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Sample records for primary xenograft model

  1. Systematic analysis of a xenograft mice model for KSHV+ primary effusion lymphoma (PEL.

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    Lu Dai

    Full Text Available Kaposi's sarcoma-associated herpesvirus is the causative agent of primary effusion lymphoma (PEL, which arises preferentially in the setting of infection with human immunodeficiency virus (HIV. Even with standard cytotoxic chemotherapy, PEL continues to cause high mortality rates, requiring the development of novel therapeutic strategies. PEL xenograft models employing immunodeficient mice have been used to study the in vivo effects of a variety of therapeutic approaches. However, it remains unclear whether these xenograft models entirely reflect clinical presentations of KSHV(+ PEL, especially given the recent description of extracavitary solid tumor variants arising in patients. In addition, effusion and solid tumor cells propagated in vivo exhibit unique biology, differing from one another or from their parental cell lines propagated through in vitro culture. Therefore, we used a KSHV(+ PEL/BCBL-1 xenograft model involving non-obese diabetic/severe-combined immunodeficient (NOD/SCID mice, and compared characteristics of effusion and solid tumors with their parent cell culture-derived counterparts. Our results indicate that although this xenograft model can be used for study of effusion and solid lymphoma observed in patients, tumor cells in vivo display unique features to those passed in vitro, including viral lytic gene expression profile, rate of solid tumor development, the host proteins and the complex of tumor microenvironment. These items should be carefully considered when the xenograft model is used for testing novel therapeutic strategies against KSHV-related lymphoma.

  2. Endogenous retrovirus induces leukemia in a xenograft mouse model for primary myelofibrosis.

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    Triviai, Ioanna; Ziegler, Marion; Bergholz, Ulla; Oler, Andrew J; Stübig, Thomas; Prassolov, Vladimir; Fehse, Boris; Kozak, Christine A; Kröger, Nicolaus; Stocking, Carol

    2014-06-10

    The compound immunodeficiencies in nonobese diabetic (NOD) inbred mice homozygous for the Prkdc(scid) and Il2rg(null) alleles (NSG mice) permit engraftment of a wide-range of primary human cells, enabling sophisticated modeling of human disease. In studies designed to define neoplastic stem cells of primary myelofibrosis (PMF), a myeloproliferative neoplasm characterized by profound disruption of the hematopoietic microenvironment, we observed a high frequency of acute myeloid leukemia (AML) in NSG mice. AML was of mouse origin, confined to PMF-xenografted mice, and contained multiple clonal integrations of ecotropic murine leukemia virus (E-MuLV). Significantly, MuLV replication was not only observed in diseased mice, but also in nontreated NSG controls. Furthermore, in addition to the single ecotropic endogenous retrovirus (eERV) located on chromosome 11 (Emv30) in the NOD genome, multiple de novo germ-line eERV integrations were observed in mice from each of four independent NSG mouse colonies. Analysis confirmed that E-MuLV originated from the Emv30 provirus and that recombination events were not necessary for virus replication or AML induction. Pathogenicity is thus likely attributable to PMF-mediated paracrine stimulation of mouse myeloid cells, which serve as targets for retroviral infection and transformation, as evidenced by integration into the Evi1 locus, a hotspot for retroviral-induced myeloid leukemia. This study thus corroborates a role of paracrine stimulation in PMF disease progression, underlines the importance of target cell type and numbers in MuLV-induced disease, and mandates awareness of replicating MuLV in NOD immunodeficient mice, which can significantly influence experimental results and their interpretation.

  3. Inhibition of Hedgehog signaling antagonizes serous ovarian cancer growth in a primary xenograft model.

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    Christopher K McCann

    Full Text Available Recent evidence links aberrant activation of Hedgehog (Hh signaling with the pathogenesis of several cancers including medulloblastoma, basal cell, small cell lung, pancreatic, prostate and ovarian. This investigation was designed to determine if inhibition of this pathway could inhibit serous ovarian cancer growth.We utilized an in vivo pre-clinical model of serous ovarian cancer to characterize the anti-tumor activity of Hh pathway inhibitors cyclopamine and a clinically applicable derivative, IPI-926. Primary human serous ovarian tumor tissue was used to generate tumor xenografts in mice that were subsequently treated with cyclopamine or IPI-926.Both compounds demonstrated significant anti-tumor activity as single agents. When IPI-926 was used in combination with paclitaxel and carboplatinum (T/C, no synergistic effect was observed, though sustained treatment with IPI-926 after cessation of T/C continued to suppress tumor growth. Hh pathway activity was analyzed by RT-PCR to assess changes in Gli1 transcript levels. A single dose of IPI-926 inhibited mouse stromal Gli1 transcript levels at 24 hours with unchanged human intra-tumor Gli1 levels. Chronic IPI-926 therapy for 21 days, however, inhibited Hh signaling in both mouse stromal and human tumor cells. Expression data from the micro-dissected stroma in human serous ovarian tumors confirmed the presence of Gli1 transcript and a significant association between elevated Gli1 transcript levels and worsened survival.IPI-926 treatment inhibits serous tumor growth suggesting the Hh signaling pathway contributes to the pathogenesis of ovarian cancer and may hold promise as a novel therapeutic target, especially in the maintenance setting.

  4. Establishment, maintenance and in vitro and in vivo applications of primary human glioblastoma multiforme (GBM) xenograft models for translational biology studies and drug discovery.

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    Carlson, Brett L; Pokorny, Jenny L; Schroeder, Mark A; Sarkaria, Jann N

    2011-03-01

    Development of clinically relevant tumor model systems for glioblastoma multiforme (GBM) is important for advancement of basic and translational biology. One model that has gained wide acceptance in the neuro-oncology community is the primary xenograft model. This model entails the engraftment of patient tumor specimens into the flank of nude mice and subsequent serial passage of these tumors in the flank of mice. These tumors are then used to establish short-term explant cultures or intracranial xenografts. This unit describes detailed procedures for establishment, maintenance, and utilization of a primary GBM xenograft panel for the purpose of using them as tumor models for basic or translational studies.

  5. Xenograft Models of Primary Acute Myeloid Leukemia for the Development of Imaging Strategies and Evaluation of Novel Targeted Therapies.

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    Gelebart, Pascal; Popa, Mihaela; McCormack, Emmet

    2016-01-01

    Despite the tremendous progress made in the comprehension of acute myeloid leukemia (AML) over the last 30 years most patients die from their disease. Our understanding of AML has relied on an intensive in-vitro research approach, based on AML cell lines as well as primary AML patient cells. However, experimental insight into the early events of AML leukemogenesis before they become clinically observable is not possible in humans. Thus, preclinical animal models have served the purpose to extend our knowledge of the disease as well as to develop innovative therapeutic strategies. Today, xenograft models using patient-derived neoplastic/leukemia cells represent the strategy of choice for preclinical studies of AML. These models exhibit several key advantages over AML cell lines. In fact, patient-derived cells, in contrast to AML cell lines, encompass the entire complexity of AML disease and can therefore provide more trustworthy results on the efficacy outcome of novel therapies. One other important aspect in the development of xenograft models of AML is the possibility to use imaging techniques to monitor in-vivo the progression of the disease. Imaging techniques also authorize the evaluation of the efficacy of an experimental treatment on tumor growth. This review will focus on the description of xenograft models of AML and will provide researchers and clinicians an overview of how these models have been used for the development of new therapeutic options and new imaging approaches to study AML in-vivo.

  6. Establishment of primary cell culture and an intracranial xenograft model of pediatric ependymoma: a prospect for therapy development and understanding of tumor biology.

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    Pavon, Lorena Favaro; Sibov, Tatiana Tais; Caminada de Toledo, Silvia Regina; Mara de Oliveira, Daniela; Cabral, Francisco Romero; Gabriel de Souza, Jean; Boufleur, Pamela; Marti, Luciana C; Malheiros, Jackeline Moraes; Ferreira da Cruz, Edgar; Paiva, Fernando F; Malheiros, Suzana M F; de Paiva Neto, Manoel A; Tannús, Alberto; Mascarenhas de Oliveira, Sérgio; Silva, Nasjla Saba; Cappellano, Andrea Maria; Petrilli, Antonio Sérgio; Chudzinski-Tavassi, Ana Marisa; Cavalheiro, Sérgio

    2018-04-24

    Ependymoma (EPN), the third most common pediatric brain tumor, is a central nervous system (CNS) malignancy originating from the walls of the ventricular system. Surgical resection followed by radiation therapy has been the primary treatment for most pediatric intracranial EPNs. Despite numerous studies into the prognostic value of histological classification, the extent of surgical resection and adjuvant radiotherapy, there have been relatively few studies into the molecular and cellular biology of EPNs. We elucidated the ultrastructure of the cultured EPN cells and characterized their profile of immunophenotypic pluripotency markers (CD133, CD90, SSEA-3, CXCR4). We established an experimental EPN model by the intracerebroventricular infusion of EPN cells labeled with multimodal iron oxide nanoparticles (MION), thereby generating a tumor and providing a clinically relevant animal model. MRI analysis was shown to be a valuable tool when combined with effective MION labeling techniques to accompany EPN growth. We demonstrated that GFAP/CD133+CD90+/CD44+ EPN cells maintained key histopathological and growth characteristics of the original patient tumor. The characterization of EPN cells and the experimental model could facilitate biological studies and preclinical drug screening for pediatric EPNs. In this work, we established notoriously challenging primary cell culture of anaplastic EPNs (WHO grade III) localized in the posterior fossa (PF), using EPNs obtained from 1 to 10-year-old patients ( n = 07), and then characterized their immunophenotype and ultrastructure to finally develop a xenograft model.

  7. Next-generation sequence analysis of cancer xenograft models.

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    Fernando J Rossello

    Full Text Available Next-generation sequencing (NGS studies in cancer are limited by the amount, quality and purity of tissue samples. In this situation, primary xenografts have proven useful preclinical models. However, the presence of mouse-derived stromal cells represents a technical challenge to their use in NGS studies. We examined this problem in an established primary xenograft model of small cell lung cancer (SCLC, a malignancy often diagnosed from small biopsy or needle aspirate samples. Using an in silico strategy that assign reads according to species-of-origin, we prospectively compared NGS data from primary xenograft models with matched cell lines and with published datasets. We show here that low-coverage whole-genome analysis demonstrated remarkable concordance between published genome data and internal controls, despite the presence of mouse genomic DNA. Exome capture sequencing revealed that this enrichment procedure was highly species-specific, with less than 4% of reads aligning to the mouse genome. Human-specific expression profiling with RNA-Seq replicated array-based gene expression experiments, whereas mouse-specific transcript profiles correlated with published datasets from human cancer stroma. We conclude that primary xenografts represent a useful platform for complex NGS analysis in cancer research for tumours with limited sample resources, or those with prominent stromal cell populations.

  8. In vivo bioluminescence imaging using orthotopic xenografts towards patient's derived-xenograft Medulloblastoma models.

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    Asadzadeh, Fatemeh; Ferrucci, Veronica; DE Antonellis, Pasqualino; Zollo, Massimo

    2017-03-01

    Medulloblastoma is a cerebellar neoplasia of the central nervous system. Four molecular subgrups have been identified (MBWNT, MBSHH, MBgroup3 and MBgroup4) with distinct genetics and clinical outcome. Among these, MBgroup3-4 are highly metastatic with the worst prognosis. The current standard therapy includes surgery, radiation and chemotherapy. Thus, specific treatments adapted to cure those different molecular subgroups are needed. The use of orthotopic xenograft models, together with the non-invasive in vivo biolumiscence imaging (BLI) technology, is emerging during preclinical studies to test novel therapeutics for medulloblastoma treatment. Orthotopic MB xenografts were performed by injection of Daoy-luc cells, that had been previously infected with lentiviral particles to stably express luciferase gene, into the fourth right ventricle of the cerebellum of ten nude mice. For the implantation, specific stereotactic coordinates were used. Seven days after the implantation the mice were imaged by acquisitions of bioluminescence imaging (BLI) using IVIS 3D Illumina Imaging System (Xenogen). Tumor growth was evaluated by quantifying the bioluminescence signals using the integrated fluxes of photons within each area of interest using the Living Images Software Package 3.2 (Xenogen-Perkin Elmer). Finally, histological analysis using hematoxylin-eosin staining was performed to confirm the presence of tumorigenic cells into the cerebellum of the mice. We describe a method to use the in vivo bioluminescent imaging (BLI) showing the potential to be used to investigate the potential antitumorigenic effects of a drug for in vivo medulloblastoma treatment. We also discuss other studies in which this technology has been applied to obtain a more comprehensive knowledge of medulloblastoma using orthotopic xenograft mouse models. There is a need to develop patient's derived-xenograft (PDX) model systems to test novel drugs for medulloblastoma treatment within each molecular sub

  9. Hypoxia and metastasis in an orthotopic cervix cancer xenograft model

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    Chaudary, Naz; Mujcic, Hilda; Wouters, Bradly G.; Hill, Richard P.

    2013-01-01

    Background: Hypoxia can promote tumor metastasis by mechanisms that are believed to result from changes in gene expression. The current study examined the role of putative metastatic genes regulated by cyclic hypoxia in relation to metastasis formation in orthotopic models of cervix cancer. Methods: Orthotopic tumors derived from ME180 human cervix cancer cells or from early generation human cervix cancer xenografts were exposed to cyclic hypoxic conditions during growth in vivo and tumor growth and lymphnode metastases were monitored. Expression of the chemokine receptor CXCR4 and various genes in the Hedgehog (Hh) pathway were inhibited using genetic (inducible shRNA vs CXCR4) small molecule (AMD3100) or antibody (5E1) treatment (CXCR4 and Hh genes, respectively) during tumor growth. Results: As reported previously, exposure of tumor bearing mice to cyclic hypoxia caused a reduction of tumor growth but a large increase in metastasis. Inhibition of CXCR4 or Hh gene activity during tumor growth further reduced primary tumor size and reduced lymphatic metastasis to levels below those seen in control mice exposed to normoxic conditions. Conclusion: Blocking CXCR4 or Hh gene expression are potential therapeutic pathways for improving cervix cancer treatment

  10. Human reconstructed skin xenografts on mice to model skin physiology.

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    Salgado, Giorgiana; Ng, Yi Zhen; Koh, Li Fang; Goh, Christabelle S M; Common, John E

    Xenograft models to study skin physiology have been popular for scientific use since the 1970s, with various developments and improvements to the techniques over the decades. Xenograft models are particularly useful and sought after due to the lack of clinically relevant animal models in predicting drug effectiveness in humans. Such predictions could in turn boost the process of drug discovery, since novel drug compounds have an estimated 8% chance of FDA approval despite years of rigorous preclinical testing and evaluation, albeit mostly in non-human models. In the case of skin research, the mouse persists as the most popular animal model of choice, despite its well-known anatomical differences with human skin. Differences in skin biology are especially evident when trying to dissect more complex skin conditions, such as psoriasis and eczema, where interactions between the immune system, epidermis and the environment likely occur. While the use of animal models are still considered the gold standard for systemic toxicity studies under controlled environments, there are now alternative models that have been approved for certain applications. To overcome the biological limitations of the mouse model, research efforts have also focused on "humanizing" the mice model to better recapitulate human skin physiology. In this review, we outline the different approaches undertaken thus far to study skin biology using human tissue xenografts in mice and the technical challenges involved. We also describe more recent developments to generate humanized multi-tissue compartment mice that carry both a functioning human immune system and skin xenografts. Such composite animal models provide promising opportunities to study drugs, disease and differentiation with greater clinical relevance. Copyright © 2017 International Society of Differentiation. Published by Elsevier B.V. All rights reserved.

  11. Biological characterization of two xenografts derived from human CUPs (carcinomas of unknown primary

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    Bernheim Alain

    2007-12-01

    Full Text Available Abstract Background Carcinomas of unknown primary site (CUP are epithelial malignancies revealed by metastatic lesions in the absence of any detectable primary tumor. Although they often adopt an aggressive clinical pattern, their basic biology remains poorly understood. Laboratory research on their biology have been hampered so far by the absence of cell lines representative of CUPs. Methods We attempted xenografts of CUP clinical specimens in immunodeficient mice and subsequent in vitro culture of transplanted malignant cells. Whenever possible, malignant xenografted or cultured cells were characterized by microsatellite genotyping, immunohistology, electron microscopy, multifish chromosome analysis and search of TP 53 gene mutations. Results Successful xenografts were achieved in 2 cases out of 4. One of them (Capi1 was lost after 3 passages whereas the other one (Capi3 has been adapted to in vitro culture and is currently available to the scientific community with reliable identification based on microsatellite genotyping. Both Capi1 and Capi3 have histological characteristics of adenocarcinomas and display intense expression of EMA, CEA and cytokeratin 7. Multifish chromosome analysis demonstrated a translocation involving chromosomes 4 and 21 in both specimens. Distinct rare missense mutations of the TP53 gene were detected in Capi1 (codon 312 and Capi3 (codon 181; the codon 181 mutation is consistent with a previously reported similar finding in a small series of CUP specimens. Finally, intense membrane expression of c-kit was recorded in Capi3. Conclusion Our data suggest that xenografted tumors can be obtained from a substantial fraction of CUP clinical specimens. The hypothesis of a preferential association of CUPs with TP 53 mutations of codon 181 deserves further investigations. The Capi3 cell line will be a useful tool for assessment of novel c-kit inhibitors.

  12. Assessment of a novel VEGF targeted agent using patient-derived tumor tissue xenograft models of colon carcinoma with lymphatic and hepatic metastases.

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    Ketao Jin

    Full Text Available The lack of appropriate tumor models of primary tumors and corresponding metastases that can reliably predict for response to anticancer agents remains a major deficiency in the clinical practice of cancer therapy. It was the aim of our study to establish patient-derived tumor tissue (PDTT xenograft models of colon carcinoma with lymphatic and hepatic metastases useful for testing of novel molecularly targeted agents. PDTT of primary colon carcinoma, lymphatic and hepatic metastases were used to create xenograft models. Hematoxylin and eosin staining, immunohistochemical staining, genome-wide gene expression analysis, pyrosequencing, qRT-PCR, and western blotting were used to determine the biological stability of the xenografts during serial transplantation compared with the original tumor tissues. Early passages of the PDTT xenograft models of primary colon carcinoma, lymphatic and hepatic metastases revealed a high degree of similarity with the original clinical tumor samples with regard to histology, immunohistochemistry, genes expression, and mutation status as well as mRNA expression. After we have ascertained that these xenografts models retained similar histopathological features and molecular signatures as the original tumors, drug sensitivities of the xenografts to a novel VEGF targeted agent, FP3 was evaluated. In this study, PDTT xenograft models of colon carcinoma with lymphatic and hepatic metastasis have been successfully established. They provide appropriate models for testing of novel molecularly targeted agents.

  13. Halofuginone suppresses growth of human uterine leiomyoma cells in a mouse xenograft model.

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    Koohestani, Faezeh; Qiang, Wenan; MacNeill, Amy L; Druschitz, Stacy A; Serna, Vanida A; Adur, Malavika; Kurita, Takeshi; Nowak, Romana A

    2016-07-01

    Does halofuginone (HF) inhibit the growth of human uterine leiomyoma cells in a mouse xenograft model? HF suppresses the growth of human uterine leiomyoma cells in a mouse xenograft model through inhibiting cell proliferation and inducing apoptosis. Uterine leiomyomas are the most common benign tumors of the female reproductive tract. HF can suppress the growth of human uterine leiomyoma cells in vitro. The mouse xenograft model reflects the characteristics of human leiomyomas. Primary leiomyoma smooth muscle cells from eight patients were xenografted under the renal capsule of adult, ovariectomized NOD-scid IL2Rγ(null) mice (NSG). Mice were treated with two different doses of HF or vehicle for 4 weeks with six to eight mice per group. Mouse body weight measurements and immunohistochemical analysis of body organs were carried out to assess the safety of HF treatment. Xenografted tumors were measured and analyzed for cellular and molecular changes induced by HF. Ovarian steroid hormone receptors were evaluated for possible modulation by HF. Treatment of mice carrying human UL xenografts with HF at 0.25 or 0.50 mg/kg body weight for 4 weeks resulted in a 35-40% (P leiomyoma cells in an in vivo model, HF was administered to mice whose tolerance and metabolism of the drug may differ from that in humans. Also, the longer term effects of HF treatment are yet unclear. The results of this study showing the effectiveness of HF in reducing UL tumor growth by interfering with the main cellular processes regulating cell proliferation and apoptosis are in agreement with previous studies on the effects of HF on other fibrotic diseases. HF can be considered as a candidate for reducing the size of leiomyomas, particularly prior to surgery. This project was funded by NIH PO1HD057877 and R01 HD064402. Authors report no competing interests. © The Author 2016. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights

  14. Dynamic modulation of phosphoprotein expression in ovarian cancer xenograft models

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    Koussounadis, Antonis; Langdon, Simon P.; Um, Inhwa; Kay, Charlene; Francis, Kyle E.; Harrison, David J.; Smith, V. Anne

    2016-01-01

    The dynamic changes that occur in protein expression after treatment of a cancer in vivo are poorly described. In this study we measure the effect of chemotherapy over time on the expression of a panel of proteins in ovarian cancer xenograft models. The objective was to identify phosphoprotein and other protein changes indicative of pathway activation that might link with drug response. Two xenograft models, platinum-responsive OV1002 and platinum-unresponsive HOX424, were used. Treatments were carboplatin and carboplatin-paclitaxel. Expression of 49 proteins over 14 days post treatment was measured by quantitative immunofluorescence and analysed by AQUA. Carboplatin treatment in the platinum-sensitive OV1002 model triggered up-regulation of cell cycle, mTOR and DDR pathways, while at late time points WNT, invasion, EMT and MAPK pathways were modulated. Estrogen receptor-alpha (ESR1) and ERBB pathways were down-regulated early, within 24 h from treatment administration. Combined carboplatin-paclitaxel treatment triggered a more extensive response in the OV1002 model modulating expression of 23 of 49 proteins. Therefore the cell cycle and DDR pathways showed similar or more pronounced changes than with carboplatin alone. In addition to expression of pS6 and pERK increasing, components of the AKT pathway were modulated with pAKT increasing while its regulator PTEN was down-regulated early. WNT signaling, EMT and invasion markers were modulated at later time points. Additional pathways were also observed with the NFκB and JAK/STAT pathways being up-regulated. ESR1 was down-regulated as was HER4, while further protein members of the ERBB pathway were upregulated late. By contrast, in the carboplatin-unresponsive HOX 424 xenograft, carboplatin only modulated expression of MLH1 while carboplatin-paclitaxel treatment modulated ESR1 and pMET. Thirteen proteins were modulated by carboplatin and a more robust set of changes by carboplatin-paclitaxel. Early changes included

  15. Human airway xenograft models of epithelial cell regeneration

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    Puchelle Edith

    2000-10-01

    Full Text Available Abstract Regeneration and restoration of the airway epithelium after mechanical, viral or bacterial injury have a determinant role in the evolution of numerous respiratory diseases such as chronic bronchitis, asthma and cystic fibrosis. The study in vivo of epithelial regeneration in animal models has shown that airway epithelial cells are able to dedifferentiate, spread, migrate over the denuded basement membrane and progressively redifferentiate to restore a functional respiratory epithelium after several weeks. Recently, human tracheal xenografts have been developed in immunodeficient severe combined immunodeficiency (SCID and nude mice. In this review we recall that human airway cells implanted in such conditioned host grafts can regenerate a well-differentiated and functional human epithelium; we stress the interest in these humanized mice in assaying candidate progenitor and stem cells of the human airway mucosa.

  16. Establishment of canine hemangiosarcoma xenograft models expressing endothelial growth factors, their receptors, and angiogenesis-associated homeobox genes

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    Kodama, Atsushi; Yanai, Tokuma; Sakai, Hiroki; Matsuura, Satoko; Murakami, Mami; Murai, Atsuko; Mori, Takashi; Maruo, Kouji; Kimura, Tohru; Masegi, Toshiaki

    2009-01-01

    Human hemangiosarcoma (HSA) tends to have a poor prognosis; its tumorigenesis has not been elucidated, as there is a dearth of HSA clinical specimens and no experimental model for HSA. However, the incidence of spontaneous HSA is relatively high in canines; therefore, canine HSA has been useful in the study of human HSA. Recently, the production of angiogenic growth factors and their receptors in human and canine HSA has been reported. Moreover, the growth-factor environment of HSA is very similar to that of pathophysiological angiogenesis, which some homeobox genes regulate in the transcription of angiogenic molecules. In the present study, we established 6 xenograft canine HSA tumors and detected the expression of growth factors, their receptors, and angiogenic homeobox genes. Six primary canine HSAs were xenografted to nude mice subcutaneously and serially transplanted. Subsequently, the expressions of vascular endothelial growth factor (VEGF)-A, basic fibroblast growth factors (bFGF), flt-1 and flk-1 (receptors of VEGF-A), FGFR-1, and angiogenic homeobox genes HoxA9, HoxB3, HoxB7, HoxD3, Pbx1, and Meis1 were investigated in original and xenograft tumors by histopathology, immunostaining, and reverse transcription polymerase chain reaction (RT-PCR), using canine-specific primer sets. Histopathologically, xenograft tumors comprised a proliferation of neoplastic cells that were varied in shape, from spindle-shaped and polygonal to ovoid; some vascular-like structures and vascular clefts of channels were observed, similar to those in the original tumors. The expression of endothelial markers (CD31 and vWF) was detected in xenograft tumors by immunohistochemistry and RT-PCR. Moreover, the expression of VEGF-A, bFGF, flt-1, flk-1, FGFR-1, HoxA9, HoxB3, HoxB7, HoxD3, Pbx1, and Meis1 was detected in xenograft tumors. Interestingly, expressions of bFGF tended to be higher in 3 of the xenograft HSA tumors than in the other tumors. We established 6 xenograft canine HSA

  17. Xenograft transplantation of human malignant astrocytoma cells into immunodeficient rats: an experimental model of glioblastoma.

