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Promises and pitfalls of targeted agents in chronic lymphocytic leukemia

Cancer Drug Resistance 2020年第3期3卷 415-444页

作者： Thomas E.Lew Mary Ann Anderson john f.seymour Department of Clinical Haematology The Royal Melbourne Hospital and Peter MacCallum Cancer CentreParkville 3050Australia. Blood Cells and Blood Cancer Division Walter and Eliza Hall Institute of Medical ResearchParkville 3050Australia. faculty of Medicine Dentistry and Health SciencesThe University of MelbourneParkville 3050Australia.

Targeted agents have significantly improved outcomes for patients with chronic lymphocytic leukemia,particularly high-risk subgroups for whom chemoimmunotherapy previously offered limited efficacy.Two classes of agent in particular,the Bruton tyrosine kinase inhibitors(e.g.,ibrutinib)and the B-cell lymphoma 2 inhibitor,venetoclax,induce high response rates and durable remissions in the relapsed/refractory and frontline settings.However,maturing clinical data have revealed promises and pitfalls for both agents.These drugs induce remissions and disease control in the majority of patients,often in situations where modest efficacy would be expected with traditional chemoimmunotherapy approaches.Unfortunately,in the relapsed and refractory setting,both agents appear to be associated with an inevitable risk of disease relapse and progression.Emerging patterns of resistance are being described for both agents but a common theme appears to be multiple sub-clonal drivers of disease progression.Understanding these mechanisms and developing effective and safe methods to circumvent the emergence of resistance will determine the longer-term utility of these agents to improve patients’quality and length of life.Rational drug combinations,optimised scheduling and sequencing of therapy will likely hold the key to achieving these important goals.

关键词： Chronic lymphocytic leukemia drug resistance venetoclax B-cell lymphoma 2 ibrutinib bruton tyrosine kinase idelalisib phosphatidylinositol 3-kinase

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Study of hybrid nanofluid flow in a stationary cone-disk system with temperature-dependent fluid properties

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Applied Mathematics and Mechanics(English Edition) 2024年第4期45卷 677-694页

作者： A.S.john B.MAHANTHESH G.LORENZINI Center for Mathematical Needs Department of MathematicsCHRIST(Deemed to be University)Karnataka 560029India School of Mathematical and Statistical Sciences The University of Texas Rio Grande ValleyTexas 78539U.S.A. Department of Engineering and Architecture University of ParmaParma 43124Italy

Cone-disk systems find frequent use such as conical diffusers,medical devices,various rheometric,and viscosimetry applications.In this study,we investigate the three-dimensional flow of a water-based Ag-Mg O hybrid nanofluid in a static cone-disk system while considering temperature-dependent fluid properties.How the variable fluid properties affect the dynamics and heat transfer features is studied by Reynolds's linearized model for variable viscosity and Chiam's model for variable thermal conductivity.The single-phase nanofluid model is utilized to describe convective heat transfer in hybrid nanofluids,incorporating the experimental data.This model is developed as a coupled system of convective-diffusion equations,encompassing the conservation of momentum and the conservation of thermal energy,in conjunction with an incompressibility condition.A self-similar model is developed by the Lie-group scaling transformations,and the subsequent self-similar equations are then solved numerically.The influence of variable fluid parameters on both swirling and non-swirling flow cases is analyzed.Additionally,the Nusselt number for the disk surface is calculated.It is found that an increase in the temperature-dependent viscosity parameter enhances heat transfer characteristics in the static cone-disk system,while the thermal conductivity parameter has the opposite effect.

关键词： hybrid nanofluid cone-disk system laminar flow variable fluid property Nusselt number

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New markers of fibrosis in hepatitis C:A step towards the Holy Grail?

