ヒト前立腺癌の進行モデルと新しい治療法

著者等はヒト前立腺癌の進展に関した2つの細胞モデルを開発した.LNCaP前立腺癌進展モデルは, 生体内での前立腺又は骨の間質細胞とLNCaP細胞との相互作用に基づいており, これによって腫瘍形成能と転移能を獲得したものである.派生株C4-2は去勢動物で容易に発育し, リンパ節, 精嚢腺, 骨に転移する.次のモデルARCaPは, 癌性腹水由来のヒト前立腺癌細胞で, アンドロゲン及びエストロゲンによって増殖を抑制され, 去勢下で腫瘍を形成した.ARCaPはアンドロゲン受容体及びPSAを低レベルで発現し, 同所移植によって肝, 腎, 骨等に高頻度で転移した.これらのモデルを用いて遺伝子治療の研究を行ったOur laboratory has developed two cellular models of human prostate cancer progression. The LNCaP prostate cancer progression model is based upon the well-known cellular interaction between human prostate or bone stromal cells and LNCaP cells in vivo. The marginally tumorigenic LNCaP cells acquired tumorigenic and metastatic potential upon cellular interaction with either prostate or bone fibroblasts. A subline termed C4-2 was observed to grow readily in castrated animals and acquired metastatic potential spreading from the primary tumor site to the lymph node, the seminal vesicles, and the axial skeleton, resulting in an intense osteoblastic reaction. The second model is ARCaP, where prostate cancer cells derived from the ascites fluid of a man with metastatic disease exhibited an Androgen- and estrogen-Repressed Prostate Cancer cell growth and tumor formation in either a hormone-deficient or a castrated environment. However, the growth of either the tumor cells in vitro or the tumors in vivo was suppressed by both estrogen and androgen. While the tumor cells expressed low levels of androgen receptor and prostate-specific antigen (PSA), they were highly metastatic when inoculated orthotopically. Distant metastases to a number of organs were detected, including the liver, lung, kidney, and bone. We have employed a human prostate cancer progression model as a system to study the efficacy of gene therapy. Results of the study show that whereas universal promoters, such as Cytomegalovirus (CMV) and Rous Sarcoma Virus (RSV) promoter-driven tumor suppressors (e.g. p53, p21, and p16), were effective in inhibiting prostate tumor growth, the advantages of driving the expression of therapeutic toxic genes using a tissue-specific promoter prostate-specific antigen (PSA) and a tumor--but not tissue-specific promoter, osteocalcin (OC), are preferred. In the case of the PSA promoter, we can achieve cell-kill in PSA-producing human prostate cancer cells. To circumvent the supporting role of bone stroma for prostate cancer epithelial growth, we have recently developed a novel concept where the expression of therapeutic toxic genes is driven by a tumor--but not a tissue-specific OC promoter. Osteocalcin-thymidine kinase (OC-TK) was found to efficiently eradicate the growth of osteosarcoma, prostate, and brain tumors both in vitro and in vivo. We observed that androgen-independent human prostate cancer cells lines expressed OC-TK at higher levels than androgen-dependent human prostate cancer cell lines. We have obtained data to suggest that Ad-OC-TK plus a pro-drug acyclovir (ACV) may be used as an effective therapy to treat prostate cancer bone metastasis in models where the growth of androgen-independent PC-3 and C4-2 tumors in the bone has occurred

Plug-In Hybrid Electric Vehicle Value Proposition Study: Interim Report: Phase I Scenario Evaluation

Plug-in hybrid electric vehicles (PHEVs) offer significant improvements in fuel economy, convenient low-cost recharging capabilities, potential environmental benefits, and decreased reliance on imported petroleum. However, the cost associated with new components (e.g., advanced batteries) to be introduced in these vehicles will likely result in a price premium to the consumer. This study aims to overcome this market barrier by identifying and evaluating value propositions that will increase the qualitative value and/or decrease the overall cost of ownership relative to the competing conventional vehicles and hybrid electric vehicles (HEVs) of 2030 During this initial phase of this study, business scenarios were developed based on economic advantages that either increase the consumer value or reduce the consumer cost of PHEVs to assure a sustainable market that can thrive without the aid of state and Federal incentives or subsidies. Once the characteristics of a thriving PHEV market have been defined for this timeframe, market introduction steps, such as supportive policies, regulations and temporary incentives, needed to reach this level of sustainability will be determined. PHEVs have gained interest over the past decade for several reasons, including their high fuel economy, convenient low-cost recharging capabilities, potential environmental benefits and reduced use of imported petroleum, potentially contributing to President Bush's goal of a 20% reduction in gasoline use in ten years, or 'Twenty in Ten'. PHEVs and energy storage from advanced batteries have also been suggested as enabling technologies to improve the reliability and efficiency of the electric power grid. However, PHEVs will likely cost significantly more to purchase than conventional or other hybrid electric vehicles (HEVs), in large part because of the cost of batteries. Despite the potential long-term savings to consumers and value to stakeholders, the initial cost of PHEVs presents a major market barrier to their widespread commercialization. The purpose of this project is to identify and evaluate value-added propositions for PHEVs that will help overcome this market barrier. Candidate value propositions for the initial case study were chosen to enhance consumer acceptance of PHEVs and/or compatibility with the grid. Potential benefits of such grid-connected vehicles include the ability to supply peak load or emergency power requirements of the grid, enabling utilities to size their generation capacity and contingency resources at levels below peak. Different models for vehicle/battery ownership, leasing, financing and operation, as well as the grid, communications, and vehicle infrastructure needed to support the proposed value-added functions were explored during Phase 1. Rigorous power system, vehicle, financial and emissions modeling were utilized to help identify the most promising value propositions and market niches to focus PHEV deployment initiatives

