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Novel T cells with.improved in vivo anti-tumor activity generated by RNA electroporation

Protein & Cell 2017年第7期8卷 514-526页

作者： Xiaojun Liu Sh.guang Jiang Ch.ngyun Fang h.a Li Xuh.a Zh.ng Fuqin Zh.ng carl h. june Yangbing Zh.o Key Laboratory for Experimental Teratology of Ministry of Education and Department of Immunology School of Basic Medical Sciences Shandong University Jinan 250012 China Center for Cellular Immunoth.rapies University of Pennsylvania Cancer Center Philadelphia PA 19104 USA Department of Path.logy and Laboratory Medicine Perelman School of Medicine University of Pennsylvania Philadelphia PA 19104-5156 USA

Th. generation of T cells with.maximal anti-tumor activities will significantly impact th. field of T-cell- based adoptive immunoth.rapy. In th.s report, we found th.t OKT3/IL-2-stimulated T cells were ph.notypically more h.terogeneous, with.enh.nced anti-tumor activity in vitro and wh.n locally administered in a solid tumor mouse model. To furth.r improve th. OKT3/IL-2-based T cell manufacturing procedure, we developed a novel T cell stimulation and expansion meth.d in wh.ch.periph.ral blood mononuclear cells were electroporated with.mRNA encoding a ch.meric membrane protein consisting of a single-ch.in variable fragment against CD3 and th. intracellular domains of CD28 and 4-1BB （OKT3-28BB）. Th. expanded T cells were ph.notypically and functionally similar to T cells expanded by OKT3/IL-2. Moreover, co-electroporation of CD86 and 4-1BBL could furth.r ch.nge th. ph.notype and enh.nce th. in vivo anti-tumor activity. Alth.ugh.T cells expanded by th. co- electroporation of OKT3-28BB with.CD86 and 4-1BBL sh.wed an increased central memory ph.notype, th. T cells still maintained tumor lytic activities as potent as th.se of OKT3/IL-2 or OKT3-28BB-stimulated T cells. In different tumor mouse models, T cells expanded by OKT3-28BB RNA electroporation sh.wed anti-tumor activities superior to th.se of OKT3/IL-2 T cells. h.nce, T cells with.both.a less differentiated ph.notype and potent tumor killing ability can be generated by RNA electroporation, and th.s T cell manufacturing procedure can be furth.r optimized by simply co-delivering oth.r splices of RNA, th.s providing a simple and cost-effec- tive meth.d for generating h.gh.quality T cells for adop- tive immunoth.rapy.

关键词： T lymph.cytes CAR manufacture genetransfer RNA electroporation

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Engineered T Cell Th.rapies from a Drug Development Viewpoint

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Engineering 2019年第1期5卷 140-149页

作者： Fang Ch.n Joseph.A. Fraietta carl h. june Zh.ngwei Xu J. Joseph.Melenh.rst Simon F. Lacey Department of Path.logy and Laboratory Medicine University of Pennsylvania Philadelphia PA 19104 USA Center for Cellular Immunoth.rapies University of Pennsylvania Philadelphia PA 19104 USA Parker Institute for Cancer Immunoth.rapy University of Pennsylvania Philadelphia PA 19104 USA Abramson Cancer Center University of Pennsylvania Philadelphia PA 19104 USA Department of Immunology Peking University Beijing 100871 China

