaxNova ScotiaCanada School of Physiotherapy(Faculty of Health)&Department of Medicine(Faculty of Medicine) Dalhousie UniversityHalifaxNova ScotiaCanada Geriatric Medicine Research Dalhousie University&Nova Scotia HealthHalifaxNova ScotiaCanada Centre de Formation Medicale Du Nouveau-Brunswick New Brunswick&Department of MedicineUniversite de SherbrookeSherbrookeQuebecCanada

Outpatients with an acquired brain inj.ry(ABI)experience physical,mental,and social *** can be classified into two subgroups based on mechanism of inj.ry:mild traumatic brain inj.ry(mTBI;e.g.,concussion)and other ABI(e.g.,stroke,brain aneurysm,encephalitis).Our understanding of habitual activity levels within ABI populations is limited because they are often collected using self-report *** purpose of this study was to,1)describe the habitual activity levels of outpatients with ABI using obj.ctive and self-report monitoring,and 2)compare the activity levels of outpatients with mTBI *** *** outpatients with other ABI(mean±standard deviation:[58±13]years,9 females)and 12 outpatients with mTBI([48±11]years,9 females)wore a thigh-worn activPAL 24 h/day(h/day)for *** with ABI averaged(6.0±2.3)h/day of upright time,(10.6±2.2)h/day of sedentary time,(5.6±2.7)h/day in prolonged sedentary bouts>1 h,(5960±3037)steps/day,and(11±13)minutes/day(min/day)of moderate-vigorous physical activity(MVPA).There were no differences between activPAL-derived upright,sedentary,prolonged sedentary time,and physical activity between the mTBI and other ABI groups(all,p>0.31).Outpatients with ABI overestimated their MVPA levels(t138 min/week)and underestimated sedentary time(-4.3 h/day)compared to self-report(all,pj.ctively exhibit highly inactive and sedentary *** habitual movement behaviours of our sample did not differ by mechanism of inj.ry(i.e.,mTBI versus other ABI).Targeting reductions in obj.ctively measured sedentary time are needed to progressively improve the habitual movement behaviours of outpatients with ABI.

关键词： Accelerometry Stroke Brain aneurysm Encephalitis Mild traumatic brain inj.ry Rehabilitation

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Interleukin-10 suppresses lipid metabolism-mediated intestinal inflammation

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Life Metabolism 2024年第3期3卷 3-5页

作者： Tristram A.j.ryan Ivan Zanoni Division of Immunology and Division of Gastroenterology Boston Children’s Hospital and Harvard Medical SchoolBostonMA 02115United States

In a recent paper published in Nature,York et *** that the anti-inflammatory cytokine interleukin(IL)-10 regulates sphingolipid metabolism to limit NF-κB-mediated *** of Il10 in mice,or genetic mutation of IL10 in humans,predisposes to inflammatory bowel disease,which may be overcome by restoring homeostatic sphingolipid metabolism.

关键词： metabolism inflammation

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Advancing Evaluation of Microplastics Thresholds to Inform Water Treatment Needs and Risks

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Environment & Health 2024年第7期2卷 441-452页

作者： Omar S.Chowdhury Philip j.Schmidt William B.anderson Monica B.Emelko Department of Civil and Environmental Engineering University of Waterloo200 University Avenue WestWaterlooON N2L 3G1Canada

Although human health impacts of microplastics are not well understood,concern regarding chemical contaminants retained on or within them is *** water providers are increasingly asked about these risks,but strategies for evaluating them and the extent of treatment needed to manage them are currently *** can potentially induce health effects if the concentration of contaminants adsorbed to them exceeds predetermined drinking water guidelines(e.g.,Maximum Contaminant Levels).The risk posed by microplastics due to adsorbed contaminants is difficult to determine,but a worst-case scenario can be evaluated by using adsorption ***,a“Threshold Microplastics Concentration”(TMC)framework is developed to evaluate whether waterborne microplastic concentrations can potentially result in the intake of regulated contaminants on/in microplastics at levels of human health concern and identify treatment targets for managing associated health *** the TMC does not indicate an immediate health risk;it informs the need for detailed risk assessment or further treatment evaluation to ensure particle removal targets are ***,the TMC concept and framework provide an updateable,science-based screening tool to determine if there is a need for detailed risk assessment or treatment modification due to waterborne microplastics in supplies used for potable water production.