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    Miura, Flávio Key; Alves, Maria Jose Ferreira; Rocha, Mussya Cisotto; da Silva, Roseli; Oba-Shinjo, Sueli Mieko; Marie, Suely Kazue Nagahashi

    2010-03-01

    Astrocytic gliomas are the most common intracranial central nervous system neoplasias, accounting for about 60% of all primary central nervous system tumors. Despite advances in the treatment of gliomas, no effective therapeutic approach is yet available; hence, the search for a more realistic model to generate more effective therapies is essential. To develop an experimental malignant astrocytoma model with the characteristics of the human tumor. Primary cells from subcutaneous xenograft tumors produced with malignant astrocytoma U87MG cells were inoculated intracerebrally by stereotaxis into immunosuppressed (athymic) Rowett rats. All four injected animals developed non-infiltrative tumors, although other glioblastoma characteristics, such as necrosis, pseudopalisading cells and intense mitotic activity, were observed. A malignant astrocytoma intracerebral xenograft model with poorly invasive behavior was achieved in athymic Rowett rats. Tumor invasiveness in an experimental animal model may depend on a combination of several factors, including the cell line used to induce tumor formation, the rat strains and the status of the animal's immune system.

  18. A human lung xenograft mouse model of Nipah virus infection.

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    Gustavo Valbuena

    2014-04-01

    Full Text Available Nipah virus (NiV is a member of the genus Henipavirus (family Paramyxoviridae that causes severe and often lethal respiratory illness and encephalitis in humans with high mortality rates (up to 92%. NiV can cause Acute Lung Injury (ALI in humans, and human-to-human transmission has been observed in recent outbreaks of NiV. While the exact route of transmission to humans is not known, we have previously shown that NiV can efficiently infect human respiratory epithelial cells. The molecular mechanisms of NiV-associated ALI in the human respiratory tract are unknown. Thus, there is an urgent need for models of henipavirus infection of the human respiratory tract to study the pathogenesis and understand the host responses. Here, we describe a novel human lung xenograft model in mice to study the pathogenesis of NiV. Following transplantation, human fetal lung xenografts rapidly graft and develop mature structures of adult lungs including cartilage, vascular vessels, ciliated pseudostratified columnar epithelium, and primitive "air" spaces filled with mucus and lined by cuboidal to flat epithelium. Following infection, NiV grows to high titers (10(7 TCID50/gram lung tissue as early as 3 days post infection (pi. NiV targets both the endothelium as well as respiratory epithelium in the human lung tissues, and results in syncytia formation. NiV infection in the human lung results in the production of several cytokines and chemokines including IL-6, IP-10, eotaxin, G-CSF and GM-CSF on days 5 and 7 pi. In conclusion, this study demonstrates that NiV can replicate to high titers in a novel in vivo model of the human respiratory tract, resulting in a robust inflammatory response, which is known to be associated with ALI. This model will facilitate progress in the fundamental understanding of henipavirus pathogenesis and virus-host interactions; it will also provide biologically relevant models for other respiratory viruses.

  19. Curcumin-Artemisinin Coamorphous Solid: Xenograft Model Preclinical Study

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    M. K. Chaitanya Mannava

    2018-01-01

    Full Text Available Curcumin is a natural compound present in Indian spice turmeric. It has diverse pharmacological action but low oral solubility and bioavailability continue to limit its use as a drug. With the aim of improving the bioavailability of Curcumin (CUR, we evaluated Curcumin-Pyrogallol (CUR-PYR cocrystal and Curcumin-Artemisinin (CUR-ART coamorphous solid. Both of these solid forms exhibited superior dissolution and pharmacokinetic behavior compared to pure CUR, which is practically insoluble in water. CUR-ART coamorphous solid showed two fold higher bioavailability than CUR-PYR cocrystal (at 200 mg/kg oral dose. Moreover, in simulated gastric and intestinal fluids (SGF and SIF, CUR-ART is stable up to 3 and 12 h, respectively. In addition, CUR-PYR and CUR-ART showed no adverse effects in toxicology studies (10 times higher dose at 2000 mg/kg. CUR-ART showed higher therapeutic effect and inhibited approximately 62% of tumor growth at 100 mg/kg oral dosage of CUR in xenograft models, which is equal to the positive control drug, doxorubicin (2 mg/kg by i.v. administration.

  20. A Xenograft Model of Vestibular Schwannoma and Hearing Loss.

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    Dinh, Christine T; Bracho, Olena; Mei, Christine; Bas, Esperanza; Fernandez-Valle, Cristina; Telischi, Fred; Liu, Xue-Zhong

    2018-03-19

    Microsurgical implantation of mouse merlin-deficient Schwann cells (MD-SC) into the cerebellopontine angle of immunodeficient rats will initiate tumor formation, hearing loss, and vestibular dysfunction. The progress in identifying effective drug therapies for treatment of Neurofibromatosis type II (NF2) is limited by the availability of animal models of VS that develop hearing loss and imbalance. A microsurgical technique for implanting MD-SCs onto the cochleovestibular nerve of rats was developed. Ten Rowett Nude rats were implanted with either ∼10 MD-SCs expressing luciferase (N = 5) or vehicle (N = 5). Rats received bioluminescence imaging, auditory brainstem response testing, and were observed for head tilt every 2 weeks after surgery, for a total of 6 weeks. Tumors were harvested and processed with hematoxylin & eosin staining and immunohistochemistry was performed for S100. Rats implanted with MD-SCs developed significantly higher tumor bioluminescence measurements and hearing threshold shifts at multiple frequencies by the 4th and 6th weeks post-implantation, compared with control rats. Rats implanted with MD-SCs also developed gross tumor. The tumor volume was significantly greater than nerve volumes obtained from rats in the control group. All rats with tumors developed a head tilt, while control rats had no signs of vestibular dysfunction. Tumors demonstrated histological features of schwannoma and express S100. Using this microsurgical technique, this xenograft rat model of VS develops tumors involving the cochleovestibular nerve, shifts in hearing thresholds, and vestibular dysfunction. This animal model can be used to investigate tumor-mediated hearing loss and perform preclinical drug studies for NF2.

  1. Appropriateness of using patient-derived xenograft models for pharmacologic evaluation of novel therapies for esophageal/gastro-esophageal junction cancers.

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    Lorin Dodbiba

    Full Text Available The high morbidity and mortality of patients with esophageal (E and gastro-esophageal junction (GEJ cancers, warrants new pre-clinical models for drug testing. The utility of primary tumor xenografts (PTXGs as pre-clinical models was assessed. Clinicopathological, immunohistochemical markers (p53, p16, Ki-67, Her-2/neu and EGFR, and global mRNA abundance profiles were evaluated to determine selection biases of samples implanted or engrafted, compared with the underlying population. Nine primary E/GEJ adenocarcinoma xenograft lines were further characterized for the spectrum and stability of gene/protein expression over passages. Seven primary esophageal adenocarcinoma xenograft lines were treated with individual or combination chemotherapy. Tumors that were implanted (n=55 in NOD/SCID mice had features suggestive of more aggressive biology than tumors that were never implanted (n=32. Of those implanted, 21/55 engrafted; engraftment was associated with poorly differentiated tumors (p=0.04 and older patients (p=0.01. Expression of immunohistochemical markers were similar between patient sample and corresponding xenograft. mRNA differences observed between patient tumors and first passage xenografts were largely due to loss of human stroma in xenografts. mRNA patterns of early vs late passage xenografts and of small vs large tumors of the same passage were similar. Complete resistance was present in 2/7 xenografts while the remaining tumors showed varying degrees of sensitivity, that remained constant across passages. Because of their ability to recapitulate primary tumor characteristics during engraftment and across serial passaging, PTXGs can be useful clinical systems for assessment of drug sensitivity of human E/GEJ cancers.

  2. Improvement of Radiation-Mediated Immunosuppression of Human NSCLC Tumour Xenografts in a Nude Rat Model

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    Sergey V. Tokalov

    2010-01-01

    Full Text Available Human tumour xenografts in a nude rat model have consistently been used as an essential part of preclinical studies for anticancer drugs activity in human. Commonly, these animals receive whole body irradiation to assure immunosuppression. But whole body dose delivery might be inhomogeneous and the resulting incomplete bone marrow depletion may modify tumour behaviour. To improve irradiation-mediated immunosuppression of human non-small cell lung cancer (NSCLC xenografts in a nude rat model irradiation (2 + 2 Gy from opposite sides of animals has been performed using a conventional X-ray tube. The described modification of whole body irradiation improves growth properties of human NSCLC xenografts in a nude rat model. The design of the whole body irradiation mediated immunosuppression described here for NSCLC xenografts may be useful for research applications involving other types of human tumours.

  3. Radiotherapy and chemotherapy change vessel tree geometry and metastatic spread in a small cell lung cancer xenograft mouse tumor model.

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    Thorsten Frenzel

    Full Text Available Tumor vasculature is critical for tumor growth, formation of distant metastases and efficiency of radio- and chemotherapy treatments. However, how the vasculature itself is affected during cancer treatment regarding to the metastatic behavior has not been thoroughly investigated. Therefore, the aim of this study was to analyze the influence of hypofractionated radiotherapy and cisplatin chemotherapy on vessel tree geometry and metastasis formation in a small cell lung cancer xenograft mouse tumor model to investigate the spread of malignant cells during different treatments modalities.The biological data gained during these experiments were fed into our previously developed computer model "Cancer and Treatment Simulation Tool" (CaTSiT to model the growth of the primary tumor, its metastatic deposit and also the influence on different therapies. Furthermore, we performed quantitative histology analyses to verify our predictions in xenograft mouse tumor model.According to the computer simulation the number of cells engrafting must vary considerably to explain the different weights of the primary tumor at the end of the experiment. Once a primary tumor is established, the fractal dimension of its vasculature correlates with the tumor size. Furthermore, the fractal dimension of the tumor vasculature changes during treatment, indicating that the therapy affects the blood vessels' geometry. We corroborated these findings with a quantitative histological analysis showing that the blood vessel density is depleted during radiotherapy and cisplatin chemotherapy. The CaTSiT computer model reveals that chemotherapy influences the tumor's therapeutic susceptibility and its metastatic spreading behavior.Using a system biological approach in combination with xenograft models and computer simulations revealed that the usage of chemotherapy and radiation therapy determines the spreading behavior by changing the blood vessel geometry of the primary tumor.

  4. An improved pre-clinical patient-derived liquid xenograft mouse model for acute myeloid leukemia

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    Zhisheng Her

    2017-10-01

    Full Text Available Abstract Background Xenotransplantation of patient-derived AML (acute myeloid leukemia cells in NOD-scid Il2rγ null (NSG mice is the method of choice for evaluating this human hematologic malignancy. However, existing models constructed using intravenous injection in adult or newborn NSG mice have inferior engraftment efficiency, poor peripheral blood engraftment, or are difficult to construct. Methods Here, we describe an improved AML xenograft model where primary human AML cells were injected into NSG newborn pups intrahepatically. Results Introduction of primary cells from AML patients resulted in high levels of engraftment in peripheral blood, spleen, and bone marrow (BM of recipient mice. The phenotype of engrafted AML cells remained unaltered during serial transplantation. The mice developed features that are consistent with human AML including spleen enlargement and infiltration of AML cells into multiple organs. Importantly, we demonstrated that although leukemic stem cell activity is enriched and mediated by CD34+CD117+ subpopulation, CD34+CD117− subpopulation can acquire CD34+CD117+ phenotype through de-differentiation. Lastly, we evaluated the therapeutic potential of Sorafenib and Regorafenib in this AML model and found that periphery and spleen AML cells are sensitive to these treatments, whereas BM provides a protective environment to AML. Conclusions Collectively, our improved model is robust, easy-to-construct, and reliable for pre-clinical AML studies.

  5. Cyclophosphamide Enhances Human Tumor Growth in Nude Rat Xenografted Tumor Models

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    Yingjen Jeffrey Wu

    2009-02-01

    Full Text Available The effect of the immunomodulatory chemotherapeutic agent cyclophosphamide (CTX on tumor growth was investigated in primary and metastatic intracerebral and subcutaneous rat xenograft models. Nude rats were treated with CTX (100 mg/kg, intraperitoneally 24 hours before human ovarian carcinoma (SKOV3, small cell lung carcinoma (LX-1 SCLC, and glioma (UW28, U87MG, and U251 tumor cells were inoculated subcutaneously, intraperitoneally, or in the right cerebral hemisphere or were infused into the right internal carotid artery. Tumor development was monitored and recorded. Potential mechanisms were further investigated. Only animals that received both CTX and Matrigel showed consistent growth of subcutaneous tumors. Cyclophosphamide pretreatment increased the percentage (83.3% vs 0% of animals showing intraperitoneal tumors. In intracerebral implantation tumor models, CTX pretreatment increased the tumor volume and the percentage of animals showing tumors. Cyclophosphamide increased lung carcinoma bone and facial metastases after intra-arterial injection, and 20% of animals showed brain metastases. Cyclophosphamide transiently decreased nude rat white blood cell counts and glutathione concentration, whereas serum vascular endothelial growth factor was significantly elevated. Cyclophosphamide also increased CD31 reactivity, a marker of vascular endothelium, and macrophage (CD68-positive infiltration into glioma cell-inoculated rat brains. Cyclophosphamide may enhance primary and metastatic tumor growth through multiple mechanisms, including immune modulation, decreased response to oxidative stress, increased tumor vascularization, and increased macrophage infiltration. These findings may be clinically relevant because chemotherapy may predispose human cancer subjects to tumor growth in the brain or other tissues.

  6. PDX-MI: Minimal Information for Patient-Derived Tumor Xenograft Models

    NARCIS (Netherlands)

    Meehan, Terrence F.; Conte, Nathalie; Goldstein, Theodore; Inghirami, Giorgio; Murakami, Mark A.; Brabetz, Sebastian; Gu, Zhiping; Wiser, Jeffrey A.; Dunn, Patrick; Begley, Dale A.; Krupke, Debra M.; Bertotti, Andrea; Bruna, Alejandra; Brush, Matthew H.; Byrne, Annette T.; Caldas, Carlos; Christie, Amanda L.; Clark, Dominic A.; Dowst, Heidi; Dry, Jonathan R.; Doroshow, James H.; Duchamp, Olivier; Evrard, Yvonne A.; Ferretti, Stephane; Frese, Kristopher K.; Goodwin, Neal C.; Greenawalt, Danielle; Haendel, Melissa A.; Hermans, Els; Houghton, Peter J.; Jonkers, Jos; Kemper, Kristel; Khor, Tin O.; Lewis, Michael T.; Lloyd, K. C. Kent; Mason, Jeremy; Medico, Enzo; Neuhauser, Steven B.; Olson, James M.; Peeper, Daniel S.; Rueda, Oscar M.; Seong, Je Kyung; Trusolino, Livio; Vinolo, Emilie; Wechsler-Reya, Robert J.; Weinstock, David M.; Welm, Alana; Weroha, S. John; Amant, Frédéric; Pfister, Stefan M.; Kool, Marcel; Parkinson, Helen; Butte, Atul J.; Bult, Carol J.

    2017-01-01

    Patient-derived tumor xenograft (PDX) mouse models have emerged as an important oncology research platform to study tumor evolution, mechanisms of drug response and resistance, and tailoring chemotherapeutic approaches for individual patients. The lack of robust standards for reporting on PDX models

  7. Patient-Derived Xenograft Models : An Emerging Platform for Translational Cancer Research

    NARCIS (Netherlands)

    Hidalgo, Manuel; Amant, Frederic; Biankin, Andrew V.; Budinska, Eva; Byrne, Annette T.; Caldas, Carlos; Clarke, Robert B.; de Jong, Steven; Jonkers, Jos; Maelandsmo, Gunhild Mari; Roman-Roman, Sergio; Seoane, Joan; Trusolino, Livio; Villanueva, Alberto

    Recently, there has been an increasing interest in the development and characterization of patient-derived tumor xenograft (PDX) models for cancer research. PDX models mostly retain the principal histologic and genetic characteristics of their donor tumor and remain stable across passages. These

  8. The HSP90 inhibitor 17-AAG exhibits potent antitumor activity for pheochromocytoma in a xenograft model.

    Science.gov (United States)

    Xu, Yunze; Zhu, Qi; Chen, Dongning; Shen, Zhoujun; Wang, Weiqing; Ning, Guang; Zhu, Yu

    2015-07-01

    This study aims to investigate the effect of heat shock protein 90 (HSP90) inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG) in the malignant pheochromocytoma using a xenograft mouse model. Treatment with 17-AAG induced a marked reduction in the volume and weight of PC12 pheochromocytoma cell tumor xenografts in mice. Furthermore, 17-AAG also significantly inhibited the expression of HSP90 and its client proteins. Our results validated HSP90 as an important target in pheochromocytoma and provided rationale for the testing of HSP90 inhibitors as a promising therapeutic agent in the antitumor therapy of pheochromocytoma.

  9. Validation of a mouse xenograft model system for gene expression analysis of human acute lymphoblastic leukaemia

    Directory of Open Access Journals (Sweden)

    Francis Richard W

    2010-04-01

    Full Text Available Abstract Background Pre-clinical models that effectively recapitulate human disease are critical for expanding our knowledge of cancer biology and drug resistance mechanisms. For haematological malignancies, the non-obese diabetic/severe combined immunodeficient (NOD/SCID mouse is one of the most successful models to study paediatric acute lymphoblastic leukaemia (ALL. However, for this model to be effective for studying engraftment and therapy responses at the whole genome level, careful molecular characterisation is essential. Results Here, we sought to validate species-specific gene expression profiling in the high engraftment continuous ALL NOD/SCID xenograft. Using the human Affymetrix whole transcript platform we analysed transcriptional profiles from engrafted tissues without prior cell separation of mouse cells and found it to return highly reproducible profiles in xenografts from individual mice. The model was further tested with experimental mixtures of human and mouse cells, demonstrating that the presence of mouse cells does not significantly skew expression profiles when xenografts contain 90% or more human cells. In addition, we present a novel in silico and experimental masking approach to identify probes and transcript clusters susceptible to cross-species hybridisation. Conclusions We demonstrate species-specific transcriptional profiles can be obtained from xenografts when high levels of engraftment are achieved or with the application of transcript cluster masks. Importantly, this masking approach can be applied and adapted to other xenograft models where human tissue infiltration is lower. This model provides a powerful platform for identifying genes and pathways associated with ALL disease progression and response to therapy in vivo.

  10. A Patient-Derived Xenograft Model of Parameningeal Embryonal Rhabdomyosarcoma for Preclinical Studies

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    Jody E. Hooper

    2015-01-01

    Full Text Available Embryonal rhabdomyosarcoma (eRMS is one of the most common soft tissue sarcomas in children and adolescents. Parameningeal eRMS is a variant that is often more difficult to treat than eRMS occurring at other sites. A 14-year-old female with persistent headaches and rapid weight loss was diagnosed with parameningeal eRMS. She progressed and died despite chemotherapy with vincristine, actinomycin-D, and cyclophosphamide plus 50.4 Gy radiation therapy to the primary tumor site. Tumor specimens were acquired by rapid autopsy and tumor tissue was transplanted into immunodeficient mice to create a patient-derived xenograft (PDX animal model. As autopsy specimens had an ALK R1181C mutation, PDX tumor bearing animals were treated with the pan-kinase inhibitor lestaurtinib but demonstrated no decrease in tumor growth, suggesting that single agent kinase inhibitor therapy may be insufficient in similar cases. This unique parameningeal eRMS PDX model is publicly available for preclinical study.

  11. Distinct choline metabolic profiles are associated with differences in gene expression for basal-like and luminal-like breast cancer xenograft models

    International Nuclear Information System (INIS)

    Moestue, Siver A; Borgan, Eldrid; Huuse, Else M; Lindholm, Evita M; Sitter, Beathe; Børresen-Dale, Anne-Lise; Engebraaten, Olav; Mælandsmo, Gunhild M; Gribbestad, Ingrid S

    2010-01-01

    Increased concentrations of choline-containing compounds are frequently observed in breast carcinomas, and may serve as biomarkers for both diagnostic and treatment monitoring purposes. However, underlying mechanisms for the abnormal choline metabolism are poorly understood. The concentrations of choline-derived metabolites were determined in xenografted primary human breast carcinomas, representing basal-like and luminal-like subtypes. Quantification of metabolites in fresh frozen tissue was performed using high-resolution magic angle spinning magnetic resonance spectroscopy (HR MAS MRS). The expression of genes involved in phosphatidylcholine (PtdCho) metabolism was retrieved from whole genome expression microarray analyses. The metabolite profiles from xenografts were compared with profiles from human breast cancer, sampled from patients with estrogen/progesterone receptor positive (ER+/PgR+) or triple negative (ER-/PgR-/HER2-) breast cancer. In basal-like xenografts, glycerophosphocholine (GPC) concentrations were higher than phosphocholine (PCho) concentrations, whereas this pattern was reversed in luminal-like xenografts. These differences may be explained by lower choline kinase (CHKA, CHKB) expression as well as higher PtdCho degradation mediated by higher expression of phospholipase A2 group 4A (PLA2G4A) and phospholipase B1 (PLB1) in the basal-like model. The glycine concentration was higher in the basal-like model. Although glycine could be derived from energy metabolism pathways, the gene expression data suggested a metabolic shift from PtdCho synthesis to glycine formation in basal-like xenografts. In agreement with results from the xenograft models, tissue samples from triple negative breast carcinomas had higher GPC/PCho ratio than samples from ER+/PgR+ carcinomas, suggesting that the choline metabolism in the experimental models is representative for luminal-like and basal-like human breast cancer. The differences in choline metabolite

  12. EGFR gene overexpression retained in an invasive xenograft model by solid orthotopic transplantation of human glioblastoma multiforme into nude mice.

    Science.gov (United States)

    Yi, Diao; Hua, Tian Xin; Lin, Huang Yan

    2011-03-01

    Orthotopic xenograft animal model from human glioblastoma multiforme (GBM) cell lines often do not recapitulate an extremely important aspect of invasive growth and epidermal growth factor receptor (EGFR) gene overexpression of human GBM. We developed an orthotopic xenograft model by solid transplantation of human GBM into the brain of nude mouse. The orthotopic xenografts sharing the same histopathological features with their original human GBMs were highly invasive and retained the overexpression of EGFR gene. The murine orthotopic GBM models constitute a valuable in vivo system for preclinical studies to test novel therapies for human GBM.

  13. Mouse Xenograft Model for Mesothelioma | NCI Technology Transfer Center | TTC

    Science.gov (United States)

    The National Cancer Institute is seeking parties interested in collaborative research to co-develop, evaluate, or commercialize a new mouse model for monoclonal antibodies and immunoconjugates that target malignant mesotheliomas. Applications of the technology include models for screening compounds as potential therapeutics for mesothelioma and for studying the pathology of mesothelioma.

  14. A novel xenograft model of cutaneous T-cell lymphoma

    DEFF Research Database (Denmark)

    Krejsgaard, Thorbjørn; Kopp, Katharina; Ralfkiaer, Elisabeth

    2010-01-01

    Cutaneous T-cell lymphomas (CTCLs) are characterized by accumulation of malignant T cells in the skin. Early disease resembles benign skin disorders but during disease progression cutaneous tumors develop, and eventually the malignant T cells can spread to lymph nodes and internal organs. However...... and lymphatic tumors, originated from the transplanted malignant T cells. In conclusion, we describe a novel mouse model of tumor stage CTCL for future studies of disease dissemination and preclinical evaluations of new therapeutic strategies....

