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MEK inhibition activates STAT signaling to increase breast cancer immunogenicity via MHC-I expression

Cancer Drug Resistance 2020年第3期3卷 603-612页

作者： Derek A.Franklin Jamaal l.James margaret l.axelrod Justin M.Balko Department of Medicine Vanderbilt University Medical CenterNashvilleTN 37232USA. Department of Pathology Microbiologyand ImmunologyVanderbilt University Medical CenterNashvilleTN 37232USA. Breast Cancer Research Program Vanderbilt University Medical CenterNashvilleTN 37232USA.

Aim:Immunotherapy and immune checkpoint inhibitors(ICI)have changed cancer care for many patients;however,breast cancers have exhibited minimal response to single agent ICI *** is a significant need to identify novel targets capable of increasing cancer cell immunogenicity and response to ICIs in breast *** activated protein kinase(MAPK)signaling is essential for many cellular processes but the relationship between MAPK signaling and cancer cell immunogenicity is less well *** reports suggest that MEK inhibition(MEKi)affects the tumor-immune microenvironment by altering the expression of interferon responsive PD-l1 and MHC-I through unknown ***:Using western blotting and flow cytometry,we sought to determine whether MEKi affects JAK-STAT signaling upstream of PD-l1 and MHC-I expression in a panel of mouse mammary cancer and triple negative breast cancer cell ***:The cell lines tested exhibited increased STAT activation in response to MEKi ***,MEKi-induced MHC-I and PD-l1 expression are dependent upon STAT1 in MMTV-Neu ***,MEKiinduced STAT activation and interferon-responsive protein expression are abrogated with ErbB-family inhibitor co-treatment in MMTV-Neu cells,suggesting ErbB receptor signaling dependence,but not in basal-like cell ***,analysis of basal-like breast cancer patient samples exhibited an inverse relationship between STAT1 and Ras/MAPK activation ***:These findings suggest that MAPK signaling and STAT activation are inversely related in both mouse and human mammary *** work also supports further study of MEKi to increase STAT signaling and potentially,immunotherapy responses through increased MHC-I and PD-l1 expression.

关键词： Mitogen activated protein kinase signaling immunogenicity MHC-I PD-l1

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A Griesbachian(Early Triassic) Mollusc Fauna from the Sidazhai Section, Southwest China, with Paleoecological Insights on the Proliferation of Genus Claraia(Bivalvia)

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Journal of Earth Science 2018年第4期29卷 794-805页

作者： Yunfei Huang Jinnan Tong margaret l Fraiser School of Geosciences Yangtze University State Key laboratory of Biogeology and Environmental Geology China University of Geosciences Department of Geosciences University of Wisconsin-Milwaukee

After the end-Permian mass extinction, genus Claraia （Bivalvia） was the most abundant and most noticeable fossil during the survival and recovery stage. However, the reasons for the proliferation of Claraia are still debated. This paper describes a new Griesbachian （Early Triassic） mollusc fauna from deep-water settings in South China in the aftermath of end-Permian mass extinction. This fauna yielded five bivalve species in two genera （Claraia griesbachi, C. wangi, C. stachei, C. radialis, and Promyalina putiatinensis） and two ammonoid species （Ophiceras sp. and Ussuridiscus sp.） and could be assigned to the Claraia wangi-C, griesbachi assemblage zone, indicating a Middle-late Griesbachian Age. The bivalves were dominated by Claraia griesbachi and were featured by articulated Claraia fossils. As Claraia was epibyssate, it was an excellent autochthonous fauna. While the shallow and deep marine water became dysoxic to anoxic globally, as indicated by recent studies of the early Early Triassic, we suggest the genus Claraia could tolerate dysoxic and/or anoxic conditions and its proliferation could be attributed to its physiological features which were adapted to the stressed environment. The wide distribution of Claraia was probably related to its planktonic larval stage. Where the larva of Claraia could have been transported by ocean flow and increased its potential for long-distance dispersal. In addition, Claraia was a significant disaster and opportunistic taxon during the Early Triassic based on observations in South China.

关键词： bivalves Claraia disaster species paleoecology Early Triassic.

