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Increased Tim-3 expression alleviates liver injury by regulating macrophage activation in MCD-induced NASH mice

Cellular & Molecular Immunology 2019年第11期16卷 878-886页

作者： Xianhong Du Zhuanchang Wu Yong Xu Yuan Liu Wen Liu Tixiao Wang Chunyang Li Cuijuan Zhang Fan Yi Lifen Gao Xiaohong Liang Chunhong Ma Key Laboratory for experimental Teratology of Ministry of Education Department of ImmunologyShandong University School of Basic Medical ScienceJinanShandong 250012PR China Department of Radiation oncology Qilu Hospital of Shandong UniversityJinanShandongPR China Key Laboratory for experimental Teratology of Ministry of Education Department of Histology and EmbryologyShandong University School of Basic Medical ScienceJinanShandongPR China Institute of Pathology and Pathophysiology Shandong University School of MedicineJinanPR China Key Laboratory of Infection and Immunity of Shandong Province School of Basic Medical SciencesShandong UniversityJinanChina

As an immune checkpoint,Tim-3 plays roles in the regulation of both adaptive and innate immune cells including macrophages and is greatly involved in chronic liver ***,the precise roles of Tim-3 in nonalcoholic steatohepatitis(NASH)remain *** the current study,we analyzed Tim-3 expression on different subpopulations of liver macrophages and further investigated the potential roles of Tim-3 on hepatic macrophages in methionine and choline-deficient diet(MCD)-induced NASH *** results of flow cytometry demonstrated the significantly increased expression of Tim-3 on all detected liver macrophage subsets in MCD mice,including F4/80^(+)CD11b^(+),F4/80^(+)CD68^(+),and F4/80^(+)CD169^(+)***,Tim-3 knockout(KO)significantly accelerated MCD-induced liver steatosis,displaying higher serum ALT,larger hepatic vacuolation,more liver lipid deposition,and more severe liver ***,compared with wild-type C57BL/6 mice,Tim-3 KO MCD mice demonstrated an enhanced expression of NOX2,NLRP3,and caspase-1 p20 together with increased generation of IL-1βand IL-18 in *** vitro studies demonstrated that Tim-3 negatively regulated the production of reactive oxygen species(ROS)and related downstream pro-inflammatory cytokine secretion of IL-1βand IL-18 in *** administration of N-Acetyl-L-cysteine(NAC),a small molecular inhibitor of ROS,remarkably suppressed caspase-1 p20 expression and IL-1βand IL-18 production in livers of Tim-3 KO mice,thus significantly reducing the severity of steatohepatitis induced by *** conclusion,Tim-3 is a promising protector in MCD-induced steatohepatitis by controlling ROS and the associated pro-inflammatory cytokine production in macrophages.

关键词： macrophage NASH ROS Tim-3

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Apparent diffusion coefficient by diffusion-weighted magnetic resonance imaging as a sole biomarker for staging and prognosis of gastric cancer

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Chinese Journal of Cancer Research 2017年第2期29卷 118-126页

作者： Francesco Giganti Alessandro Ambrosi Damiano Chiari Elena Orsenigo Antonio Esposito Elena Mazza Luca Albarello Carlo Staudacher Alessandro Del Maschio Francesco De Cobelli Department of Radiology and experimental Imaging Center San Raffaele Scientific Institute Milan Italy Vita-Salute San Raffaele University Milan Italy Department of Surgery San Raffaele Scientific Institute Milan Italy Department of oncology San Raffaele Scientific Institute Milan Italy Pathology unit San Raffaele Scientific Institute Milan Italy

Objective： To investigate the role of apparent diffusion coefficient （ADC） from diffusion-weighted magnetic resonance imaging （DW-MRI） when applied to the 7th TNM classification in the staging and prognosis of gastric cancer （GC）. Methods： Between October 2009 and May 2014, a total of 89 patients with non-metastatic, biopsy proven GC underwent 1.5T DW-MRI, and then treated with radical surgery. Tumor ADC was measured retrospectively and compared with final histology following the 7th TNM staging （local invasion, nodal involvement and according to the different groups -- stage Ⅰ, Ⅱ and Ⅲ）. Kaplan-Meier curves were also generated. The follow-up period is updated to May 2016. Results： Median follow-up period was 33 months and 45/89 （51%） deaths from GC were observed. ADC was significantly different both for local invasion and nodal involvement （P〈0.001）. Considering final histology as the reference standard, a preoperative ADC cut-offof 1.80×10-3 mm^2/s could distinguish between stages I and Ⅱ and an ADC value of ≤1.36-10-3 mm^2/s was associated with stage Ⅲ（P〈0.001）. Kaplan-Meier curves demonstrated that the survival rates for the three prognostic groups were significantly different according to final histology and ADC cut-offs （P〈0.001）. Conclusions： ADC is different according to local invasion, nodal involvement and the 7th TNM stage groups for GC, representing a potential, additional prognostic biomarker. The addition of DW-MRI could aid in the staging and risk stratification of GC.

