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Specific CD8^+ T cell response immunotherapy for hepatocellular carcinoma and viral hepatitis

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World Journal of Gastroenterology 2016年第28期22卷 6469-6483页

作者： elia Moreno-Cubero Juan-Ramón Larrubia Translational Hepatology Unit Guadalajara University Hospital University of Alcalá Department of Biology of Systems University of Alcalá Department of Medicine and Medical Specialties University of Alcalá

Hepatocellular carcinoma (HCC), chronic hepatitis B (CHB) and chronic hepatitis C (CHC) are characterized by exhaustion of the specific CD8+ T cell response. This process involves enhancement of negative co-stimulatory molecules, such as programmed cell death protein-1 (PD-1), cytotoxic T-lymphocyte antigen-4 (CTLA-4), 2B4, Tim-3, CD160 and LAG-3, which is linked to intrahepatic overexpression of some of the cognate ligands, such as PD-L1, on antigen presenting cells and thereby favouring a tolerogenic environment. Therapies that disrupt these negative signalling mechanisms represent promising therapeutic tools with the potential to restore reactivity of the specific CD8+ T cell response. In this review we discuss the impressive in vitro and in vivo results that have been recently achieved in HCC, CHB and CHC by blocking these negative receptors with monoclonal antibodies against these immune checkpoint modulators. The article mainly focuses on the role of CTLA-4 and PD-1 blocking monoclonal antibodies, the first ones to have reached clinical practice. The humanized monoclonal antibodies against CTLA-4 (tremelimumab and ipilimumab) and PD-1 (nivolumab and pembrolizumab) have yielded good results in testing of HCC and chronic viral hepatitis patients. Trelimumab, in particular, has shown a significant increase in the time to progression in HCC, while nivolumab has shown a remarkable effect on hepatitis C viral load reduction. The research on the role of ipilimumab, nivolumab and pembrolizumab on HCC is currently underway.

关键词： Hepatocellular carcinoma CD8+ T cells Immune checkpoint modulation Chronic viral hepatitis Cytotoxic T-lymphocyte antigen-4 Programmed cell death protein-1

Mitochondria as a therapeutic:a potential new frontier in driving the shift from tissue repair to regeneration

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Regenerative Biomaterials 2023年第1期10卷 1332-1355页

作者： evan n.Main Thaiz M.Cruz Gary L.Bowlin Department of Biomedical Engineering University of Memphis330 Engineering Technology BuildingMemphisTN 38152USA

Fibrosis,or scar tissue development,is associated with numerous pathologies and is often considered a worst-case scenario in terms of wound healing or the implantation of a *** that remains is a disorganized,densely packed and poorly vascularized bundle of connective tissue,which was once functional *** creates a significant obstacle to the restoration of tissue function or integration with any ***,it is of paramount importance in tissue engineering and regenerative medicine to emphasize regeneration,the successful recovery of native tissue function,as opposed to repair,the replacement of the native tissue(often with scar tissue).A technique dubbed‘mitochondrial transplantation’is a burgeoning field of research that shows promise in in vitro,in vivo and various clinical applications in preventing cell death,reducing inflammation,restoring cell metabolism and proper oxidative balance,among other reported ***,there is currently a lack of research regarding the potential for mitochondrial therapies within tissue engineering and regenerative ***,this review explores these promising findings and outlines the potential for mitochondrial transplantation-based therapies as a new frontier of scientific research with respect to driving regeneration in wound healing and host-biomaterial interactions,the current successes of mitochondrial transplantation that warrant this potential and the critical questions and remaining obstacles that remain in the field.

