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T cell receptor (TCR) signaling in health and disease

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Signal Transduction and Targeted Therapy 2022年第1期7卷 38-63页

作者： Kinjal Shah Amr Al-Haidari Jianmin Sun Julhash U.Kazi Division of Translational cancer Research Department of Laboratory MedicineLund UniversityLundSweden Lund Stem Cell Center Department of Laboratory MedicineLund UniversityLundSweden Clinical Genetics and Pathology SkSne University HospitalRegion SkineLundSweden Clinical Sciences Department Surgery Research UnitLund UniversityMalmoSweden NHC Key Laboratory of Metabolic Cardiovascular Diseases Research Science and Technology centerSchool of Basic Medical SciencesNingxia Medical UniversityYinchuanChina

Interaction of the T cell receptor(TCR)with an MHC-antigenic peptide complex results in changes at the molecular and cellular levels in T *** outside environmental cues are translated into various signal transduction pathways within the cell,which mediate the activation of various genes with the help of specific transcription *** signaling networks propagate with the help of various effector enzymes,such as kinases,phosphatases,and *** of these disparate signal transduction pathways is done with the help of adaptor proteins that are non-enzymatic in function and that serve as a scaffold for various protein-protein *** process aids in connecting the proximal to distal signaling pathways,thereby contributing to the full activation of T *** review provides a comprehensive snapshot of the various molecules involved in regulating T cell receptor signaling,covering both enzymes and adaptors,and will discuss their role in human disease.

关键词： TCR connecting thereby

Neo-adjuvant radiotherapy in rectal cancer

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World Journal of Gastroenterology 2013年第46期19卷 8489-8501页

作者： Bengt Glimelius Department of Radiology Oncology and Radiation Science Uppsala University

In rectal cancer treatment,attention has focused on the local primary tumour and the regional tumour cell deposits to diminish the risk of a loco-regional *** large randomized trials have also shown that combinations of surgery,radiotherapy and chemotherapy have markedly reduced the risk of a locoregional recurrence,but this has not yet had any major influence on overall *** best results have been achieved when the radiotherapy has been given *** radiotherapy improves loco-regional control even when surgery has been optimized to improve lateral clearance,i.e.,when a total mesorectal excision has been *** relative reduction is then 50%-70%.The value of radiotherapy has not been tested in combination with more extensive surgery including lateral lymph node clearance,as practised in some Asian *** details about how the radiotherapy is performed are still open for discussion,and practice varies between countries.A highly fractionated radiation schedule(5 Gy×5),proven efficacious in many trials,has gained much popularity in some countries,whereas a conventionally fractionated regimen(1.8-2.0 Gy×25-28),often combined with chemotherapy,is used in other *** additional therapy adds morbidity to the morbidity that surgery causes,and should therefore be administered only when the risk of loco-regional recurrence is sufficiently *** best integration of the weakest modality,to date the drugs(conventional cytotoxics and biologicals)is not known.A new generation of trials exploring the best sequence of treatments is ***,there is a great need to develop predictors of response,so that treatment can be further individualized and not solely based upon clinical factors and anatomic imaging.

关键词： Chemotherapy Chemoradiotherapy Local control Multidisciplinary Organ preservation Radio-therapy Randomized trials Rectal cancer

Inhibition of p53 inhibitors:progress,challenges and perspectives

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Journal of Molecular Cell Biology 2019年第7期11卷 586-599页

作者： Gema Sanz Madhurendra Singh Sylvain Peuget Galina Selivanova Department of Microbiology Tumor and Cell BiologyBiomedicum 8CKarolinska InstituteSE17165Sweden

p53 is the major tumor suppressor and the most frequently inactivated gene in cancer.p53 could be disabled either by mutations or by upstream negative regulators,including,but not limited to MDM2 and MDMX.p53 activity is required for the prevention as well as for the eradication of *** of p53 activity in mouse models leads to the suppression of established tumors of different *** findings provide a strong support to the anti-cancer strategy aimed for p53 *** this review,we summarize recent progress in the development of small molecules,which restore the tumor suppressor function of wild-type p53 and discuss their clinical *** discuss different aspects of p53-mediated response,which contribute to suppression of tumors,including non-canonical p53 activities,such as regulation of immune *** targeting p53 inhibitors is a very promising approach,there are certain limitations and concerns that the intensive research and clinical evaluation of compounds will hopefully help to overcome.