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World Journal of Hepatology 2024年第2期16卷 112-114页

作者： Konstantinos john Dabos Department of Hepatology St Hohn's HospitalLivingston EH546PPWest LothianUnited Kingdom

In the present issue of the World Journal of Hepatology,ferrassi et al examine the problem of liver fibrosis staging in chronic hepatitis C.They identify novel biomarkers in an effort to predict accurate fibrosis staging with the aid of the metabolome of Hepatitis C patients.Overall I think ferrassi et al took a different approach in identifying fibrosis biomarkers,by looking at the patients’metabolome.Their biomarkers clearly separate patients from controls.They can also separate out,patients with minimal fibrosis(f0-f1 stage)and patients with cirrhosis(f4 stage).Obviously,if these biomarkers were to be widely used,tests for all the important metabolites would need to be readily available for use in hospitals or outpatient setting and that may prove difficult and above all,costly.Nevertheless,this step could eventually lead to a metabolomic approach for novel biomarkers of fibrosis.Obviously,it would need to be validated,but could represent a step towards the Holy Grail of Hepatology.

关键词： Hepatitis C metabolomics fibrosis Non invasive markers Metavir

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What diameter?What height?Influence of measures of average tree size on area-based allometric volume relationships

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forest Ecosystems 2024年第1期11卷 100-109页

作者： Yilin Wang john A.Kershaw Mark J.Ducey Yuan Sun James B.McCarter Integrated forest Mensuration and Systems Analysis Laboratory Faculty of Forestry and Environmental ManagementUniversity of New BrunswickFrederictonNBCanada Department of Natural Resources and the Environment University of New HampshireDurhamNHUSA College of forestry Nanjing Forestry UniversityNanjing210037China Scientific Programmer RayonierYuleeFLUSA

Volume is an important attribute used in many forest management decisions.Data from 83 fixed-area plots located in central New Brunswick,Canada,are used to examine how different measures of stand-level diameter and height influence volume prediction using a stand-level variant of Honer's(1967)volume equation.When density was included in the models(Volume=f(Diameter,Height,Density))choice of diameter measure was more important than choice of height measure.When density was not included(Volume=f(Diameter,Height)),the opposite was true.for models with density included,moment-based estimators of stand diameter and height performed better than all other measures.for models without density,largest tree estimators of stand diameter and height performed better than other measures.The overall best equation used quadratic mean diameter,Lorey's height,and density(root mean square error=5.26 m^3·ha^(-1);1.9%relative error).The best equation without density used mean diameter of the largest trees needed to calculate a stand density index of 400 and the mean height of the tallest 400 trees per ha(root mean square error=32.08 m^(3)·ha^(-1);11.8%relative error).The results of this study have some important implications for height subsampling and LiDAR-derived forest inventory analyses.

关键词： Allometric relationships Stand structure Volume estimation Stand-level attributes

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Orbits inside fatou sets

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Acta Mathematica Sinica,English Series 2024年

作者： john Erik fORN?SS Mi HU Department of Mathematical Sciences Norwegian University of Science and Technology Department of Mathematics University of Oslo Department of Mathematical Physical and Computer Sciences University of Parma

In this paper,we investigate the precise behavior of orbits inside attracting basins of rational functions on P1and entire functions f in C.Let R（z） be a rational function on P1,A（p） be the basin of attraction of an attracting fixed point p of R,and?i（i=1,2,···） be the connected components of A（p）.Assume?1contains p.Let p0∈?1close to p.Then there exists a constant C so that for any z0∈?i,there is a point q∈∪kR-k（p0）,k≥0 so that the Kobayashi distance d?i（z0,q）≤C.for entire functions f,we generally can not have similar results as for rational functions.However,if f has finitely many critical points,then similar results hold.