关键词： mitochondrial transplantation host-biomaterial integration biomaterials wound healing fibrosis

Hepatitis C virus-specific cytotoxic T cell response restoration after treatment-induced hepatitis C virus control

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World Journal of Gastroenterology 2015年第12期21卷 3480-3491页

作者： Juan-Ramón Larrubia elia Moreno-Cubero Joaquín Miquel Eduardo Sanz-de-Villalobos Translational Hepatology Unit Guadalajara University Hospital University of Alcalá Department of Medicine and Medical Specialties University of Alcalá Department of Biology of Systems University of Alcalá

Hepatitis C virus(HCV)-specific cytotoxic T cell(CTL) response plays a major role in viral control during spontaneous infection resolution. These cells develop an exhausted and pro-apoptotic status during chronic onset, being unable to get rid of HCV. The role of this response in contributing to sustained viral response(SVR) after anti-HCV is controversial. Recent studies show that after successful interferon-based anti-HCV treatment, HCV traces are still detectable and this correlates with a peak of HCV-specific CTL response activation, probably responsible for maintaining SVR by subsequent complete HCV clearing. Moreover, SVR patients' serum is still able to induce HCV infection in na?ve chimpanzees, suggesting that the infection could be under the control of the immune system after a successful treatment, being transmissible in absence of this adaptive response. At least theoretically, treatmentinduced viral load decrease could allow an effective HCV-specific CTL response reestablishment. This effect has been recently described with anti-HCV interferonfree regimes, based on direct-acting antivirals. nevertheless, this is to some extent controversial with interferon-based therapies, due to the detrimental immunoregulatory α-interferon effect on T cells. Moreover, HCV-specific CTL response features during anti-HCV treatment could be a predictive factor of SVR that could have clinical implications in patient management. In this review, the recent knowledge about the role of HCV-specific CTL response in the development of SVR after anti-HCV treatment is discussed.

关键词： Hepatitis C virus Chronic hepatitis Hepatitis C vi

Surface science approach to the heterogeneous cycloaddition of CO_(2) to epoxides catalyzed by site-isolated metal complexes and single atoms: a review

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Green Chemical Engineering 2022年第3期3卷 210-227页

作者： Valerio D'elia Arjan W.Kleij Department of Materials Science and Engineering School of Molecular Science and EngineeringVidyasirimedhi Institute of Science and Technology(VISTEC)555 Moo 121210PayupnaiWangChanRayongThailand Institute of Chemical Research of Catalonia(ICIQ) Barcelona Institute of Science&TechnologyAv.Paisos Catalans 1643007TarragonaSpain Institute of Catalan Research and Advanced Studies(ICREA) Pg.Lluis Companys 2308010BarcelonaSpain

The cycloaddition of CO_(2) to epoxides to afford cyclic organic carbonates is an increasingly relevant non-reductive strategy to convert CO_(2) to useful products able to serve as high-boiling solvents,chemical intermediates,and monomers for the preparation of more sustainable *** development of efficient and robust hetero-geneous catalysts for such transformation is,therefore,crucial and can be carried out by several strategies that often require the preparation of sophisticated and/or expensive organic networks,linkers,or compounds.A different approach to the preparation of heterogeneous catalysts for CO_(2)-epoxide coupling is by applying surface science methodologies to graft molecular fragments or single atoms on various supports leading to well-defined active *** this context,surface organometallic chemistry(SOMC),along with comparable methodologies,is a valuable approach for the preparation of efficient,single-site Lewis acids and catalysts for the target cycloaddition reaction on metal oxides,whereas,other grafting methodologies,can be applied to prepare analogous catalysts on different kinds of ***,we discuss very recent advances in the application of surface methodologies for the preparation of single atom catalysts as an increasingly relevant approach towards highly active Lewis acids for the cycloaddition of CO_(2) to ***,we show that Lewis acids and catalysts prepared by facile surface methodologies hold significant potential for future application is the synthesis of cyclic carbonates from CO_(2).

关键词： Cyclic carbonates Surface science Single atoms Surface organometallic chemistry Catalysis

Significance of ipsilateral breast tumor recurrence after breast conserving treatment: role of surgical removal

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Chinese Journal of Cancer Research 2013年第1期25卷 22-31页

作者： Romano Demicheli Ilaria Ardoino Federico Ambrogi Roberto Agresti elia Biganzoli Scientific Directorate IRCCS National Cancer Institute Medical Statistics and Biometry University of Milan Breast Surgery IRCCS National Cancer Institute Medical Statistics and Biometry IRCCS National Cancer Institute