  15. Therapeutic activity of two xanthones in a xenograft murine model of human chronic lymphocytic leukemia

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    Berthou Christian

    2010-12-01

    Full Text Available Abstract Background We previously reported that allanxanthone C and macluraxanthone, two xanthones purified from Guttiferae trees, display in vitro antiproliferative and proapoptotic activities in leukemic cells from chronic lymphocytic leukemia (CLL and leukemia B cell lines. Results Here, we investigated the in vivo therapeutic effects of the two xanthones in a xenograft murine model of human CLL, developed by engrafting CD5-transfected chronic leukemia B cells into SCID mice. Treatment of the animals with five daily injections of either allanxanthone C or macluraxanthone resulted in a significant prolongation of their survival as compared to control animals injected with the solvent alone (p = 0.0006 and p = 0.0141, respectively. The same treatment of mice which were not xenografted induced no mortality. Conclusion These data show for the first time the in vivo antileukemic activities of two plant-derived xanthones, and confirm their potential interest for CLL therapy.

  16. Patient Derived Xenograft Models: An Emerging Platform for Translational Cancer Research

    Science.gov (United States)

    Hidalgo, Manuel; Amant, Frederic; Biankin, Andrew V.; Budinská, Eva; Byrne, Annette T.; Caldas, Carlos; Clarke, Robert B.; de Jong, Steven; Jonkers, Jos; Mælandsmo, Gunhild Mari; Roman-Roman, Sergio; Seoane, Joan; Trusolino, Livio; Villanueva, Alberto

    2014-01-01

    Recently, there has been increasing interest in the development and characterization of patient derived tumor xenograft (PDX) models for cancer research. PDX models mostly retain the principal histological and genetic characteristics of their donor tumor and remain stable across passages. These models have been shown to be predictive of clinical outcomes and are being used for preclinical drug evaluation, biomarker identification, biological studies, and personalized medicine strategies. This paper summarizes the current state of the art in this field including methodological issues, available collections, practical applications, challenges and shortcoming, and future directions, and introduces a European consortium of PDX models. PMID:25185190

  17. Development of a Patient-Derived Xenograft (PDX of Breast Cancer Bone Metastasis in a Zebrafish Model

    Directory of Open Access Journals (Sweden)

    Laura Mercatali

    2016-08-01

    Full Text Available Bone metastasis is a complex process that needs to be better understood in order to help clinicians prevent and treat it. Xenografts using patient-derived material (PDX rather than cancer cell lines are a novel approach that guarantees more clinically realistic results. A primary culture of bone metastasis derived from a 67-year-old patient with breast cancer was cultured and then injected into zebrafish (ZF embryos to study its metastatic potential. In vivo behavior and results of gene expression analyses of the primary culture were compared with those of cancer cell lines with different metastatic potential (MCF7 and MDA-MB-231. The MCF7 cell line, which has the same hormonal receptor status as the bone metastasis primary culture, did not survive in the in vivo model. Conversely, MDA-MB-231 disseminated and colonized different parts of the ZF, including caudal hematopoietic tissues (CHT, revealing a migratory phenotype. Primary culture cells disseminated and in later stages extravasated from the vessels, engrafting into ZF tissues and reaching the CHT. Primary cell behavior reflected the clinical course of the patient’s medical history. Our results underline the potential for using PDX models in bone metastasis research and outline new methods for the clinical application of this in vivo model.

  18. Stereotactic intracranial implantation and in vivo bioluminescent imaging of tumor xenografts in a mouse model system of glioblastoma multiforme.

    Science.gov (United States)

    Baumann, Brian C; Dorsey, Jay F; Benci, Joseph L; Joh, Daniel Y; Kao, Gary D

    2012-09-25

    Glioblastoma multiforme (GBM) is a high-grade primary brain cancer with a median survival of only 14.6 months in humans despite standard tri-modality treatment consisting of surgical resection, post-operative radiation therapy and temozolomide chemotherapy. New therapeutic approaches are clearly needed to improve patient survival and quality of life. The development of more effective treatment strategies would be aided by animal models of GBM that recapitulate human disease yet allow serial imaging to monitor tumor growth and treatment response. In this paper, we describe our technique for the precise stereotactic implantation of bio-imageable GBM cancer cells into the brains of nude mice resulting in tumor xenografts that recapitulate key clinical features of GBM. This method yields tumors that are reproducible and are located in precise anatomic locations while allowing in vivo bioluminescent imaging to serially monitor intracranial xenograft growth and response to treatments. This method is also well-tolerated by the animals with low perioperative morbidity and mortality.

  19. Molecular analysis of primary gastric cancer, corresponding xenografts, and 2 novel gastric carcinoma cell lines reveals novel alterations in gastric carcinogenesis

    NARCIS (Netherlands)

    Milne, Anya N. A.; Sitarz, Robert; Carvalho, Ralph; Polak, Mirjam M.; Ligtenberg, Madolijn; Pauwels, Patrick; Offerhaus, G. Johan A.; Weterman, Marian A. J.

    2007-01-01

    We report the molecular characterization of 8 primary gastric carcinomas, corresponding xenografts, and 2 novel gastric carcinoma cell lines. We compared the tumors and cell lines, with respect to histology, immunohistochemistry, copy number, and hypermethylation of up to 38 genes using

  20. Concurrent Longitudinal EPR Monitoring of Tissue Oxygenation, Acidosis, and Reducing Capacity in Mouse Xenograft Tumor Models.

    Science.gov (United States)

    Bobko, Andrey A; Evans, Jason; Denko, Nicholas C; Khramtsov, Valery V

    2017-06-01

    Tissue oxygenation, extracellular acidity, and tissue reducing capacity are among crucial parameters of tumor microenvironment (TME) of significant importance for tumor pathophysiology. In this paper, we demonstrate the complementary application of particulate lithium octa-n-butoxy-naphthalocyanine and soluble nitroxide paramagnetic probes for monitoring of these TME parameters using electron paramagnetic resonance (EPR) technique. Two different types of therapeutic interventions were studied: hypothermia and systemic administration of metabolically active drug. In summary, the results demonstrate the utility of EPR technique for non-invasive concurrent longitudinal monitoring of physiologically relevant chemical parameters of TME in mouse xenograft tumor models, including that under therapeutic intervention.

  1. The effects of a picosecond pulsed electric field on angiogenesis in the cervical cancer xenograft models.

    Science.gov (United States)

    Wu, Limei; Yao, Chenguo; Xiong, Zhengai; Zhang, Ruizhe; Wang, Zhiliang; Wu, Yutong; Qin, Qin; Hua, Yuanyuan

    2016-04-01

    The application of picosecond pulsed electric field (psPEF) is a new biomedical engineering technique used in cancer therapy. However, its effects on cervical cancer angiogenesis are not clear. Therefore, the aim of the present study is to investigate the effects of psPEF on angiogenesis in cervical cancer xenograft models. Xenograft tumors were created by subcutaneously inoculating nude mice (athymic BALB/c nu/nu mice) with HeLa cells, then were placed closely between tweezer-type plate electrodes and subjected to psPEF with a gradually increased electric field intensity (0kV/cm, 50kV/cm, 60kV/cm, 70kV/cm). The direct effect on tumor tissue was observed by hematoxylin and eosin (H&E) staining and transmission electron microscopy (TEM). The changes of blood vessels and oxygen saturation (sO2) of tumors were monitored in vivo by photoacoustic tomography (PAT). The microvessel density (MVD), vascular endothelial growth factor (VEGF) and hypoxia-inducible transcription factors (HIF-1α and HIF-2α) were detected by immunohistochemical technique (IHC). Their protein expressions and gene transcription levels were evaluated using western blot (WB) and quantitative reverse transcription and polymerase chain reaction (RT-PCR). PsPEF induced obvious necrosis of cervical cancer tissue; with the increasing of electric field intensity, the MVD, vascular PA signal and sO2 values declined significantly. The protein expression and gene transcription levels of VEGF, HIF1α and HIF2α were significantly decreased at the same time. PsPEF exhibited dramatic anti-tumor and anti-angiogenesis effects in cervical cancer xenograft models by exerting direct effect on cancer cells and vascular endothelial cells and indirect effect on tumor angiogenesis-related factors. Copyright © 2016 Elsevier Inc. All rights reserved.

  2. Tumor xenograft modeling identifies an association between TCF4 loss and breast cancer chemoresistance

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    Gorka Ruiz de Garibay

    2018-05-01

    Full Text Available Understanding the mechanisms of cancer therapeutic resistance is fundamental to improving cancer care. There is clear benefit from chemotherapy in different breast cancer settings; however, knowledge of the mutations and genes that mediate resistance is incomplete. In this study, by modeling chemoresistance in patient-derived xenografts (PDXs, we show that adaptation to therapy is genetically complex and identify that loss of transcription factor 4 (TCF4; also known as ITF2 is associated with this process. A triple-negative BRCA1-mutated PDX was used to study the genetics of chemoresistance. The PDX was treated in parallel with four chemotherapies for five iterative cycles. Exome sequencing identified few genes with de novo or enriched mutations in common among the different therapies, whereas many common depleted mutations/genes were observed. Analysis of somatic mutations from The Cancer Genome Atlas (TCGA supported the prognostic relevance of the identified genes. A mutation in TCF4 was found de novo in all treatments, and analysis of drug sensitivity profiles across cancer cell lines supported the link to chemoresistance. Loss of TCF4 conferred chemoresistance in breast cancer cell models, possibly by altering cell cycle regulation. Targeted sequencing in chemoresistant tumors identified an intronic variant of TCF4 that may represent an expression quantitative trait locus associated with relapse outcome in TCGA. Immunohistochemical studies suggest a common loss of nuclear TCF4 expression post-chemotherapy. Together, these results from tumor xenograft modeling depict a link between altered TCF4 expression and breast cancer chemoresistance.

  3. CysLT(1)R antagonists inhibit tumor growth in a xenograft model of colon cancer.

    Science.gov (United States)

    Savari, Sayeh; Liu, Minghui; Zhang, Yuan; Sime, Wondossen; Sjölander, Anita

    2013-01-01

    The expression of the inflammatory G-protein coupled receptor CysLT1R has been shown to be upregulated in colon cancer patients and associated with poor prognosis. The present study investigated the correlation between CysLT1R and colon cancer development in vivo using CysLT1R antagonists (ZM198,615 or Montelukast) and the nude mouse xenograft model. Two drug administration regimens were established. The first regimen was established to investigate the importance of CysLT1R in tumor initiation. Nude mice were inoculated with 50 µM CysLT1R antagonist-pretreated HCT-116 colon cancer cells and received continued treatment (5 mg/kg/day, intraperitoneally). The second regimen aimed to address the role of CysLT1R in tumor progression. Nude mice were inoculated with non-pretreated HCT-116 cells and did not receive CysLT1R antagonist treatment until recordable tumor appearance. Both regimens resulted in significantly reduced tumor size, attributed to changes in proliferation and apoptosis as determined by reduced Ki-67 levels and increased levels of p21(WAF/Cip1) (Pcolon cancer cell line HCT-116 and CysLT1R antagonists. In addition to significant reductions in cell proliferation, adhesion and colony formation, we observed induction of cell cycle arrest and apoptosis in a dose-dependent manner. The ability of Montelukast to inhibit growth of human colon cancer xenograft was further validated by using two additional colon cancer cell lines, SW-480 and HT-29. Our results demonstrate that CysLT1R antagonists inhibit growth of colon cancer xenografts primarily by reducing proliferation and inducing apoptosis of the tumor cells.

  4. Predictive markers of efficacy for an angiopoietin-2 targeting therapeutic in xenograft models.

    Directory of Open Access Journals (Sweden)

    Gallen Triana-Baltzer

    Full Text Available The clinical efficacy of anti-angiogenic therapies has been difficult to predict, and biomarkers that can predict responsiveness are sorely needed in this era of personalized medicine. CVX-060 is an angiopoietin-2 (Ang2 targeting therapeutic, consisting of two peptides that bind Ang2 with high affinity and specificity, covalently fused to a scaffold antibody. In order to optimize the use of this compound in the clinic the construction of a predictive model is described, based on the efficacy of CVX-060 in 13 cell line and 2 patient-derived xenograft models. Pretreatment size tumors from each of the models were profiled for the levels of 27 protein markers of angiogenesis, SNP haplotype in 5 angiogenesis genes, and somatic mutation status for 11 genes implicated in tumor growth and/or vascularization. CVX-060 efficacy was determined as tumor growth inhibition (TGI% at termination of each study. A predictive statistical model was constructed based on the correlation of these efficacy data with the marker profiles, and the model was subsequently tested by prospective analysis in 11 additional models. The results reveal a range of CVX-060 efficacy in xenograft models of diverse tissue types (0-64% TGI, median = 27% and define a subset of 3 proteins (Ang1, EGF, Emmprin, the levels of which may be predictive of TGI by Ang2 blockade. The direction of the associations is such that better efficacy correlates with high levels of target and low levels of compensatory/antagonizing molecules. This effort has revealed a set of candidate predictive markers for CVX-060 efficacy that will be further evaluated in ongoing clinical trials.

  5. The T61 human breast cancer xenograft: an experimental model of estrogen therapy of breast cancer

    DEFF Research Database (Denmark)

    Brunner, N; Spang-Thomsen, M; Cullen, K

    1996-01-01

    Endocrine therapy is one of the principal treatment modalities of breast cancer, both in an adjuvant setting and in advanced disease. The T61 breast cancer xenograft described here provides an experimental model of the effects of estrogen treatment at a molecular level. T61 is an estrogen receptor......-II), but not transforming growth factor beta-I (TGF-beta1). Of these, IGF-II is the only peptide whose expression is altered by endocrine therapy. Treatment of T61-bearing nude mice with physiologic doses of estrogen is accompanied by loss of IGF-II mRNA expression within 24 hours, and rapid regression of tumor. T61 tumor...

  6. Radioiodinated VEGF to image tumor angiogenesis in a LS180 tumor xenograft model

    International Nuclear Information System (INIS)

    Yoshimoto, Mitsuyoshi; Kinuya, Seigo; Kawashima, Atsuhiro; Nishii, Ryuichi; Yokoyama, Kunihiko; Kawai, Keiichi

    2006-01-01

    Introduction: Angiogenesis is essential for tumor growth or metastasis. A method involving noninvasive detection of angiogenic activity in vivo would provide diagnostic information regarding antiangiogenic therapy targeting vascular endothelial cells as well as important insight into the role of vascular endothelial growth factor (VEGF) and its receptor (flt-1 and KDR) system in tumor biology. We evaluated radioiodinated VEGF 121 , which displays high binding affinity for KDR, and VEGF 165 , which possesses high binding affinity for flt-1 and low affinity for KDR, as angiogenesis imaging agents using the LS180 tumor xenograft model. Methods: VEGF 121 and VEGF 165 were labeled with 125 I by the chloramine-T method. Biodistribution was observed in an LS180 human colon cancer xenograft model. Additionally, autoradiographic imaging and immunohistochemical staining of tumors were performed with 125 I-VEGF 121 . Results: 125 I-VEGF 121 and 125 I-VEGF 165 exhibited strong, continuous uptake by tumors and the uterus, an organ characterized by angiogenesis. 125 I-VEGF 121 uptake in tumors was twofold higher than that of 125 I-VEGF 165 (9.12±98 and 4.79±1.08 %ID/g at 2 h, respectively). 125 I-VEGF 121 displayed higher tumor to nontumor (T/N) ratios in most normal organs in comparison with 125 I-VEGF 165 . 125 I-VEGF 121 accumulation in tumors decreased with increasing tumor volume. Autoradiographic and immunohistochemical analyses confirmed that the difference in 125 I-VEGF 121 tumor accumulation correlated with degree of tumor vascularity. Conclusion: Radioiodinated VEGF 121 is a promising tracer for noninvasive delineation of angiogenesis in vivo

  7. Utility of a human-mouse xenograft model and in vivo near-infrared fluorescent imaging for studying wound healing.

    Science.gov (United States)

    Shanmugam, Victoria K; Tassi, Elena; Schmidt, Marcel O; McNish, Sean; Baker, Stephen; Attinger, Christopher; Wang, Hong; Shara, Nawar; Wellstein, Anton

    2015-12-01

    To study the complex cellular interactions involved in wound healing, it is essential to have an animal model that adequately mimics the human wound microenvironment. Currently available murine models are limited because wound contraction introduces bias into wound surface area measurements. The purpose of this study was to demonstrate utility of a human-mouse xenograft model for studying human wound healing. Normal human skin was harvested from elective abdominoplasty surgery, xenografted onto athymic nude (nu/nu) mice, and allowed to engraft for 3 months. The graft was then wounded using a 2-mm punch biopsy. Wounds were harvested on sequential days to allow tissue-based markers of wound healing to be followed sequentially. On the day of wound harvest, mice were injected with XenoLight RediJect cyclooxygenase-2 (COX-2) probe and imaged according to package instructions. Immunohistochemistry confirms that this human-mouse xenograft model is effective for studying human wound healing in vivo. Additionally, in vivo fluorescent imaging for inducible COX-2 demonstrated upregulation from baseline to day 4 (P = 0·03) with return to baseline levels by day 10, paralleling the reepithelialisation of the wound. This human-mouse xenograft model, combined with in vivo fluorescent imaging provides a useful mechanism for studying molecular pathways of human wound healing. © 2013 The Authors. International Wound Journal © 2013 Medicalhelplines.com Inc and John Wiley & Sons Ltd.

  8. Combining fisetin and ionizing radiation suppresses the growth of mammalian colorectal cancers in xenograft tumor models.

    Science.gov (United States)

    Leu, Jyh-Der; Wang, Bo-Shen; Chiu, Shu-Jun; Chang, Chun-Yuan; Chen, Chien-Chih; Chen, Fu-Du; Avirmed, Shiirevnyamba; Lee, Yi-Jang

    2016-12-01

    Fisetin (3,7,3',4'-tetrahydroxyflavone), which belongs to the flavonoid group of polyphenols and is found in a wide range of plants, has been reported to exhibit a number of biological activities in human cancer cells, including antioxidant, anti-inflammatory, antiangiogenic, anti-invasive and antiproliferative effects. Although previous in vitro studies have shown that fisetin treatment increases the apoptotic rate and enhances the radiosensitivity of human colorectal cancer cells, the in vivo effects of fisetin on tumor growth remain unclear. In the present study a murine xenograft tumor model was employed to investigate the therapeutic effects of fisetin in combination with radiation on CT-26 colon cancer cells and human HCT116 colorectal cancer cells. This revealed that intratumoral injection of fisetin significantly suppressed the growth of CT-26 tumors compared with the untreated control group, but had little effect on the growth of HCT116 tumors. However, fisetin in combination with 2-Gy radiation enhanced tumor suppressor activity in murine colon and human colorectal xenograft tumors, as compared with 2-Gy fractionated radiation administered alone for 5 days and fisetin alone. Interestingly, fisetin downregulated the expression of the oncoprotein securin in a p53-independent manner. However, securin-null HCT116 tumors showed only moderate sensitivity to fisetin treatment, and the combination of fisetin and radiation did not significantly suppress securin-null HCT116 tumor growth compared with normal HCT116 tumors. Therefore, the role of securin in mediating the effect of fisetin on colorectal cancer growth warrants further investigation. In conclusion, the results of the current study provide important preclinical data for evaluating the efficacy of fisetin and radiation combination treatment as an adjuvant chemoradiotherapy for human colorectal cancers.

  9. Antitumor Effects of Flavopiridol on Human Uterine Leiomyoma In Vitro and in a Xenograft Model

    Science.gov (United States)

    Lee, Hyun-Gyo; Baek, Jong-Woo; Shin, So-Jin; Kwon, Sang-Hoon; Cha, Soon-Do; Park, Won-Jin; Chung, Rosa; Choi, Eun-Som; Lee, Gun-Ho

    2014-01-01

    Dysregulated cyclin-dependent kinases (CDKs) are considered a potential target for cancer therapy. Flavopiridol is a potent CDK inhibitor. In this study, the antiproliferative effect of the flavonoid compound flavopiridol and its mechanism in human uterine leiomyoma cells were investigated. The present study focused on the effect of flavopiridol in cell proliferation and cell cycle progression in primary cultured human uterine leiomyoma cells. Cell viability and cell proliferation assays were conducted. Flow cytometry was performed to determine the effect of flavopiridol on cell cycle. The expression of cell cycle regulatory-related proteins was evaluated by Western blotting. Cell viability and proliferation of uterine leiomyoma cells were significantly reduced by flavopiridol treatment in a dose-dependent manner. Flow cytometry results showed that flavopiridol induced G1 phase arrest. Flavopiridol-induced growth inhibition in uterine leiomyoma cells was associated with increased expression of p21cip/wafl and p27kip1 in a dose-dependent manner. Downregulation of CDK2/4 and Cyclin A with a concomitant increase in dephosphorylation of retinoblastoma was observed. This study demonstrates that flavopiridol inhibits cell proliferation by initiating G1 cell cycle arrest in human uterine leiomyoma. We also found that flavopiridol is effective in inhibiting xenografted human uterine leiomyoma growth. These results indicate that flavopiridol could prove to be a promising chemopreventive and therapeutic agent for human uterine leiomyoma. PMID:24572052

  10. Pharmacokinetic modeling of an induction regimen for in vivo combined testing of novel drugs against pediatric acute lymphoblastic leukemia xenografts.

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    Barbara Szymanska

    Full Text Available Current regimens for induction therapy of pediatric acute lymphoblastic leukemia (ALL, or for re-induction post relapse, use a combination of vincristine (VCR, a glucocorticoid, and L-asparaginase (ASP with or without an anthracycline. With cure rates now approximately 80%, robust pre-clinical models are necessary to prioritize active new drugs for clinical trials in relapsed/refractory patients, and the ability of these models to predict synergy/antagonism with established therapy is an essential attribute. In this study, we report optimization of an induction-type regimen by combining VCR, dexamethasone (DEX and ASP (VXL against ALL xenograft models established from patient biopsies in immune-deficient mice. We demonstrate that the VXL combination was synergistic in vitro against leukemia cell lines as well as in vivo against ALL xenografts. In vivo, VXL treatment caused delays in progression of individual xenografts ranging from 22 to >146 days. The median progression delay of xenografts derived from long-term surviving patients was 2-fold greater than that of xenografts derived from patients who died of their disease. Pharmacokinetic analysis revealed that systemic DEX exposure in mice increased 2-fold when administered in combination with VCR and ASP, consistent with clinical findings, which may contribute to the observed synergy between the 3 drugs. Finally, as proof-of-principle we tested the in vivo efficacy of combining VXL with either the Bcl-2/Bcl-xL/Bcl-w inhibitor, ABT-737, or arsenic trioxide to provide evidence of a robust in vivo platform to prioritize new drugs for clinical trials in children with relapsed/refractory ALL.

  11. Correlation of Somatostatin Receptor-2 Expression with Gallium-68-DOTA-TATE Uptake in Neuroblastoma Xenograft Models.

    Science.gov (United States)

    Zhang, Libo; Vines, Douglass C; Scollard, Deborah A; McKee, Trevor; Komal, Teesha; Ganguly, Milan; Do, Trevor; Wu, Bing; Alexander, Natasha; Vali, Reza; Shammas, Amer; Besanger, Travis; Baruchel, Sylvain

    2017-01-01

    Peptide-receptor imaging and therapy with radiolabeled somatostatin analogs such as 68 Ga-DOTA-TATE and 177 Lu-DOTA-TATE have become an effective treatment option for SSTR-positive neuroendocrine tumors. The purpose of this study was to evaluate the correlation of somatostatin receptor-2 (SSTR2) expression with 68 Ga-DOTA-TATE uptake and 177 Lu-DOTA-TATE therapy in neuroblastoma (NB) xenograft models. We demonstrated variable SSTR2 expression profiles in eight NB cell lines. From micro-PET imaging and autoradiography, a higher uptake of 68 Ga-DOTA-TATE was observed in SSTR2 high-expressing NB xenografts (CHLA-15) compared to SSTR2 low-expressing NB xenografts (SK-N-BE(2)). Combined autoradiography-immunohistochemistry revealed histological colocalization of SSTR2 and 68 Ga-DOTA-TATE uptake in CHLA-15 tumors. With a low dose of 177 Lu-DOTA-TATE (20 MBq/animal), tumor growth inhibition was achieved in the CHLA-15 high SSTR2 expressing xenograft model. Although, in vitro , NB cells showed variable expression levels of norepinephrine transporter (NET), a molecular target for 131 I-MIBG therapy, low 123 I-MIBG uptake was observed in all selected NB xenografts. In conclusion, SSTR2 expression levels are associated with 68 Ga-DOTA-TATE uptake and antitumor efficacy of 177 Lu-DOTA-TATE. 68 Ga-DOTA-TATE PET is superior to 123 I-MIBG SPECT imaging in detecting NB tumors in our model. Radiolabeled DOTA-TATE can be used as an agent for NB tumor imaging to potentially discriminate tumors eligible for 177 Lu-DOTA-TATE therapy.

