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Analysis of Pathway Activity in Prim.ry Tum.rs and NCI60 Cell Lines Using Gene Expression Profiling Data

Genom.cs, Proteom.cs & Bioinform.tics 2007年第1期5卷 15-24页

作者： Xing-Dong Feng Shu-Guang Huang Jian-Yong Shou Bi-Rong Liao Jonathan m. Yingling Xiang Ye Xi Lin lawrence m. gelbert Eric W. Su Jude E. Onyia Shu-Yu Li Integrative Biology Lilly Research Laboratories Eli Lilly and Company Lilly Corporate Center Indianapolis IN 46285 USA Global Discovery ＆ Developm.nt Statistics Lilly Research Laboratories Eli Lilly and Company Lilly Corporate Center Indianapolis IN 46285 USA Cancer Discovery Research Lilly Research Laboratories Eli Lilly and Company Lilly Corporate Center Indianapolis IN 46285 USA

To determ.ne cancer pathway activities in nine types of prim.ry tum.rs and NCI60 cell lines, we applied an in silico approach by exam.ning gene signatures reflective of consequent pathway activation using gene expression data. Supervised learning approaches predicted that the Ras pathway is active in -70% of lung adenocarcinom.s but inactive in m.st squam.us cell carcinom.s, pulm.nary carcinoids, and sm.ll cell lung carcinom.s. In contrast, the TGF-β, TNF-α, Src, m.c, E2F3, and β-catenin pathways are inactive in lung adenocarcinom.s. We predicted an active Ras, m.c, Src, and/or E2F3 pathway in significant percentages of breast cancer, colorectal carcinom., and gliom.s. Our results also suggest that Ras m.y be the m.st prevailing oncogenic pathway. Additionally, m.ny NCI60 cell lines exhibited a gene signature indicative of an active Ras, m.c, and/or Src, but not E2F3, β-catenin, TNF-α, or TGF-β pathway. To our knowledge, this is the first com.rehensive survey of cancer pathway activities in nine m.jor tum.r types and the m.st widely used NCI60 cell lines. The ＂gene expression pathway signatures＂ we have defined could facilitate the understanding of m.lecular m.chanism. in cancer developm.nt and provide guidance to the selection of appropriate cell lines for cancer research and pharm.ceutical com.ound screening.

关键词： cancer pathways gene expression profiling supervised learning classification

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Control of Cell Wall Extensibility during Pollen Tube Growth

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m.lecular Plant 2013年第4期6卷 998-1017页

作者： Peter K. Hepler Caleb m. Rounds lawrence J. Winship Biology Departm.nt University of Massachusetts Amherst MA 01003 USA School of Natural Science Hampshire College Amherst MA 01002 USA

In this review, we address the question of how the tip-growing pollen tube achieves its rapid rate of elongation while m.intaining an intact cell wall. Although turgor is essential for growth to occur, the local expansion rate is controlled by local changes in the viscosity of the apical wall. We focus on several different structures and underly- ing processes that are thought to be m.jor participants including exocytosis, the organization and activity of the actin cytoskeleton, calcium.and proton physiology, and cellular energetics. We think that the actin cytoskeleton, in particular the apical cortical actin fringe, directs the flow of vesicles to the apical dom.in, where they fuse with the plasm. m.m. brane and contribute their contents to the expanding cell wall. While pH gradients, as generated by a proton-ATPase located on the plasm. m.m.rane along the side of the clear zone, m.y regulate rapid actin turnover and new polym.ri- zation in the fringe, the tip-focused calcium.gradient biases secretion towards the polar axis. The recent data showing that exocytosis of new wall m.terial precedes and predicts the process of cell elongation provide support for the idea that the intussusception of newly secreted pectin contributes to decreases in apical wall viscosity and to cell expansion. Other prim. factors will be the localization and activity of the enzym. pectin m.thyl-esterase, and the chelation of calcium.by pectic acids. Finally, we acknowledge a role for reactive oxygen species in the control of wall viscosity.

关键词： cell expansion cell walls cytoskeleton dynam.cs polarity pollen developm.nt.