Objective： To analyze the pattern over time （dynamics） of further recurrence and death after ipsilateral breast tumor recurrence （IBTR） in breast cancer patients undergoing breast conserving treatment （BCT）. Methods： A total of 338 evaluable patients experiencing IBTR were extracted from a database of 3,293 patients undergoing BCT. The hazard rates for recurrence and mortality throughout 10 years of follow-up after IBTR were assessed and were compared to the analogous estimates associated to the primary treatment. Results： In a time frame with the time origin at the surgical treatment for IBTR, the hazard rate for further recurrence displays a bimodal pattern （peaks at the second and at the sixth year）. Patients receiving mastectomy for IBTR reveal recurrence and mortality dynamics similar to that of node positive （n＋） patients receiving mastectomy as primary surgery, apart from the first two-three years, when IBTR patients do worse. If the patients with time to IBTR longer than 2.5 years are considered, differences disappear. Conclusions： The recurrence and mortality dynamics following IBTR surgical removal is similar to the corresponding dynamics following primary tumor removal. In particular, patients with time to IBTR in excess of 2.5 years behave like n＋ patients following primary tumor removal. Findings may be suitably explained by assuming that the surgical manoeuvre required by IBTR treatment is able to activate a sudden growing phase for tumor foci most of which, as suggested by the systemic model of breast cancer, would have reached the clinical level according to their own dynamics.

关键词： Breast cancer IBTR recurrence dynamics effects of surgery conservative surgery tumor homeostasis

Is it possible to stop nucleos(t)ide analogue treatment in chronic hepatitis B patients?

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World Journal of Gastroenterology 2018年第17期24卷 1825-1838页

作者： elia Moreno-Cubero Robert T Sánchez del Arco Julia Pena-Asensio Eduardo Sanz de Villalobos Joaquín Míquel Juan Ramón Larrubia Translational Hepatology Unit Guadalajara University HospitalUniversity of AlcaláGuadalajara 19002Spain Internal Medicine Service Guadalajara University HospitalUniversity of AlcaláGuadalajara 19002Spain Department of Biology of Systems University of AlcaláAlcaláde Henares(Madrid)28805Spain Department of Medicine and Medical Specialties University of AlcaláAlcaláde Henares(Madrid)28805Spain

Chronic hepatitis B(CHB) remains a challenging global health problem, with nearly one million related deaths per year. nucleos(t)ide analogue(nA) treatment suppresses viral replication but does not provide complete cure of the hepatitis B virus(HBV) infection. The accepted endpoint for therapy is the loss of hepatitis B surface antigen(HBs Ag), but this is hardly ever achieved. Therefore, indefinite treatment is usually required. Many different studies have evaluated nA therapy discontinuation after several years of nA treatment and before HBs Ag loss. The results have indicated that the majority of patients can remain off therapy, with some even reaching HBs Ag seroconversion. Fortunately, this strategy has proved to be safe, but it is essential to consider the risk of liver damage and other comorbidities and to ensure aclose follow-up of the candidates before considering this strategy. Unanswered questions remain, namely in which patients could this strategy be effective and what is the optimal time point at which to perform it. To solve this enigma, we should keep in mind that the outcome will ultimately depend on the equilibrium between HBV and the host's immune system. Viral parameters that have been described as good predictors of response in HBe Ag(+) cases, have proven useless in HBe Ag(-) ones. Since antiviral immunity plays an essential role in the control of HBV infection, we sought to review and explain potential immunological biomarkers to predict safe nA discontinuation in both groups.

关键词： CD8 Lamivudine nucleos(t)ide analogues Tenofovir Chronic hepatitis B Entecavir hepatitis B virus Treatment cessation

Polyhydroxyurethanes from Biobased Monomers and CO_(2):A Bridge between Sustainable Chemistry and CO_(2) Utilization

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Chinese Journal of Chemistry 2024年第6期42卷 652-685页

作者： Tharinee Theerathanagorn Tanika Kessaratikoon Hafeez Ur Rehman Valerio D'elia Daniel Crespy VISTEC Advanced Laboratory for Environment-Related Inorganic and Organic Syntheses Department of Materials Science and EngineeringVidyasirimedhi Institute of Science and Technology21210Wang ChanRayongThailand Department of Materials Science and Engineering Vidyasirimedhi Institute of Science and Technology21210Wang ChanRayongThailand

