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Inhibition of focal adhesion kinase enhances antitumor response of radiation therapy in pancreatic cancer through CD8+ T cells

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Cancer Biology & Medicine 2021年第1期18卷 206-214页

作者： Arsen Osipov Alex B.Blair juliane liberto Jianxin Wang Keyu Li Brian Herbst Yao Xu Shiqi Li Nan Niu Rufiaat Rashid Ding Ding Yanan Liu Zaiqi Wang Christopher L.Wolfgang Richard A.Burkhart Daniel Laheru Lei Zheng The Sydney Kimmel Comprehensive Cancer Center Johns Hopkins University School of MedicineBaltimore 21287MDUSA The Pancreatic Cancer Precision Medicine Center of Excellence Program Johns Hopkins University School of MedicineBaltimore 21287MDUSA Department of Oncology Johns Hopkins University School of MedicineBaltimore 21287MDUSA Department of Surgery Johns Hopkins University School of MedicineBaltimore 21287MDUSA Inx Med Shanghai Shanghai 201202China

Objective:Pancreatic ductal adenocarcinoma(PDAC)is a deadly malignancy,due in large part to its resistance to conventional therapies,including radiotherapy(RT).Despite RT exerting a modest antitumor response,it has also been shown to promote an immunosuppressive tumor microenvironment.Previous studies demonstrated that focal adhesion kinase inhibitors(FAKi)in clinical development inhibit the infiltration of suppressive myeloid cells and T regulatory(T regs)cells,and subsequently enhance effector T cell infiltration.FAK inhibitors in clinical development have not been investigated in combination with RT in preclinical murine models or clinical studies.Thus,we investigated the impact of FAK inhibition on RT,its potential as an RT sensitizer and immunomodulator in a murine model of PDAC.Methods:We used a syngeneic orthotopic murine model to study the effect of FAKi on hypofractionated RT.Results:In this study we showed that IN10018,a small molecular FAKi,enhanced antitumor response to RT.Antitumor activity of the combination of FAKi and RT is T cell dependent.FAKi in combination with RT enhanced CD8+T cell infiltration significantly in comparison to the radiation or FAKi treatment alone(P<0.05).FAKi in combination with radiation inhibited the infiltration of granulocytes but enhanced the infiltration of macrophages and T regs in comparison with the radiation or FAKi treatment alone(P<0.01).Conclusions:These results support the clinical development of FAKi as a radiosensitizer for PDAC and combining FAKi with RT to prime the tumor microenvironment of PDAC for immunotherapy.

关键词： Focal adhesion protein-tyrosine kinases radiotherapy pancreatic neoplasms immunomodulation

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Predicting the activity of single atom catalysts

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Science China Chemistry 2024年

作者： Giovanni Di liberto Gianfranco Pacchioni Universitàdi Milano–Bicocca Dipartimento di Scienza dei Materiali

For a long time,the existence of single-atom catalysts(SACs),consisting of isolated atoms stabilized in a specific support,was not detected due to limitations in available characterization techniques.Over the past two decades,however,the ability to synthesize and characterize these systems has opened the way toward designing and testing a new class of potential catalysts[1].

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Curse and blessing:upregulation of oncogenes upon treatment with hypomethylating agents in myelodysplastic syndrome

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Signal Transduction and Targeted Therapy 2022年第9期7卷 3150-3151页

作者： juliane Grimm Mascha Binder Department of Internal Medicine IN Oncology/HematologyUniversity Hospital Halle(Saale)Halle(Saale)Germany

In a recently published study in The New England Journal of Medicine,Liu and colleagues were able to demonstrate that-apart from the antileukemic effects previously reported for hypomethylating agents(HMAs)-treatment with these drugs can also lead to demethylation and subsequent upregulation of oncogenes resulting in shorter survival in patients with myelo-dysplastic syndrome(MDS).