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Assessment of the performance of the TOPGNSS and ANN-MB antennas for ionospheric measurements using low-cost u-blox GNSS receivers

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Geodesy and Geodynamics 2024年第3期15卷 291-301页

作者： Daniel Okoh Aderonke Obafaye Oluwakemi Dare-Idowu Babatunde Rabiu Anton Kashcheyev Claudio Cesaroni john Bosco Habarulema Bruno Nava United Nations African Regional Centre for Space Science and Technology Education-English(UN-ARCSSTE-E) Obafemi Awolowo University CampusIle IfeNigeria National Institute for Geophysics and Volcanology(INGV) 00143 RomeItaly Institute for Space Science and Engineering African University of Science and TechnologyAbujaNigeria University of New Brunswick FrederictonCanada South African National Space Agency(SANSA) P.O Box 32Hermanus 7200South Africa Department of Physics and Electronics Rhodes University6140 MakhandaSouth Africa The Abdus Salam International Centre for Theoretical Physics Strada Costiera11I-34151 TriesteItaly

Low-cost GNSS receivers have recently been gaining reliability as good candidates for ionospheric studies. In line with these gains are genuine concerns about improving the performance of these receivers. In this work, we present a comprehensive investigation of the performances of two antennas(the u-blox ANN-MB and the TOPGNSS TOP-106) used on a low-cost GNSS receiver known as the u-blox ZED-f9P. The two antennas were installed on two identical and co-located u-blox receivers. Data used from both receivers cover the period from January to June 2022. Results from the study indicate that the signal strengths are dominantly greater for the receiver with the TOPGNSS antenna than for the receiver with the ANN-MB antenna, implying that the TOPGNSS antenna is better than the ANN-MB antenna in terms of providing greater signal strengths. Summarily, the TOPGNSS antenna also performed better in minimizing the occurrence of cycle slips on phase TEC measurements. There are no conspicuous differences between the variances(computed as 5-min standard deviations) of phase TEC measurements for the two antennas, except for a period around May-June when the TOPGNSS gave a better performance in terms of minimizing the variances in phase TEC. Remarkably, the ANN-MB antenna gave a better performance than the TOPGNSS antenna in terms of minimizing the variances in pseudorange TEC for some satellite observations. for precise horizontal(North and East) positioning, the receiver with the TOPGNSS antenna gave better results, while the receiver with the ANN-MB antenna gave better vertical(Up) positioning. The errors for the receivers of both antennas are typically within about 5 m(the monthly mean was usually smaller than 1 m) in the horizontal direction and within about 10 m(the monthly mean was usually smaller than 4 m) in the vertical direction.

关键词： GNSS Ionosphere Low-cost Antenna TOPGNSS U-blox

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The risk of prostate cancer on incidental finding of an avid prostate uptake on 2-deoxy-2-[^(18)f]fluoro-D-glucose positron emission tomography/computed tomography for non-prostate cancer-related pathology:A single centre retrospective study

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Asian Journal of Urology 2024年第1期11卷 33-41页

作者： Anthony franklin Troy Gianduzzo Boon Kua David Wong Louise McEwan James Walters Rachel Esler Matthew J.Roberts Geoff Coughlina john W.Yaxley Department of Urology The Wesley HospitalBrisbaneQLDAustralia Wesley Medical Research BrisbaneQLDAustralia School of Medicine The University of QueenslandBrisbaneQLDAustralia Department of Radiology Wesley Medical ImagingBrisbaneQLDAustralia Department of Urology Royal Brisbane and Women's HospitalBrisbaneQLDAustralia