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Associations between health-related fitness and patient-reported symptoms in newly diagnosed breast cancer patients

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Journal of Sport and Health Science 2024年第6期13卷 851-862页

作者： Ki-Yong An Fernanda Z.Arthuso Myriam Filion Spencer J.Allen Stephanie M.Ntoukas Gordon J.Bell Jessica McNeil Qinggang Wang margaret l.McNeely Jeff K.Vallance lin Yang S.Nicole Culos-Reed leanne Dickau John R.Mackey Christine M.Friedenreich Kerry S.Courneya Faculty of Kinesiology Sportand RecreationCollege of Health SciencesUniversity of AlbertaEdmonton T6G 2H9Canada Department of Kinesiology School of Health and Human SciencesUniversity of North Carolina at GreensboroGreensboroNC 27412USA Department of Cancer Epidemiology and Prevention Research Cancer Care AlbertaAlberta Health ServicesCalgary T2S 3C3Canada Faculty of Rehabilitation Medicine University of AlbertaEdmonton T6G 2H9Canada Faculty of Health Disciplines Athabasca UniversityAthabasca T9S 3A3Canada Department of Oncology Cumming School of MedicineUniversity of CalgaryCalgary T2N 4N1Canada Faculty of Kinesiology University of CalgaryCalgary T2N 1N4Canada Faculty of Medicine and Dentistry University of AlbertaEdmonton T6G 2H9Canada

Background:Newly diagnosed breast cancer patients experience symptoms that may affect their quality of life,treatment outcomes,and *** and managing breast cancer-related symptoms soon after diagnosis is *** purpose of this study was to investigate the associations between health-related fitness(HRF)and patient-reported symptoms in newly diagnosed breast cancer ***:This study utilized baseline data from the Alberta Moving Beyond Breast Cancer Cohort Study that were collected within 90 days of *** measures included peak cardiopulmonary fitness(peak volume of oxygen consumption(VO_(2peak))),maximal muscular strength and endurance,flexibility,and body *** measures included depression,sleep quality,and *** multivariable logistic regression was performed for ***:Of 1458 participants,51.5%reported poor sleep quality,26.5%reported significant fatigue,and 10.4%reported moderate *** multivariable-adjusted models,lower relative VO_(2peak)was independently associated with a greater likelihood of all symptom measures,including moderate depression(pleep quality(p=0.009),significant fatigue(p=0.008),any symptom(pltiple symptoms(pld associations with all symptom measures such that all 3 lower quartiles exhibited similar elevated risk compared to the highest *** strength of the threshold associations varied by the symptom measure with odds ratios ranging from-1.5 for poor sleep quality to-3.0 for moderate depression and multiple ***,lower relative upper body muscular endurance was also independently associated with fatigue in a dose-response manner(p=0.001),and higher body weight was independently associated with poor sleep quality in an inverted U pattern(p=0.021).Conclusion:Relative VO_(2peak)appears to be a critical HRF component associated with multiple patient-reported symptoms in newly diag

关键词： Breast cancer Fatigue Depression Sleep quality Cardiorespiratory fitness

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Epidemiology of age-related macular degeneration (AMD): associations with cardiovascular disease phenotypes and lipid factors

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Eye and Vision 2016年第1期3卷 263-282页

作者： Katie l.Pennington margaret M.DeAngelis Department of Ophthalmology John A.Moran Eye CenterUniversity of UtahSalt Lake CityUTUSA

Age-related macular degeneration(AMD)is the leading cause of irreversible blindness in adults over 50 years ***,epidemiological,and molecular studies are beginning to unravel the intricate mechanisms underlying this complex disease,which implicate the lipid-cholesterol pathway in the pathophysiology of disease development and *** of the genetic and environmental risk factors associated with AMD are also associated with other complex degenerative diseases of advanced age,including cardiovascular disease(CVD).In this review,we present epidemiological findings associating AMD with a variety of lipid pathway genes,cardiovascular phenotypes,and relevant environmental *** a number of studies showing significant associations between AMD and these lipid/cardiovascular factors,results have been mixed and as such the relationships among these factors and AMD remain *** is imperative that researchers not only tease out the various contributions of such factors to AMD development but also the connections between AMD and CVD to develop optimal precision medical care for aging adults.

关键词： Atherosclerosis Hypertension Retina Statins Stroke Cholesterol Obesity BMI Antioxidants Genetic association

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Structural sensitivity in HIV modeling: A case study of vaccination

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Infectious Disease Modelling 2017年第4期2卷 399-411页

作者： Cora l.Bernard margaret l.Brandeau Department of Management Science and Engineering Stanford UniversityStanfordCAUSA

Structural assumptions in infectious disease models,such as the choice of network or compartmental model type or the inclusion of different types of heterogeneity across individuals,might affect model predictions as much as or more than the choice of input *** explore the potential implications of structural assumptions on HIV model predictions and policy *** illustrate the value of inference robustness assessment through a case study of the effects of a hypothetical HIV vaccine in multiple population subgroups over eight related transmission models,which we sequentially modify to vary over two dimensions:parameter complexity(e.g.,the inclusion of age and HCV comorbidity)and contact/simulation complexity(e.g.,aggregated compartmental ***/disaggregated compartmental *** models).We find that estimates of HIV incidence reductions from network models and individual compartmental models vary,but those differences are overwhelmed by the differences in HIV incidence between such models and the aggregated compartmental models(which aggregate groups of individuals into compartments).Complexities such as age structure appear to buffer the effects of aggregation and increase the threshold of net vaccine effectiveness at which aggregated models begin to overestimate *** differences introduced by parameter complexity in estimated incidence reduction also translate into substantial differences in cost-effectiveness *** complexity does not appear to play a consistent role in differentiating the projections of network models.

