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

Centro educativo para niños con capacidades especiales: físicas, psicosociales e intelectuales “Jesús para los niños” Cañar, Ecuador

Esta tesis aborda el diseño de un nuevo centro educativo llamado "Jesús para los niños", ubicado en la ciudad de Cañar. El objetivo principal de este centro es proporcionar una educación inclusiva y de calidad a niños de 5 a 11 años con discapacidades físicas, psicoso- ciales e intelectuales, promoviendo su bienestar, participación y óptimo aprendizaje. Se pretende abordar esta necesidad debido a que el establecimiento actual no cumple con los parámetros necesa- rios para brindar una educación de calidad. La investigación se basa en un enfoque multidisciplinario que combi- na aspectos de la arquitectura escolar inclusiva , pedagogía y ergo- nomía . Se lleva a cabo un análisis exhaustivo de las características y requisitos de los estudiantes con necesidades educativas especia- les, teniendo en cuenta aspectos físicos, cognitivos y emocionales. El diseño propuesto cumple con las normativas locales y los princi- pios de accesibilidad universal. Se ofrecen espacios flexibles, áreas de terapia, aulas adaptadas y espacios al aire libre que fomentan la exploración y la interacción social. Además, se enfatiza la importan- cia de la iluminación natural, la ventilación adecuada y el control acústico, otros, para crear un entorno propicio para el aprendizaje y el bienestar de los niños.This thesis deals with the design of a new educational center called "Jesús para los niños", located in the city of Cañar. The main objecti- ve of this center is to provide an inclusive and quality education to children from 5 to 11 years old with physical, psychosocial and intellectual disabilities, promoting their well-being, participation and optimal learning. It is intended to address this need because the current establishment does not meet the necessary parameters to provide quality education. The research is based on a multidisciplinary approach that combines aspects of inclusive school architecture, pedagogy, and ergonomics. An exhaustive analysis of the characteristics and requirements of students with special educational needs is carried out, taking into account physical, cognitive and emotional aspects. The proposed design complies with local regulations and universal accessibility principles. Flexible spaces, therapy areas, adapted classrooms, and outdoor spaces are offered that encourage explora- tion and social interaction. In addition, the importance of natural lighting, adequate ventilation and acoustic control, others, are emphasized to create an environment conducive to learning and the well-being of children.0009-0006-3110-972

Implementación de un plan de gestión de mantenimiento integral a través de un software para la proyección y planificación de las actividades de mantenimiento automotriz para la flota de vehículos del Municipio de Cañar.

El presente proyecto tiene como finalidad, elaborar un plan de gestión de mantenimiento integral mediante un software de proyección y planificación de las actividades de mantenimiento automotriz para la flota de vehículos GAD Municipal Intercultural de Cañar, con el propósito de identificar el estado actual de dicha flota vehicular, valorar el proceso administrativo del mantenimiento de la misma y elaborar planes de mantenimiento para los vehículos por categorías específicas. Para la elaboración del plan de mantenimiento se realizaron consultas previas al personal técnico y administrativo para diagnosticar el estado vehicular y fallas más frecuentes apreciando los vehículos considerados “operativos”, asimismo, el proceso administrativo del GADICC para la adquisición de repuestos y mantenimientos fuera del municipio. Además, se tomaron ciertas consideraciones como: mantener la codificación de repuestos e identificación vehicular, para no distorsionar la planificación estratégica administrativa. Sin embargo, se propuso una codificación alternativa a todos los vehículos para proporcionar mayores facilidades informativas, igualmente se proporcionó flujogramas organizacionales para una mejor distribución de trabajos de taller, fichas técnicas que indican los procedimientos de trabajo paso a paso de forma que el operario sea efectivo al momento de realizar las reparaciones mecánicas, tablas de mantenimiento preventivo según el kilometraje y horas de trabajo de los vehículos, asegurando de esa manera la disminución de fallas. Se estableció un proceso de mejora en el taller automotriz para lo cual se decidió proponer la compra de herramientas y equipos que aceleren el proceso de mantenimiento. Finalmente se realizó un análisis económico del proyecto, dando como resultado la viabilidad del mismo, dado que se tiene una tasa interna de retorno de 5.56% para 2 años de implementación del plan, incluyendo el software de gestión del mantenimiento el cual ya en su primera etapa de funcionamiento ha mejorado la eficiencia del proceso en un 11,02%.The purpose of this project is to develop a comprehensive maintenance management plan using automotive maintenance preparation and planning software for the fleet of vehicles of the GAD Municipal Intercultural of Cañar, with the purpose of identifying the current state of the fleet, assess the administrative process of maintenance of the same and develop maintenance plans for vehicles by specific categories. In order to prepare the maintenance plan, prior consultations with the technical and administrative personnel were carried out to diagnose the vehicle condition and the most frequent faults by assessing the vehicles considered as “operational”, as well as the administrative process of the GADICC for the purchase of parts and maintenance outside the municipality. In addition, certain considerations were taken as: to maintain the codification of spare parts and vehicular identification, in order not to distort the strategic administrative planning. However, alternative coding was proposed for all vehicles to provide more informational facilities, organizational flowcharts were also provided for a better distribution of workshop work, technical data sheets that indicate step-by-step work procedures so that the operator is effective at the moment of making the mechanical repairs, tables of preventive maintenance according to the mileage and hours of work of the vehicles, thus assuring the reduction of faults. An improvement process was established in the automotive workshop for which it was decided to propose the purchase of tools and equipment to speed up the maintenance process. Finally, an economic analysis of the Project was carried out, resulting in the feasibility of the Project, given that there is an internal rate of return of 5,56% per 2 years of plan implementation, including the maintenance management software, which already in its first stage of operation has improved the efficiency of the process by 11.02%