关键词： drugs myelo treatment

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A Few Questions about Single-Atom Catalysts:When Modeling Helps

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Accounts of Materials Research 2022年第9期3卷 986-995页

作者： Giovanni Di liberto Sergio Tosoni Luis A.Cipriano Gianfranco Pacchioni Dipartimento di Scienza dei Materiali Universitàdi Milano-Bicocca20125 MilanoItaly

CONSPECTUS:Single-atom catalysis(SAC)is a fascinating and rapidly growing field in heterogeneous catalysis.In less than 20 years,this has become one of the most widely investigated subjects by the catalytic community for various good reasons:the ability to synthesize active catalysts using a minimum amount of precious metals,the expected higher selectivity of SACs compared to assemblies of nanoparticles of variable sizes,and the fact that SACs represent a bridge between homogeneous and heterogeneous catalysis.

关键词： catalysis catalysis sizes

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Coding variants of the interleukin-11 receptor with reduced protein maturation show protease-dependent trans-signaling and transduce normal STAT3 signaling

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Genes & Diseases 2023年第2期10卷 373-376页

作者： Birte Kespohl Roland Hartig Yvonne Garbers juliane Lokau Christoph Garbers Department of Pathology Otto-von-Guericke-UniversityMedical Faculty39120 MagdeburgGermany Health Campus Immunology Infectiology and InflammationOtto-von-Guericke-University39120 MagdeburgGermany Center for Health and Medical Prevention (ChaMP) Otto-von-Guericke-University39120 MagdeburgGermany Institute for Molecular and Clinical Immunology and Service Unit Multiparametric Bioimaging and Cytometry Medical FacultyUniversity of Magdeburg39120 MagdeburgGermany Institute of Communication Management Faculty of ManagementCulture and Technology (Lingen Campus)Osnabrück University of Applied Sciences49809 LingenGermany

Interleukin-11(IL-11)is a member of the IL-6 family of cytokines.1 IL-11 activates its target cells via binding to the IL-11 receptor(IL-11R),which also exists in soluble forms generated by proteolytic cleavage(sIL-11R,required for trans-signaling).2 Formation of the IL-11/IL-11R complex leads to the recruitment and homodimerization of two molecules of the signal-transducingβ-receptor gp130,which then activates intracellular signaling cascades,including the Jak/STAT,PI3K and ERK pathways.

关键词： STAT3 PI3K gp130

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Liver stiffness in pregnant women with intrahepatic cholestasis of pregnancy:A case control study

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World Journal of Hepatology 2023年第7期15卷 904-913页

作者： juliane Nees Franziska J Ammon Johannes Mueller Herbert Fluhr Sebastian Mueller Department of Gynecology and Obstetrics University Hospital HeidelbergHeidelberg 69120Germany Center for Alcohol Research University Hospital HeidelbergHeidelberg 69120Germany Division of Obstetrics Department of Obstetrics and GynecologyMedical University of GrazGraz 8036Austria

BACKGROUND Intrahepatic cholestasis of pregnancy(ICP)is a rare but severe complication for both the mother and the unborn child.The diagnosis is primarily based on elevated serum levels of bile acids.In a large ICP cohort,we here study in detail liver stiffness(LS)using transient elastography(TE),now widely used to noninvasively screen for liver cirrhosis within minutes.AIM To specifically explore LS in a large cohort of women with ICP compared to a control group with uncomplicated pregnancy.METHODS LS and hepatic steatosis marker controlled attenuation parameter(CAP)were measured in 100 pregnant women with ICP using TE(Fibroscan,Echosens,Paris,France)between 2010 and 2020.In 17 cases,LS could be measured postpartum.450 women before and 38 women after delivery with uncomplicated pregnancy served as control group.Routine laboratory,levels of bile acids and apoptosis marker caspase-cleaved cytokeratin 18 fragment(M30)were also measured.RESULTS Women with ICP had significantly elevated transaminases but normal gammaglutamyl transferase(GGT).Mean LS was significantly increased at 7.3±3.0 kPa compared to the control group at 6.2±2.3 kPa(P<0.0001).Postpartum LS decreased significantly in both groups but was still higher in ICP(5.8±1.7 kPa vs 4.2±0.9 kPa,P<0.0001),respectively.In ICP,LS was highly significantly correlated with levels of bile acids and M30 but not transaminases.No correlation was seen with GGT that even increased significantly after delivery in the ICP group.Bile acids were mostly correlated with the liver apoptosis marker M30,LS and levels of alanine aminotransferase,aspartate aminotransferase,and bilirubin.In multivariate analysis,LS remained the sole parameter that was independently associated with elevated bile acids.CONCLUSION In conclusion,LS is significantly elevated in ICP which is most likely due to toxic bile acid accumulation and hepatocyte apoptosis.In association with conventional laboratory markers,LS provides additional non-invasive information to rapidly identify women at risk for ICP.