关键词： HIV transmission HIV vaccine Structural sensitivity analysis Inference robustness assessment Network model Dynamic compartmental model

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Feeling Good and Functioning Well in Mathematics Education: Exploring Students' Conceptions of Mathematical Well-Being and Values

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ECNU Review of Education 2021年第2期4卷 349-375页

作者： Julia l.Hill margaret l.Kern Wee Tiong Seah Jan van Driel Melbourne Graduate School of Education The University of Melbourne

Purpose:The high incidenee of mathematics anxiety and disengagement in mathematics points to poor student well-being in many mathematics *** well-being may arise in part from poor alignment between student values and classroom ***,what student well-being is and how to support it within specific subjects is poorly understood,and intersection between students'values and well-being in mathematics education is *** article proposes a seven-dimensional framework of student well-being in mathematics education and examines alignment between well-being and ***/Approach/Methods:One hun dred n inetee n eighth-grade Australia n students responded to three opervended questions investigating their conceptions of mathematical wellbeing(MWB)and what they valued most when learning or doing *** were analyzed using a combined deductive/inductive thematic ***:Findings supported the MWB framework and con firmed an alig nment betwee n stude nts'values and well-being in mathematics ***/Value:Our study provides a framework for conceptualizing student well-being in mathematics education,points to areas that aim to improve student well-being,and highlights congruences and discordances between well-being and values.

关键词： Mathematical values mathematical well-being mathematics education student voice theoretical model valuing

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Hypoxia and its impact on the tumour microenvironment of gastroesophageal cancers

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World Journal of Gastrointestinal Oncology 2021年第5期13卷 312-331页

作者： Ross King Conall Hayes Claire l Donohoe margaret R Dunne Maria Davern Noel E Donlon Department of Surgery St.James’s Hospital CampusTrinity Translational Medicine InstituteDublin D8Ireland

The malfeasant role of the hypoxic tumour microenvironment(TME)in cancer progression was recognized decades ago but the exact mechanisms that augment the hallmarks of cancer and promote treatment resistance continue to be *** cancers(GOCs)represent a major burden of worldwide disease,responsible for the deaths of over 1 million people *** the impact of hypoxia in GOCs enables a better overall understanding of the disease pathogenesis while shining a light on novel therapeutic strategies and facilitating precision treatment approaches with the ultimate goal of improving outcomes for patients with these *** review discusses the underlying principles and processes of the hypoxic response and the effect of hypoxia in promoting the hallmarks of cancer in the context of *** focus on its bidirectional influence on inflammation and how it drives angiogenesis,innate and adaptive immune evasion,metastasis,and the reprogramming of cellular *** contribution of the hypoxic GOC TME to treatment resistance is examined and a brief overview of the pharmacodynamics of hypoxiatargeted therapeutics is *** principal methods that are used in measuring hypoxia and how they may enhance prognostication or provide rationale for individually tailored management in the case of tumours with significant hypoxic regions are also discussed.

关键词： Esophageal cancer Gastric cancer Tumor hypoxia Tumour microenvironment Gastroesophageal cancer

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Monoclonal antibody-based cancer therapies

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Chinese Journal of Chemical Engineering 2021年第2期34卷 301-307页

作者： Yingnan Si Arin l.Melkonian Keegan C.Curry Yuanxin Xu Maranda Tidwell Mingming liu Ahmed F.Zaky Xiaoguang(margaret)liu Department of Biomedical Engineering University of Alabama at Birmingham(UAB)1825 University BlvdBirminghamAL 35294USA Department of Medicine UAB17202nd Ave S.BirminghamAL 35294USA Chinese Medicine Hospital 98 Shengcheng StreetShouguang 262700China Department of Anesthesiology and Perioperative Medicine UAB62519th Street SouthBirminghamAL 35294USA

Targeted therapy has been widely demonstrated as an effective strategy to treat cancers,the leading cause of death in the *** minireview summarizes the technical platforms and methodologies utilized to develop and engineer therapeutic monoclonal antibodies and antibody-drug ***,the USA FDA approved monoclonal antibody(mAb)-based targeted therapies are *** the representative innovative chimeric,humanized and fully human anti-cancer antibodies and antibody-drug conjugates are ***,the past and predictive market trend of therapeutic antibodies is discussed.