Vascular endothelial growth factor regulates myeloid cell leukemia-1 expression through neuropilin-1-dependent activation of c-MET signaling in human prostate cancer cells

<p>Abstract</p> <p>Background</p> <p>Myeloid cell leukemia-1 (Mcl-1) is a member of the Bcl-2 family, which inhibits cell apoptosis by sequestering pro-apoptotic proteins Bim and Bid. Mcl-1 overexpression has been associated with progression in leukemia and some solid tumors including prostate cancer (PCa). However, the regulatory mechanism for Mcl-1 expression in PCa cells remains elusive.</p> <p>Results</p> <p>Immunohistochemical analyses revealed that Mcl-1 expression was elevated in PCa specimens with high Gleason grades and further significantly increased in bone metastasis, suggesting a pivotal role of Mcl-1 in PCa metastasis. We further found that vascular endothelial growth factor (VEGF) is a novel regulator of Mcl-1 expression in PCa cells. Inhibition of endogenous Mcl-1 induced apoptosis, indicating that Mcl-1 is an important survival factor in PCa cells. Neuropilin-1 (NRP1), the "co-receptor" for VEGF₁₆₅isoform, was found to be highly expressed in PCa cells, and indispensible in the regulation of Mcl-1. Intriguingly, VEGF₁₆₅promoted physical interaction between NRP1 and hepatocyte growth factor (HGF) receptor c-MET, and facilitated c-MET phosphorylation <it>via </it>a NRP1-dependent mechanism. VEGF₁₆₅induction of Mcl-1 may involve rapid activation of Src kinases and signal transducers and activators of transcription 3 (Stat3). Importantly, NRP1 overexpression and c-MET activation were positively associated with progression and bone metastasis in human PCa specimens and xenograft tissues.</p> <p>Conclusions</p> <p>This study demonstrated that Mcl-1 overexpression is associated with PCa bone metastasis. Activation of VEGF₁₆₅-NRP1-c-MET signaling could confer PCa cells survival advantages by up-regulating Mcl-1, contributing to PCa progression.</p

Chemical Vapor Deposition of High-Quality Large-Sized MoS2 Crystals on Silicon Dioxide Substrates

Large???sized MoS2 crystals can be grown on SiO2/Si substrates via a two???stage chemical vapor deposition method. The maximum size of MoS2 crystals can be up to about 305 ??m. The growth method can be used to grow other transition metal dichalcogenide crystals and lateral heterojunctions. The electron mobility of the MoS2 crystals can reach ???30 cm2 V???1 s???1, which is comparable to those of exfoliated flakes.ope