Polyhydroxyurethanes(PHUs)have received considerable attention in the last decade as potential alternatives to traditional phosgene-based polyurethanes(PUs).The development of suitable 5CC(five membered-ring cyclic carbonate)precursors bearing multiple carbonate moieties(multi-5CCs)is a key requisite for preparing PHUs by polyaddition reaction with bis-or *** sustainable PHUs from CO_(2)-based five-membered cyclic carbonates(5CCs)obtained from biobased epoxides is a valuable strategy to bridge CO_(2) utilization and the upcycling of renewable *** this context,while many multi-5CC monomers reported in the literature are oil-based,recent efforts have led to the development of a large variety of multifunctional 5CCs that are produced by the combination of CO_(2) and renewable resources such as fatty acids and vegetable oils,lignin,terpenes,and *** this work,recent crucial advances(2019—2023)on PHUs prepared from bis-and multi-5CCs produced from CO_(2) and(partially/potentially)biobased substrates are reviewed with respect to their synthesis,thermal and mechanical properties,and their recent,emerging applications.

关键词： CO_(2) conversion Polyhydroxyurethanes Cyclic carbonates Biobased compounds Fatty acids Functional polymers Monomers Renewable resources

Design of functional biomaterials as substrates for corneal endothelium tissue engineering

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Regenerative Biomaterials 2022年第1期9卷 1018-1036页

作者： Begona M.Bosch elia Bosch-Rue Marina Perpiñan-Blasco Roman A.Perez Bioengineering Institute of Technology(BIT) Universitat Internacional de CatalunyaBarcelona 08195Spain Basic Sciences Department Universitat Internacional de CatalunyaBarcelona 08195Spain

Corneal endothelium defects are one of the leading causes of blindness *** actual treatment is transplantation,which requires the use of human cadaveric donors,but it faces several problems,such as global shortage of ***,new alternatives are being developed and,among them,cell therapy has gained interest in the last years due to its promising results in tissue ***,the direct administration of cells may sometimes have limited success due to the immune response,hence requiring the combination with extracellular mimicking *** this review,we present different methods to obtain corneal endothelial cells from diverse cell sources such as pluripotent or multipotent stem ***,we discuss different substrates in order to allow a correct implantation as a cell sheet and to promote an enhanced cell *** this reason,natural or synthetic matrixes that mimic the native environment have been *** matrixes have been optimized in terms of their physicochemical properties,such as stiffness,topography,composition and *** further enhance the matrixes properties,these can be tuned by incorporating certain molecules that can be delivered in a sustained manner in order to enhance biological ***,we elucidate future directions for corneal endothelial regeneration,such as 3D printing,in order to obtain patient-specific substrates.

关键词： corneal endothelium tissue engineering cell therapy biomaterials

Method of cells-based multiscale modeling of elastic properties of filament wound C/C-SiC including free Si and matrix porosity

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Journal of Materials Science & Technology 2019年第12期35卷 2906-2918页

作者： evan J.Pineda Marek Fassin Stefanie Reese Jaan-Willem Simon nASA Glenn Research Center 21000 Brookpark RoadMS 49/7ClevelandOH 44135United States Institute for Applied Mechanics RWTH Aachen UniversityMies-van-der-Rohe-Str.152074 AachenGermany

Three different multiscale models, based on the method of cells(generalized and high fidelity) micromechanics models were developed and used to predict the elastic properties of C/C-SiC composites. In particular, the following multiscale modeling strategies were employed: Concurrent modeling of all phases using the generalized method of cells, synergistic(two-way coupling in space) multiscale modeling with the generalized method of cells, and hierarchical(one-way coupling in space) multiscale modeling with the high fidelity generalized method of cells. The three models are validated against data from a hierarchical multiscale finite element model in the literature for a repeating unit cell of C/***, the multiscale models are used in conjunction with classical lamination theory to predict the stiffness of C/C-SiC plates manufactured via a wet filament winding and liquid silicon infiltration process recently developed by the German Aerospace Institute. Finally, un-reacted Si(or free Si) and porosity in the C matrix are included in the multiscale model, and the effect of these new phases on the stiffness and local stresses are considered.

关键词： Multiscale modeling C/C-SiC Ceramic matrix composites