Cancer is one of th. leading causes of death.worldwide. Recent advances in cellular th.rapy h.ve demonstrated th.t th.s platform h.s th. potential to give patients with.certain cancers a second ch.nce at life. Unlike ch.mical compounds and proteins, cells are living, self-replicating drugs th.t can be engineered to possess exquisite specificity. For example, T cells can be genetically modified to express ch.meric antigen receptors (CARs), endowing th.m with.th. capacity to recognize and kill tumor cells and form a memory pool th.t is ready to strike back against persisting malignant cells. Anti-CD19 ch.meric antigen receptor T cells (CART19s) h.ve demonstrated a remarkable degree of clinical efficacy for certain malignancies. Th. process of developing CART19 essentially follows th. conventional “one gene, one drug, one disease” paradigm derived from Paul Eh.lich.s “magic bullet” concept. With.major players with.n th. ph.rmaceutical industry joining forces to commercialize th.s new category of “living drugs,” it is useful to use CART19 as an example to examine th. similarities and differences in its development, compared with.th.t of a conventional drug. In th.s way, we can assimilate existing knowledge and identify th. most effective approach.for advancing similar strategies. Th.s article reviews th. use of biomarker-based assays to guide th. optimization of CAR constructs, preclinical studies, and th. evaluation of clinical efficacy;adverse effects (AEs);and CART19 cellular kinetics. Advanced tech.ologies and computational tools th.t enable th. discovery of optimal targets, novel CAR binding domains, and biomarkers predicting clinical response and AEs are also discussed. We believe th.t th. success of CART19 will lead to th. development of oth.r engineered T cell th.rapies in th. same manner th.t th. discovery of arsph.namine initiated th. era of synth.tic ph.rmaceuticals.

关键词： Engineered T cell th.rapies Ch.meric antigen receptor Drug development process Biomarkers CD19-specific ch.meric antigen receptor Anti-CD19 ch.meric antigen receptor T cells

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Th. BLOCh.CONSTANT OF h.LOMORPh.C MAPPINGS IN SEVERAL COMPLEX VARIABLES

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Ch.nese Science Bulletin 1992年第18期37卷 1512-1515页

作者：龚升 carl h. FITZGERALD Department of Math.matics University of Science and Technology of China Hefei 230026 PRC Department of Math.matics University of Califomia San Deigo La Jolla CA 92093 USA

Ⅰ. INTRODUCTIONTh.re is a long h.story in th. study on th. Bloch.constant of h.lomorph.c functions in th. unit disc of complex plane. Up to now, we do not know its exact value yet. Recently

关键词： Bloch constant h.lomorph.c mapping.

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A simulation-based meth.d to investigate occupant-centric controls

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Building Simulation 2021年第4期14卷 1017-1030页

作者： Moh.med M.Ouf june Young Park h.Burak Gunay Department of Building Civil and Environmental EngineeringConcordia University1515Rue Sainte-Catherine O.MontrealQCH3G 1MCanada Department of Civil Engineering The University of Texas at ArlingtonArlingtonTX76019USA Department of Civil Engineering Carleton University1125 Colonel By DriveOttawaONK1S 5B6Canada

Occupant-centric control (OCC) strategies rely on different algorith.s to learn and predict occupants’ patterns and preferences, th.n utilize th.se predictions to optimize building operations. h.wever, testing different OCC algorith.s or fine-tuning th.ir configurations in real buildings can be a length. process. To th.s end, we present a framework for testing OCCs in a simulation environment prior to field implementation. Th. proposed workflow entails using synth.tic occupant beh.viour models and simulating OCC strategies to learn th.ir preferences. Th. goal is to enable quick comparison of different OCC configurations under various scenarios by modifying occupant beh.viour assumptions, as well as climate and design parameters. For proof-of-concept, th. proposed meth.d was applied in a case-study to simulate OCCs for ligh.ing and h.ating/cooling setpoint adjustments in a single office under various occupant types, as well as OCC settings and design configurations. Results demonstrated th. benefits of th. proposed framework and its potential for providing a more h.listic evaluation of OCCs under different scenarios. Using th. proposed framework, building designers and operators can identify potential issues with.OCCs and fine-tune th.ir settings prior to field implementation.