关键词： drinking water treatment chemical contaminants adsorption capacity risk management maximum contaminant level

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The secondary inj.ry cascade after spinal cord inj.ry:an analysis of local cytokine/chemokine regulation

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Neural Regeneration Research 2024年第6期19卷 1308-1317页

作者： Daniel j.Hellenbrand Charles M.Quinn Zachariah j.Piper ryan T.Elder Raveena R.Mishra Taylor L.Marti Phoebe M.Omuro Rylie M.Roddick j.e Sung Lee William L.Murphy Amgad S.Hanna Department of Neurosurgery University of Wisconsin-Madison School of Medicine and Public HealthMadisonWIUSA Department of Biomedical Engineering University of Wisconsin-MadisonMadisonWIUSA Department of Orthopedics and Rehabilitation University of Wisconsin-MadisonMadisonWIUSA Department of Materials Science and Engineering University of Wisconsin-MadisonMadisonWIUSA Forward BIO Institute University of Wisconsin-MadisonMadisonWIUSA

After spinal cord inj.ry,there is an extensive infiltration of immune cells,which exacerbates the inj.ry and leads to further neural ***,a maj.r aim of current research involves targeting the immune response as a treatment for spinal cord *** much research has been performed analyzing the complex inflammatory process following spinal cord inj.ry,there remain maj.r discrepancies within previous literature regarding the timeline of local cytokine *** obj.ctives of this study were to establish an overview of the timeline of cytokine regulation for 2 weeks after spinal cord inj.ry,identify sexual dimorphisms in terms of cytokine levels,and determine local cytokines that significantly change based on the severity of spinal cord *** were inflicted with either a mild contusion,moderate contusion,severe contusion,or complete transection,7 mm of spinal cord centered on the inj.ry was harvested at varying times post-inj.ry,and tissue homogenates were analyzed with a Cytokine/Chemokine 27-Plex *** demonstrated pro-inflammatory cytokines including tumor necrosis factorα,interleukin-1β,and interleukin-6 were all upregulated after spinal cord inj.ry,but returned to uninj.red levels within approximately 24 hours post-inj.ry,while chemokines including monocyte chemoattractant protein-1 remained upregulated for days *** contrast,several anti-inflammatory cytokines and growth factors including interleukin-10 and vascular endothelial growth factor were downregulated by 7 days *** spinal cord inj.ry,tissue inhibitor of metalloproteinase-1,which specifically affects astrocytes involved in glial scar development,increased more than all other cytokines tested,reaching 26.9-fold higher than uninj.red *** a mild inj.ry,11 cytokines demonstrated sexual dimorphisms;however,after a severe contusion only leptin levels were different between female and male *** conclusion,pro-inflammatory cytokines in

关键词： astrocytes chemokines cytokines inflammation macrophages microglia secondary damage spinal cord inj.ry

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Lipid nanoparticles deliver mRNA to the blood-brain barrier

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Nano Research 2024年第10期17卷 9126-9134页

作者： Yanina Kuzminich Avraham Shakked Randi Calkins Sebastian Rudden Camille j.nes j.ssie Doan Bora j.ng Elisa Schrader Echeverri ryan Zenhausern Liming Lian David Loughrey Hannah E.Peck Rachelle Wiese Dorothy Koveal Philip j.Santangelo j.mes E.Dahlman George C.Woodruff School of Mechanical Engineering Georgia Institute of TechnologyAtlantaGA 30332USA Parker H.Petit Institute for Bioengineering and Biosciences Georgia Institute of TechnologyAtlantaGA 30332USA Wallace H.Coulter Department of Biomedical Engineering Emory University School of Medicine and Georgia Institute of TechnologyAtlantaGA 30332USA

Lipid nanoparticles(LNPs)have delivered RNA to hepatocytes in patients after intravenous *** clinical data support efforts to design LNPs that transfect cells in the central nervous system(CNS).However,delivery to the CNS has been difficult,in large part because quantifying on-target delivery alongside common off-target cell types in adult mice remains *** we report methods to isolate different cell types from the CNS,and subsequently present mRNA delivery readouts using a liver-detargeted *** data suggest that LNPs without targeting ligands can transfect cerebral endothelial cells in mice after intravenous *** the difficulty of crossing the blood-brain barrier,they also underscore the value of quantifying delivery in the CNS with cell-type resolution instead of whole-tissue resolution.

关键词： lipid nanoparticle mRNA nanomedicine central nervous system blood-brain barrier

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