  12. Correlation of Somatostatin Receptor-2 Expression with Gallium-68-DOTA-TATE Uptake in Neuroblastoma Xenograft Models

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    Libo Zhang

    2017-01-01

    Full Text Available Peptide-receptor imaging and therapy with radiolabeled somatostatin analogs such as 68Ga-DOTA-TATE and 177Lu-DOTA-TATE have become an effective treatment option for SSTR-positive neuroendocrine tumors. The purpose of this study was to evaluate the correlation of somatostatin receptor-2 (SSTR2 expression with 68Ga-DOTA-TATE uptake and 177Lu-DOTA-TATE therapy in neuroblastoma (NB xenograft models. We demonstrated variable SSTR2 expression profiles in eight NB cell lines. From micro-PET imaging and autoradiography, a higher uptake of 68Ga-DOTA-TATE was observed in SSTR2 high-expressing NB xenografts (CHLA-15 compared to SSTR2 low-expressing NB xenografts (SK-N-BE(2. Combined autoradiography-immunohistochemistry revealed histological colocalization of SSTR2 and 68Ga-DOTA-TATE uptake in CHLA-15 tumors. With a low dose of 177Lu-DOTA-TATE (20 MBq/animal, tumor growth inhibition was achieved in the CHLA-15 high SSTR2 expressing xenograft model. Although, in vitro, NB cells showed variable expression levels of norepinephrine transporter (NET, a molecular target for 131I-MIBG therapy, low 123I-MIBG uptake was observed in all selected NB xenografts. In conclusion, SSTR2 expression levels are associated with 68Ga-DOTA-TATE uptake and antitumor efficacy of 177Lu-DOTA-TATE. 68Ga-DOTA-TATE PET is superior to 123I-MIBG SPECT imaging in detecting NB tumors in our model. Radiolabeled DOTA-TATE can be used as an agent for NB tumor imaging to potentially discriminate tumors eligible for 177Lu-DOTA-TATE therapy.

  13. Application of a Patient Derived Xenograft Model for Predicative Study of Uterine Fibroid Disease.

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    Martin Fritsch

    Full Text Available Human uterine fibroids, benign tumors derived from the smooth muscle layers of the uterus, impose a major health burden to up to 50% of premenopausal women in their daily life. To improve our understanding of this disease, we developed and characterized a patient-derived xenograft model by subcutaneous transplantation of pieces of human uterine fibroid tissue into three different strains of severe combined immunodeficient mice. Engrafted uterine fibroid tissue preserved the classical morphology with interwoven bundles of smooth muscle cells and an abundant deposition of collagenous matrix, similar to uterine fibroids in situ. The grafts expressed both estrogen receptor 1 and progesterone receptor. Additionally, both receptors were up-regulated by estrogen treatment. Growth of the fibroid grafts was dependent on 17β-estradiol and progesterone supplementation at levels similar to women with the disease and was studied for up to 60 days at maximum. Co-treatment with the antiprogestin mifepristone reduced graft growth (four independent donors, p<0.0001 two-sided t-test, as did treatment with the mTOR inhibitor rapamycin (three independent donors, p<0.0001 two-sided t-test. This in vivo animal model preserves the main histological and functional characteristics of human uterine fibroids, is amenable to intervention by pharmacological treatment, and can thus serve as an adequate model for the development of novel therapies.

  14. FDG small animal PET permits early detection of malignant cells in a xenograft murine model

    International Nuclear Information System (INIS)

    Nanni, Cristina; Spinelli, Antonello; Trespidi, Silvia; Ambrosini, Valentina; Castellucci, Paolo; Farsad, Mohsen; Franchi, Roberto; Fanti, Stefano; Leo, Korinne di; Tonelli, Roberto; Pession, Andrea; Pettinato, Cinzia; Rubello, Domenico

    2007-01-01

    The administration of new anticancer drugs in animal models is the first step from in vitro to in vivo pre-clinical protocols. At this stage it is crucial to ensure that cells are in the logarithmic phase of growth and to avoid vascular impairment, which can cause inhomogeneous distribution of the drug within the tumour and thus lead to bias in the final analysis of efficacy. In subcutaneous xenograft murine models, positivity for cancer is visually recognisable 2-3 weeks after inoculation, when a certain amount of necrosis is usually already present. The aim of this study was to evaluate the accuracy of FDG small animal PET for the early detection of malignant masses in a xenograft murine model of human rhabdomyosarcoma. A second goal was to analyse the metabolic behaviour of this xenograft tumour over time. We studied 23 nude mice, in which 7 x 10 6 rhabdomyosarcoma cells (RH-30 cell line) were injected in the dorsal subcutaneous tissues. Each animal underwent four FDG PET scans (GE, eXplore Vista DR) under gas anaesthesia. The animals were studied 2, 5, 14 and 20 days after inoculation. We administered 20 MBq of FDG via the tail vein. Uptake time was 60 min, and acquisition time, 20 min. Images were reconstructed with OSEM 2D iterative reconstruction and the target to background ratio (TBR) was calculated for each tumour. Normal subcutaneous tissue had a TBR of 0.3. Necrosis was diagnosed when one or more cold areas were present within the mass. All the animals were sacrificed and histology was available to verify PET results. PET results were concordant with the findings of necropsy and histology in all cases. The incidence of the tumour was 69.6% (16/23 animals); seven animals did not develop a malignant mass. Ten of the 23 animals had a positive PET scan 2 days after inoculation. Nine of these ten animals developed a tumour; the remaining animal became negative, at the third scan. The positive predictive value of the early PET scan was 90% (9/10 animals

  15. Intratumoral Heterogeneity of Breast Cancer Xenograft Models: Texture Analysis of Diffusion-Weighted MR Imaging

    Energy Technology Data Exchange (ETDEWEB)

    Yun, Bo La; Cho, Nariya; Li, Mulun; Song, In Chan; Moon, Woo Kyung [Dept. of Radiology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul (Korea, Republic of); Jang, Min Hye; Park, So Yeon; Kim, Bo Young [Seoul National University Bundang Hospital, Seongnam (Korea, Republic of); Kang, Ho Chul [Dept. of Computer Science and Engineering, Seoul National University, Seoul (Korea, Republic of)

    2014-10-15

    To investigate whether there is a relationship between texture analysis parameters of apparent diffusion coefficient (ADC) maps and histopathologic features of MCF-7 and MDA-MB-231 xenograft models. MCF-7 estradiol (+), MCF-7 estradiol (-), and MDA-MB-231 xenograft models were made with approval of the animal care committee. Twelve tumors of MCF-7 estradiol (+), 9 tumors of MCF-7 estradiol (-), and 6 tumors in MDA-MB-231 were included. Diffusion-weighted MR images were obtained on a 9.4-T system. An analysis of the first and second order texture analysis of ADC maps was performed. The texture analysis parameters and histopathologic features were compared among these groups by the analysis of variance test. Correlations between texture parameters and histopathologic features were analyzed. We also evaluated the intraobserver agreement in assessing the texture parameters. MCF-7 estradiol (+) showed a higher standard deviation, maximum, skewness, and kurtosis of ADC values than MCF-7 estradiol (-) and MDA-MB-231 (p < 0.01 for all). The contrast of the MCF-7 groups was higher than that of the MDA-MB-231 (p 0.004). The correlation (COR) of the texture analysis of MCF-7 groups was lower than that of MDA-MB-231 (p < 0.001). The histopathologic analysis showed that Ki-67mean and Ki-67diff of MCF-7 estradiol (+) were higher than that of MCF-7 estradiol (-) or MDA-MB-231 (p < 0.05). The microvessel density (MVD)mean and MVDdiff of MDA-MB-231 were higher than those of MCF-7 groups (p < 0.001). A diffuse-multifocal necrosis was more frequently found in MDA-MB-231 (p < 0.001). The proportion of necrosis moderately correlated with the contrast (r = -0.438, p = 0.022) and strongly with COR (r = 0.540, p 0.004). Standard deviation (r = 0.622, r = 0.437), skewness (r = 0.404, r 0.484), and kurtosis (r = 0.408, r = 0.452) correlated with Ki-67 mean and Ki-67diff (p < 0.05 for all). COR moderately correlated with Ki-67diff (r -0.388, p = 0.045). Skewness (r = -0.643, r = -0

  16. Patient-derived xenograft models to improve targeted therapy in epithelial ovarian cancer treatment

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    Clare eScott

    2013-12-01

    Full Text Available Despite increasing evidence that precision therapy targeted to the molecular drivers of a cancer has the potential to improve clinical outcomes, high-grade epithelial ovarian cancer patients are currently treated without consideration of molecular phenotype, and predictive biomarkers that could better inform treatment remain unknown. Delivery of precision therapy requires improved integration of laboratory-based models and cutting-edge clinical research, with pre-clinical models predicting patient subsets that will benefit from a particular targeted therapeutic. Patient-derived xenografts (PDX are renewable tumor models engrafted in mice, generated from fresh human tumors without prior in vitro exposure. PDX models allow an invaluable assessment of tumor evolution and adaptive response to therapy.PDX models have been applied to preclinical drug testing and biomarker identification in a number of cancers including ovarian, pancreatic, breast and prostate cancers. These models have been shown to be biologically stable and accurately reflect the patient tumor with regards to histopathology, gene expression, genetic mutations and therapeutic response. However, pre-clinical analyses of molecularly annotated PDX models derived from high-grade serous ovarian cancer (HG-SOC remain limited. In vivo response to conventional and/or targeted therapeutics has only been described for very small numbers of individual HG-SOC PDX in conjunction with sparse molecular annotation and patient outcome data. Recently, two consecutive panels of epithelial ovarian cancer PDX correlate in vivo platinum response with molecular aberrations and source patient clinical outcomes. These studies underpin the value of PDX models to better direct chemotherapy and predict response to targeted therapy. Tumor heterogeneity, before and following treatment, as well as the importance of multiple molecular aberrations per individual tumor underscore some of the important issues

  17. Antitumor effect of novel anti-podoplanin antibody NZ-12 against malignant pleural mesothelioma in an orthotopic xenograft model.

    Science.gov (United States)

    Abe, Shinji; Kaneko, Mika Kato; Tsuchihashi, Yuki; Izumi, Toshihiro; Ogasawara, Satoshi; Okada, Naoto; Sato, Chiemi; Tobiume, Makoto; Otsuka, Kenji; Miyamoto, Licht; Tsuchiya, Koichiro; Kawazoe, Kazuyoshi; Kato, Yukinari; Nishioka, Yasuhiko

    2016-09-01

    Podoplanin (aggrus) is highly expressed in several types of cancers, including malignant pleural mesothelioma (MPM). Previously, we developed a rat anti-human podoplanin mAb, NZ-1, and a rat-human chimeric anti-human podoplanin antibody, NZ-8, derived from NZ-1, which induced antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity against podoplanin-positive MPM cell lines. In this study, we showed the antitumor effect of NZ-1, NZ-8, and NZ-12, a novel rat-human chimeric anti-human podoplanin antibody derived from NZ-1, in an MPM orthotopic xenograft SCID mouse model. Treatment with NZ-1 and rat NK (CD161a(+) ) cells inhibited the growth of tumors and the production of pleural effusion in NCI-H290/PDPN or NCI-H226 orthotopic xenograft mouse models. NZ-8 and human natural killer (NK) (CD56(+) ) cells also inhibited tumor growth and pleural effusion in MPM orthotopic xenograft mice. Furthermore, NZ-12 induced potent ADCC mediated by human MNC, compared with either NZ-1 or NZ-8. Antitumor effects were observed following treatment with NZ-12 and human NK (CD56(+) ) cells in MPM orthotopic xenograft mice. In addition, combined immunotherapy using the ADCC activity of NZ-12 mediated by human NK (CD56(+) ) cells with pemetrexed, led to enhanced antitumor effects in MPM orthotopic xenograft mice. These results strongly suggest that combination therapy with podoplanin-targeting immunotherapy using both NZ-12 and pemetrexed might provide an efficacious therapeutic strategy for the treatment of MPM. © 2016 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

  18. Enhanced antitumor efficacy and reduced systemic toxicity of sulfatide-containing nanoliposomal doxorubicin in a xenograft model of colorectal cancer.

    Directory of Open Access Journals (Sweden)

    Jia Lin

    Full Text Available Sulfatide is a glycosphingolipid known to interact with several extracellular matrix proteins, such as tenascin-C which is overexpressed in many types of cancer including that of the colon. In view of the limited success of chemotherapy in colorectal cancer and high toxicity of doxorubicin (DOX, a sulfatide-containing liposome (SCL encapsulation approach was taken to overcome these barriers. This study assessed the in vitro cytotoxicity, biodistribution, therapeutic efficacy and systemic toxicity in vivo of sulfatide-containing liposomal doxorubicin (SCL-DOX using human colonic adenocarcinoma HT-29 xenograft as the experimental model. In vitro, SCL-DOX was shown to be delivered into the nuclei and displayed prolonged retention compared with the free DOX. The use of this nanodrug delivery system to deliver DOX for treatment of tumor-bearing mice produced a much improved therapeutic efficacy in terms of tumor growth suppression and extended survival in contrast to the free drug. Furthermore, treatment of tumor-bearing mice with SCL-DOX resulted in a lower DOX uptake in the principal sites of toxicity of the free drug, namely the heart and skin, as well as reduced myelosuppression and diminished cardiotoxicity. Such natural lipid-guided nanodrug delivery systems may represent a new strategy for the development of effective anticancer chemotherapeutics targeting the tumor microenvironment for both primary tumor and micrometastases.

  19. Antitumor activity of [Pt(O,O'-acac)(γ-acac)(DMS)] in mouse xenograft model of breast cancer.

    Science.gov (United States)

    Muscella, A; Vetrugno, C; Migoni, D; Biagioni, F; Fanizzi, F P; Fornai, F; De Pascali, S A; Marsigliante, S

    2014-01-23

    The higher and selective cytotoxicity of [Pt(O,O'-acac)(γ-acac)(DMS)] toward cancer cell in both immortalized cell lines and in breast cancer cells in primary cultures, stimulated a pre-clinical study so as to evaluate its therapeutic potential in vivo. The efficacy of [Pt(O,O'-acac)(γ-acac)(DMS)] was assessed using a xenograft model of breast cancer developed by injection of MCF-7 cells in the flank of BALB/c nude mice. Treatment of solid tumor-bearing mice with [Pt(O,O'-acac)(γ-acac)(DMS)] induced up to 50% reduction of tumor mass compared with an average 10% inhibition recorded in cisplatin-treated animals. Thus, chemotherapy with [Pt(O,O'-acac)(γ-acac)(DMS)] was much more effective than cisplatin. We also demonstrated enhanced in vivo pharmacokinetics, biodistribution and tolerability of [Pt(O,O'-acac)(γ-acac)(DMS)] when compared with cisplatin administered in Wistar rats. Pharmacokinetics studies with [Pt(O,O'-acac)(γ-acac)(DMS)] revealed prolonged Pt persistence in systemic blood circulation and decreased nefrotoxicity and hepatotoxicity, major target sites of cisplatin toxicity. Overall, [Pt(O,O'-acac)(γ-acac)(DMS)] turned out to be extremely promising in terms of greater in vivo anticancer activity, reduced nephrotoxicity and acute toxicity compared with cisplatin.

  20. Antitumor activity of the multikinase inhibitor regorafenib in patient-derived xenograft models of gastric cancer.

    Science.gov (United States)

    Huynh, Hung; Ong, Richard; Zopf, Dieter

    2015-10-29

    Unresectable gastric cancer is associated with poor outcomes, with few treatment options available after failure of cytotoxic chemotherapy. Clinical trials of targeted therapies have generally shown no survival benefit in gastric cancer, with the exceptions of the antibodies ramucirumab (anti-VEGFR2) and trastuzumab (anti-HER2/neu). Given the efficacy of the multikinase inhibitor regorafenib in other gastrointestinal tumors, we investigated its potential in gastric cancer. The antitumor activity of oral regorafenib was assessed in eight murine patient-derived gastric cancer xenograft models. Dose-response experiments assessed the efficacy and tolerability of oral regorafenib 5, 10, and 15 mg/kg/day in two models, with 10 mg/kg/day selected for further investigation in all eight models. Tumor weight and volume was monitored during treatment; tumor cell proliferation, angiogenesis, apoptosis, and intracellular signaling were assessed using immunohistochemistry and Western blotting of total tumor lysates at the end of treatment. Regorafenib showed dose-dependent inhibition of tumor growth and was well tolerated, with no significant decreases in bodyweight or evident toxicity. Regorafenib 10 mg/kg/day significantly inhibited tumor growth in all eight models (72 to 96 %; all p Regorafenib reduced tumor angiogenesis 3- to 11-fold versus controls in all models (all p Regorafenib was effective in patient-derived models of gastric cancer of different histological subtypes, with inhibition of tumor growth, angiogenesis, and tumor-cell proliferation observed in almost all models. These findings are consistent with the observed activity of regorafenib in preclinical models of other gastrointestinal tumors, and support further clinical investigation in gastric cancer.

  1. Imaging Tumor Variation in Response to Photodynamic Therapy in Pancreatic Cancer Xenograft Models

    International Nuclear Information System (INIS)

    Samkoe, Kimberley S.; Chen, Alina; Rizvi, Imran; O'Hara, Julia A.; Hoopes, P. Jack; Pereira, Stephen P.; Hasan, Tayyaba; Pogue, Brian W.

    2010-01-01

    Purpose: A treatment monitoring study investigated the differential effects of orthotopic pancreatic cancer models in response to interstitial photodynamic therapy (PDT), and the validity of using magnetic resonance imaging as a surrogate measure of response was assessed. Methods and Materials: Different orthotopic pancreatic cancer xenograft models (AsPC-1 and Panc-1) were used to represent the range of pathophysiology observed in human beings. Identical dose escalation studies (10, 20, and 40J/cm) using interstitial verteporfin PDT were performed, and magnetic resonance imaging with T2-weighted and T1-weighted contrast were used to monitor the total tumor volume and the vascular perfusion volume, respectively. Results: There was a significant amount of necrosis in the slower-growing Panc-1 tumor using high light dose, although complete necrosis was not observed. Lower doses were required for the same level of tumor kill in the faster-growing AsPC-1 cell line. Conclusions: The tumor growth rate and vascular pattern of the tumor affect the optimal PDT treatment regimen, with faster-growing tumors being relatively easier to treat. This highlights the fact that therapy in human beings shows a heterogeneous range of outcomes, and suggests a need for careful individualized treatment outcomes assessment in clinical work.

  2. Interleukin-12 Inhibits Tumor Growth in a Novel Angiogenesis Canine Hemangiosarcoma Xenograft Model

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    Nasim Akhtar

    2004-03-01

    Full Text Available We established a canine hemangiosarcoma cell line derived from malignant endothelial cells comprising a spontaneous tumor in a dog to provide a renewable source of endothelial cells for studies of angiogenesis in malignancy. Pieces of the hemangiosarcoma biopsy were engrafted subcutaneously in a bg/nu/XID mouse allowing the tumor cells to expand in vivo. A cell line, SB-HSA, was derived from the xenograft. SB-HSA cells expressed vascular endothelial growth factor (VEGF receptors 1 and 2, CD31, CD146, and αvβ3 integrin, and produced several growth factors and cytokines, including VEGF, basic fibroblast growth factor, and interleukin (IL-8 that are stimulatory to endothelial cell growth. These results indicated that the cells recapitulated features of mitotically activated endothelia. In vivo, SB-HSA cells stimulated robust angiogenic responses in mice and formed tumor masses composed of aberrant vascular channels in immunocompromised mice providing novel opportunities for investigating the effectiveness of antiangiogenic agents. Using this model, we determined that IL-12, a cytokine with both immunostimulatory and antiangiogenic effects, suppressed angiogenesis induced by, and tumor growth of, SB-HSA cells. The endothelial cell model we have described offers unique opportunities to pursue further investigations with IL-12, as well as other antiangiogenic approaches in cancer therapy.

  3. Intracranial AAV-sTRAIL combined with lanatoside C prolongs survival in an orthotopic xenograft mouse model of invasive glioblastoma.

    Science.gov (United States)

    Crommentuijn, Matheus H W; Maguire, Casey A; Niers, Johanna M; Vandertop, W Peter; Badr, Christian E; Würdinger, Thomas; Tannous, Bakhos A

    2016-04-01

    Glioblastoma (GBM) is the most common malignant brain tumor in adults. We designed an adeno-associated virus (AAV) vector for intracranial delivery of secreted, soluble tumor necrosis factor-related apoptosis-inducing ligand (sTRAIL) to GBM tumors in mice and combined it with the TRAIL-sensitizing cardiac glycoside, lanatoside C (lan C). We applied this combined therapy to two different GBM models using human U87 glioma cells and primary patient-derived GBM neural spheres in culture and in orthotopic GBM xenograft models in mice. In U87 cells, conditioned medium from AAV2-sTRAIL expressing cells combined with lan C induced 80% cell death. Similarly, lan C sensitized primary GBM spheres to sTRAIL causing over 90% cell death. In mice bearing intracranial U87 tumors treated with AAVrh.8-sTRAIL, administration of lan C caused a decrease in tumor-associated Fluc signal, while tumor size increased within days of stopping the treatment. Another round of lan C treatment re-sensitized GBM tumor to sTRAIL-induced cell death. AAVrh.8-sTRAIL treatment alone and combined with lanatoside C resulted in a significant decrease in tumor growth and longer survival of mice bearing orthotopic invasive GBM brain tumors. In summary, AAV-sTRAIL combined with lanatoside C induced cell death in U87 glioma cells and patient-derived GBM neural spheres in culture and in vivo leading to an increased in overall mice survival. Copyright © 2015 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

  4. Novel LIMK2 Inhibitor Blocks Panc-1 Tumor Growth in a mouse xenograft model.

    Science.gov (United States)

    Rak, Roni; Haklai, Roni; Elad-Tzfadia, Galit; Wolfson, Haim J; Carmeli, Shmuel; Kloog, Yoel

    2014-01-01

    LIM kinases (LIMKs) are important cell cytoskeleton regulators that play a prominent role in cancer manifestation and neuronal diseases. The LIMK family consists of two homologues, LIMK1 and LIMK2, which differ from one another in expression profile, intercellular localization, and function. The main substrate of LIMK is cofilin, a member of the actin-depolymerizing factor (ADF) protein family. When phosphorylated by LIMK, cofilin is inactive. LIMKs play a contributory role in several neurodevelopmental disorders and in cancer growth and metastasis. We recently reported the development and validation of a novel LIMK inhibitor, referred to here as T56-LIMKi, using a combination of computational methods and classical biochemistry techniques. Here we report that T56-LIMKi inhibits LIMK2 with high specificity, and shows little or no cross-reactivity with LIMK1. We found that T56-LIMKi decreases phosphorylated cofilin (p-cofilin) levels and thus inhibits growth of several cancerous cell lines, including those of pancreatic cancer, glioma and schwannoma. Because the most promising in-vitro effect of T56-LIMKi was observed in the pancreatic cancer cell line Panc-1, we tested the inhibitor on a nude mouse Panc-1 xenograft model. T56-LIMKi reduced tumor size and p-cofilin levels in the Panc-1 tumors, leading us to propose T56-LIMKi as a candidate drug for cancer therapy.

  5. Anticancer Efficacy of Cordyceps militaris Ethanol Extract in a Xenografted Leukemia Model

    Directory of Open Access Journals (Sweden)

    Jae Gwang Park

    2017-01-01

    Full Text Available Cordyceps militaris is used widely as a traditional medicine in East Asia. Although a few studies have attempted to elucidate the anticancer activities of C. militaris, the precise mechanism of C. militaris therapeutic effects is not fully understood. We examined the anticancer activities of C. militaris ethanolic extract (Cm-EE and its cellular and molecular mechanisms. For this purpose, a xenograft mouse model bearing murine T cell lymphoma (RMA cell-derived cancers was established to investigate in vivo anticancer mechanisms. MTT [3-(4,5-dimethylthiazol-2-yl-2,5-diphenyltetrazolium bromide] assay, immunoblotting analysis, and flow cytometric assay were employed to check in vitro cytotoxicity, molecular targets, and proapoptotic action of Cm-EE. Interestingly, cancer sizes and mass were reduced in a C. militaris-administered group. Levels of the phosphorylated forms of p85 and AKT were clearly decreased in the group administered with Cm-EE. This result indicated that levels of phosphoglycogen synthase kinase 3β (p-GSK3β and cleaved caspase-3 were increased with orally administered Cm-EE. In addition, Cm-EE directly inhibited the viability of cultured RMA cells and C6 glioma cells. The number of proapoptotic cells was significantly increased in a Cm-EE treated group compared with a control group. Our results suggested that C. militaris might be able to inhibit cancer growth through regulation of p85/AKT-dependent or GSK3β-related caspase-3-dependent apoptosis.