关键词： occupant-centric controls building simulations energy efficiency comfort building operations ligh.ing h.AC controls

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Role of sand size on bacterial retention in bioch.r-amended sand filters

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Bioch.r 2019年第4期1卷 353-363页

作者： carl h.Bolster USDA-ARS 2413 Nashville Rd.B-5Bowling GreenKY 42101USA

Th. addition of bioch.r to sand columns can enh.nce th. retention of bacteria and th.s may provide a management strategy for removing bacteria from tile-drainage *** th.s study,th. role of sand size as a factor in controlling microbial reten-tion in bioch.r-amended sand columns was *** column experiments were conducted to quantify th. removal of two bacterial isolates(*** and Salmonella)and polystyrene microsph.res in 10-cm-long columns packed with.clean sand of th.ee different sizes(0.25,0.71,and 1.19 mm)at four bioch.r concentrations(0%,5%,10%,and 15%).Sorption studies were also performed to h.lp identify th. relative roles of sorption and ph.sical straining on th. removal of bacteria and microsph.res with.n th. *** th. large sand,th. log10 removal values(LRV)for *** increased from 0.22 to 0.49 for th. 0%and 15%bioch.r concentrations,respectively,wh.le LRV for Salmonella increased from 0.19 to *** th. small sand,increasing bioch.r concentration from 0%to 15%increased LRV from 0.11 to 1.9 for *** and from 0.20 to 4.6 for *** comparison,LRV for microsph.res in th. 15%bioch.r columns was only minimally h.gh.r th.n th. unamended columns for all th.ee sand *** from th. sorption studies sh.w th.t h.gh.sorption coefficients generally correlated with.h.gh.LRV indicating th.t sorption rath.r th.n ph.sical straining was th. primary mech.nism of retention in th. *** from th.s study furth.r our understanding of bacterial retention in bioch.r-amended porous media.

关键词： Bioch.r E.coli Salmonella Sand filter

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Comparing unamended and Fe-coated bioch.r on removal efficiency of bacteria,microsph.res,and dissolved ph.sph.rus in sand filters

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Bioch.r 2021年第3期3卷 329-338页

作者： carl h.Bolster USDA-ARS 2413 Nashville Rd.B-5Bowling GreenKY 42101USA

Th. effects of uncoated and Fe-coated bioch.rs(BC)on th. removal of bacteria,microsph.res,and dissolved reactive ph.sph.rus(DRP)in sand filters were *** were packed with.1.2 or 2.0-mm sand mixed with.30%(vol/vol)uncoated BC,Fe-coated BC,or a control with.ut *** of ***,Salmonella,and Enterococci increased from 23,42,and 25%in th. unamended 1.2-mm sand to 48,80,and 75%in th. uncoated BC treatment,th.ugh.only th. increase for Enterococci was significant(ph. Fe-coated BC,removal efficiencies were 89,93,and 94%,respectively,wh.ch.were all significantly(ph.n th. unamended sand but only th. removal of *** was significantly greater th.n th. uncoated BC sand *** th. 2.0-mm sands,th. only significant increase in removal following BC addition was observed for *** in microsph.re removal were generally consistent with.*** of DRP in th. unamended and uncoated BC filters was 33 and 13%(p>0.05),respectively,wh.reas removal in th. Fe-coated BC filters was 98%(ph.sorption experiments indicate th.t both.BCs similarly increased bacterial sorption to *** contrast,DRP sorption to th. unamended and uncoated BC-amended sands were similar(p>0.05)with.DRP sorption to th. Fe-coated BC-amended sand being significantly greater(ph.t Fe-coated BC is more effective at retaining DRP th.n bacteria and microsph.res in sand filters.

关键词： Bioch.r E.coli Enterococci Microsph.re Ph.sph.rus Salmonella Sand filter

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A DISTORTION Th.OREM FOR BIh.LOMORPh.C MAPPINGS IN C^2

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Ch.nese Science Bulletin 1990年第5期35卷 353-356页

作者：龚昇 carl h. FITZGERALD ROGER W. BARNARD University of Science and Tech.ology of Ch.na Hefei 230026 PRC Department of Math.matics University of California San Diego La Jolla CA 92093 USA Department of Math.matics Texas Tech. University Lubbock Texas 79409 USA

ⅠTh. classical distortion th.orems for families of univalent functions h.ve been studied not later th.n 1907 wh.n Kbe discovered h.s 'Verzerrangsatz'.

关键词： bih.iomorph.c mapping distortion th.orem convex mapping.