Objective:To review the risk of prostate cancer(PCa)in men with incidentally reported increased intraprostatic uptake at 2-deoxy-2-[18f]fluoro-d-glucose positron emission tomography/computed tomography(18f-fDG PET/CT)ordered at Department of Urology,The Wesley Hospital,Brisbane,QLD,Australia for non-PCa related pathology.Methods:Retrospective analysis of consecutive men between August 2014 and August 2019 presenting to a single institution for 18f-fDG PET/CT for non-prostate related conditions was conducted.Men were classified as benign,indeterminate,or malignant depending of the results of prostate-specific antigen(PSA),PSA velocity,biopsy histopathology,and three-Tesla(3 T)multiparametric MRI(mpMRI)Prostate Imaging Reporting and Data System score,or gallium-68-prostate-specific membrane antigen(68Ga-PSMA)PET/CT results.Results:Three percent(273/9122)of men demonstrated 18f-fDG avidity within the prostate.Eighty-five percent(231/273)were further investigated,including with PSA tests(227/231,98.3%),3 T mpMRI(68/231,29.4%),68Ga-PSMA PET/CT(33/231,14.3%),and prostate biopsy(57/231,24.7%).Results were considered benign in 130/231(56.3%),indeterminate in 31/231(13.4%),and malignant in 70/231(30.3%).PCa was identified in 51/57(89.5%)of the men who proceeded to biopsy,including 26/27(96.3%)men with Prostate Imaging Reporting and Data System scores 4-5 mpMRI and six men with a positive 68Ga-PSMA PET/CT.The most common Gleason score on biopsy was greater than or equal to 4+5(14/51,27.5%).68Ga-PSMA PET/CT was concordant with the 18f-fDG findings in 26/33(78.8%).All 13 men with a positive concordant 18f-fDG,3 T mpMRI,and 68Ga-PSMA PET/CT had PCa on biopsy.There was no statistically significant difference in the 18f-fDG maximum standardized uptake value between the benign or malignant groups(5.7 vs.6.1;p=0.580).Conclusion:In this study,after an incidental finding of an avid intraprostatic lesion on 18f-fDG PET/CT,70 of the 231 cases(30.3%;0.8%of the entire cohort)had results consistent with PCa,most commonly as Gleason scor

关键词： Prostatecancer Positionemission tomography Multiparametric magneticresonance imaging Prostatebiopsy

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Dock-able linear and homodetic di, tri, tetra and pentapeptide library from canonical amino acids: SARS-CoV-2 Mpro as a case study

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Journal of Pharmaceutical Analysis 2023年第5期13卷 523-534页

作者： Sarfraz Ahmad Muhammad Usman Mirza john f.Trant Department of Chemistry and Biochemistry University of WindsorWindsor N9B 3P4OntarioCanada Binary Star Research Services LaSalle N9J 3X8OntarioCanada

Peptide-based therapeutics are increasingly pushing to the forefront of biomedicine with their promise of high specificity and low toxicity.Although noncanonical residues can always be used,employing only the natural 20 residues restricts the chemical space to a finite dimension allowing for comprehensive in silico screening.Towards this goal,the dataset comprising all possible di-,tri-,and tetra-peptide combinations of the canonical residues has been previously reported.However,with increasing computational power,the comprehensive set of pentapeptides is now also feasible for screening as the comprehensive set of cyclic peptides comprising four or five residues.Here,we provide both the complete and prefiltered libraries of all di-,tri-,tetra-,and penta-peptide sequences from 20 canonical amino acids and their homodetic(N-to-C-terminal)cyclic homologues.The fASTA,simplified molecular-input line-entry system(SMILES),and structure-data file(SDf)-three dimension(3D)libraries can be readily used for screening against protein targets.We also provide a simple method and tool for conducting identity-based filtering.Access to this dataset will accelerate small peptide screening workflows and encourage their use in drug discovery campaigns.As a case study,the developed library was screened against severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)main protease to identify potential small peptide inhibitors.

关键词： Dipeptides Tripeptides Tetrapeptides Pentapeptides N-to-C-terminal cyclic peptides Peptide library

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Synchronous formation of the‘forearc’Bay of Islands ophiolite and its basal high-temperature metamorphic sole constrained by U-Pb zircon ages

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Geoscience frontiers 2023年第6期14卷 234-272页

作者： Weiyao Yan john f.Casey Department of Earth and Atmospheric Sciences University of HoustonHoustonTXUSA