  6. Effects of aurothiomalate treatment on canine osteosarcoma in a murine xenograft model.

    Science.gov (United States)

    Scharf, Valery F; Farese, James P; Siemann, Dietmar W; Abbott, Jeffrey R; Kiupel, Matti; Salute, Marc E; Milner, Rowan J

    2014-03-01

    Osteosarcoma is a highly fatal cancer, with most patients ultimately succumbing to metastatic disease. The purpose of this study was to evaluate the effects of the antirheumatoid drug aurothiomalate on canine and human osteosarcoma cells and on canine osteosarcoma growth and metastasis in a mouse xenograft model. We hypothesized that aurothiomalate would decrease osteosarcoma cell survival, tumor cellular proliferation, tumor growth, and metastasis. After performing clonogenic assays, aurothiomalate or a placebo was administered to 54 mice inoculated with canine osteosarcoma. Survival, tumor growth, embolization, metastasis, histopathology, cell proliferation marker Ki67, and apoptosis marker caspase-3 were compared between groups. Statistical analysis was carried out using the Kaplan-Meier method with the log-rank test and one-way analysis of variance with the Tukey's test or Dunn's method. Aurothiomalate caused dose-dependent inhibition of osteosarcoma cell survival (Posteosarcoma cell survival and reduced tumor cell proliferation, growth, embolization, and pulmonary metastasis. Given aurothiomalate's established utility in canine and human medicine, our results suggest that this compound may hold promise as an adjunctive therapy for osteosarcoma. Further translational research is warranted to better characterize the dose response of canine and human osteosarcoma to aurothiomalate.

  7. Chick embryo xenograft model reveals a novel perineural niche for human adipose-derived stromal cells

    Directory of Open Access Journals (Sweden)

    Ingrid R. Cordeiro

    2015-09-01

    Full Text Available Human adipose-derived stromal cells (hADSC are a heterogeneous cell population that contains adult multipotent stem cells. Although it is well established that hADSC have skeletal potential in vivo in adult organisms, in vitro assays suggest further differentiation capacity, such as into glia. Thus, we propose that grafting hADSC into the embryo can provide them with a much more instructive microenvironment, allowing the human cells to adopt diverse fates or niches. Here, hADSC spheroids were grafted into either the presumptive presomitic mesoderm or the first branchial arch (BA1 regions of chick embryos. Cells were identified without previous manipulations via human-specific Alu probes, which allows efficient long-term tracing of heterogeneous primary cultures. When grafted into the trunk, in contrast to previous studies, hADSC were not found in chondrogenic or osteogenic territories up to E8. Surprisingly, 82.5% of the hADSC were associated with HNK1+ tissues, such as peripheral nerves. Human skin fibroblasts showed a smaller tropism for nerves. In line with other studies, hADSC also adopted perivascular locations. When grafted into the presumptive BA1, 74.6% of the cells were in the outflow tract, the final goal of cardiac neural crest cells, and were also associated with peripheral nerves. This is the first study showing that hADSC could adopt a perineural niche in vivo and were able to recognize cues for neural crest cell migration of the host. Therefore, we propose that xenografts of human cells into chick embryos can reveal novel behaviors of heterogeneous cell populations, such as response to migration cues.

  8. Genetically engineered mesenchymal stromal cells produce IL-3 and TPO to further improve human scaffold-based xenograft models.

    Science.gov (United States)

    Carretta, Marco; de Boer, Bauke; Jaques, Jenny; Antonelli, Antonella; Horton, Sarah J; Yuan, Huipin; de Bruijn, Joost D; Groen, Richard W J; Vellenga, Edo; Schuringa, Jan Jacob

    2017-07-01

    Recently, NOD-SCID IL2Rγ -/- (NSG) mice were implanted with human mesenchymal stromal cells (MSCs) in the presence of ceramic scaffolds or Matrigel to mimic the human bone marrow (BM) microenvironment. This approach allowed the engraftment of leukemic samples that failed to engraft in NSG mice without humanized niches and resulted in a better preservation of leukemic stem cell self-renewal properties. To further improve our humanized niche scaffold model, we genetically engineered human MSCs to secrete human interleukin-3 (IL-3) and thrombopoietin (TPO). In vitro, these IL-3- and TPO-producing MSCs were superior in expanding human cord blood (CB) CD34 + hematopoietic stem/progenitor cells. MLL-AF9-transduced CB CD34 + cells could be transformed efficiently along myeloid or lymphoid lineages on IL-3- and TPO-producing MSCs. In vivo, these genetically engineered MSCs maintained their ability to differentiate into bone, adipocytes, and other stromal components. Upon transplantation of MLL-AF9-transduced CB CD34 + cells, acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) developed in engineered scaffolds, in which a significantly higher percentage of myeloid clones was observed in the mouse compartments compared with previous models. Engraftment of primary AML, B-cell ALL, and biphenotypic acute leukemia (BAL) patient samples was also evaluated, and all patient samples could engraft efficiently; the myeloid compartment of the BAL samples was better preserved in the human cytokine scaffold model. In conclusion, we show that we can genetically engineer the ectopic human BM microenvironment in a humanized scaffold xenograft model. This approach will be useful for functional study of the importance of niche factors in normal and malignant human hematopoiesis. Copyright © 2017 ISEH - International Society for Experimental Hematology. All rights reserved.

  9. Orthotopic glioblastoma stem-like cell xenograft model in mice to evaluate intra-arterial delivery of bevacizumab: from bedside to bench.

    Science.gov (United States)

    Burkhardt, Jan-Karl; Hofstetter, Christoph P; Santillan, Alejandro; Shin, Benjamin J; Foley, Conor P; Ballon, Douglas J; Pierre Gobin, Y; Boockvar, John A

    2012-11-01

    Bevacizumab (BV), a humanized monocolonal antibody directed against vascular endothelial growth factor (VEGF), is a standard intravenous (IV) treatment for recurrent glioblastoma multiforme (GBM), that has been introduced recently as an intra-arterial (IA) treatment modality in humans. Since preclinical models have not been reported, we sought to develop a tumor stem cell (TSC) xenograft model to investigate IA BV delivery in vivo. Firefly luciferase transduced patient TSC were injected into the cortex of 35 nude mice. Tumor growth was monitored weekly using bioluminescence imaging. Mice were treated with either intraperitoneal (IP) or IA BV, with or without blood-brain barrier disruption (BBBD), or with IP saline injection (controls). Tumor tissue was analyzed using immunohistochemistry and western blot techniques. Tumor formation occurred in 31 of 35 (89%) mice with a significant signal increase over time (p=0.018). Post mortem histology revealed an infiltrative growth of TSC xenografts in a similar pattern compared to the primary human GBM. Tumor tissue analyzed at 24 hours after treatment revealed that IA BV treatment with BBBD led to a significantly higher intratumoral BV concentration compared to IA BV alone, IP BV or controls (pmouse model that allows us to study IA chemotherapy. However, further studies are needed to analyze the treatment effects after IA BV to assess tumor progression and overall animal survival. Copyright © 2012 Elsevier Ltd. All rights reserved.

  10. Pentastatin-1, a collagen IV derived 20-mer peptide, suppresses tumor growth in a small cell lung cancer xenograft model.

    Science.gov (United States)

    Koskimaki, Jacob E; Karagiannis, Emmanouil D; Tang, Benjamin C; Hammers, Hans; Watkins, D Neil; Pili, Roberto; Popel, Aleksander S

    2010-02-01

    Angiogenesis is the formation of neovasculature from a pre-existing vascular network. Progression of solid tumors including lung cancer is angiogenesis-dependent. We previously introduced a bioinformatics-based methodology to identify endogenous anti-angiogenic peptide sequences, and validated these predictions in vitro in human umbilical vein endothelial cell (HUVEC) proliferation and migration assays. One family of peptides with high activity is derived from the alpha-fibrils of type IV collagen. Based on the results from the in vitro screening, we have evaluated the ability of a 20 amino acid peptide derived from the alpha5 fibril of type IV collagen, pentastatin-1, to suppress vessel growth in an angioreactor-based directed in vivo angiogenesis assay (DIVAA). In addition, pentastatin-1 suppressed tumor growth with intraperitoneal peptide administration in a small cell lung cancer (SCLC) xenograft model in nude mice using the NCI-H82 human cancer cell line. Pentastatin-1 decreased the invasion of vessels into angioreactors in vivo in a dose dependent manner. The peptide also decreased the rate of tumor growth and microvascular density in vivo in a small cell lung cancer xenograft model. The peptide treatment significantly decreased the invasion of microvessels in angioreactors and the rate of tumor growth in the xenograft model, indicating potential treatment for angiogenesis-dependent disease, and for translational development as a therapeutic agent for lung cancer.

  11. Pentastatin-1, a collagen IV derived 20-mer peptide, suppresses tumor growth in a small cell lung cancer xenograft model

    International Nuclear Information System (INIS)

    Koskimaki, Jacob E; Karagiannis, Emmanouil D; Tang, Benjamin C; Hammers, Hans; Watkins, D Neil; Pili, Roberto; Popel, Aleksander S

    2010-01-01

    Angiogenesis is the formation of neovasculature from a pre-existing vascular network. Progression of solid tumors including lung cancer is angiogenesis-dependent. We previously introduced a bioinformatics-based methodology to identify endogenous anti-angiogenic peptide sequences, and validated these predictions in vitro in human umbilical vein endothelial cell (HUVEC) proliferation and migration assays. One family of peptides with high activity is derived from the α-fibrils of type IV collagen. Based on the results from the in vitro screening, we have evaluated the ability of a 20 amino acid peptide derived from the α5 fibril of type IV collagen, pentastatin-1, to suppress vessel growth in an angioreactor-based directed in vivo angiogenesis assay (DIVAA). In addition, pentastatin-1 suppressed tumor growth with intraperitoneal peptide administration in a small cell lung cancer (SCLC) xenograft model in nude mice using the NCI-H82 human cancer cell line. Pentastatin-1 decreased the invasion of vessels into angioreactors in vivo in a dose dependent manner. The peptide also decreased the rate of tumor growth and microvascular density in vivo in a small cell lung cancer xenograft model. The peptide treatment significantly decreased the invasion of microvessels in angioreactors and the rate of tumor growth in the xenograft model, indicating potential treatment for angiogenesis-dependent disease, and for translational development as a therapeutic agent for lung cancer

  12. Increased Plasma Colloid Osmotic Pressure Facilitates the Uptake of Therapeutic Macromolecules in a Xenograft Tumor Model

    Directory of Open Access Journals (Sweden)

    Matthias Hofmann

    2009-08-01

    Full Text Available Elevated tumor interstitial fluid pressure (TIFP is a characteristic of most solid tumors. Clinically, TIFP may hamper the uptake of chemotherapeutic drugs into the tumor tissue reducing their therapeutic efficacy. In this study, a means of modulating TIFP to increase the flux of macromolecules into tumor tissue is presented, which is based on the rationale that elevated plasma colloid osmotic pressure (COP pulls water from tumor interstitium lowering the TIFP. Concentrated human serum albumin: (20% HSA, used as an agent to enhance COP, reduced the TIFP time-dependently from 8 to 2 mm Hg in human tumor xenograft models bearing A431 epidermoid vulva carcinomas. To evaluate whether this reduction facilitates the uptake of macromolecules, the intratumoral distribution of fluorescently conjugated dextrans (2.5 mg/ml and cetuximab (2.0 mg/ml was probed using novel time domain nearinfrared fluorescence imaging. This method permitted discrimination and semiquantification of tumor-accumulated conjugate from background and unspecific probe fluorescence. The coadministration of 20% HSA together with either dextrans or cetuximab was found to lower the TIFP significantly and increase the concentration of the substances within the tumor tissue in comparison to control tumors. Furthermore, combined administration of 20%HSA plus cetuximab reduced the tumor growth significantly in comparison to standard cetuximab treatment. These data demonstrate that increased COP lowers the TIFP within hours and increases the uptake of therapeutic macromolecules into the tumor interstitium leading to reduced tumor growth. This model represents a novel approach to facilitate the delivery of therapeutics into tumor tissue, particularly monoclonal antibodies.

  13. Combination of Vandetanib, Radiotherapy, and Irinotecan in the LoVo Human Colorectal Cancer Xenograft Model

    International Nuclear Information System (INIS)

    Wachsberger, Phyllis; Burd, Randy; Ryan, Anderson; Daskalakis, Constantine; Dicker, Adam P.

    2009-01-01

    Purpose: The tumor growth kinetics of the human LoVo colorectal xenograft model was assessed in response to vandetanib, an orally available receptor tyrosine kinase inhibitor, radiotherapy (RT), or irinotecan (CPT-11), as single therapies and in combination. Methods and Materials: LoVo cells were injected subcutaneously into the right hind limb (5x10 6 cells in 100μL phosphate-buffered saline) of athymic NCR NUM mice and tumors were grown to a volume of 200-300 mm 3 before treatment. Vandetanib was administered at 50 mg/kg daily orally for 14 days starting on Day 1. RT was given as three fractions (3x3 Gy) on Days 1, 2, and 3. CPT-11 was given at 15 mg/kg intraperitoneally on Days 1 and 3. Tumor volumes were measured on a daily basis and calculated by measuring tumor diameters with digital calipers in two orthogonal dimensions. Results: All three single treatments (vandetanib, CPT-11, and radiation) significantly slowed LoVo colorectal tumor growth. Vandetanib significantly increased the antitumor effects of CPT-11 and radiation when given in combination with either of these treatments. These treatment combinations resulted in a slow tumor growth rate during the 2 weeks of vandetanib administration. The triple combination of vandetanib, CPT-11, and radiation produced the most marked improvement in response as observed by measurable shrinkage of tumors during the first week of treatment. Conclusions: The tumor growth delay kinetics observed in this study of the LoVo colorectal model suggest concurrent and sustained post-sequencing of vandetanib with cytotoxic therapy may be beneficial in tumors of this type.

  14. The utilization of SA-gal in pre-targeting RIT of colon carcinoma xenograft models

    International Nuclear Information System (INIS)

    Wu Hubing; Huang Zuhan; Peng Wuhe; Gao Xiao

    2001-01-01

    To investigate the improved clearance effect of avidin (Av) and streptavidin-gal (SA - gal) for blood radiolabeled biotinylated antibody in pre-targeting radio-immuno therapy (RIT) of colon carcinoma xenograft models. Biotinylated antibody radiolabeled with 131 I was injected into the nude mice bearing the colon carcinoma via the tail vein. 24 h later, in 2 test groups, SA-gal or Av at a 10 - fold molar excess of antibody was intraperitoneally injected into the animals whereas no any chase agents were given to the control animals. Animals were killed for biodistribution study at 30h after 131 I-labelled biotinylated antibody administration. Results showed that Av and SA-gal took the effect of chase very fast. At 6h after injection, the blood level of radioactivity decreased very fast. The tumor/blood ratios of control group, Av chase group, SA-gal chase group were 0.42, 2.09, 5.23 respectively, P < 0.05 and P < 0.01 for the latter two groups as compared other control groups. Compared with Av, SA-gal showed better chase effect, its T/B ratios was 5.23, significantly higher than 2.09 of Av (P < 0.01). In the tissue biodistributions, relatively high non-specific radioactivity uptakes in non-liver organs were seen in Av chase group. Utilized in pre-targeting RIT, both Av and SA-gal could make the blood level of radioactivity decrease quickly and considerably improves tumor T/NT ratios. The chase effect of SA-gal was superior to that of avidin

  15. Preclinical evaluation of transcriptional targeting strategy for human hepatocellular carcinoma in an orthotopic xenograft mouse model.

    Science.gov (United States)

    Sia, Kian Chuan; Huynh, Hung; Chung, Alexander Yaw Fui; Ooi, London Lucien Peng Jin; Lim, Kiat Hon; Hui, Kam Man; Lam, Paula Yeng Po

    2013-08-01

    Gene regulation of many key cell-cycle players in S-, G(2) phase, and mitosis results from transcriptional repression in their respective promoter regions during the G(0) and G(1) phases of cell cycle. Within these promoter regions are phylogenetically conserved sequences known as the cell-cycle-dependent element (CDE) and cell-cycle genes homology regions (CHR) sites. Thus, we hypothesize that transcriptional regulation of cell-cycle regulation via the CDE/CHR region together with liver-specific apolipoprotein E (apoE)-hAAT promoter could bring about a selective transgene expression in proliferating human hepatocellular carcinoma. We show that the newly generated vector AH-6CC-L2C could mediate hepatocyte-targeted luciferase gene expression in tumor cells and freshly isolated short-term hepatocellular carcinoma cultures from patient biopsy. In contrast, normal murine and human hepatocytes infected with AH-6CC-L2C expressed minimal or low luciferase activities. In the presence of prodrug 5-fluorocytosine (5-FC), AH-6CC-L2C effectively suppressed the growth of orthotopic hepatocellular carcinoma patient-derived xenograft mouse model via the expression of yeast cytosine deaminase (yCD) that converts 5-FC to anticancer metabolite 5-fluoruracil. More importantly, we show that combination treatment of AH-6CC-L2C with an EZH2 inhibitor, DZNep, that targets EpCAM-positive hepatocellular carcinoma, can bring about a greater therapeutic efficacy compared with a single treatment of virus or inhibitor. Our study showed that targeting proliferating human hepatocellular carcinoma cells through the transcriptional control of therapeutic gene could represent a feasible approach against hepatocellular carcinoma.

  16. A novel, diffusely infiltrative xenograft model of human anaplastic oligodendroglioma with mutations in FUBP1, CIC, and IDH1.

    Directory of Open Access Journals (Sweden)

    Barbara Klink

    Full Text Available Oligodendroglioma poses a biological conundrum for malignant adult human gliomas: it is a tumor type that is universally incurable for patients, and yet, only a few of the human tumors have been established as cell populations in vitro or as intracranial xenografts in vivo. Their survival, thus, may emerge only within a specific environmental context. To determine the fate of human oligodendroglioma in an experimental model, we studied the development of an anaplastic tumor after intracranial implantation into enhanced green fluorescent protein (eGFP positive NOD/SCID mice. Remarkably after nearly nine months, the tumor not only engrafted, but it also retained classic histological and genetic features of human oligodendroglioma, in particular cells with a clear cytoplasm, showing an infiltrative growth pattern, and harboring mutations of IDH1 (R132H and of the tumor suppressor genes, FUBP1 and CIC. The xenografts were highly invasive, exhibiting a distinct migration and growth pattern around neurons, especially in the hippocampus, and following white matter tracts of the corpus callosum with tumor cells accumulating around established vasculature. Although tumors exhibited a high growth fraction in vivo, neither cells from the original patient tumor nor the xenograft exhibited significant growth in vitro over a six-month period. This glioma xenograft is the first to display a pure oligodendroglioma histology and expression of R132H. The unexpected property, that the cells fail to grow in vitro even after passage through the mouse, allows us to uniquely investigate the relationship of this oligodendroglioma with the in vivo microenvironment.

  17. Xenograft tumors derived from malignant pleural effusion of the patients with non-small-cell lung cancer as models to explore drug resistance.

    Science.gov (United States)

    Xu, Yunhua; Zhang, Feifei; Pan, Xiaoqing; Wang, Guan; Zhu, Lei; Zhang, Jie; Wen, Danyi; Lu, Shun

    2018-05-09

    Non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations or anaplastic lymphoma kinase (ALK) fusions show dramatic responses to specific tyrosine kinase inhibitors (TKIs); however, after 10-12 months, secondary mutations arise that confer resistance. We generated a murine xenograft model using patient-derived NSCLC cells isolated from the pleural fluid of two patients with NSCLC to investigate the mechanisms of resistance against the ALK- and EGFR-targeted TKIs crizotinib and osimertinib, respectively. Genotypes of patient biopsies and xenograft tumors were determined by whole exome sequencing (WES), and patients and xenograft-bearing mice received targeted treatment (crizotinib or osimertinib) accordingly. Xenograft mice were also treated for prolonged periods to identify whether the development of drug resistance and/or treatment responses were associated with tumor size. Finally, the pathology of patients biopsies and xenograft tumors were compared histologically. The histological characteristics and chemotherapy responses of xenograft tumors were similar to the actual patients. WES showed that the genotypes of the xenograft and patient tumors were similar (an echinoderm microtubule-associated protein-like 4-ALK (EML4-ALK) gene fusion (patient/xenograft: CTC15035 EML4-ALK ) and EGFR L858R and T790M mutations (patient/xenograft: CTC15063 EGFR L858R, T790M )). After continuous crizotinib or osimertinib treatment, WES data suggested that acquired ALK E1210K mutation conferred crizotinib resistance in the CTC15035 EML4-ALK xenograft, while decreased frequencies of EGFR L858R and T790M mutations plus the appearance of v-RAF murine sarcoma viral oncogene homolog B (BRAF) G7V mutations and phosphatidylinositol-4-phosphate 3-kinase catalytic subunit type 2 alpha (PIK3C2A) A86fs frame shift mutations led to osimertinib resistance in the CTC15063 EGFR L858R, T790M xenografts. We successfully developed a new method of generating

  18. A small molecule inhibitor of ETV1, YK-4-279, prevents prostate cancer growth and metastasis in a mouse xenograft model.

    Directory of Open Access Journals (Sweden)

    Said Rahim

    Full Text Available The erythroblastosis virus E26 transforming sequences (ETS family of transcription factors consists of a highly conserved group of genes that play important roles in cellular proliferation, differentiation, migration and invasion. Chromosomal translocations fusing ETS factors to promoters of androgen responsive genes have been found in prostate cancers, including the most clinically aggressive forms. ERG and ETV1 are the most commonly translocated ETS proteins. Over-expression of these proteins in prostate cancer cells results in a more invasive phenotype. Inhibition of ETS activity by small molecule inhibitors may provide a novel method for the treatment of prostate cancer.We recently demonstrated that the small molecule YK-4-279 inhibits biological activity of ETV1 in fusion-positive prostate cancer cells leading to decreased motility and invasion in-vitro. Here, we present data from an in-vivo mouse xenograft model. SCID-beige mice were subcutaneously implanted with fusion-positive LNCaP-luc-M6 and fusion-negative PC-3M-luc-C6 tumors. Animals were treated with YK-4-279, and its effects on primary tumor growth and lung metastasis were evaluated. YK-4-279 treatment resulted in decreased growth of the primary tumor only in LNCaP-luc-M6 cohort. When primary tumors were grown to comparable sizes, YK-4-279 inhibited tumor metastasis to the lungs. Expression of ETV1 target genes MMP7, FKBP10 and GLYATL2 were reduced in YK-4-279 treated animals. ETS fusion-negative PC-3M-luc-C6 xenografts were unresponsive to the compound. Furthermore, YK-4-279 is a chiral molecule that exists as a racemic mixture of R and S enantiomers. We established that (S-YK-4-279 is the active enantiomer in prostate cancer cells.Our results demonstrate that YK-4-279 is a potent inhibitor of ETV1 and inhibits both the primary tumor growth and metastasis of fusion positive prostate cancer xenografts. Therefore, YK-4-279 or similar compounds may be evaluated as a potential

  19. A robust and rapid xenograft model to assess efficacy of chemotherapeutic agents for human acute myeloid leukemia

    International Nuclear Information System (INIS)

    Saland, E; Boutzen, H; Castellano, R; Pouyet, L; Griessinger, E; Larrue, C; Toni, F de; Scotland, S; David, M; Danet-Desnoyers, G; Vergez, F; Barreira, Y; Collette, Y; Récher, C; Sarry, J-E

    2015-01-01

    Relevant preclinical mouse models are crucial to screen new therapeutic agents for acute myeloid leukemia (AML). Current in vivo models based on the use of patient samples are not easy to establish and manipulate in the laboratory. Our objective was to develop robust xenograft models of human AML using well-characterized cell lines as a more accessible and faster alternative to those incorporating the use of patient-derived AML cells. Five widely used AML cell lines representing various AML subtypes were transplanted and expanded into highly immunodeficient non-obese diabetic/LtSz-severe combined immunodeficiency IL2Rγ c null mice (for example, cell line-derived xenografts). We show here that bone marrow sublethal conditioning with busulfan or irradiation has equal efficiency for the xenotransplantation of AML cell lines. Although higher number of injected AML cells did not change tumor engraftment in bone marrow and spleen, it significantly reduced the overall survival in mice for all tested AML cell lines. On the basis of AML cell characteristics, these models also exhibited a broad range of overall mouse survival, engraftment, tissue infiltration and aggressiveness. Thus, we have established a robust, rapid and straightforward in vivo model based on engraftment behavior of AML cell lines, all vital prerequisites for testing new therapeutic agents in preclinical studies

  20. Melatonin exerts anti-oral cancer effect via suppressing LSD1 in patient-derived tumor xenograft models

    Science.gov (United States)

    Yang, Cheng-Yu; Lin, Chih-Kung; Tsao, Chang-Huei; Hsieh, Cheng-Chih; Lin, Gu-Jiun; Ma, Kuo-Hsing; Shieh, Yi-Shing; Sytwu, Huey-Kang; Chen, Yuan-Wu

    2017-01-01

    Aberrant activation of histone lysine-specific demethylase (LSD1) increases tumorigenicity; hence, LSD1 is considered a therapeutic target for various human cancers. Although melatonin, an endogenously produced molecule, may defend against various cancers, the precise mechanism involved in its anti-oral cancer effect remains unclear. Patient-derived tumor xenograft (PDTX) models are preclinical models that can more accurately reflect human tumor biology compared with cell line xenograft models. Here, we evaluated the anticancer activity of melatonin by using LSD1-overexpressing oral cancer PDTX models. By assessing oral squamous cell carcinoma (OSCC) tissue arrays through immunohistochemistry, we examined whether aberrant LSD1 overexpression in OSCC is associated with poor prognosis. We also evaluated the action mechanism of melatonin against OSCC with lymphatic metastases by using the PDTX models. Our results indicated that melatonin, at pharmacological concentrations, significantly suppresses cell proliferation in a dose- and time-dependent manner. The observed suppression of proliferation was accompanied by the melatonin-mediated inhibition of LSD1 in oral cancer PDTXs and oral cancer cell lines. In conclusion, we determined that the beneficial effects of melatonin in reducing oral cancer cell proliferation are associated with reduced LSD1 expression in vivo and in vitro. PMID:28422711

  1. Correlation of Somatostatin Receptor-2 Expression with Gallium-68-DOTA-TATE Uptake in Neuroblastoma Xenograft Models

    OpenAIRE

    Zhang, Libo; Vines, Douglass C.; Scollard, Deborah A.; McKee, Trevor; Komal, Teesha; Ganguly, Milan; Do, Trevor; Wu, Bing; Alexander, Natasha; Vali, Reza; Shammas, Amer; Besanger, Travis; Baruchel, Sylvain

    2017-01-01

    Peptide-receptor imaging and therapy with radiolabeled somatostatin analogs such as 68Ga-DOTA-TATE and 177Lu-DOTA-TATE have become an effective treatment option for SSTR-positive neuroendocrine tumors. The purpose of this study was to evaluate the correlation of somatostatin receptor-2 (SSTR2) expression with 68Ga-DOTA-TATE uptake and 177Lu-DOTA-TATE therapy in neuroblastoma (NB) xenograft models. We demonstrated variable SSTR2 expression profiles in eight NB cell lines. From micro-PET imagin...