关键词： Apparent diffusion coefficient diffusion-weighted magnetic resonance imaging gastric cancer prognosis TNM staging

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Renal cell carcinoma:An update for the practicing urologist

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Asian Journal of Urology 2015年第1期2卷 19-25页

作者： Sumanta K.Pal Paulo Bergerot Robert A.Figlin Department of medical oncology&experimental Therapeutics City of Hope Comprehensive Cancer CenterDuarteCAUSA Health Department of Federal District(SES)e HRAN BrasiliaBrazil Department of Medicine Cedars-Sinai Medical CenterLos AngelesCAUSA

Systemic therapy for metastatic renal cell carcinoma(mRCC)has evolved drastically,with agents targeting vascular endothelial growth factor(VEGF)and the mammalian target of rapamycin(mTOR)now representing a standard of *** present paper is to review the current status of relevant clinical trials that were either recently completed or ongoing.(1)Though observation remains a standard of care following resection of localized disease,multiple trials are underway to assess VEGF-and mTOR-directed therapies in this setting.(2)While the preponderance of retrospective data favors cytoreductive nephrectomy in the context of targeted agents,prospective data to support this approach is still forthcoming.(3)The first-line management of mRCC may change substantially with multiple studies exploring vaccines,immune checkpoint inhibitors,and novel targeted agents currently *** general,prospective studies that will report within the next several years will be critical in defining the role of adjuvant therapy and cytoreductive *** the same span of time,the current treatment paradigm for first-line therapy may evolve.

关键词： Renal cell carcinoma Sdjuvant therapy Cytoreductive nephrectomy Vaccines Immunotherapy PD-1 Cabozantinib

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Plate vs reverse shoulder arthroplasty for proximal humeral fractures:The psychological health influence the choice of device?

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World Journal of Orthopedics 2022年第3期13卷 297-306页

作者： Giuseppe Maccagnano Giuseppe Solarino Vito Pesce Giovanni Vicenti Michele Coviello Vittorio Saverio Nappi Orazio Valerio Giannico Angela Notarnicola Biagio Moretti Department of Clinical and experimental Medicine Faculty of Medicine and SurgeryUniversity of FoggiaOrthopaedics UnitGeneral HospitalFoggia 71122Italy Department of Basic medical Science Neuroscience and Sensory OrgansFaculty of Medicine and SurgeryUniversity of BariOrthopaedics UnitGeneral HospitalBari 70124Italy Orthopaedics unit Di Venere General HospitalBari 70124Italy Department of Biomedical Sciences and Human oncology University of Bari Aldo MoroBari 70124Italy

BACKGROUND Proximal humeral fractures represent the third most common observed osteoporotic fracture;the treatment in three and four-part proximal humeral fractures in patients over 65 years is still *** the treatments described in literature,open reduction and internal fixation(O.R.I.F)and reverse shoulder arthroplasty(RSA)are gaining an increasing *** To investigate the correct treatment for three and four-part proximal humeral fractures according to psychological *** It was conducted a prospective study with a series of 63 patients treated with O.R.I.F.(group A)and with RSA(group B)for three and four-part proximal humeral fractures according to Neer classification system.A conservative treatment group,as control,was finally *** independent observer performed clinical and a psychological evaluation at one(T0),six(T1)and twelve months(T2)*** Constant’s score and The Disabilities of the Arm,Shoulder and Hand(DASH score)were used for clinical evaluation,while General Anxiety Disorder-7(GAD-7)and Caregiver Strain Scale(CSS)were used for psychological *** At one month follow up in group A the mean values were DASH score 50.8,Constant score 36.1,GAD-7 score 5.4,CSS *** the group B,the average values at T0 were:DASH score 54.6,Constant score 32.0;GAD-7 score 6.4,CSS *** six months in group A the average values were DASH score 42.1,Constant score 47.3,GAD-7 score 4.3,CSS *** the group B,the average values at T1 were:DASH score 39.1,Constant score 43.2,GAD-7 score 5.7,CSS *** twelve months in the group A,the mean values were DASH score 32.8,Constant score 60.0,GAD-7 score 3.2,CSS *** the group B shown these mean values:DASH score 33.6,Constant score 52.9,GAD-7 score 4.3,CSS *** demonstrated a better clinical and psychological outcome at T2 in the group treated with osteosynthesis compared to the group treated with arthroplasty(Constant P=0.049,GAD-7 P=0.012 and CSS P=0.005