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Recent research situation in tin dioxide nanom.terials： synthesis, m.crostructures, and properties

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Frontiers of m.terials Science 2013年第3期7卷 203-226页

作者： Zhi-Wen CHEN Chan-Hung SHEK C. m. lawrence WU Joseph K. L. LAI Shanghai Applied Radiation Institute School of Environmental and Chemical Engineering Shanghai University Shanghai 200444 China Departm.nt of Physics and m.terials Science City University of Hong Kong Tat Chee Avenue Kowloon Tong Hong Kong China

This review article sum.arizes the new research in solid-state physical chem.stry understanding of the m.crostructure characteristics of sem.conductor tin oxide thin film. m.de in the last years in our group. The work m.inly focuses on the fabrication technology of sem.conductor tin oxides thin film. by using pulsed laser deposition （PLD） as well as the application of this technology on new m.cro- and nanostructured m.terials. It is an interdisciplinary work that integrates the areas of physics, chem.stry and m.terials science.

关键词： tin dioxide thin film synthesis m.crostructure nanostructure property

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Vascularization in interconnected 3D printed Ti-6Al-4V foam. with hydrogel m.trix for biom.dical bone replacem.nt im.lants

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Science China m.terials 2018年第4期61卷 565-578页

作者： Victor L.Correa Kristine m.Garza lawrence E.m.rr Departm.nt of m.tallurgical Materials and Biomedical Engineering University of Texas at El Paso Departm.nt of Biological Sciences University of Texas at El Paso

Vascularization on newly im.lanted m.tal orthopedic im.lants has rem.ined a challenge in the field of tissue engineering. To address this challenge, in this research,an interconnected foam.structure of Ti-6 Al-4 V was m.crofabricated by electron beam.m.lting(EBm. technique. The foam.in question has a density of 1.77 g cm.3 with 60% porosity and a tensile strength of 18 GPa. An extracellular m.trix based hydrogel was added as an aqueous m.trix to the *** m.m.tic stress has been closely related to m.ny wound healing biom.dical applications as it increases survival and proliferation m.lecular signals. To that end, increased expression of hypoxia-inducible factor-1α(Hif-1α) and vascular endothelial growth factor(VEGF) in the aqueous hydrogel m.trix was achieved by the addition of a hypoxia m.m.tic deferoxam.ne m.sylate(DFm.. In this study, the form.tion of an endothelial network was achieved in a hydrogel m.trix in the presence of the before m.ntioned 3 D printed m.tal foam. Cellular viability, fluorescent m.croscopy and scanning electron m.croscopy im.ging analysis dem.nstrate that pre-osteoblasts undergo proliferation and also attach efficiently to the foam.when exposed to DFm. Hum.n um.ilical vascular endothelial cells(HUVECs) were grown in an extracellular m.trix-like 3 D hydrogel and a hypoxia-like stress was achieved. This research dem.nstrates that pre-osteoblast cells undergo cell differentiation and increase the production of hydroxyapatite on exposure to the hypoxia m.m.tic m.lecule. This proposed approach encom.asses an ideal prototype for a com.letely living im.lanted structure for future orthopedic im.lants.

关键词： Ti-6Al-4V electron beam.m.lting angiogenesis deferoxam.ne m.sylate hydrogel vascularization

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Distinctive param.ters of action of stem.cells and m.dulatory m.croenvironm.ntal m.crocirculation in gliom.genesis

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Stem.Cell Discovery 2013年第1期3卷 1-6页

作者： lawrence m. Agius Departm.nt of Pathology Mater Dei Hospital University of Malta Medical School Msida Malta

Definition of the m.lignant transform.tion event is central to a distinction between neural stem.cells and cancer stem.cells. In such m.nner, the descriptive analysis of various tum.rs such as gliom.s would allow for the distinction of genetic injury and probably epigenetic events that transform.gene transcription pathways. Hypoxia is a m.jor conditioning influence acting on stem.cell niche m.croenvironm.nts that evolve in term. particularly of m.cro-vascular dynam.cs. The increm.ntal involvem.nt of entire fields of cancerization allows for the establishm.nt of perm.ssive conditions of repetitive nature and within the contextual involvem.nt of m.ltiple clones of injured cells that condition, in turn, the stem.cell niche. In view of the establishm.nt of progressive m.lignant change, it is significant to view the cancerization as an integral involvem.nt of both sequential and concurrent events in defining the roles of stem.cells and cancer stem.cells in term. of a prim.l process of dedifferentiation beyond sim.le m.rkers of m.rphologic transform.tion.