  2. TMOD-05. MOLECULAR CHARACTERIZATION OF ORTHOTOPIC PATIENT-DERIVED XENOGRAFT MODELS OF PEDIATRIC BRAIN TUMORS AND THEIR USE IN PRECLINICAL EXPERIMENTS

    Science.gov (United States)

    Brabetz, Sebastian; Schmidt, Christin; Groebner, Susanne N.; Mack, Norman; Seker-Cin, Huriye; Jones, David T.W.; Chavez, Lukas; Milde, Till; Witt, Olaf; Leary, Sarah E.; Li, Xiao-Nan; Wechsler-Reya, Robert J.; Olson, James M.; Pfister, Stefan M.; Kool, Marcel

    2017-01-01

    Abstract Genomic studies have shown that multiple molecular subtypes of pediatric brain tumors exist that are biologically and clinically highly distinct. These findings ask for novel subtype specific treatments. To develop these we need more and better preclinical models that correctly reflect the proper tumor (sub)type. Orthotopic patient-derived xenograft (PDX) models generated by intracranial injection of primary patient material into the brain of NSG mice offer the unique possibility to test novel substances in primary patient tissue in an in vivo environment. Prior to drug selection and testing, extensive molecular characterizations of PDX and matching primary tumor/blood (DNA methylation, DNA sequencing, and gene expression) are needed to see how the PDX represents the original disease and to learn about targetable oncogenic drivers in each model. In collaboration with several groups around the world we have generated and fully characterized thus far 75 PDX models reflecting 15 distinct subtypes of pediatric brain cancer. PDX models always retain their molecular subtype and in the vast majority of cases also mutations and copy number alterations compared to matching primary tumors. Most aggressive tumors, harboring MYC(N) amplifications, are overrepresented in the cohort, but also subtypes which have not been available for preclinical testing before due to lack of genetically engineered mouse models or suitable cell lines, such as Group 4 medulloblastoma, are included. All models and corresponding molecular data will become available for the community for preclinical research. Examples of such preclinical experiments will be presented. PDX models of pediatric brain tumors are still quite rare. Our repertoire of PDX models and corresponding molecular characterizations allow researchers all over the world to find the right models for their specific scientific questions. It will provide an unprecedented resource to study tumor biology and pave the way for

  3. The Novel IκB Kinase β Inhibitor, IMD-0560, Has Potent Therapeutic Efficacy in Ovarian Cancer Xenograft Model Mice.

    Science.gov (United States)

    Sawada, Ikuko; Hashimoto, Kae; Sawada, Kenjiro; Kinose, Yasuto; Nakamura, Koji; Toda, Aska; Nakatsuka, Erika; Yoshimura, Akihiko; Mabuchi, Seiji; Fujikawa, Tomoyuki; Itai, Akiko; Kimura, Tadashi

    2016-05-01

    Aberrant activation of nuclear factor-kappa β (NF-κB) signaling has been correlated with poor outcome among patients with ovarian cancer. Although the therapeutic potential of NF-κB pathway disruption in cancers has been extensively studied, most classical NF-κB inhibitors are poorly selective, exhibit off-target effects, and have failed to be applied in clinical use. IMD-0560, N-[2,5-bis (trifluoromethyl) phenyl]-5-bromo-2-hydroxybenzamide, is a novel low-molecular-weight compound that selectively inhibits the IκB kinase complex and works as an inhibitor of NF-κB signaling. The aim of this study was to assess the therapeutic potential of IMD-0560 against ovarian cancer in vitro and in vivo. NF-κB activity (phosphorylation) was determined in 9 ovarian cancer cell lines and the inhibitory effect of IMD-0560 on NF-κB activation was analyzed by Western blotting. Cell viability, cell cycle, vascular endothelial growth factor (VEGF) expression, and angiogenesis were assessed in vitro to evaluate the effect of IMD-0560 on ovarian cancer cells. In vivo efficacy of IMD-0560 was also investigated using an ovarian cancer xenograft mouse model. The NF-κB signaling pathway was constitutively activated in 8 of 9 ovarian cancer cell lines. IMD-0560 inhibited NF-κB activation and suppressed ovarian cancer cell proliferation by inducing G1 phase arrest. IMD-0560 decreased VEGF secretion from cancer cells and inhibited the tube formation of human umbilical vein endothelial cells. IMD-0560 significantly inhibited peritoneal metastasis and prolonged the survival in an ovarian cancer xenograft mice model. Immunohistochemical staining of excised tumors revealed that IMD-0560 suppressed VEGF expression, tumor angiogenesis, and cancer cell proliferation. IMD-0560 showed promising therapeutic efficacy against ovarian cancer xenograft mice by inducing cell cycle arrest and suppressing VEGF production from cancer cells. IMD-0560 may be a potential future option in regimens for the

  4. Trastuzumab anti-tumor efficacy in patient-derived esophageal squamous cell carcinoma xenograft (PDECX mouse models

    Directory of Open Access Journals (Sweden)

    Wu Xianhua

    2012-08-01

    Full Text Available Abstract Background Trastuzumab is currently approved for the clinical treatment of breast and gastric cancer patients with HER-2 positive tumors, but not yet for the treatment of esophageal carcinoma patients, whose tumors typically show 5 ~ 35% HER-2 gene amplification and 0 ~ 56% HER-2 protein expression. This study aimed to investigate the therapeutic efficacy of Trastuzumab in patient-derived esophageal squamous cell carcinoma xenograft (PDECX mouse models. Methods PDECX models were established by implanting patient esophageal squamous cell carcinoma (ESCC tissues into immunodeficient (SCID/nude mice. HER-2 gene copy number (GCN and protein expression were determined in xenograft tissues and corresponding patient EC samples by FISH and IHC analysis. Trastuzumab anti-tumor efficacy was evaluated within these PDECX models (n = 8 animals/group. Furthermore, hotspot mutations of EGFR, K-ras, B-raf and PIK3CA genes were screened for in the PDECX models and their corresponding patient’s ESCC tissues. Similarity between the PDECX models and their corresponding patient’s ESCC tissue was confirmed by histology, morphology, HER-2 GCN and mutation. Results None of the PDECX models (or their corresponding patient’s ESCC tissues harbored HER-2 gene amplification. IHC staining showed HER-2 positivity (IHC 2+ in 2 PDECX models and negativity in 3 PDECX models. Significant tumor regression was observed in the Trastuzumab-treated EC044 HER-2 positive model (IHC 2+. A second HER-2 positive (IHC 2+ model, EC039, harbored a known PIK3CA mutation and showed strong activation of the AKT signaling pathway and was insensitive to Trastuzumab treatment, but could be resensitised using a combination of Trastuzumab and AKT inhibitor AZD5363. In summary, we established 5 PDECX mouse models and demonstrated tumor regression in response to Trastuzumab treatment in a HER-2 IHC 2+ model, but resistance in a HER-2 IHC 2+/PIK3CA mutated model. Conclusions

  5. Modeling of Chronic Myeloid Leukemia : An Overview of In Vivo Murine and Human Xenograft Models

    NARCIS (Netherlands)

    Sontakke, Pallavi; Jaques, Jenny; Vellenga, Edo; Schuringa, Jan Jacob

    2016-01-01

    Over the past years, a wide variety of in vivo mouse models have been generated in order to unravel the molecular pathology of Chronic Myeloid Leukemia (CML) and to develop and improve therapeutic approaches. These models range from (conditional) transgenic models, knock-in models, and murine bone

  6. DCE-MRI of patient-derived xenograft models of uterine cervix carcinoma: associations with parameters of the tumor microenvironment

    Directory of Open Access Journals (Sweden)

    Anette Hauge

    2017-11-01

    Full Text Available Abstract Background Abnormalities in the tumor microenvironment are associated with resistance to treatment, aggressive growth, and poor clinical outcome in patients with advanced cervical cancer. The potential of dynamic contrast-enhanced (DCE MRI to assess the microvascular density (MVD, interstitial fluid pressure (IFP, and hypoxic fraction of patient-derived cervical cancer xenografts was investigated in the present study. Methods Four patient-derived xenograft (PDX models of squamous cell carcinoma of the uterine cervix (BK-12, ED-15, HL-16, and LA-19 were subjected to Gd-DOTA-based DCE-MRI using a 7.05 T preclinical scanner. Parametric images of the volume transfer constant (K trans and the fractional distribution volume (v e of the contrast agent were produced by pharmacokinetic analyses utilizing the standard Tofts model. Whole tumor median values of the DCE-MRI parameters were compared with MVD and the fraction of hypoxic tumor tissue, as determined histologically, and IFP, as measured with a Millar catheter. Results Both on the PDX model level and the single tumor level, a significant inverse correlation was found between K trans and hypoxic fraction. The extent of hypoxia was also associated with the fraction of voxels with unphysiological v e values (v e > 1.0. None of the DCE-MRI parameters were related to MVD or IFP. Conclusions DCE-MRI may provide valuable information on the hypoxic fraction of squamous cell carcinoma of the uterine cervix, and thereby facilitate individualized patient management.

  7. Potent efficacy signals from systemically administered oncolytic herpes simplex virus (HSV1716 in hepatocellular carcinoma xenograft models

    Directory of Open Access Journals (Sweden)

    Braidwood L

    2014-10-01

    Full Text Available Lynne Braidwood, Kirsty Learmonth, Alex Graham, Joe Conner Virttu Biologics Ltd, Department of Neurology, Southern General Hospital, Glasgow, UK Abstract: Oncolytic herpes simplex virus (HSV1716, lacking the neurovirulence factor ICP34.5, has highly selective replication competence for cancer cells and has been used in clinical studies of glioma, melanoma, head and neck squamous cell carcinoma, pediatric non-central nervous system solid tumors, and malignant pleural mesothelioma. To date, 88 patients have received HSV1716 and the virus is well tolerated, with selective replication in tumor cells and no spread to surrounding normal tissue. We assessed the potential value of HSV1716 in preclinical studies with two human hepatocellular carcinoma cell lines, HuH7 and HepG2-luc. HSV1716 displayed excellent replication kinetics in vitro in HepG2-luc cells, a cell line engineered to express luciferase, and virus-mediated cell killing correlated with loss of light emissions from the cells. In vivo, the HepG2-luc cells readily formed light-emitting xenografts that were easily visualized by an in vivo imaging system and efficiently eliminated by HSV1716 oncolysis after intratumoral injection. HSV1716 also demonstrated strong efficacy signals in subcutaneous HuH7 xenografts in nude mice after intravenous administration of virus. In the HuH7 model, the intravenously injected virus replicated prolifically immediately after efficient tumor localization, resulting in highly significant reductions in tumor growth and enhanced survival. Our preclinical results demonstrate excellent tumor uptake of HSV1716, with prolific replication and potent oncolysis. These observations warrant a clinical study of HSV1716 in hepatocellular carcinoma. Keywords: oncolytic herpes simplex virus, HSV1716, hepatocellular carcinoma, xenografts, efficacy 

  8. Single and 30 fraction tumor control doses correlate in xenografted tumor models: implications for predictive assays

    International Nuclear Information System (INIS)

    Gerweck, Leo E.; Dubois, Willum; Baumann, Michael; Suit, Herman D.

    1995-01-01

    Purpose/Objective: In a previous publication we reported that laboratory assays of tumor clonogen number, in combination with intrinsic radiosensitivity measured in-vitro, accurately predicted the rank-order of single fraction 50% tumor control doses, in six rodent and xenografted human tumors. In these studies, tumor hypoxia influenced the absolute value of the tumor control doses across tumor types, but not their rank-order. In the present study we hypothesize that determinants of the single fraction tumor control dose, may also strongly influence the fractionaled tumor control doses, and that knowledge of tumor clonogen number and their sensitivity to fractionated irradiation, may be useful for predicting the relative sensitivity of tumors treated by conventional fractionated irradiation. Methods/Materials: Five tumors of human origin were used for these studies. Special care was taken to ensure that all tumor control dose assays were performed over the same time frame, i.e., in-vitro cells of a similar passage were used to initiate tumor sources which were expanded and used in the 3rd or 4th generation. Thirty fraction tumor control doses were performed in air breathing mice, under normal blood flow conditions (two fractions/day). The results of these studies have been previously published. For studies under uniformly (clamp) hypoxic conditions, tumors arising from the same transplantation were randomized into single or fractionated dose protocols. For estimation of the fractionated TCD50 under hypoxic conditions, tumors were exposed to six 5.4 Gy fractions (∼ 2 Gy equivalent under air), followed by graded 'top-up' dose irradiation for determination of the TCD50; the time interval between doses was 6-9 hours. The single dose equivalent of the six 5.4 Gy doses was used to calculate an extrapolated 30 fraction hypoxic TCD50. Results: Fractionation substantially increased the dose required for tumor control in 4 of the 5 tumors investigated. For these 4 tumors

  9. Therapeutic effects of microbubble added to combined high-intensity focused ultrasound and chemotherapy in a pancreatic cancer xenograft model

    Energy Technology Data Exchange (ETDEWEB)

    Yu, Mi Hye [Dept. of Radiology, Konkuk University Medical Center, Seoul (Korea, Republic of); Lee, Jae Young; Kim, Bo Ram; Park, Eun Joo; Kim, Hoe Suk; Han, Joon Koo [Dept. of Radiology, Seoul National University Hospital, Seoul (Korea, Republic of); Kim, Hae Ri [Dept. of Pre-Dentistry, Gangneung-Wonju National University College of Dentistry, Gangneung (Korea, Republic of); Choi, Byung Ihn [Dept. of Radiology, Chung-Ang University Hospital, Seoul (Korea, Republic of)

    2016-09-15

    To investigate whether high-intensity focused ultrasound (HIFU) combined with microbubbles enhances the therapeutic effects of chemotherapy. A pancreatic cancer xenograft model was established using BALB/c nude mice and luciferase-expressing human pancreatic cancer cells. Mice were randomly assigned to five groups according to treatment: control (n = 10), gemcitabine alone (GEM; n = 12), HIFU with microbubbles (HIFU + MB, n = 11), combined HIFU and gemcitabine (HIGEM; n = 12), and HIGEM + MB (n = 13). After three weekly treatments, apoptosis rates were evaluated using the terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling assay in two mice per group. Tumor volume and bioluminescence were monitored using high-resolution 3D ultrasound imaging and in vivo bioluminescence imaging for eight weeks in the remaining mice. The HIGEM + MB group showed significantly higher apoptosis rates than the other groups (p < 0.05) and exhibited the slowest tumor growth. From week 5, the tumor-volume-ratio relative to the baseline tumor volume was significantly lower in the HIGEM + MB group than in the control, GEM, and HIFU + MB groups (p < 0.05). Despite visible distinction, the HIGEM and HIGEM + MB groups showed no significant differences. High-intensity focused ultrasound combined with microbubbles enhances the therapeutic effects of gemcitabine chemotherapy in a pancreatic cancer xenograft model.

  10. Therapeutic Effects of Microbubbles Added to Combined High-Intensity Focused Ultrasound and Chemotherapy in a Pancreatic Cancer Xenograft Model

    Energy Technology Data Exchange (ETDEWEB)

    Yu, Mi Hye [Department of Radiology, Konkuk University Medical Center, Seoul 05030 (Korea, Republic of); Lee, Jae Young [Department of Radiology, Seoul National University Hospital, Seoul 03080 (Korea, Republic of); Kim, Hae Ri [Department of Pre-Dentistry, Gangneung-Wonju National University College of Dentistry, Gangneung 25457 (Korea, Republic of); Kim, Bo Ram; Park, Eun-Joo; Kim, Hoe Suk; Han, Joon Koo [Department of Radiology, Seoul National University Hospital, Seoul 03080 (Korea, Republic of); Choi, Byung Ihn [Department of Radiology, Chung-Ang University Hospital, Seoul 06973 (Korea, Republic of)

    2016-11-01

    To investigate whether high-intensity focused ultrasound (HIFU) combined with microbubbles enhances the therapeutic effects of chemotherapy. A pancreatic cancer xenograft model was established using BALB/c nude mice and luciferase-expressing human pancreatic cancer cells. Mice were randomly assigned to five groups according to treatment: control (n = 10), gemcitabine alone (GEM; n = 12), HIFU with microbubbles (HIFU + MB, n = 11), combined HIFU and gemcitabine (HIGEM; n = 12), and HIGEM + MB (n = 13). After three weekly treatments, apoptosis rates were evaluated using the terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling assay in two mice per group. Tumor volume and bioluminescence were monitored using high-resolution 3D ultrasound imaging and in vivo bioluminescence imaging for eight weeks in the remaining mice. The HIGEM + MB group showed significantly higher apoptosis rates than the other groups (p < 0.05) and exhibited the slowest tumor growth. From week 5, the tumor-volume-ratio relative to the baseline tumor volume was significantly lower in the HIGEM + MB group than in the control, GEM, and HIFU + MB groups (p < 0.05). Despite visible distinction, the HIGEM and HIGEM + MB groups showed no significant differences. High-intensity focused ultrasound combined with microbubbles enhances the therapeutic effects of gemcitabine chemotherapy in a pancreatic cancer xenograft model.

  11. Ternary copper(II) complex: NCI60 screening, toxicity studies, and evaluation of efficacy in xenograft models of nasopharyngeal carcinoma

    Science.gov (United States)

    Chu, Tai-Lin; Abdul Aziz, Norazlin; Mohd Kornain, Noor-Kaslina; Samiulla, D. S.; Lo, Kwok-Wai; Ng, Chew-Hee

    2018-01-01

    Copper(II) ternary complex, [Cu(phen)(C-dmg)(H2O)]NO3 was evaluated against a panel of cell lines, tested for in vivo efficacy in nasopharyngeal carcinoma xenograft models as well as for toxicity in NOD scid gamma mice. The Cu(II) complex displayed broad spectrum cytotoxicity against multiple cancer types, including lung, colon, central nervous system, melanoma, ovarian, and prostate cancer cell lines in the NCI-60 panel. The Cu(II) complex did not cause significant induction of cytochrome P450 (CYP) 3A and 1A enzymes but moderately inhibited CYP isoforms 1A2, 2C9, 2C19, 2D6, 2B6, 2C8 and 3A4. The complex significantly inhibited tumor growth in nasopharyngeal carcinoma xenograft bearing mice models at doses which were well tolerated without causing significant or permanent toxic side effects. However, higher doses which resulted in better inhibition of tumor growth also resulted in toxicity. PMID:29329342

  12. Utilization of SA-gal as clearing agent in pre-targeting RII of colon carcinoma xenograft bearing models

    International Nuclear Information System (INIS)

    Wu Hubing; Huang Zuhan; Peng Wuhe; Gao Xiao

    2001-01-01

    Objective: To conjugate galactose streptavidin (SA-gal) and use it as a clearing agent in pre-targeting radioimmunoimaging (RII) of colon carcinoma xenograft models. Methods: SA-gal was obtained by incubating galactose moiety with streptavidin at a molar ratio of 45 : 1. For imaging in vivo, biotinylated antibody radiolabelled with 131 I was injected into the nude mice bearing the colon carcinoma xenograft via the tail vein. 24 h later, SA-gal were intraperitoneally injected at a ratio of 10-fold (molar) excess to antibody. At 0.5 h and 6 h after SA-gal administration, the animals of different test groups were killed for biodistribution study or imaging. No clearing agent was administrated to the animals of two control groups and they were also killed for biodistribution study or imaging at 24 h or 30 h after injection of 131 I labelled antibody. Results: 1) Galactose moiety was bound to SA at a molar ratio of 20 : 1. 2) In pre-targeting RII, SA-gal undertook the chase effect very fast. At 0.5 h after injection, the blood level of radioactivity decreased very fast and tumor-to-blood (T/B) ratio increased from 0.32 to 1.44. At 6 h after SA-gal administration, T/B ratio reached 5.23, significantly higher than 0.41 of the control group (P 131 I-biotinylated antitumor antibody RII

  13. Natural killer cell lines preferentially kill clonogenic multiple myeloma cells and decrease myeloma engraftment in a bioluminescent xenograft mouse model.

    Science.gov (United States)

    Swift, Brenna E; Williams, Brent A; Kosaka, Yoko; Wang, Xing-Hua; Medin, Jeffrey A; Viswanathan, Sowmya; Martinez-Lopez, Joaquin; Keating, Armand

    2012-07-01

    Novel therapies capable of targeting drug resistant clonogenic MM cells are required for more effective treatment of multiple myeloma. This study investigates the cytotoxicity of natural killer cell lines against bulk and clonogenic multiple myeloma and evaluates the tumor burden after NK cell therapy in a bioluminescent xenograft mouse model. The cytotoxicity of natural killer cell lines was evaluated against bulk multiple myeloma cell lines using chromium release and flow cytometry cytotoxicity assays. Selected activating receptors on natural killer cells were blocked to determine their role in multiple myeloma recognition. Growth inhibition of clonogenic multiple myeloma cells was assessed in a methylcellulose clonogenic assay in combination with secondary replating to evaluate the self-renewal of residual progenitors after natural killer cell treatment. A bioluminescent mouse model was developed using the human U266 cell line transduced to express green fluorescent protein and luciferase (U266eGFPluc) to monitor disease progression in vivo and assess bone marrow engraftment after intravenous NK-92 cell therapy. Three multiple myeloma cell lines were sensitive to NK-92 and KHYG-1 cytotoxicity mediated by NKp30, NKp46, NKG2D and DNAM-1 activating receptors. NK-92 and KHYG-1 demonstrated 2- to 3-fold greater inhibition of clonogenic multiple myeloma growth, compared with killing of the bulk tumor population. In addition, the residual colonies after treatment formed significantly fewer colonies compared to the control in a secondary replating for a cumulative clonogenic inhibition of 89-99% at the 20:1 effector to target ratio. Multiple myeloma tumor burden was reduced by NK-92 in a xenograft mouse model as measured by bioluminescence imaging and reduction in bone marrow engraftment of U266eGFPluc cells by flow cytometry. This study demonstrates that NK-92 and KHYG-1 are capable of killing clonogenic and bulk multiple myeloma cells. In addition, multiple myeloma

  14. Aminomethylphosphonic acid inhibits growth and metastasis of human prostate cancer in an orthotopic xenograft mouse model.

    Science.gov (United States)

    Parajuli, Keshab Raj; Zhang, Qiuyang; Liu, Sen; You, Zongbing

    2016-03-01

    Aminomethylphosphonic acid (AMPA) has been shown to inhibit prostate cancer cell growth in vitro. The purpose of the present study was to determine if AMPA could inhibit growth and metastasis of prostate cancer in vivo. Human prostate cancer PC-3-LacZ-luciferase cells were implanted into the ventral lateral lobes of the prostate in 39 athymic Nu/Nu nude male mice. Seven days later, mice were randomized into the control group (n = 14, treated intraperitoneally with phosphate buffered saline), low dose group (n = 10, treated intraperitoneally with AMPA at 400 mg/kg body weight/day), and high dose group (n = 15, treated intraperitoneally with AMPA at 800 mg/kg body weight/day). Tumor growth and metastasis were examined every 4-7 days by bioluminescence imaging of live mice. We found that AMPA treatment significantly inhibited growth and metastasis of orthotopic xenograft prostate tumors and prolonged the survival time of the mice. AMPA treatment decreased expression of BIRC2 and activated caspase 3, leading to increased apoptosis in the prostate tumors. AMPA treatment decreased expression of cyclin D1. AMPA treatment also reduced angiogenesis in the prostate tumors. Taken together, these results demonstrate that AMPA can inhibit prostate cancer growth and metastasis, suggesting that AMPA may be developed into a therapeutic agent for the treatment of prostate cancer.