关键词： Proximal humerus fractures Open reduction and fixation Reverse shoulder arthroplasty Psychological health General Anxiety Disorder-7 scale Caregiver Strain scale

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Beamline design for multipurpose muon beams at CSNS EMuS

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Nuclear Science and Techniques 2024年第5期35卷 1-12页

作者： Yang Hong Ying-Peng Song Lu-Ping Zhou Jing-Yu Tang Zhi-Hao Zhou Nikolaos Vassilopoulos Institute of High Energy Physics Chinese Academy of Sciences(CAS)Beijing 100049China Spallation Neutron Source Science Center Dongguan 523803China University of Chinese Academy of Sciences Beijing 100049China Radiotherapy Physics and Technology Center Cancer CenterWest China HospitalSichuan UniversityChengdu 610041China Xi’an Jiaotong University Health Science Center Xi’an 710049China Department of Radiation oncology First Affiliated Hospital of Xi’an Jiaotong UniversityXi’an 710049China School of Nuclear Science and Technology University of Science and Technology of ChinaHefei 230027China

A new muon beam facility,called the experimental Muon Source(EMuS),was proposed for construction at the China Spallation Neutron Source(CSNS).The design of the complex muon beamlines for the EMuS baseline scheme,which is based on superconducting solenoids,superferric dipoles and room-temperature magnets,is presented *** muon beams,including surface muons,decay muons and low energy muons,have been developed for multipurpose *** optics design and simulation results of the trunk beamline and branch beamlines are *** a proton beam power of 25 kW at a standalone target station that consists of a conical graphite target and high-field superconducting solenoids,the muon beam intensity in the trunk beamline varies from 10^(7)/s for surface muons to 10^(10)/s for high-momentum decay *** at the endstations,these values vary from 10^(5)/s for surface muons to 10^(8)/s for decay muons.

关键词： Surface muons Decay muons Muon beamline Superconducting solenoids Multi-channel electrostatic separator

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Cystine transporter SLC7A11/xCT in cancer:ferroptosis,nutrient dependency,and cancer therapy

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Protein & Cell 2021年第8期12卷 599-620页

作者： Pranavi Koppula Li Zhuang Boyi Gan Department of experimental Radiation oncology The University of Texas MD Anderson Cancer CenterHoustonTXUSA The University of Texas MD Anderson UTHealth Graduate School of Biomedical Sciences HoustonTXUSA

The cystine/glutamate antiporter SLC7A11(also commonly known as xCT)functions to import cystine for glutathione biosynthesis and antioxidant defense and is overexpressed in multiple human *** studies revealed that SLC7A11 overexpression promotes tumor growth partly through suppressing ferroptosis,a form of regulated cell death induced by excessive lipid ***,cancer cells with high expression of SLC7A11(SLC7A11^(high))also have to endure the significant cost associated with SLC7A11-mediated metabolic reprogramming,leading to glucose-and glutamine-dependency in SLC7A11^(high) cancer cells,which presents potential metabolic vulnerabilities for therapeutic targeting in SLC7A11^(high) *** this review,we summarize diverse regulatory mechanisms of SLC7A11 in cancer,discuss ferroptosis-dependent and-independent functions of SLC7A11 in promoting tumor development,explore the mechanistic basis of SLC7A11-induced nutrient dependency in cancer cells,and conceptualize therapeutic strategies to target SLC7A11 in cancer *** review will provide the foundation for further understanding SLC7A11 in ferroptosis,nutrient dependency,and tumor biology and for developing novel effective cancer therapies.