关键词： p53 tumor suppression anti-cancer therapy targeted drugs transcription factor immune response

Androgen receptor gene CAG and GGN repeat lengths as predictors of recovery of spermatogenesis following testicular germ cell cancer treatment

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Asian Journal of Andrology 2017年第5期19卷 538-542页

作者： Karolina Bogefors Yvonne Lundberg Giwercman Jakob Eberhard Olof Stahl Eva Cavallin-Stahl Gabriella Cohn-Cedermark Stefan Arver Aleksander Giwercman Reproductive Medicine Centre Skane University Hospital Malmo Sweden Department of Oncology Skane University Hospital Malmo Sweden Department of Translational Medicine Lund University Malmo Sweden Department of Oncology Skane University Hospital Lund Sweden Radiumhemmet Karolinska HospitalStockholm Sweden Centre of Andrology and Sexual Medicine Karolinska Hospital Stockholm Sweden

Spermatogenesis is an androgen-regulated process that depends on the action of androgen receptor （AR）. Sperm production may be affected in men treated for testicular cancer （TC）, and it is important to identify the factors influencing the timing of spermatogenesis recovery following cancer treatment. It is known that the CAG and GGN repeat numbers affect the activity of the AR; therefore, the aim of this study is to investigate if the CAG and GGN polymorphisms in the AR gene predict recovery of sperm production after TC treatment. TC patients （n = 130） delivered ejaculates at the following time points： postorchiectomy and at 6, 12, 24, 36, and 60 months posttherapy （TO, T6, T12, T24, T36, and T60）. The CAG lengths were categorized into three groups, 〈22 CAG, 22-23 CAG, and 〉23 CAG, and the GGN tracts were also categorized into three groups, 〈23 GGN, 23 GGN, and 〉23 GGN. At T12, men with 22-23 CAG presented with a statistically significantly （P = 0.045） lower sperm concentration than those with other CAG numbers （8.4 × 10^6 ml^-1 vs 16 × 10^6 ml^-1; 95% CI： 1.01-2.65）. This association was robust to omitting adjustment for treatment type and sperm concentration at TO （P= 0.021; 3.7× 10^6 ml^-1 vs 10 × 10^6 ml^-1; 95% CI： 1.13-4.90）. The same trends were observed for total sperm number. The least active AR variant seems to be associated with a more rapid recovery of spermatogenesis. This finding adds to our understanding of the biology of postcancer therapy recovery of fertility in males and has clinical implications.

关键词： androgen receptor CAG and GGN repeat sperm number testicular cancer

Morphological alterations and redox changes associated with hepatic warm ischemia-reperfusion injury

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World Journal of Hepatology 2017年第34期9卷 1261-1269页

作者： Rim Jawad Melroy D'souza Lisa Arodin Selenius Marita Wallenberg Lundgren Olof Danielsson Greg Nowak Mikael Bjornstedt Bengt Isaksson Division of Pathology Department of Laboratory Medicine Karolinska Institutet Department of Clinical Science Intervention and Technology (CLINTEC) Division of Surgery Karolinska Institutet Karolinska University Hospital Department of Clinical Science Intervention and Technology (CLINTEC) Division of Transplantation Surgery Karolinska Institutet Karolinska University Hospital