Guidelines of the American Society of Mammalogists for the use of wild mammals in research

Guidelines for use of wild mammal species are updated from the American Society of Mammalogists (ASM) 2007 publication. These revised guidelines cover current professional techniques and regulations involving mammals used in research and teaching. They incorporate additional resources, summaries of procedures, and reporting requirements not contained in earlier publications. Included are details on marking, housing, trapping, and collecting mammals. It is recommended that institutional animal care and use committees (IACUCs), regulatory agencies, and investigators use these guidelines as a resource for protocols involving wild mammals. These guidelines were prepared and approved by the ASM, working with experienced professional veterinarians and IACUCs, whose collective expertise provides a broad and comprehensive understanding of the biology of nondomesticated mammals in their natural environments. The most current version of these guidelines and any subsequent modifications are available at the ASM Animal Care and Use Committee page of the ASM Web site (http://mammalsociety.org/committees/index.asp).American Society of Mammalogist

During COVID Sickle Cell Continues: Coping Among Young Adults

To culminate a virtual photovoice research project, artists created a photo exhibition. During this photo exhibition, you will hear from those living with sickle cell disease as they share their realities and experiences of navigating the COVID-19 pandemic. The title carries great significance: \u27During COVID, Sickle Cell Continues.\u27 It echoes the fact that despite civil unrest, a global pandemic, and political shifts, sickle cell disease persists. Our artists share photographs that capture their experiences, and a Q&A session with some of the artists takes place at the end

2016 Guidelines of the American Society of Mammalogists for the use of wild mammals in research and education.

Guidelines for use of wild mammal species in research are updated from Sikes et al. (2011). These guidelines cover current professional techniques and regulations involving the use of mammals in research and teaching; they also incorporate new resources, procedural summaries, and reporting requirements. Included are details on capturing, marking, housing, and humanely killing wild mammals. It is recommended that Institutional Animal Care and Use Committees (IACUCs), regulatory agencies, and investigators use these guidelines as a resource for protocols involving wild mammals, whether studied in the field or in captivity. These guidelines were prepared and approved by the American Society of Mammalogists (ASM), in consultation with professional veterinarians experienced in wildlife research and IACUCs, whose collective expertise provides a broad and comprehensive understanding of the biology of nondomesticated mammals. The current version of these guidelines and any subsequent modifications are available online on the Animal Care and Use Committee page of the ASM website (http://mammalogy.org/uploads/committee_files/CurrentGuidelines.pdf). Additional resources pertaining to the use of wild animals in research are available at: http://www.mammalsociety.org/committees/animal-care-and-use#tab3. Resumen—Los lineamientos para el uso de especies de mamíferos de vida silvestre en la investigación con base en Sikes et al. (2011) se actualizaron. Dichos lineamientos cubren técnicas y regulaciones rofesionales actuales que involucran el uso de mamíferos en la investigación y enseñanza; también incorporan recursos nuevos, resúmenes de procedimientos y requisitos para reportes. Se incluyen detalles acerca de captura, marcaje, manutención en cautiverio y eutanasia de mamíferos de vida silvestre. Se recomienda que los comités institucionales de uso y cuidado animal (cifras en inglés: IACUCs), las agencias reguladoras y los investigadores se adhieran a dichos lineamientos como fuente base de protocolos que involucren mamíferos de vida silvestre, ya sea investigaciones de campo o en cautiverio. Dichos lineamientos fueron preparados y aprobados por la ASM, en consulta con profesionales veterinarios experimentados en investigaciones de vida silvestre y IACUCS, de quienes cuya experiencia colectiva provee un entendimiento amplio y exhaustivo de la biología de mamíferos no-domesticados. La presente version de los lineamientos y modificaciones posteriores están disponibles en línea en la página web de la ASM, bajo Cuidado Animal y Comité de Uso: http://mammalogy.org/uploads/committee_files/CurrentGuidelines.pdf). Recursos adicionales relacionados con el uso de animales de vida silvestre para la investigación se encuentran disponibles en (http://www.mammalsociety.org/committees/animal-care-and-use#tab3)