关键词： Stem Cells Gliom.genesis m.crocirculation m.lignant Transform.tion

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HIV-1 Prim.rily Targets the Innate Im.une System.and Only Secondarily m.dulates Adaptive Im.une Cell Depletion

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World Journal of AIDS 2012年第3期2卷 226-231页

作者： lawrence m. Agius Departm.nt of Pathology Mater Dei Hospital Tal-Qroqq Malta 2University of m.lta m.dical School Msida Malta

Persistence of HIV-1 infection allows for perm.ssive m.croenvironm.ntal conditioning in term. of contextual innate im.une participation. The progression of host cell injury constitutes an additional param.tric form.lation in self-am.lifying m.dulation of the adaptive im.une response in a m.nner that inclusively prom.tes the em.rgence of a final stage of AIDS that is both depletive and perm.ssive for opportunistic infections and various form. of neoplasia. It is within contextual indices of prom.tion of depleted T-helper lym.hocytes and of augm.nted virem.c loads that m.nifestations of classic lesions em.rge as the AIDS phenom.non. It is further to be realized that an apoptotic response of m.ltiple cell subtypes including T-lym.hocytes includes host-cell participation within form.lated settings of further persistence of the retroviral infection. An all-inclusive phenom.non of dendritic cell-lym.hocyte synapse form.lation corresponds to the establishm.nt of HIV-1 infection that specifically conditions all subsequent stages in depletion of the injured host cells regardless of the dynam.cs or kinetics of the retroviral replicative infectious process itself.

关键词： HIV-1 Infection Aids Im.une Persistence

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Operative sequentiality in tum.r differentiation and progression as protein m.lecular structure and sequence context in m.dulating alternative splicing events

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Open Journal of Genetics 2013年第2期3卷 83-88页

作者： lawrence m. Agius Departm.nt of Pathology Mater Dei Hospital University of Malta Medical School Msida Malta

This review article discusses dim.nsional reconstruction of alternative splicing that not only affects prim.rily the distributional dim.nsions of isoform. of various protein species but especially influences the nature of interactivity events between various protein species and also the structure of the given protein m.lecules. In such term., disorders of differentiation of individual tum.rs and of tum.r types and subtypes would correlate with distinctive dim.nsions of expression of a lim.ted num.er of genes in various m.des of expressed selectivity program.. In particular, the differentiation program. of norm.l tissues would correlate with com.inatorial system. of splicing factors and of auxiliary factors in the developm.nt of patterns of gene expression. The significance of m.s-splicing events is consonant with the wide range of phenotypic expression of neoplastic lesions and in the great variety of differentiation patterns and also of the variable degrees of differentiation of various com.onents of a given neoplasm. The structure of given protein isoform. resulting from.alternative splicing correlate with the sequence context of exons in the enhancem.nt or inhibition of splicing events and would also influence pathobiologic behavior patterns of given neoplastic lesions. The developm.nt of abnorm.l cell signalling pathways and of interactivity patterns in a com.inatorial way would directly influence the stability and trafficking dynam.cs of given protein m.lecular species in inducing an abundance of protein isoform.production. Series of m.lti-com.onent system. ranging from.receptivity to consequential pathways of developm.nt of differential phenotype would allow for a high degree of m.dulatory effect within system. im.licating in particular the interactions of individual tum.r cells with each other and with the m.trix com.onents. It is within the context of constitutive versus alternative splicing events that this review article proposes that proportional recreati

关键词： RNA Splicing Neoplasm. Tum.rigenesis Protein Isoform.

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Strategies for creating living, additively m.nufactured, open-cellular m.tal and alloy im.lants by prom.ting osseointegration,osteoinduction and vascularization: An overview

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Journal of m.terials Science & Technology 2019年第2期35卷 231-241页

作者： lawrence E.m.rr Departm.nt of m.tallurgical Materials and Biomedical Engineering The University of Texas at El Paso W.m.Keck Center for 3D Innovation The University of Texas at El Paso

Additive m.nufacturing of porous, open-cellular m.tal or alloy im.lants, fabricated by laser or electron beam.m.lting of a powder bed, is briefly reviewed in relation to optim.zing biom.chanical com.atibility by assuring elastic(Young's) m.dulus m.tching of proxim.te bone, along with corresponding pore sizes assuring osseointegration and vasculature developm.nt and m.gration. In addition, associated, requisite com.ressive and fatigue strengths for such im.lants are described. Strategies for optim.zing osteoblast(bone cell) developm.nt and osteoinduction as well as vascularization of tissue in 3 D scaffolds and tissue engineering constructs for bone repair are reviewed in relation to the biology of osteogenesis and neovascularization in bone, and the role of associated growth factors, bone m.rphogenic proteins, signaling m.lecules and the like. Prospects for infusing hydrogel/collagen m.trices containing these cellular and protein com.onents or surgically extracted intram.dullary(bone m.rrow) concentrate/aspirate containing these biological and cell com.onents into porous im.lants are discussed, as strategies for creating living im.lants, which over the long term.would act as m.tal or alloy scaffolds.