  15. Local delivery of cannabinoid-loaded microparticles inhibits tumor growth in a murine xenograft model of glioblastoma multiforme.

    Directory of Open Access Journals (Sweden)

    Dolores Hernán Pérez de la Ossa

    Full Text Available Cannabinoids, the active components of marijuana and their derivatives, are currently investigated due to their potential therapeutic application for the management of many different diseases, including cancer. Specifically, Δ(9-Tetrahydrocannabinol (THC and Cannabidiol (CBD - the two major ingredients of marijuana - have been shown to inhibit tumor growth in a number of animal models of cancer, including glioma. Although there are several pharmaceutical preparations that permit the oral administration of THC or its analogue nabilone or the oromucosal delivery of a THC- and CBD-enriched cannabis extract, the systemic administration of cannabinoids has several limitations in part derived from the high lipophilicity exhibited by these compounds. In this work we analyzed CBD- and THC-loaded poly-ε-caprolactone microparticles as an alternative delivery system for long-term cannabinoid administration in a murine xenograft model of glioma. In vitro characterization of THC- and CBD-loaded microparticles showed that this method of microencapsulation facilitates a sustained release of the two cannabinoids for several days. Local administration of THC-, CBD- or a mixture (1:1 w:w of THC- and CBD-loaded microparticles every 5 days to mice bearing glioma xenografts reduced tumour growth with the same efficacy than a daily local administration of the equivalent amount of those cannabinoids in solution. Moreover, treatment with cannabinoid-loaded microparticles enhanced apoptosis and decreased cell proliferation and angiogenesis in these tumours. Our findings support that THC- and CBD-loaded microparticles could be used as an alternative method of cannabinoid delivery in anticancer therapies.

  16. Novel cancer gene variants and gene fusions of triple-negative breast cancers (TNBCs) reveal their molecular diversity conserved in the patient-derived xenograft (PDX) model.

    Science.gov (United States)

    Jung, Jaeyun; Jang, Kiwon; Ju, Jung Min; Lee, Eunji; Lee, Jong Won; Kim, Hee Jung; Kim, Jisun; Lee, Sae Byul; Ko, Beom Seok; Son, Byung Ho; Lee, Hee Jin; Gong, Gyungyup; Ahn, Sei Yeon; Choi, Jung Kyoon; Singh, Shree Ram; Chang, Suhwan

    2018-04-20

    Despite the improved 5-year survival rate of breast cancer, triple-negative breast cancer (TNBC) remains a challenge due to lack of effective targeted therapy and higher recurrence and metastasis than other subtypes. To identify novel druggable targets and to understand its unique biology, we tried to implement 24 patient-derived xenografts (PDXs) of TNBC. The overall success rate of PDX implantation was 45%, much higher than estrogen receptor (ER)-positive cases. Immunohistochemical analysis revealed conserved ER/PR/Her2 negativity (with two exceptions) between the original and PDX tumors. Genomic analysis of 10 primary tumor-PDX pairs with Ion AmpliSeq CCP revealed high degree of variant conservation (85.0% to 96.9%) between primary and PDXs. Further analysis showed 44 rare variants with a predicted high impact in 36 genes including Trp53, Pten, Notch1, and Col1a1. Among them, we confirmed frequent Notch1 variant. Furthermore, RNA-seq analysis of 24 PDXs revealed 594 gene fusions, of which 163 were in-frame, including AZGP1-GJC3 and NF1-AARSD1. Finally, western blot analysis of oncogenic signaling proteins supporting molecular diversity of TNBC PDXs. Overall, our report provides a molecular basis for the usefulness of the TNBC PDX model in preclinical study. Copyright © 2018. Published by Elsevier B.V.

  17. High-dose stabilized chlorite matrix WF10 prolongs cardiac xenograft survival in the hamster-to-rat model without inducing ultrastructural or biochemical signs of cardiotoxicity

    DEFF Research Database (Denmark)

    Hansen, A; Kemp, K; Kemp, E

    2001-01-01

    of high dose WF10 as a single drug regimen in the hamster-to-rat xenotransplantation model and searched for possible cardiotoxic side effects. WF10 prolonged cardiac xenograft survival, but did not induce tolerence or inhibit pathological signs of acute rejection. Hamsters from the donor population...

  18. Fluorescent humanized anti-CEA antibody specifically labels metastatic pancreatic cancer in a patient-derived orthotopic xenograft (PDOX) mouse model

    Science.gov (United States)

    Lwin, Thinzar M.; Miyake, Kentaro; Murakami, Takashi; DeLong, Jonathan C.; Yazaki, Paul J.; Shivley, John E.; Clary, Bryan; Hoffman, Robert M.; Bouvet, Michael

    2018-03-01

    Specific tumor targeting can result in selective labeling of cancer in vivo for surgical navigation. In the present study, we show that the use of an anti-CEA antibody conjugated to the near-infrared (NIR) fluorescent dye, IRDye800CW, can selectively target and label pancreatic cancer and its metastases in a clinically relevant patient derived xenograft mouse model.

  19. Targeting mesothelin receptors with drug-loaded bacterial nanocells suppresses human mesothelioma tumour growth in mouse xenograft models.

    Directory of Open Access Journals (Sweden)

    Mohamed A Alfaleh

    Full Text Available Human malignant mesothelioma is a chemoresistant tumour that develops from mesothelial cells, commonly associated with asbestos exposure. Malignant mesothelioma incidence rates in European countries are still rising and Australia has one of the highest burdens of malignant mesothelioma on a population basis in the world. Therapy using systemic delivery of free cytotoxic agents is associated with many undesirable side effects due to non-selectivity, and is thus dose-limited which limits its therapeutic potential. Therefore, increasing the selectivity of anti-cancer agents has the potential to dramatically enhance drug efficacy and reduce toxicity. EnGeneIC Dream Vectors (EDV are antibody-targeted nanocells which can be loaded with cytotoxic drugs and delivered to specific cancer cells via bispecific antibodies (BsAbs which target the EDV and a cancer cell-specific receptor, simultaneously. BsAbs were designed to target doxorubicin-loaded EDVs to cancer cells via cell surface mesothelin (MSLN. Flow cytometry was used to investigate cell binding and induction of apoptosis, and confocal microscopy to visualize internalization. Mouse xenograft models were used to assess anti-tumour effects in vivo, followed by immunohistochemistry for ex vivo evaluation of proliferation and necrosis. BsAb-targeted, doxorubicin-loaded EDVs were able to bind to and internalize within mesothelioma cells in vitro via MSLN receptors and induce apoptosis. In mice xenografts, the BsAb-targeted, doxorubicin-loaded EDVs suppressed the tumour growth and also decreased cell proliferation. Thus, the use of MSLN-specific antibodies to deliver encapsulated doxorubicin can provide a novel and alternative modality for treatment of mesothelioma.

  20. OSI-930: a novel selective inhibitor of Kit and kinase insert domain receptor tyrosine kinases with antitumor activity in mouse xenograft models.

    Science.gov (United States)

    Garton, Andrew J; Crew, Andrew P A; Franklin, Maryland; Cooke, Andrew R; Wynne, Graham M; Castaldo, Linda; Kahler, Jennifer; Winski, Shannon L; Franks, April; Brown, Eric N; Bittner, Mark A; Keily, John F; Briner, Paul; Hidden, Chris; Srebernak, Mary C; Pirrit, Carrie; O'Connor, Matthew; Chan, Anna; Vulevic, Bojana; Henninger, Dwight; Hart, Karen; Sennello, Regina; Li, An-Hu; Zhang, Tao; Richardson, Frank; Emerson, David L; Castelhano, Arlindo L; Arnold, Lee D; Gibson, Neil W

    2006-01-15

    OSI-930 is a novel inhibitor of the receptor tyrosine kinases Kit and kinase insert domain receptor (KDR), which is currently being evaluated in clinical studies. OSI-930 selectively inhibits Kit and KDR with similar potency in intact cells and also inhibits these targets in vivo following oral dosing. We have investigated the relationships between the potency observed in cell-based assays in vitro, the plasma exposure levels achieved following oral dosing, the time course of target inhibition in vivo, and antitumor activity of OSI-930 in tumor xenograft models. In the mutant Kit-expressing HMC-1 xenograft model, prolonged inhibition of Kit was achieved at oral doses between 10 and 50 mg/kg and this dose range was associated with antitumor activity. Similarly, prolonged inhibition of wild-type Kit in the NCI-H526 xenograft model was observed at oral doses of 100 to 200 mg/kg, which was the dose level associated with significant antitumor activity in this model as well as in the majority of other xenograft models tested. The data suggest that antitumor activity of OSI-930 in mouse xenograft models is observed at dose levels that maintain a significant level of inhibition of the molecular targets of OSI-930 for a prolonged period. Furthermore, pharmacokinetic evaluation of the plasma exposure levels of OSI-930 at these effective dose levels provides an estimate of the target plasma concentrations that may be required to achieve prolonged inhibition of Kit and KDR in humans and which would therefore be expected to yield a therapeutic benefit in future clinical evaluations of OSI-930.

  1. Development of a preclinical orthotopic xenograft model of ewing sarcoma and other human malignant bone disease using advanced in vivo imaging.

    Directory of Open Access Journals (Sweden)

    Britta Vormoor

    Full Text Available Ewing sarcoma and osteosarcoma represent the two most common primary bone tumours in childhood and adolescence, with bone metastases being the most adverse prognostic factor. In prostate cancer, osseous metastasis poses a major clinical challenge. We developed a preclinical orthotopic model of Ewing sarcoma, reflecting the biology of the tumour-bone interactions in human disease and allowing in vivo monitoring of disease progression, and compared this with models of osteosarcoma and prostate carcinoma. Human tumour cell lines were transplanted into non-obese diabetic/severe combined immunodeficient (NSG and Rag2(-/-/γc(-/- mice by intrafemoral injection. For Ewing sarcoma, minimal cell numbers (1000-5000 injected in small volumes were able to induce orthotopic tumour growth. Tumour progression was studied using positron emission tomography, computed tomography, magnetic resonance imaging and bioluminescent imaging. Tumours and their interactions with bones were examined by histology. Each tumour induced bone destruction and outgrowth of extramedullary tumour masses, together with characteristic changes in bone that were well visualised by computed tomography, which correlated with post-mortem histology. Ewing sarcoma and, to a lesser extent, osteosarcoma cells induced prominent reactive new bone formation. Osteosarcoma cells produced osteoid and mineralised "malignant" bone within the tumour mass itself. Injection of prostate carcinoma cells led to osteoclast-driven osteolytic lesions. Bioluminescent imaging of Ewing sarcoma xenografts allowed easy and rapid monitoring of tumour growth and detection of tumour dissemination to lungs, liver and bone. Magnetic resonance imaging proved useful for monitoring soft tissue tumour growth and volume. Positron emission tomography proved to be of limited use in this model. Overall, we have developed an orthotopic in vivo model for Ewing sarcoma and other primary and secondary human bone malignancies, which

  2. Recombinant methioninase effectively targets a Ewing's sarcoma in a patient-derived orthotopic xenograft (PDOX) nude-mouse model.

    Science.gov (United States)

    Murakami, Takashi; Li, Shukuan; Han, Qinghong; Tan, Yuying; Kiyuna, Tasuku; Igarashi, Kentaro; Kawaguchi, Kei; Hwang, Ho Kyoung; Miyake, Kentaro; Singh, Arun S; Nelson, Scott D; Dry, Sarah M; Li, Yunfeng; Hiroshima, Yukihiko; Lwin, Thinzar M; DeLong, Jonathan C; Chishima, Takashi; Tanaka, Kuniya; Bouvet, Michael; Endo, Itaru; Eilber, Fritz C; Hoffman, Robert M

    2017-05-30

    Methionine dependence is due to the overuse of methionine for aberrant transmethylation reactions in cancer. Methionine dependence may be the only general metabolic defect in cancer. In order to exploit methionine dependence for therapy, our laboratory previously cloned L-methionine α-deamino-γ-mercaptomethane lyase [EC 4.4.1.11]). The cloned methioninase, termed recombinant methioninase, or rMETase, has been tested in mouse models of human cancer cell lines. Ewing's sarcoma is recalcitrant disease even though development of multimodal therapy has improved patients'outcome. Here we report efficacy of rMETase against Ewing's sarcoma in a patient-derived orthotopic xenograft (PDOX) model. The Ewing's sarcoma was implanted in the right chest wall of nude mice to establish a PDOX model. Eight Ewing's sarcoma PDOX mice were randomized into untreated control group (n = 4) and rMETase treatment group (n = 4). rMETase (100 units) was injected intraperitoneally (i.p.) every 24 hours for 14 consecutive days. All mice were sacrificed on day-15, 24 hours after the last rMETase administration. rMETase effectively reduced tumor growth compared to untreated control. The methionine level both of plasma and supernatants derived from sonicated tumors was lower in the rMETase group. Body weight did not significantly differ at any time points between the 2 groups. The present study is the first demonstrating rMETase efficacy in a PDOX model, suggesting potential clinical development, especially in recalcitrant cancers such as Ewing's sarcoma.

  3. Hydrogel-based 3D model of patient-derived prostate xenograft tumors suitable for drug screening.

    Science.gov (United States)

    Fong, Eliza L S; Martinez, Mariane; Yang, Jun; Mikos, Antonios G; Navone, Nora M; Harrington, Daniel A; Farach-Carson, Mary C

    2014-07-07

    The lack of effective therapies for bone metastatic prostate cancer (PCa) underscores the need for accurate models of the disease to enable the discovery of new therapeutic targets and to test drug sensitivities of individual tumors. To this end, the patient-derived xenograft (PDX) PCa model using immunocompromised mice was established to model the disease with greater fidelity than is possible with currently employed cell lines grown on tissue culture plastic. However, poorly adherent PDX tumor cells exhibit low viability in standard culture, making it difficult to manipulate these cells for subsequent controlled mechanistic studies. To overcome this challenge, we encapsulated PDX tumor cells within a three-dimensional hyaluronan-based hydrogel and demonstrated that the hydrogel maintains PDX cell viability with continued native androgen receptor expression. Furthermore, a differential sensitivity to docetaxel, a chemotherapeutic drug, was observed as compared to a traditional PCa cell line. These findings underscore the potential impact of this novel 3D PDX PCa model as a diagnostic platform for rapid drug evaluation and ultimately push personalized medicine toward clinical reality.

  4. Systemically administered AAV9-sTRAIL combats invasive glioblastoma in a patient-derived orthotopic xenograft model

    Directory of Open Access Journals (Sweden)

    Matheus HW Crommentuijn

    2016-01-01

    Full Text Available Adeno-associated virus (AAV vectors expressing tumoricidal genes injected directly into brain tumors have shown some promise, however, invasive tumor cells are relatively unaffected. Systemic injection of AAV9 vectors provides widespread delivery to the brain and potentially the tumor/microenvironment. Here we assessed AAV9 for potential glioblastoma therapy using two different promoters driving the expression of the secreted anti-cancer agent sTRAIL as a transgene model; the ubiquitously active chicken β-actin (CBA promoter and the neuron-specific enolase (NSE promoter to restrict expression in brain. Intravenous injection of AAV9 vectors encoding a bioluminescent reporter showed similar distribution patterns, although the NSE promoter yielded 100-fold lower expression in the abdomen (liver, with the brain-to-liver expression ratio remaining the same. The main cell types targeted by the CBA promoter were astrocytes, neurons and endothelial cells, while expression by NSE promoter mostly occurred in neurons. Intravenous administration of either AAV9-CBA-sTRAIL or AAV9-NSE-sTRAIL vectors to mice bearing intracranial patient-derived glioblastoma xenografts led to a slower tumor growth and significantly increased survival, with the CBA promoter having higher efficacy. To our knowledge, this is the first report showing the potential of systemic injection of AAV9 vector encoding a therapeutic gene for the treatment of brain tumors.

  5. High-Dose, Single-Fraction Irradiation Rapidly Reduces Tumor Vasculature and Perfusion in a Xenograft Model of Neuroblastoma

    Energy Technology Data Exchange (ETDEWEB)

    Jani, Ashish; Shaikh, Fauzia; Barton, Sunjay [Department of Radiation Oncology, Columbia University Medical Center, New York, New York (United States); Willis, Callen [Department of Surgery, Columbia University Medical Center, New York, New York (United States); Banerjee, Debarshi [Department of Pediatrics, Columbia University Medical Center, New York, New York (United States); Mitchell, Jason [Department of Surgery, Columbia University Medical Center, New York, New York (United States); Hernandez, Sonia L. [Department of Surgery, University of Chicago, Chicago, Illinois (United States); Hei, Tom [Department of Radiation Oncology, Columbia University Medical Center, New York, New York (United States); Kadenhe-Chiweshe, Angela [Department of Surgery, Columbia University Medical Center, New York, New York (United States); Yamashiro, Darrell J. [Department of Surgery, Columbia University Medical Center, New York, New York (United States); Department of Pediatrics, Columbia University Medical Center, New York, New York (United States); Department of Pathology and Cell Biology, Columbia University Medical Center, New York, New York (United States); Connolly, Eileen P., E-mail: epc2116@cumc.columbia.edu [Department of Radiation Oncology, Columbia University Medical Center, New York, New York (United States)

    2016-04-01

    Purpose: To characterize the effects of high-dose radiation therapy (HDRT) on neuroblastoma tumor vasculature, including the endothelial cell (EC)–pericyte interaction as a potential target for combined treatment with antiangiogenic agents. Methods and Materials: The vascular effects of radiation therapy were examined in a xenograft model of high-risk neuroblastoma. In vivo 3-dimensional contrast-enhanced ultrasonography (3D-CEUS) imaging and immunohistochemistry (IHC) were performed. Results: HDRT significantly reduced tumor blood volume 6 hours after irradiation compared with the lower doses used in conventionally fractionated radiation. There was a 63% decrease in tumor blood volume after 12-Gy radiation compared with a 24% decrease after 2 Gy. Analysis of tumor vasculature by lectin angiography showed a significant loss of small vessel ends at 6 hours. IHC revealed a significant loss of ECs at 6 and 72 hours after HDRT, with an accompanying loss of immature and mature pericytes at 72 hours. Conclusions: HDRT affects tumor vasculature in a manner not observed at lower doses. The main observation was an early reduction in tumor perfusion resulting from a reduction of small vessel ends with a corresponding loss of endothelial cells and pericytes.

  6. Intracranial AAV-IFN-β gene therapy eliminates invasive xenograft glioblastoma and improves survival in orthotopic syngeneic murine model.

    Science.gov (United States)

    GuhaSarkar, Dwijit; Neiswender, James; Su, Qin; Gao, Guangping; Sena-Esteves, Miguel

    2017-02-01

    The highly invasive property of glioblastoma (GBM) cells and genetic heterogeneity are largely responsible for tumor recurrence after the current standard-of-care treatment and thus a direct cause of death. Previously, we have shown that intracranial interferon-beta (IFN-β) gene therapy by locally administered adeno-associated viral vectors (AAV) successfully treats noninvasive orthotopic glioblastoma models. Here, we extend these findings by testing this approach in invasive human GBM xenograft and syngeneic mouse models. First, we show that a single intracranial injection of AAV encoding human IFN-β eliminates invasive human GBM8 tumors and promotes long-term survival. Next, we screened five AAV-IFN-β vectors with different promoters to drive safe expression of mouse IFN-β in the brain in the context of syngeneic GL261 tumors. Two AAV-IFN-β vectors were excluded due to safety concerns, but therapeutic studies with the other three vectors showed extensive tumor cell death, activation of microglia surrounding the tumors, and a 56% increase in median survival of the animals treated with AAV/P2-Int-mIFN-β vector. We also assessed the therapeutic effect of combining AAV-IFN-β therapy with temozolomide (TMZ). As TMZ affects DNA replication, an event that is crucial for second-strand DNA synthesis of single-stranded AAV vectors before active transcription, we tested two TMZ treatment regimens. Treatment with TMZ prior to AAV-IFN-β abrogated any benefit from the latter, while the reverse order of treatment doubled the median survival compared to controls. These studies demonstrate the therapeutic potential of intracranial AAV-IFN-β therapy in a highly migratory GBM model as well as in a syngeneic mouse model and that combination with TMZ is likely to enhance its antitumor potency. © 2016 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.

  7. Ovarian tumor attachment, invasion and vascularization reflect unique microenvironments in the peritoneum:Insights from xenograft and mathematical models

    Directory of Open Access Journals (Sweden)

    Mara P. Steinkamp

    2013-05-01

    Full Text Available Ovarian cancer relapse is often characterized by metastatic spread throughout the peritoneal cavity with tumors attached to multiple organs. In this study, interaction of ovarian tumor cells with the peritoneal tumor microenvironment was evaluated in a xenograft model based on intraperitoneal injection of fluorescent SKOV3.ip1 ovarian cancer cells. Intra-vital microscopy of mixed GFP-RFP cell populations injected into the peritoneum demonstrated that tumor cells aggregate and attach as mixed spheroids, emphasizing the importance of homotypic adhesion in tumor formation. Electron microscopy provided high resolution structural information about local attachment sites. Experimental measurements from the mouse model were used to build a three-dimensional cellular Potts ovarian tumor model (OvTM that examines ovarian tumor cell attachment, chemotaxis, growth and vascularization. OvTM simulations provide insight into the relative influence of tumor cell-cell adhesion, oxygen availability, and local architecture on tumor growth and morphology. Notably, tumors on the mesentery, omentum or spleen readily invade the open architecture, while tumors attached to the gut encounter barriers that restrict invasion and instead rapidly expand into the peritoneal space. Simulations suggest that rapid neovascularization of SKOV3.ip1 tumors is triggered by constitutive release of angiogenic factors in the absence of hypoxia. This research highlights the importance of cellular adhesion and tumor microenvironment in the seeding of secondary ovarian tumors on diverse organs within the peritoneal cavity. Results of the OvTM simulations indicate that invasion is strongly influenced by features underlying the mesothelial lining at different sites, but is also affected by local production of chemotactic factors. The integrated in vivo mouse model and computer simulations provide a unique platform for evaluating targeted therapies for ovarian cancer relapse.

  8. Microarray profiling shows distinct differences between primary tumors and commonly used preclinical models in hepatocellular carcinoma

    International Nuclear Information System (INIS)

    Wang, Weining; Iyer, N. Gopalakrishna; Tay, Hsien Ts’ung; Wu, Yonghui; Lim, Tony K. H.; Zheng, Lin; Song, In Chin; Kwoh, Chee Keong; Huynh, Hung; Tan, Patrick O. B.; Chow, Pierce K. H.

    2015-01-01

    Despite advances in therapeutics, outcomes for hepatocellular carcinoma (HCC) remain poor and there is an urgent need for efficacious systemic therapy. Unfortunately, drugs that are successful in preclinical studies often fail in the clinical setting, and we hypothesize that this is due to functional differences between primary tumors and commonly used preclinical models. In this study, we attempt to answer this question by comparing tumor morphology and gene expression profiles between primary tumors, xenografts and HCC cell lines. Hep G2 cell lines and tumor cells from patient tumor explants were subcutaneously (ectopically) injected into the flank and orthotopically into liver parenchyma of Mus Musculus SCID mice. The mice were euthanized after two weeks. RNA was extracted from the tumors, and gene expression profiling was performed using the Gene Chip Human Genome U133 Plus 2.0. Principal component analyses (PCA) and construction of dendrograms were conducted using Partek genomics suite. PCA showed that the commonly used HepG2 cell line model and its xenograft counterparts were vastly different from all fresh primary tumors. Expression profiles of primary tumors were also significantly divergent from their counterpart patient-derived xenograft (PDX) models, regardless of the site of implantation. Xenografts from the same primary tumors were more likely to cluster together regardless of site of implantation, although heat maps showed distinct differences in gene expression profiles between orthotopic and ectopic models. The data presented here challenges the utility of routinely used preclinical models. Models using HepG2 were vastly different from primary tumors and PDXs, suggesting that this is not clinically representative. Surprisingly, site of implantation (orthotopic versus ectopic) resulted in limited impact on gene expression profiles, and in both scenarios xenografts differed significantly from the original primary tumors, challenging the long

  9. Development of a Novel Preclinical Pancreatic Cancer Research Model: Bioluminescence Image-Guided Focal Irradiation and Tumor Monitoring of Orthotopic Xenografts1

    OpenAIRE

    Tuli, Richard; Surmak, Andrew; Reyes, Juvenal; Hacker-Prietz, Amy; Armour, Michael; Leubner, Ashley; Blackford, Amanda; Tryggestad, Erik; Jaffee, Elizabeth M; Wong, John; DeWeese, Theodore L; Herman, Joseph M

    2012-01-01

    PURPOSE: We report on a novel preclinical pancreatic cancer research model that uses bioluminescence imaging (BLI)-guided irradiation of orthotopic xenograft tumors, sparing of surrounding normal tissues, and quantitative, noninvasive longitudinal assessment of treatment response. MATERIALS AND METHODS: Luciferase-expressing MiaPaCa-2 pancreatic carcinoma cells were orthotopically injected in nude mice. BLI was compared to pathologic tumor volume, and photon emission was assessed over time. B...