关键词： SLC7A11 xCT cystine cysteine ferroptosis nutrient dependency cancer therapy

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DDX39B drives colorectal cancer progression by promoting the stability and nuclear translocation of PKM2

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Signal Transduction and Targeted Therapy 2022年第9期7卷 3536-3550页

作者： Gang Zhao Hang Yuan Qin Li Jie Zhang Yafei Guo Tianyu Feng Rui Gu Deqiong Ou Siqi Li Kai Li Ping Lin Lab of experimental oncology State Key Laboratory of Biotherapy and Cancer Centerand Frontiers Science Center for Disease-Related Molecular NetworkWest China HospitalSichuan UniversityChengduSichuan 610041China

Metastasis is a major cause of colorectal cancer(CRC)mortality,but its molecular mechanisms are still not fully ***,we show that upregulated DDX39B correlates with liver metastases and aggressive phenotypes in ***39B is an independent prognostic factor associated with poor clinical outcome in CRC *** demonstrate that Sp1 potently activates DDX39B transcription by directly binding to the GC box of the DDX39B promoter in CRC ***39B overexpression augments the proliferation,migration,and invasion of CRC cells,while the opposite results are obtained in DDX39B-deficient CRC ***,DDX39B interacts directly with and stabilizes PKM2 by competitively suppressing STUB1-mediated PKM2 ubiquitination and ***,DDX39B recruits importin a5 to accelerate the nuclear translocation of PKM2 independent of ERK1/2-mediated phosphorylation of PKM2,leading to the transactivation of oncogenes and glycolysis-related ***,DDX39B enhances glucose uptake and lactate production to activate Warburg effect in *** identify that Arg319 of DDX39B is required for PKM2 binding as well as PKM2 nuclear accumulation and for DDX39B to promote CRC growth and *** addition,blocking PKM2 nuclear translocation or treatment with glycolytic inhibitor 2-deoxy-D-glucose efficiently abolishes DDX39B-triggered malignant development in *** together,ourfindings uncover akey role forDDX39B in modulating glycolytic reprogramming and aggressive progression,and implicate DDX39B as a potential therapeutic target in CRC.

关键词： PKM2 colorectal invasion

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NGR-tagged nano-gold： A new CD13-selective carrier for cytokine delivery to tumors

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Nano Research 2016年第5期9卷 1393-1408页

作者： Flavio Curnis Martina Fiocch Angelina Sacchi Alessandro Gori Anna Gasparri Angelo Corti Division of experimental oncology IRCCS San Raffaele Scientific Institute Milan 20132 Italy Istituto di Chimica del Riconoscimento Molecolare CNR Milan 20131 Italy Vita Salute San Raffaele University Milan 20132 Italy

Colloidal gold （Au）, a well-tolerated several applications in nanomedicine. nanomaterial, is currently exploited for We show that gold nanoparticles tagged with a novel tumor-homing peptide containing Asn-Gly-Arg （NGR）, a ligand of CD13 expressed by the tumor neovasculature, can be exploited as carriers for cytokine delivery to tumors. Biochemical and functional studies showed that the NGR molecular scaffoldflinker used for gold functionalization is critical for CD13 recognition. Using fibrosarcorna-bearing mice, NGR-tagged nanodrugs could deliver extremely low, yet pharmacologically active doses of tumor necrosis factor （TNF）, an anticancer cytokine, to tumors with no evidence of toxicity. Mechanistic studies confirmed that CD13 targeting was a primary mechanism of drug delivery and excluded a major role of integrin targeting consequent to NGR deamidation, a degradation reaction that generates the isoAsp-Gly-Arg （isoDGR） integrin ligand. NGR-tagged gold nanoparticles can be used, in principle, as a novel platform for single- or multi-cytokine delivery to tumor endothelial cells for cancer therapy.

关键词： Asn-Gly-Arg (NGR) isoAsp-Gly-Arg (isoDGR) CD13 integrin tumor necrosis factor albumin gold nanoparticles

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Everolimus halts hepatic cystogenesis in a rodent model of polycystic-liver-disease

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World Journal of Gastroenterology 2017年第30期23卷 5499-5507页

作者： Frederik Temmerman Feng Chen Louis Libbrecht Ingrid Vander Elst Petra Windmolders Yuanbo Feng Yicheng Ni Humbert De Smedt Frederik Nevens Jos van Pelt Laboratory of Hepatology Department of Clinical and Experimental Medicine Faculty of Medicine University of Leuven Department of Gastroenterology and Hepatology University Hospitals KU Leuven Department of Radiology The first Affiliated Hospital School of Medicine Zhejiang University Department of Pathology Ghent University Hospital Department of Imaging and Pathology Faculty of Medicine Laboratory of Molecular and Cellular Signalling unit of Clinical Digestive oncology Department of Oncology KU Leuven and Leuven Cancer Institute (LKI)