关键词： Monoclonal antibody Antibody-drug conjugate Anti-cancer therapy Market

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A Solution to the C-Value Paradox and the Function of Junk DNA： The Genome Balance Hypothesis

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Molecular Plant 2015年第6期8卷 899-910页

作者： Michael Freeling Jie Xu margaret Woodhouse Damon lisch Department of Plant and Microbial Biology University of California Berkeley CA 94720 USA Maize Research Institute Sichuan Agricultural University Wenjiang Sichuan 611130 China Department of Botany and Plant Pathology Purdue University West Lafayette IN 47907 USA

The Genome Balance Hypothesis originated from a recent study that provided a mechanism for the phenom- enon of genome dominance in ancient polyploids： unique 24nt RNA coverage near genes is greater in genes on the recessive subgenome irrespective of differences in gene expression. 24nt RNAs target transposons. Transposon position effects are now hypothesized to balance the expression of networked genes and pro- vide spring-like tension between pericentromeric heterochromatin and microtubules. The balance （coordi- nation） of gene expression and centromere movement is under selection. Our hypothesis states that this balance can be maintained by many or few transposons about equally well. We explain known balanced dis- tributions of junk DNA within genomes and between subgenomes in allopolyploids （and our hypothesis passes ＂the onion test＂ for any so-called solution to the C-value paradox）, importantly, when the allotetra- ploid maize chromosomes delete redundant genes, their nearby transposons are also lost; this result is ex- plained if transposons near genes function. The Genome Balance Hypothesis is hypothetical because the position effect mechanisms implicated are not proved to apply to all junk DNA, and the continuous nature of the centromeric and gene position effects have not yet been studied as a single phenomenon.

关键词： junk DNA transposons C-value paradox gene regulation balance

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Demonstration of the test-retest reliability and sensitivity of the lower limb Functional Index-10 as a measure of functional recovery post burn injury:a cross-sectional repeated measures study design

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Burns & Trauma 2016年第2期4卷 153-159页

作者： margaret E.Ryland Tiffany l.Grisbrook Fiona M.Wood Michael Phillips Dale W.Edgar School of Physiotherapy and Exercise Science Curtin UniversityBentley 6102WAAustralia School of Physiotherapy and Exercise Science Curtin UniversityBentley 6102WAAustralia Fiona Wood Foundation of Western Australia Fiona Stanley Hospital11 Warren DriveMurdoch 6150WAAustralia Fiona Wood Foundation of Western Australia Fiona Stanley Hospital11 Warren DriveMurdoch 6150WAAustralia State Adult Burn Unit Fiona Stanley HospitalLevel 411 Warren Smith DriveMurdoch 6150WAAustralia Burn Injury Research Unit The University of Western AustraliaCrawley 6009WAAustralia Harry Perkins Institute of Medical Research The University of Western AustraliaCrawley 6009WAAustralia Fiona Wood Foundation of Western Australia Fiona Stanley Hospital11 Warren DriveMurdoch 6150WAAustralia State Adult Burn Unit Fiona Stanley HospitalLevel 411 Warren Smith DriveMurdoch 6150WAAustralia Burn Injury Research Unit The University of Western AustraliaCrawley 6009WAAustralia Burn Injury Research Node The University of Notre Dame Australia19 Mouat StFremantle 6160WAAustralia

Background:lower limb burns can significantly delay recovery of *** lower limb functional outcomes is challenging in the unique burn patient population and necessitates the use of reliable and valid *** aims of this study were to examine the test-retest reliability,sensitivity,and internal consistency of Sections 1 and 3 of the lower limb Functional Index-10(llFI-10)questionnaire for measuring functional ability in patients with lower limb burns over ***:Twenty-nine adult patients who had sustained a lower limb burn injury in the previous 12 months completed the test-retest procedure of the *** addition,the minimal detectable change(MDC)was calculated for Section 1 and 3 of the *** 1 is focused on the activity limitations experienced by patients with a lower limb disorder whereas Section 3 involves patients indicating their current percentage of pre-injury ***:Section 1 of the llFI-10 demonstrated excellent test-retest reliability(intra-class correlation coefficient(ICC)0.98,95%CI 0.96–0.99)whilst Section 3 demonstrated high test-retest reliability(ICC 0.88,95%CI 0.79–0.94).MDC scores for Sections 1 and 3 were 1.27 points and 30.22%,*** consistency was demonstrated with a significant negative association(rs=?0.83)between Sections 1 and 3 of the llFI-10(plusions:This study demonstrates that Section 1 and 3 of the llFI-10 are reliable for measuring functional ability in patients who have sustained lower limb burns in the previous 12 months,and furthermore,Section 1 is sensitive to changes in patient function over time.

关键词： Outcome measure Questionnaire lower limb function Internal consistency Minimal detectable change Burn

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