PDGF Upregulates Mcl-1 Through Activation of β-Catenin and HIF-1α-Dependent Signaling in Human Prostate Cancer Cells

BACKGROUND: Aberrant platelet derived growth factor (PDGF) signaling has been associated with prostate cancer (PCa) progression. However, its role in the regulation of PCa cell growth and survival has not been well characterized. METHODOLOGY/PRINCIPAL FINDINGS: Using experimental models that closely mimic clinical pathophysiology of PCa progression, we demonstrated that PDGF is a survival factor in PCa cells through upregulation of myeloid cell leukemia-1 (Mcl-1). PDGF treatment induced rapid nuclear translocation of β-catenin, presumably mediated by c-Abl and p68 signaling. Intriguingly, PDGF promoted formation of a nuclear transcriptional complex consisting of β-catenin and hypoxia-inducible factor (HIF)-1α, and its binding to Mcl-1 promoter. Deletion of a putative hypoxia response element (HRE) within the Mcl-1 promoter attenuated PDGF effects on Mcl-1 expression. Blockade of PDGF receptor (PDGFR) signaling with a pharmacological inhibitor AG-17 abrogated PDGF induction of Mcl-1, and induced apoptosis in metastatic PCa cells. CONCLUSIONS/SIGNIFICANCE: Our study elucidated a crucial survival mechanism in PCa cells, indicating that interruption of the PDGF-Mcl-1 survival signal may provide a novel strategy for treating PCa metastasis

LIV-1 Promotes Prostate Cancer Epithelial-to-Mesenchymal Transition and Metastasis through HB-EGF Shedding and EGFR-Mediated ERK Signaling

LIV-1, a zinc transporter, is an effector molecule downstream from soluble growth factors. This protein has been shown to promote epithelial-to-mesenchymal transition (EMT) in human pancreatic, breast, and prostate cancer cells. Despite the implication of LIV-1 in cancer growth and metastasis, there has been no study to determine the role of LIV-1 in prostate cancer progression. Moreover, there was no clear delineation of the molecular mechanism underlying LIV-1 function in cancer cells. In the present communication, we found increased LIV-1 expression in benign, PIN, primary and bone metastatic human prostate cancer. We characterized the mechanism by which LIV-1 drives human prostate cancer EMT in an androgen-refractory prostate cancer cells (ARCaP) prostate cancer bone metastasis model. LIV-1, when overexpressed in ARCaPE (derivative cells of ARCaP with epithelial phenotype) cells, promoted EMT irreversibly. LIV-1 overexpressed ARCaPE cells had elevated levels of HB-EGF and matrix metalloproteinase (MMP) 2 and MMP 9 proteolytic enzyme activities, without affecting intracellular zinc concentration. The activation of MMPs resulted in the shedding of heparin binding-epidermal growth factor (HB-EGF) from ARCaPE cells that elicited constitutive epidermal growth factor receptor (EGFR) phosphorylation and its downstream extracellular signal regulated kinase (ERK) signaling. These results suggest that LIV-1 is involved in prostate cancer progression as an intracellular target of growth factor receptor signaling which promoted EMT and cancer metastasis. LIV-1 could be an attractive therapeutic target for the eradication of pre-existing human prostate cancer and bone and soft tissue metastases

Cultured circulating tumor cells and their derived xenografts for personalized oncology

AbstractRecent cancer research has demonstrated the existence of circulating tumor cells (CTCs) in cancer patient's blood. Once identified, CTC biomarkers will be invaluable tools for clinical diagnosis, prognosis and treatment. In this review, we propose ex vivo culture as a rational strategy for large scale amplification of the limited numbers of CTCs from a patient sample, to derive enough CTCs for accurate and reproducible characterization of the biophysical, biochemical, gene expressional and behavioral properties of the harvested cells. Because of tumor cell heterogeneity, it is important to amplify all the CTCs in a blood sample for a comprehensive understanding of their role in cancer metastasis. By analyzing critical steps and technical issues in ex vivo CTC culture, we developed a cost-effective and reproducible protocol directly culturing whole peripheral blood mononuclear cells, relying on an assumed survival advantage in CTCs and CTC-like cells over the normal cells to amplify this specified cluster of cancer cells