Custom Integrated Circuits

Contains reports on twelve research projects.Analog Devices, Inc.International Business Machines, Inc.Joint Services Electronics Program (Contract DAAL03-86-K-0002)Joint Services Electronics Program (Contract DAAL03-89-C-0001)U.S. Air Force - Office of Scientific Research (Grant AFOSR 86-0164)Rockwell International CorporationOKI Semiconductor, Inc.U.S. Navy - Office of Naval Research (Contract N00014-81-K-0742)Charles Stark Draper LaboratoryNational Science Foundation (Grant MIP 84-07285)National Science Foundation (Grant MIP 87-14969)Battelle LaboratoriesNational Science Foundation (Grant MIP 88-14612)DuPont CorporationDefense Advanced Research Projects Agency/U.S. Navy - Office of Naval Research (Contract N00014-87-K-0825)American Telephone and TelegraphDigital Equipment CorporationNational Science Foundation (Grant MIP-88-58764

Met-Independent Hepatocyte Growth Factor-mediated regulation of cell adhesion in human prostate cancer cells

BACKGROUND: Prostate cancer cells communicate reciprocally with the stromal cells surrounding them, inside the prostate, and after metastasis, within the bone. Each tissue secretes factors for interpretation by the other. One stromally-derived factor, Hepatocyte Growth Factor (HGF), was found twenty years ago to regulate invasion and growth of carcinoma cells. Working with the LNCaP prostate cancer progression model, we found that these cells could respond to HGF stimulation, even in the absence of Met, the only known HGF receptor. The new HGF binding partner we find on the cell surface may help to clarify conflicts in the past literature about Met expression and HGF response in cancer cells. METHODS: We searched for Met or any HGF binding partner on the cells of the PC3 and LNCaP prostate cancer cell models, using HGF immobilized on agarose beads. By using mass spectrometry analyses and sequencing we have identified nucleolin protein as a novel HGF binding partner. Antibodies against nucleolin (or HGF) were able to ameliorate the stimulatory effects of HGF on met-negative prostate cancer cells. Western blots, RT-PCR, and immunohistochemistry were used to assess nucleolin levels during prostate cancer progression in both LNCaP and PC3 models. RESULTS: We have identified HGF as a major signaling component of prostate stromal-conditioned media (SCM) and have implicated the protein nucleolin in HGF signal reception by the LNCaP model prostate cancer cells. Antibodies that silence either HGF (in SCM) or nucleolin (on the cell surfaces) eliminate the adhesion-stimulatory effects of the SCM. Likewise, addition of purified HGF to control media mimics the action of SCM. C4-2, an LNCaP lineage-derived, androgen-independent human prostate cancer cell line, responds to HGF in a concentration-dependent manner by increasing its adhesion and reducing its migration on laminin substratum. These HGF effects are not due to shifts in the expression levels of laminin-binding integrins, nor can they be linked to expression of the known HGF receptor Met, as neither LNCaP nor clonally-derived C4-2 sub-line contain any detectable Met protein. Even in the absence of Met, small GTPases are activated, linking HGF stimulation to membrane protrusion and integrin activation. Membrane-localized nucelolin levels increase during cancer progression, as modeled by both the PC3 and LNCaP prostate cancer progression cell lines. CONCLUSION: We propose that cell surface localized nucleolin protein may function in these cells as a novel HGF receptor. Membrane localized nucleolin binds heparin-bound growth factors (including HGF) and appears upregulated during prostate cancer progression. Antibodies against nucleolin are able to ameliorate the stimulatory effects of HGF on met-negative prostate cancer cells. HGF-nucleolin interactions could be partially responsible for the complexity of HGF responses and met expression reported in the literature

Should the poultry red mite Dermanyssus gallinae be of wider concern for veterinary and medical science?

The poultry red mite Dermanyssus gallinae is best known as a threat to the laying-hen industry; adversely affecting production and hen health and welfare throughout the globe, both directly and through its role as a disease vector. Nevertheless, D. gallinae is being increasingly implemented in dermatological complaints in non-avian hosts, suggesting that its significance may extend beyond poultry. The main objective of the current work was to review the potential of D. gallinae as a wider veterinary and medical threat. Results demonstrated that, as an avian mite, D. gallinae is unsurprisingly an occasional pest of pet birds. However, research also supports that these mites will feed from a range of other animals including: cats, dogs, rodents, rabbits, horses and man. We conclude that although reported cases of D. gallinae infesting mammals are relatively rare, when coupled with the reported genetic plasticity of this species and evidence of permanent infestations on non-avian hosts, potential for host-expansion may exist. The impact of, and mechanisms and risk factors for such expansion are discussed, and suggestions for further work made. Given the potential severity of any level of host-expansion in D. gallinae, we conclude that further research should be urgently conducted to confirm the full extent of the threat posed by D. gallinae to (non-avian) veterinary and medical sectors

Empirical Legal Studies Before 1940: A Bibliographic Essay

The modern empirical legal studies movement has well-known antecedents in the law and society and law and economics traditions of the latter half of the 20th century. Less well known is the body of empirical research on legal phenomena from the period prior to World War II. This paper is an extensive bibliographic essay that surveys the English language empirical legal research from approximately 1940 and earlier. The essay is arranged around the themes in the research: criminal justice, civil justice (general studies of civil litigation, auto accident litigation and compensation, divorce, small claims, jurisdiction and procedure, civil juries), debt and bankruptcy, banking, appellate courts, legal needs, legal profession (including legal education), and judicial staffing and selection. Accompanying the essay is an extensive bibliography of research articles, books, and reports