关键词： Intrahepatic cholestasis of pregnancy Transient elastography Bile acids Liver stiffness High risk pregnancy

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World Journal of Gastroenterology 2022年第12期28卷 1226-1238页

作者： Nadia Marascio Salvatore Rotundo Angela Quirino Giovanni Matera Maria Carla liberto Chiara Costa Alessandro Russo Enrico Maria Trecarichi Carlo Torti Department of Health Sciences Unit of MicrobiologyUniversity“Magna Graecia”of CatanzaroCatanzaro 88100Italy Department of Medical and Surgical Sciences Unit of Infectious and Tropical Diseases"Magna Graecia"University of CatanzaroCatanzaro 88100Italy

Hepatitis E virus(HEV)and hepatitis C virus(HCV)are both RNA viruses with a tropism for liver parenchyma but are also capable of extrahepatic manifestations.Hepatitis E is usually a viral acute fecal-oral transmitted and self-limiting disease presenting with malaise,jaundice,nausea and vomiting.Rarely,HEV causes a chronic infection in immunocompromised persons and severe fulminant hepatitis in pregnant women.Parenteral HCV infection is typically asymptomatic for decades until chronic complications,such as cirrhosis and cancer,occur.Despite being two very different viruses in terms of phylogenetic and clinical presentations,HEV and HCV show many similarities regarding possible transmission through organ transplantation and blood transfusion,pathogenesis(production of antinuclear antibodies and cryoglobulins)and response to treatment with some direct-acting antiviral drugs.Although both HEV and HCV are well studied individually,there is a lack of knowledge about coinfection and its consequences.The aim of this review is to analyze current literature by evaluating original articles and case reports and to hypothesize some interactions that can be useful for research and clinical practice.

关键词： Hepatitis C virus Hepatitis E virus Co-infection Genomic variability Extrahepatic diseases Vaccine

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Dual and opposing roles of EIN3 reveal a generation conflict during seed growth

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Molecular Plant 2022年第2期15卷 363-371页

作者： juliane Heydlauff Isil Erbasol Serbes Dieu Vo Yanbo Mao Sonja Gieseking Thomas Nakel Theresa Harten Ronny Völz Anja Hoffmann Rita GroΒ-Hardt University of Bremen Centre for Biomolecular Interactions Bremen(CBIB)Leobenerstrasse 528359 BremenGermany ZMBP University of TübingenAuf der Morgenstelle 3272076 TübingenGermany

Seed size critically affects grain yield of crops and hence represents a key breeding target.The develop-ment of embryo-nourishing endosperm is a key driver of seed expansion.We here report unexpected dual roles of the transcription factor EIN3 in regulating seed size.These EIN3 functions have remained largely undiscovered because they oppose each other.Capitalizing on the analysis of multiple ethylene biosynthesis mutants,we demonstrate that EIN3 represses endosperm and seed development in a pathway regulated by ethylene.We,in addition,provide evidence that EIN3-mediated synergid nucleus disintegration promotes endosperm expansion.Interestingly,synergid nucleus disintegration is not affected in various ethylene biosynthesis mutants,suggesting that this promoting function of EIN3 is inde-pendent of ethylene.Whereas the growth-inhibitory ethylene-dependent EIN3 action appears to be encoded by sporophytic tissue,the growth-promoting role of EIN3 is induced by fertilization,revealing a generation conflict that converges toward the key signaling component EIN3.