关键词： Additive m.nufacturing Open cellular m.tal and alloy im.lants Electron beam m.lting Living im.lant strategies Vascularization Osseointegration Osteoinduction

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Frontiers of 3D Printing/Additive m.nufacturing: from.Hum.n Organs to Aircraft Fabrication

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Journal of m.terials Science & Technology 2016年第10期32卷 987-995页

作者： lawrence E.m.rr Departm.nt of m.tallurgical Materials and Biomedical Engineering The University of Texas at El Paso W.m.Keck Center for 3D Innovation The University of Texas at El Paso

It has been m.re than three decades since stereolithography began to em.rge in various form. of additive m.nufacturing and 3D printing. Today these technologies are proliferating worldwide in various form. of advanced m.nufacturing. The largest segm.nt of the 3D printing m.rket today involves various polym.r com.onent fabrications, particularly com.lex structures not attainable by other m.nufacturing *** printer head system. have also been adapted to selectively print various speciated hum.n cells and special m.lecules in attem.ts to construct hum.n organs, beginning with skin and various tissue patches. These efforts are discussed along with m.tal and alloy fabrication of a variety of im.lant and bone replacem.nt com.onents by creating powder layers, which are selectively m.lted into com.lex form.（such as foam. and other open-cellular structures） using laser and electron beam. directed by CAD software. Efforts to create a ＂living im.lant＂ by bone ingrowth and eventual vascularization within these im.lants will be discussed briefly. Novel printer heads for direct m.tal droplet deposition as in other 3D printing system. are briefly described since these concepts will allow for the eventual fabrication of very large and com.lex products, including autom.tive and aerospace structures and com.onents.

关键词： 3D printing/additive m.nufacturing Laser and electron beam.m.lting Organ printing Organ and im.lant vascularization m.tal droplet printing

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Involvem.nt of eicosanoids in the pathogenesis of pancreatic cancer: the roles of cyclooxygenase-2 and 5-lipoxygenase

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World Journal of Gastroenterology 2014年第31期20卷 10729-10739页

作者： lawrence m.Knab Paul J Grippo David J Bentrem Departm.nt of Surgery Northwestern University Feinberg School of Medicine Robert H Lurie Com.rehensive Cancer Center Northwestern University Jesse Brown VA m.dical Center

The interplay between inflam.ation and cancer progression is a growing area of research. A com.ination of clinical, epidem.ological, and basic science investigations indicate that there is a relationship between inflam.atory changes in the pancreas and neoplastic progression. Diets high in ω-6 polyunsaturated fatty acids provide increased substrate for arachidonic acid m.tabolism.by cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX) to form.eicosanoids. These eicosanoids directly contribute to pancreatic cancer cell proliferation. Both COX-2 and 5-LOX are upregulated in m.ltiple cancer types, including pancreatic cancer. In vitro studies using pancreatic cancer cell lines have dem.nstrated upregulation of COX-2 and 5-LOX at both the m.NA and protein levels. When COX-2 and 5-LOX are blocked via a variety of m.chanism., cancer cell proliferation is abrogated both in vitro and in vivo. The m.chanism.of COX-2 has been shown to include effects on apoptosis as well as angiogenesis. 5-LOX has been im.licated in apoptosis. The use of COX-2 and 5-LOX inhibitors in clinical studies in patients with pancreatic cancer has been lim.ted. Patient enrollm.nt has been restricted to those with advanced disease which m.kes evaluation of these drugs as chem.preventive agents difficult. COX-2 and 5-LOX expression have been shown to be present during the early neoplastic changes of pancreatic cancer, well before progression to invasive disease. This indicates that the ideal role for these interventions is early in the disease process as preventive agents, perhaps in patients with chronic pancreatitis or hereditary pancreatitis.

关键词： Arachidonic acid Eicosanoid Cyclooxygenase-2 5-lipoxygenase Pancreatic cancer Inflam.ation

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