AIM To study the effects of warm ischemia-reperfusion(I/R) injury on hepatic morphology at the ultrastructural level and to analyze the expression of the thioredoxin(TRX)and glutaredoxin(GRX) *** Eleven patients undergoing liver resection were subjected to portal triad clamping(PTC). Liver biopsies were collected at three time points; first prior to PTC(baseline), 20 min after PTC(post-ischemia) and 20 min after reperfusion(post-reperfusion). Electron microscopy and morphometry were used to study and quantify ultrastructural changes, respectively. Additionally, gene expression analysis of TRX and GRX isoforms was performed by quantitative PCR. For further validation of redox protein status, immunogold staining was performed for the isoforms GRX1 and *** Post-ischemia, a significant loss of the liver sinusoidal endothelial cell(LSEC) lining was observed(P = 0.0003) accompanied by a decrease of hepatocyte microvilli in the space of Disse. Hepatocellular morphology was well preserved apart from the appearance of crystalline mitochondrial inclusions in 7 out of 11 patients. Postreperfusion biopsies had similar features as post-ischemia with the exception of signs of a reactivation of the LSECs. No changes in the expression of redox-regulatory genes could be observed at mR NA level of the isoforms of the TRX family but immunoelectron microscopy indicated a redistribution of TRX1 within the *** At the ultrastructural level, the major impact of hepatic warm I/R injury after PTC was borne by the LSECs with detachment and reactivation at ischemia and reperfusion, respectively. Hepatocytes morphology were well preserved. Crystalline inclusions in mitochondria were observed in the hepatocyte after ischemia.

关键词： Hepatic ischemia-reperfusion injury Ischemia reperfusion injury Warm ischemia-reperfusion injury Glutaredoxins Thioredoxins Electron microscopy Oxidative stress Portal triad clamping

Telomerase as a “stemness” enzyme

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Science China(Life Sciences) 2014年第6期57卷 564-570页

作者： KONG Feng ZHENG ChengYun XU DaWei Central Research Laboratory the Second Hospital of Shandong University Department of Hematology the Second Hospital of Shandong University Department of Medicine Division of Hematology and Centre for Molecular MedicineKarolinska Institutet and Karolinska UniversityHospital Solna

Pluripotent or multipotent stem cells are involved in development and tissue homeostasis;they have the ability to self-renew and differentiate into various types of functional *** maintain these properties,stem cells must undergo sustained or unlimited proliferation that requires the stabilization of telomeres,which are essential for chromosome end ***,an RNA-dependent DNA polymerase,synthesizes telomeric *** the lengthening of telomeres the lifespans of cells are extended,or indefinite proliferation is conferred;this is intimately associated with stem cell *** review highlights our current understanding of telomerase as a"stemness"enzyme and discusses the underlying implications.

关键词： stem cells telomerase telomere genomic stability iPS cells TERC TERT

Aberrant DNA repair as a potential contributor for the clonal evolution in subsets of anaplastic thyroid carcinomas arising through dedifferentiation: implications for future therapeutic algorithms?

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cancer Drug Resistance 2020年第4期3卷 992-1000页

作者： Carl Christofer Juhlin Department of Oncology-Pathology Karolinska InstitutetStockholm SE-17176Sweden Department of Pathology and Cytology Karolinska University HospitalStockholm SE-17176Sweden

Well-differentiated thyroid carcinoma(WDTC,including papillary thyroid carcinoma and follicular thyroid carcinoma)are fairly slow-growing tumors with an overall low mortality due to the efficacy of combinatory surgery and postoperative radioiodine *** of WDTCs may dedifferentiate into poorly differentiated thyroid carcinoma(PDTC)and anaplastic thyroid carcinoma(ATC),of which especially the latter has an exceptionally poor patient *** underlying genetics responsible for this tumor progression is only partly understood,and is complicated by the fact that subgroups of ATCs are thought to arise de novo without a demonstrable,pre-existing *** so,recent advances using next generation sequencing(NGS)techniques have identified a genetic link between WDTCs and ATCs,suggesting a step-wise accumulation of mutations driving the loss of differentiation for most *** this Commentary,recent findings from an NGS study on synchronous FTC,PDTC,and ATC tumor components from the same patient are *** using whole-genome data,clonality analyses identified a chief ancestral clone carrying mutations in TP53-associated signaling networks regulating genes involved in DNA repair,with sub-clones in each tumor component that were identified also in the less differentiated,neighboring ***,mutational signatures suggested a general mismatch repair(MMR)deficiency along with microsatellite *** findings support the chained progression model of dedifferentiation in thyroid cancer,and pinpoint a central role for defective DNA *** effective treatment modalities for ATCs are urgently needed,studies regarding therapeutic agents specifically targeting defective MMR in dedifferentiated thyroid carcinoma could be pursued.