关键词： seed size EIN3 ethylene biosynthesis fertilization generation conflict synergid disintegration

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Environmental exposure as a risk-modifying factor in liver diseases:Knowns and unknowns

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Acta Pharmaceutica Sinica B 2021年第12期11卷 3768-3778页

作者： juliane I.Beier Gavin E.Arteel Department of Medicine Division of GastroenterologyHepatology and NutritionUniversity of PittsburghPittsburghPA 15213USA Pittsburgh Liver Research Center and University of Pittsburgh PittsburghPA 15213USA Department of Environmental and Occupational Health University of PittsburghPA 15213USA

Liver diseases are considered to predominantly possess an inherited or xenobiotic etiology.However,inheritance drives the ability to appropriately adapt to environmental stressors,and disease is the culmination of a maladaptive response.Thus "pure" genetic and "pure" xenobiotic liver diseases are modified by each other and other factors,identified or unknown.The purpose of this review is to highlight the knowledgebase of environmental exposure as a potential risk modifying agent for the development of liver disease by other causes.This exercise is not to argue that all liver diseases have an environmental component,but to challenge the assumption that the current state of our knowledge is sufficient in all cases to conclusively dismiss this as a possibility.This review also discusses key new tools and approaches that will likely be critical to address this question in the future.Taken together,identifying the key gaps in our understanding is critical for the field to move forward,or at the very least to "know what we don't know."

关键词： Hepatic injury Exposomics Liver disease Drug-induced liver injury Alcoholic liver disease Non-alcoholic liver disease Inherited liver disease Autoimmune liver disease

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Family Medicine and Community Health 2023年第4期11卷 4-12页

作者： juliane Regina Framme Su-Jong Kim-Dorner Bettina Heidtmann Thomas Michael Kapellen Karin Lange Olga Kordonouri Heike Saßmann Medical Psychology Hannover Medical SchoolHannoverGermany Paediatric Endocrinology and Diabetology Catholic Childrens Hospital WilhelmstiftHamburgGermany Hospital for Children and Adolescents University of Leipzig Medical CenterLeipzigGermany Department of Paediatrics MEDIAN Children's Hospital"Am Nicolausholz"Bad KösenGermany Diabetes Center for Children and Adolescents Auf der Bult Children's HospitalHannoverGermany

Objective The COVID-19 pandemic had an impact on everyday life and in general,reduced the health-related quality of life(HRQoL)of adolescents.In this study,we assess the HRQoL of adolescents with type 1 diabetes(T1D)in Germany since the second wave of the COVID-19 pandemic by using self-report and parent-proxy reports,to identify risk factors,to compare to peers and to examine the agreement of HRQoL between parents and their children.Methods A total of 445 adolescents(12–18 years)and 413 parents participated in an anonymous cross-sectional survey conducted at three German diabetes centres from January 2021 to June 2022.Inclusion criteria were diabetes duration≥1year and German-speaking.Teen HRQoL was assessed by using self-report and parent-proxy report versions of the KIDSCREEN-10 index.Results The majority of adolescents reported average(75.5%)HRQoL.Approximately 11.3%of teens reported high and 13.2%low HRQoL.Teen’s female gender,older age,higher diabetes burden and parental depression symptoms contributed to lower self-reported HRQoL among teens.For parent-proxy reports,increasing diabetes burdens,parental depression symptoms,non-migrant status,high education and ketoacidosis contributed to lower scores on teen HRQoL.The mean scores of the KIDSCREEN-10 index for adolescents did not differ from the German norm.In comparison to healthy peers during the first wave of the pandemic,adolescents in the current study reported higher HRQoL.The overall teen-parent agreement was fair although parents reported significantly lower teen HRQoL than adolescents did.Conclusions HRQoL of most adolescents with T1D during the COVID-19 pandemic was average with parents reporting significantly lower scores.Self-reported and parent-proxy-reported HRQoL and the level of agreement due to different perspectives can provide important information for clinical care and intervention planning.

关键词： adolescent wave life

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