AIM To develop a MRI-based method for accurate determination of liver volume(LV) and to explore the effect of long-term everolimus(EVR) treatment on LV in PCK rats with hepatomegaly. METHODS Thirty-one female PCK rats(model for polycystic-liverdisease: PCLD) were randomized into 3 groups and treatment was started at 16 wk, at the moment of extensive hepatomegaly(comparable to what is done in the human disease). Animals received: controls(n = 14), lanreotide(LAN: 3 mg/kg per 2 wk)(n = 10) or everolimus(EVR: 1 mg/kg per day)(n = 7). LV was measured at week 16, 24, 28. At week 28, all rats were sacrificed and liver tissue was harvested. Fibrosis was evaluated using quantitative image analysis. In addition, gene(quantitative RT-PCR) and protein expression(by Western blot) of the PI3K/Ak T/m TOR signaling pathway was investigated. RESULTS LV determination by MRI correlated excellent with the ex vivo measurements(r = 0.99, P < 0.001). The relative changes in LV at the end of treatment were:(controls) +31.8%;(LAN) +5.1% and(EVR) +8.8%, indicating a significantly halt of LV progression compared with controls(respectively, P = 0.01 and P = 0.04). Furthermore, EVR significantly reduced the amount of liver fibrosis(P = 0.004) thus might also prevent the development of portal hypertension. There was no difference in phosphorylation of Akt(Threonine 308) between LAN-treated PCK rats control PCK rats, whereas S6 was significantly more phosphorylated in the LAN group. Phosphorylation of Akt was not different between controls and EVR treated rats, however, for S6 there was significantly less phosphorylation in the EVR treated rats. Thus, both drugs interact with the PI3K/Ak T/m TOR signaling cascade but acting at different molecular *** Everolimus halts cyst growth comparable to lanreotide and reduces the development of fibrosis. m TORinhibition should be further explored in PCLD patients especially those that need immunosuppression.

关键词： Fibrocystic liver disease mTOR inhibitor somatostatin analogue liver volume measurement Magnetic resonance imaging

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Human umbilical cord-derived mesenchymal stem cells: Current trends and future perspectives

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Asian pacific Journal of Reproduction 2019年第3期8卷 93-101页

作者： Diego Rossetti Silvia Di Angelo Antonio David Lukanovi Tina Kunic Camilla Certelli Carmine Vascone Zaki Sleiman unit of Gynecology and Obstetrics Desenzano del Garda HospitalSection of GavardoGavardoBresciaItaly Department of Biomedicine and Prevention Section of Gynecology and ObstetricsUniversity of Rome Tor VergataRomeItaly Department of Obstetrics and Gynecology University Medical Center LjubljanaLjubljanaSlovenia Gynecologic oncology unit Department of Experimental Clinical Oncology"Regina Elena"National Cancer InstituteRomeItaly Pineta Grande Hospital Castel VolturnoCasertaItaly Surgical Research Laboratory Medical SchoolSaint Joseph UniversityDamas StreetBeirutLebanon Department of Obstetrics and Gynaecology Lebanese American UniversityBeirutLebanon

Among resources of mesenchymal stem cells, human umbilical cord appears to be a rising source capable of differentiating into all germ layers, reaching and repairing lesion areas, and promoting wound repair, and it has also the capacity to influence the immune response. Human umbilical cord-derived mesenchymal stem cells are considered to be an optimal resource compared with other mesenchymal stem cells sources because they require a non-invasive recovery. All these characteristics allow their use in heterogeneous applications. Human umbilical cord-derived mesenchymal stem cells can regenerate tissues, stimulate angiogenesis, modulate inflammatory pathway signals and recruit endogenous stem cell. Human umbilical cord-derived mesenchymal stem cells suppress mitogen-induced signals and modulate the activation and proliferation of several immune cells, modifying lymphocyte phenotypes activity. In culture, human umbilical cord-derived mesenchymal stem cellss show the capacity to create several tissues such as bone, cartilage, and fat. Human umbilical cord-derived mesenchymal stem cells can be isolated from the different compartments of umbilical cord and processed by using different techniques. Clinical applications of human umbilical cord-derived mesenchymal stem cells include graft-versus-host disease, autoimmune diseases such as Sj?gren's syndrome and diabetes mellitus types 1 and 2, gynecological disorders like endometriosis. Recent studies have shown possible application on rheumatoid arthritis, osteoarthritis, and neuronal degenerative diseases. This review is focused on the resources, molecular profiles, propriety, in vitro characterizations, clinical applications and possible future usage of human umbilical cord-derived mesenchymal stem cells.

关键词： Human umbilical cord stem cells Immunomodulation Cryopreservation Stem therapy

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