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Turbulence and Fossil Turbulence in Oceans and Lakes

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Ch.nese Journal of Oceanology and Limnology 2004年第1期22卷 1-23页

作者： Pak-Tao Leung carl h. Gibson Department of Mech.nical and Aerospace Engineering University of California San DiegoDepartments of Mechanical and Aerospace Engineering and Scripps Institution of Oceanography University of California San Diego La Jolla CA 92093-0411 USA La Jolla CA 92093-0411 USA

Turbulence is defined as an eddy-like state of fluid motion wh.re th. inertial-vortex forces of th. eddies are larger th.n any of th. oth.r forces th.t tend to damp th. eddies out. Energy cascades of irrotational flows from large scales to small are non-turbulent, even if th.y supply energy to turbulence. Turbulent flows are rotational and cascade from small scales to large, with.feedback. Viscous forces limit th. smallest turbulent eddy size to th. Kolmogorov scale. In stratified fluids, buoyancy forces limit large vertical overturns to th. Ozmidov scale and convert th. largest turbulent eddies into a unique class of saturated, non-propagating, internal waves, termed fossil-vorticity-turbulence. Th.se waves h.ve th. same energy but different properties and spectral forms th.n th. original turbulence patch. Th. Gibson (1980, 1986) th.ory of fossil turbulence applies universal similarity th.ories of turbulence and turbulent mixing to th. vertical evolution of an isolated patch.of turbulence in a stratified fluid as its growth.is constrained and fossilized by buoyancy forces. Quantitative h.drodynamic-ph.se-diagrams (h.Ds) from th. th.ory are used to classify microstructure patch.s according to th.ir h.drodynamic states. Wh.n analyzed in h.D space, previously publish.d oceanic datasets sh.wed th.ir dominant microstructure patch.s are fossilized at large scales in all layers. Laboratory and field measurements suggested ph.toplankton species with.different swimming abilities adjust th.ir growth.strategies by pattern recognition of turbulence-fossil-turbulence dissipation and persistence times th.t predict survival-relevant surface layer sea ch.nges. New data collected near a h.nolulu waste-water outfall sh.wed th. small-to-large evolution of oceanic turbulence microstructure from active to fossil states, and revealed th. ability of fossil-density-turbulence patch.s to absorb, and vertically radiate, internal wave energy, information, and enh.nced turbulent-mixing-rates

关键词： fossil turbulence turbulence turbulent mixing and diffusion ocean wastewater outfalls ph.toplankton remote sensing

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Th. GROWTh.AND 1/4-Th.OREMS FOR STARLIKE MAPPINGS IN C^n

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Ch.nese Science Bulletin 1990年第5期35卷 357-359页

作者： carl h. FITZ GERALD 龚昇 ROGER W. BARNARD Department of Math.matics University of California San Diego La Jolla CA 92093 USA University of Science and Tech.ology of Ch.na Hefei 230026 PRC Department of Math.matics Texas Tech. University Lubbock Texas 79409 USA

ⅠMore th.n fifty years ago, h.nri Cartant ~j suggested th.t geometric function th.ory ofone complex variable sh.uld be extended to bih.lomorph.c mappings of several complexvariables. In particular, h. cited th. special classes of starlike and convex mappings asappropriate topics for generalization. In noting some of th. difficulties of generalization, h.pointed out th. Growth.Th.orem as one of th. results th.t would not extend to th.polydisc (nor to th. ball). Also, h. observed th.t for normalized bih.lomorph.c

关键词： starlike mapping convex mapping Koebe 1/4-Th.orem.

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Th. Sch.arzian Derivative in Several Complex Variables

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Science Ch.na Math.matics 1993年第5期36卷 513-523页

作者：龚昇 carl h.FitzGerald Department of Math.matics University of Science and Technology of China Hefei 230026 PRC Department of Math.matics University of California San Diego La Jolla CA 92093 USA

Th. Sch.arzian derivative of h.lomorph.c mappings on some classical domains is defined. Some Sch.arzian properties are studied.

关键词： Seh.arzian derivative classical domains.

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