关键词： DNA repair mismatch repair P53 thyroid carcinoma dedifferentiation anaplastic thyroid carcinoma clone treatment

Renal cell carcinoma escapes NK cell-mediated immune surveillance through the downregulation of DNAM-1

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cancer Communications 2023年第7期43卷 855-859页

作者： Veronika Kremer Shi Yong Neo Yaxuan Liu Yi Chen Arnika Kathleen Wagner Ying Yang Ziqing Chen Christina Seitz Nicholas Patrick Tobin Maarten Alexander Ligtenberg Evren Alici Xinsong Chen Felix Haglund Barbara Seliger Ulrika Harmenberg Eugenia Colón Ann-Helén Scherman Plogell Lisa Lei Liu Andreas Lundqvist Department of Oncology-Pathology Karolinska InstitutetStockholmSweden Singapore Immunology Network Agency for ScienceTechnology and ResearchSingaporeSingapore Department of Medicine Columbia University Irving Medical CenterNew YorkUSA Department of Medicine Huddinge Karolinska InstitutetStockholmSweden Department of Molecular Biology Princeton UniversityNew JerseyUSA Institute of Environmental Medicine Karolinska InstitutetStockholmSweden Department of Molecular Oncology The Netherlands Cancer InstituteAmsterdamNetherlands Institute for Medical Immunology Martin-Luther University Halle-WittenbergHalleGermany Institute of Translational Immunology Medical School Theodor FontaneBrandenburg an der Havel14770and Fraunhofer Institute for Cell Therapy and ImmunologyLeipzigGermany Department ofWomen’s and Children’s Health Karolinska Institutet and S:t Göran’s Hospital-UnilabsStockholmSweden Department of Urology Stockholm South General HospitalStockholmSweden

Dear Editor,The activating receptor DNAX accessory molecule-1(DNAM-1)plays an important role in T and natural killer(NK)cell-mediated cytotoxicity via the interaction with its ligands poliovirus receptor(PVR,CD155)and Nectin-2(CD112).Compared with peripheral blood NK cells,tumor-infiltrating NK cells show reduced expression of DNAM-1 across several solid tumors,including ovarian and breast cancer resulting in impaired NK cell *** studies reported an inverse correlation between DNAM-1 expression and its ligands in leukemic blasts and ovarian cancer[1].

关键词： impaired cancer killer

Mitochondria-localized β-actin is essential for priming innate antiviral immune signaling by regulating IRF3 protein stability

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Cellular & Molecular Immunology 2019年第10期16卷 837-840页

作者： Xin Xie Martin Endara-Coll Raza Mahmood Robertas Jankauskas Tamara Gjorgjieva Piergiorgio Percipalle Science Division Biology ProgramNew York University Abu Dhabi(NYUAD)P.O.Box 129188 Abu DhabiUnited Arab Emirates Department of Molecular Biosciences The Wenner-Gren InstituteStockholm UniversitySE-10691StockholmSweden New York University Center for Genomics and Systems Biology NYUNew YorkNYUSA

Antiviral innate immunity acts as a defensive barrier to viral infection in both immune and nonimmune *** viral nucleic acids present in the cytoplasm after viral replication can activate sensors such as the RIG-I-lik... 详细信息

关键词： immunity immune stability