The welded metamorphic sole at the base of the Bay of Islands Ophiolite Complex(BOIC)in the Northern Appalachians of Newfoundland shows a typical inverted pressure-temperature(P-T)metamorphic gradient from HT-MP granulite to LT-LP greenschist facies.It incorporates mafic volcanic/plutonic protoliths mixed with pelagic,hemi-pelagic and coarser epiclastic sedimentary protoliths.New LA-ICP-MS U–Pb concordia ages,trace elements,and Ti-in-zircon geothermometry for -250 zircon analyses from three metabasites of the upper HT sole amphibolites with N-MORB-like protoliths are reported.Two samples collected within meters of the ophiolite peridotite-sole contact of the Blow Me Down Mountain and North Arm Mountain massifs yielded the oldest comparable concordia ages of 487.7±2.6 Ma and 489.1±3.1 Ma,respectively,that are both within error of the igneous age of 488.3±1.5 Ma of the directly overlying BOIC ophiolite,which formed at a supra-subduction zone(SSZ)forearc spreading center.A third slightly younger age of 484.2±2.4 Ma was obtained for an upper HT amphibolite sample with similar phase assemblages but collected30 m below the peridotite contact of the Table Mountain massif.Zircon crystals analyzed have similar size and morphologies,subparallel rare earth element(REE)variation patterns,and steep heavy REE-enrichments((Lu/Gd)_(cn)>20),significant positive Ce anomalies(dominantly>5)and slight positive to dominantly negative Eu anomalies(1.2–0.4).Zircon shows Th/U mean values of 0.37–0.48 with little to no rim to core variation.Minimum Ti-in-zircon mean crystallization temperatures range from764–787℃.These neocrystallized zircon crystals appear to be derived from thin leucosomes within the three amphibolites.Two other samples also from the upper HT sole show evidence of inherited detrital zircon with core dates spanning the Cambrian Notre Dame Arc through older Laurentian-like basement and rift age ranges.Subcretion of the sole took place below a hot forearc asthenospheric wedge,that is,a consequence of the newly-formed BOI

关键词： Ophiolite metamorphic sole U-Pb zircon ages Hot subduction interface Supra-subduction forearc spreading center Arc-continent collision Taconic Orogeny

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Effect of L-theanine combined with geniposide on depression-like behavior induced by the chronic unpredictable mild stress(CUMS) in mice

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food Science and Human Wellness 2024年

作者： Qi-Ming Yu Yan Zhu Tao Jiang Ying Gao Nan Ling Na Wang john Shi Wei-Chun Pan Qi-Zhen Du Jun-feng Yin Tea Research Institute Chinese Academy of Agricultural Sciences Key Laboratory of Tea Biology and Resources Utilization Ministry of Agriculture College of food and Health Sciences Zhejiang A & f University Zhejiang Gongshang University Guelph food Research Center Agriculture and Agri-food Canada College of Public Health Guilin Medical University

Depression is a prevalent mental disorder with limited effective treatments， posing a significant global issue. This study explored L-theanine and geniposide， key components in "food-medicine homology" materials， to determine if their combination (TG) could alleviate depression-like behaviors and hippocampal neuronal damage in a chronic unpredictable mild stress (CUMS) mouse model. Male C57BL/6J mice were divided into control， CUMS model， and CUMS+TG groups with varying doses. The CUMS group displayed depression-like behaviors， including reduced activity and sucrose preference. TG treatment partially reversed these changes， significantly increasing antioxidant enzyme activities， decreasing pro-inflammatory cytokine levels， and improving neuromodulator levels. RNA-seq analysis identified the transthyretin (TTR) gene， upregulated in the model group but downregulated after TG treatment. TG treatment modulated intestinal microbiota composition compared to the CUMS group， including increased firmicutes， reduced Bacteroidetes and Prevotella， and variable changes in Bifidobacterium abundance. In conclusion， our study indicates that CUMS exposure upregulates stress hormones and TTR expression， associated with neuroinflammation， oxidative stress， monoamine depletion， depression-like behaviors， and intestinal microbiota dysbiosis. TG treatment alleviates these effects and modulates intestinal microbiota， suggesting L-theanine and geniposide’s potential as a novel depression therapy.

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