  10. Therapeutic efficacy of aldoxorubicin in an intracranial xenograft mouse model of human glioblastoma.

    Science.gov (United States)

    Marrero, Luis; Wyczechowska, Dorota; Musto, Alberto E; Wilk, Anna; Vashistha, Himanshu; Zapata, Adriana; Walker, Chelsey; Velasco-Gonzalez, Cruz; Parsons, Christopher; Wieland, Scott; Levitt, Daniel; Reiss, Krzysztof; Prakash, Om

    2014-10-01

    Glioblastoma multiforme (GBM) is the most aggressive primary brain tumor with a median survival of 12 to 15 months after diagnosis. Acquired chemoresistance, high systemic toxicity, and low penetration of the blood brain barrier by many anticancer drugs contribute to the failure of anti-GBM therapies. To circumvent some of these obstacles, we tested a novel prodrug approach to evaluate anti-GBM efficacy by utilizing serum albumin-binding doxorubicin (Doxo), aldoxorubicin (Aldoxo), which is less toxic, is released from albumin in an acidic environment and accumulates in tumor tissues. A human GBM cell line that expresses a luciferase reporter (U87-luc) was stereotactically injected into the left striatum of the brain of immunodeficient mice. Following initial tumor growth for 12 days, mice were injected once a week in the tail-vein with Aldoxo [24 mg/kg or 18 mg/kg of doxorubicin equivalents-3/4 maximum tolerated dose (MTD)], Doxo [6 mg/kg (3/4 MTD)], or vehicle. Aldoxo-treated mice demonstrated significantly slower growth of the tumor when compared to vehicle-treated or Doxo-treated mice. Five out of eight Aldoxo-treated mice remained alive more than 60 days with a median survival of 62 days, while the median survival of vehicle- and Doxo-treated mice was only 26 days. Importantly, Aldoxo-treated mice exhibited high levels of Doxo within the tumor tissue, accompanied by low tumor cell proliferation (Ki67) and abundant intratumoral programmed cell death (cleaved caspase-3). Effective accumulation of Aldoxo in brain tumor tissues but not normal brain, its anti-tumor efficacy, and low toxicity, provide a strong rationale for evaluating this novel drug conjugate as a treatment for patients afflicted with GBM.

  11. Therapeutic Efficacy of Aldoxorubicin in an Intracranial Xenograft Mouse Model of Human Glioblastoma

    Directory of Open Access Journals (Sweden)

    Luis Marrero

    2014-10-01

    Full Text Available Glioblastoma multiforme (GBM is the most aggressive primary brain tumor with a median survival of 12 to 15 months after diagnosis. Acquired chemoresistance, high systemic toxicity, and low penetration of the blood brain barrier by many anticancer drugs contribute to the failure of anti-GBM therapies. To circumvent some of these obstacles, we tested a novel prodrug approach to evaluate anti-GBM efficacy by utilizing serum albumin-binding doxorubicin (Doxo, aldoxorubicin (Aldoxo, which is less toxic, is released from albumin in an acidic environment and accumulates in tumor tissues. A human GBM cell line that expresses a luciferase reporter (U87-luc was stereotactically injected into the left striatum of the brain of immunodeficient mice. Following initial tumor growth for 12 days, mice were injected once a week in the tail-vein with Aldoxo [24 mg/kg or 18 mg/kg of doxorubicin equivalents—3/4 maximum tolerated dose (MTD], Doxo [6 mg/kg (3/4 MTD], or vehicle. Aldoxo-treated mice demonstrated significantly slower growth of the tumor when compared to vehicle-treated or Doxo-treated mice. Five out of eight Aldoxo-treated mice remained alive more than 60 days with a median survival of 62 days, while the median survival of vehicle- and Doxo-treated mice was only 26 days. Importantly, Aldoxo-treated mice exhibited high levels of Doxo within the tumor tissue, accompanied by low tumor cell proliferation (Ki67 and abundant intratumoral programmed cell death (cleaved caspase-3. Effective accumulation of Aldoxo in brain tumor tissues but not normal brain, its anti-tumor efficacy, and low toxicity, provide a strong rationale for evaluating this novel drug conjugate as a treatment for patients afflicted with GBM.

  12. EGFRvIII-specific chimeric antigen receptor T cells migrate to and kill tumor deposits infiltrating the brain parenchyma in an invasive xenograft model of glioblastoma.

    Science.gov (United States)

    Miao, Hongsheng; Choi, Bryan D; Suryadevara, Carter M; Sanchez-Perez, Luis; Yang, Shicheng; De Leon, Gabriel; Sayour, Elias J; McLendon, Roger; Herndon, James E; Healy, Patrick; Archer, Gary E; Bigner, Darell D; Johnson, Laura A; Sampson, John H

    2014-01-01

    Glioblastoma (GBM) is the most common primary malignant brain tumor in adults and is uniformly lethal. T-cell-based immunotherapy offers a promising platform for treatment given its potential to specifically target tumor tissue while sparing the normal brain. However, the diffuse and infiltrative nature of these tumors in the brain parenchyma may pose an exceptional hurdle to successful immunotherapy in patients. Areas of invasive tumor are thought to reside behind an intact blood brain barrier, isolating them from effective immunosurveillance and thereby predisposing the development of "immunologically silent" tumor peninsulas. Therefore, it remains unclear if adoptively transferred T cells can migrate to and mediate regression in areas of invasive GBM. One barrier has been the lack of a preclinical mouse model that accurately recapitulates the growth patterns of human GBM in vivo. Here, we demonstrate that D-270 MG xenografts exhibit the classical features of GBM and produce the diffuse and invasive tumors seen in patients. Using this model, we designed experiments to assess whether T cells expressing third-generation chimeric antigen receptors (CARs) targeting the tumor-specific mutation of the epidermal growth factor receptor, EGFRvIII, would localize to and treat invasive intracerebral GBM. EGFRvIII-targeted CAR (EGFRvIII+ CAR) T cells demonstrated in vitro EGFRvIII antigen-specific recognition and reactivity to the D-270 MG cell line, which naturally expresses EGFRvIII. Moreover, when administered systemically, EGFRvIII+ CAR T cells localized to areas of invasive tumor, suppressed tumor growth, and enhanced survival of mice with established intracranial D-270 MG tumors. Together, these data demonstrate that systemically administered T cells are capable of migrating to the invasive edges of GBM to mediate antitumor efficacy and tumor regression.

  13. EGFRvIII-specific chimeric antigen receptor T cells migrate to and kill tumor deposits infiltrating the brain parenchyma in an invasive xenograft model of glioblastoma.

    Directory of Open Access Journals (Sweden)

    Hongsheng Miao

    Full Text Available Glioblastoma (GBM is the most common primary malignant brain tumor in adults and is uniformly lethal. T-cell-based immunotherapy offers a promising platform for treatment given its potential to specifically target tumor tissue while sparing the normal brain. However, the diffuse and infiltrative nature of these tumors in the brain parenchyma may pose an exceptional hurdle to successful immunotherapy in patients. Areas of invasive tumor are thought to reside behind an intact blood brain barrier, isolating them from effective immunosurveillance and thereby predisposing the development of "immunologically silent" tumor peninsulas. Therefore, it remains unclear if adoptively transferred T cells can migrate to and mediate regression in areas of invasive GBM. One barrier has been the lack of a preclinical mouse model that accurately recapitulates the growth patterns of human GBM in vivo. Here, we demonstrate that D-270 MG xenografts exhibit the classical features of GBM and produce the diffuse and invasive tumors seen in patients. Using this model, we designed experiments to assess whether T cells expressing third-generation chimeric antigen receptors (CARs targeting the tumor-specific mutation of the epidermal growth factor receptor, EGFRvIII, would localize to and treat invasive intracerebral GBM. EGFRvIII-targeted CAR (EGFRvIII+ CAR T cells demonstrated in vitro EGFRvIII antigen-specific recognition and reactivity to the D-270 MG cell line, which naturally expresses EGFRvIII. Moreover, when administered systemically, EGFRvIII+ CAR T cells localized to areas of invasive tumor, suppressed tumor growth, and enhanced survival of mice with established intracranial D-270 MG tumors. Together, these data demonstrate that systemically administered T cells are capable of migrating to the invasive edges of GBM to mediate antitumor efficacy and tumor regression.

  14. Effect of dasatinib in a xenograft mouse model of canine histiocytic sarcoma and in vitro expression status of its potential target EPHA2.

    Science.gov (United States)

    Ito, K; Miyamoto, R; Tani, H; Kurita, S; Kobayashi, M; Tamura, K; Bonkobara, M

    2018-02-01

    Canine histiocytic sarcoma (HS) is an aggressive and highly metastatic tumor. Previously, the kinase inhibitor dasatinib was shown to have potent growth inhibitory activity against HS cells in vitro, possibly via targeting the EPHA2 receptor. Here, the in vivo effect of dasatinib in HS cells was investigated using a xenograft mouse model. Moreover, the expression status of EPHA2 was examined in six HS cell lines, ranging from insensitive to highly sensitive to dasatinib. In the HS xenograft mouse model, dasatinib significantly suppressed tumor growth, as illustrated by a decrease in mitotic and Ki67 indices and an increase in apoptotic index in tumor tissues. On Western blot analysis, EPHA2 was only weakly detected in all HS cell lines, regardless of sensitivity to dasatinib. Dasatinib likely results in the inhibition of xenograft tumor growth via a mechanism other than targeting EPHA2. The findings of this study suggest that dasatinib is a targeted therapy drug worthy of further exploration for the treatment of canine HS. © 2017 John Wiley & Sons Ltd.

  15. Multicolor fluorescent intravital live microscopy (FILM) for surgical tumor resection in a mouse xenograft model.

    Science.gov (United States)

    Thurber, Greg M; Figueiredo, Jose L; Weissleder, Ralph

    2009-11-30

    Complete surgical resection of neoplasia remains one of the most efficient tumor therapies. However, malignant cell clusters are often left behind during surgery due to the inability to visualize and differentiate them against host tissue. Here we establish the feasibility of multicolor fluorescent intravital live microscopy (FILM) where multiple cellular and/or unique tissue compartments are stained simultaneously and imaged in real time. Theoretical simulations of imaging probe localization were carried out for three agents with specificity for cancer cells, stromal host response, or vascular perfusion. This transport analysis gave insight into the probe pharmacokinetics and tissue distribution, facilitating the experimental design and allowing predictions to be made about the localization of the probes in other animal models and in the clinic. The imaging probes were administered systemically at optimal time points based on the simulations, and the multicolor FILM images obtained in vivo were then compared to conventional pathological sections. Our data show the feasibility of real time in vivo pathology at cellular resolution and molecular specificity with excellent agreement between intravital and traditional in vitro immunohistochemistry. Multicolor FILM is an accurate method for identifying malignant tissue and cells in vivo. The imaging probes distributed in a manner similar to predictions based on transport principles, and these models can be used to design future probes and experiments. FILM can provide critical real time feedback and should be a useful tool for more effective and complete cancer resection.

  16. Multicolor fluorescent intravital live microscopy (FILM for surgical tumor resection in a mouse xenograft model.

    Directory of Open Access Journals (Sweden)

    Greg M Thurber

    2009-11-01

    Full Text Available Complete surgical resection of neoplasia remains one of the most efficient tumor therapies. However, malignant cell clusters are often left behind during surgery due to the inability to visualize and differentiate them against host tissue. Here we establish the feasibility of multicolor fluorescent intravital live microscopy (FILM where multiple cellular and/or unique tissue compartments are stained simultaneously and imaged in real time.Theoretical simulations of imaging probe localization were carried out for three agents with specificity for cancer cells, stromal host response, or vascular perfusion. This transport analysis gave insight into the probe pharmacokinetics and tissue distribution, facilitating the experimental design and allowing predictions to be made about the localization of the probes in other animal models and in the clinic. The imaging probes were administered systemically at optimal time points based on the simulations, and the multicolor FILM images obtained in vivo were then compared to conventional pathological sections. Our data show the feasibility of real time in vivo pathology at cellular resolution and molecular specificity with excellent agreement between intravital and traditional in vitro immunohistochemistry.Multicolor FILM is an accurate method for identifying malignant tissue and cells in vivo. The imaging probes distributed in a manner similar to predictions based on transport principles, and these models can be used to design future probes and experiments. FILM can provide critical real time feedback and should be a useful tool for more effective and complete cancer resection.

  17. Nilotinib Enhances Tumor Angiogenesis and Counteracts VEGFR2 Blockade in an Orthotopic Breast Cancer Xenograft Model with Desmoplastic Response

    Directory of Open Access Journals (Sweden)

    Sara Zafarnia

    2017-11-01

    Full Text Available Vascular endothelial growth factor (VEGF/VEGF receptor (VEGFR-targeted therapies predominantly affect nascent, immature tumor vessels. Since platelet-derived growth factor receptor (PDGFR blockade inhibits vessel maturation and thus increases the amount of immature tumor vessels, we evaluated whether the combined PDGFR inhibition by nilotinib and VEGFR2 blockade by DC101 has synergistic therapy effects in a desmoplastic breast cancer xenograft model. In this context, besides immunohistological evaluation, molecular ultrasound imaging with BR55, the clinically used VEGFR2-targeted microbubbles, was applied to monitor VEGFR2-positive vessels noninvasively and to assess the therapy effects on tumor angiogenesis. DC101 treatment alone inhibited tumor angiogenesis, resulting in lower tumor growth and in significantly lower vessel density than in the control group after 14 days of therapy. In contrast, nilotinib inhibited vessel maturation but enhanced VEGFR2 expression, leading to markedly increased tumor volumes and a significantly higher vessel density. The combination of both drugs led to an almost similar tumor growth as in the DC101 treatment group, but VEGFR2 expression and microvessel density were higher and comparable to the controls. Further analyses revealed significantly higher levels of tumor cell–derived VEGF in nilotinib-treated tumors. In line with this, nilotinib, especially in low doses, induced an upregulation of VEGF and IL-6 mRNA in the tumor cells in vitro, thus providing an explanation for the enhanced angiogenesis observed in nilotinib-treated tumors in vivo. These findings suggest that nilotinib inhibits vessel maturation but counteracts the effects of antiangiogenic co-therapy by enhancing VEGF expression by the tumor cells and stimulating tumor angiogenesis.

  18. Porphyrin lipid nanoparticles for enhanced photothermal therapy in a patient-derived orthotopic pancreas xenograft cancer model

    Science.gov (United States)

    MacLaughlin, Christina M.; Ding, Lili; Jin, Cheng; Cao, Pingjiang; Siddiqui, Iram; Hwang, David M.; Chen, Juan; Wilson, Brian C.; Zheng, Gang; Hedley, David W.

    2016-03-01

    Local disease control is a major problem in the treatment of pancreatic cancer, because curative-intent surgery is only possible in a minority of patients, and radiotherapy cannot be delivered in curative doses. Despite the promise of photothermal therapy (PTT) for ablation of pancreatic tumors, this approach remains under investigated. Using photothermal sensitizers in combination with laser light for PTT can result in more efficient conversion of light energy to heat, and confinement of thermal destruction to the tumor, thus sparing adjacent organs and vasculature. Porphyrins have been previously employed as photosensitizers for PDT and PTT, however their incorporation in to "porphysomes", lipid-based nanoparticles each containing ~80,000 porphyrins through conjugation of pyropheophorbide to phospholipids, carries two distinct advantages: 1) high-density porphyrin packing imparts the nanoparticles with enhanced photonic properties for imaging and phototherapy; 2) the enhanced permeability and retention effect may be exploited for optimal delivery of porphysomes to the tumor region thus high payload porphyrin delivery. The feasibility of porphysome-enhanced PTT for pancreatic cancer treatment was investigated using a patient-derived orthotopic pancreas xenograft tumor model. Uptake of porphysomes at the orthotopic tumor site was validated using ex vivo fluorescence imaging of intact organs of interest. The accumulation of porphysomes in orthotopic tumor microstructure was also confirmed by fluorescence imaging of excised tissue slices. PTT progress was monitored as changes in tumor surface temperature using IR optical imaging. Histological analyses were conducted to examine microstructure changes in tissue morphology, and the viability of remaining tumor tissues following exposure to heat. These studies may also provide insight as to the contribution of heat sink in application of thermal therapies to highly vascularized pancreatic tumors.

  19. Raloxifene inhibits tumor growth and lymph node metastasis in a xenograft model of metastatic mammary cancer

    Directory of Open Access Journals (Sweden)

    Li Zhong-Lian

    2010-10-01

    Full Text Available Abstract Background The effects of raloxifene, a novel selective estrogen receptor modulator, were studied in a mouse metastatic mammary cancer model expressing cytoplasmic ERα. Methods Mammary tumors, induced by inoculation of syngeneic BALB/c mice with BJMC3879luc2 cells, were subsequently treated with raloxifene at 0, 18 and 27 mg/kg/day using mini-osmotic pumps. Results In vitro study demonstrated that the ERα in BJMC3879luc2 cells was smaller (between 50 and 64 kDa than the normal-sized ERα (66 kDa and showed cytoplasmic localization. A statistically significant but weak estradiol response was observed in this cell line. When BJMC3879luc2 tumors were implanted into mice, the ERα mRNA levels were significantly higher in females than in males. In vitro studies showed that raloxifene induced mitochondria-mediated apoptosis and cell-cycle arrest in the G1-phase and a decrease in the cell population in the S-phase. In animal experiments, tumor volumes were significantly suppressed in the raloxifene-treated groups. The multiplicity of lymph node metastasis was significantly decreased in the 27 mg/kg group. Levels of apoptosis were significantly increased in the raloxifene-treated groups, whereas the levels of DNA synthesis were significantly decreased in these groups. No differences in microvessel density in tumors were observed between the control and raloxifene-treated groups. The numbers of dilated lymphatic vessels containing intraluminal tumor cells were significantly reduced in mammary tumors in the raloxifene-treated groups. The levels of ERα mRNA in mammary tumors tended to be decreased in the raloxifene-treated groups. Conclusion These results suggest that the antimetastatic activity of raloxifene in mammary cancer expressing cytoplasmic ERα may be a crucial finding with clinical applications and that raloxifene may be useful as an adjuvant therapy and for the chemoprevention of breast cancer development.

  20. Rapamycin targeting mTOR and hedgehog signaling pathways blocks human rhabdomyosarcoma growth in xenograft murine model

    Energy Technology Data Exchange (ETDEWEB)

    Kaylani, Samer Z. [Division of Hematology and Oncology, Department of Pediatrics, University of Alabama at Birmingham, 1600 7th Avenue South, ACC 414, Birmingham, AL 35233 (United States); Xu, Jianmin; Srivastava, Ritesh K. [Department of Dermatology and Skin Diseases Research Center, University of Alabama at Birmingham, 1530 3rd Avenue South, VH 509, Birmingham, AL 35294-0019 (United States); Kopelovich, Levy [Division of Cancer Prevention, National Cancer Institute, Bethesda (United States); Pressey, Joseph G. [Division of Hematology and Oncology, Department of Pediatrics, University of Alabama at Birmingham, 1600 7th Avenue South, ACC 414, Birmingham, AL 35233 (United States); Athar, Mohammad, E-mail: mathar@uab.edu [Department of Dermatology and Skin Diseases Research Center, University of Alabama at Birmingham, 1530 3rd Avenue South, VH 509, Birmingham, AL 35294-0019 (United States)

    2013-06-14

    Graphical abstract: Intervention of poorly differentiated RMS by rapamycin: In poorly differentiated RMS, rapamycin blocks mTOR and Hh signaling pathways concomitantly. This leads to dampening in cell cycle regulation and induction of apoptosis. This study provides a rationale for the therapeutic intervention of poorly differentiated RMS by treating patients with rapamycin alone or in combination with other chemotherapeutic agents. -- Highlights: •Rapamycin abrogates RMS tumor growth by modulating proliferation and apoptosis. •Co-targeting mTOR/Hh pathways underlie the molecular basis of effectiveness. •Reduction in mTOR/Hh pathways diminish EMT leading to reduced invasiveness. -- Abstract: Rhabdomyosarcomas (RMS) represent the most common childhood soft-tissue sarcoma. Over the past few decades outcomes for low and intermediate risk RMS patients have slowly improved while patients with metastatic or relapsed RMS still face a grim prognosis. New chemotherapeutic agents or combinations of chemotherapies have largely failed to improve the outcome. Based on the identification of novel molecular targets, potential therapeutic approaches in RMS may offer a decreased reliance on conventional chemotherapy. Thus, identification of effective therapeutic agents that specifically target relevant pathways may be particularly beneficial for patients with metastatic and refractory RMS. The PI3K/AKT/mTOR pathway has been found to be a potentially attractive target in RMS therapy. In this study, we provide evidence that rapamycin (sirolimus) abrogates growth of RMS development in a RMS xenograft mouse model. As compared to a vehicle-treated control group, more than 95% inhibition in tumor growth was observed in mice receiving parenteral administration of rapamycin. The residual tumors in rapamycin-treated group showed significant reduction in the expression of biomarkers indicative of proliferation and tumor invasiveness. These tumors also showed enhanced apoptosis

  1. Targeted tumor theranostics using folate-conjugated and camptothecin-loaded acoustic nanodroplets in a mouse xenograft model.

    Science.gov (United States)

    Chen, Wei-Tsung; Kang, Shih-Tsung; Lin, Jian-Liang; Wang, Chung-Hsin; Chen, Ran-Chou; Yeh, Chih-Kuang

    2015-01-01

    In this study, we aimed to validate the feasibility of receptor-targeted tumor theranostics with folate-conjugated (FA) and camptothecin-loaded (CPT) acoustic nanodroplets (NDs) (collectively termed FA-CPT-NDs). The ND formulation was based on lipid-stabilized low-boiling perfluorocarbon that can undergo acoustic droplet vaporization (ADV) under ultrasound (US) exposure. Conjugation of folate enhanced the selective delivery to tumors expressing high levels of folate receptor (FR) under mediation by the enhanced permeability and retention effect. In vitro and in vivo studies were performed using FR-positive KB and FR-negative HT-1080 cell lines and mouse xenograft tumor models. Simultaneous therapy and imaging were conducted with a clinical US imaging system at mechanical indices of up to 1.4 at a center frequency of 10 MHz. The results demonstrated that FA-CPT-NDs selectively attached to KB cells, but not HT-1080 cells. The targeted ADV caused instant and delayed damage via mechanical disruption and chemical toxicity to decrease the viability of KB cells by up to 45%, a much higher decrease than that achieved by the NDs without folate conjugation. The in vivo experiments showed that FR-mediated targeting successfully enhanced the EPR of FA-CPT-NDs in KB tumors mainly on the tumor periphery as indicated by immunofluorescence microscopy and US B-mode imaging. Treatments with FA-CPT-NDs at a CPT dose of 50 μg/kg inhibited the growth of KB tumors for up to six weeks, whereas treatment with NDs lacking folate produced a 4.6-fold increase in tumor volume. For HT-1080 tumors, neither the treatments with FA-CPT-NDs nor those with the NDs lacking folate presented tumor growth inhibition. In summary, FR-targeted tumor theranostics has been successfully implemented with FA-CPT-NDs and a clinical US unit. The ligand-directed and EPR-mediated accumulation provides active and passive targeting capabilities, permitting the antitumor effects of FA-CPT-NDs to be exerted

  2. Patient-Derived Xenografts of Non Small Cell Lung Cancer: Resurgence of an Old Model for Investigation of Modern Concepts of Tailored Therapy and Cancer Stem Cells

    Directory of Open Access Journals (Sweden)

    Massimo Moro

    2012-01-01

    Full Text Available Current chemotherapy regimens have unsatisfactory results in most advanced solid tumors. It is therefore imperative to devise novel therapeutic strategies and to optimize selection of patients, identifying early those who could benefit from available treatments. Mouse models are the most valuable tool for preclinical evaluation of novel therapeutic strategies in cancer and, among them, patient-derived xenografts models (PDX have made a recent comeback in popularity. These models, obtained by direct implants of tissue fragments in immunocompromised mice, have great potential in drug development studies because they faithfully reproduce the patient’s original tumor for both immunohistochemical markers and genetic alterations as well as in terms of response to common therapeutics They also maintain the original tumor heterogeneity, allowing studies of specific cellular subpopulations, including their modulation after drug treatment. Moreover PDXs maintain at least some aspects of the human microenvironment for weeks with the complete substitution with murine stroma occurring only after 2-3 passages in mouse and represent therefore a promising model for studies of tumor-microenvironment interaction. This review summarizes our present knowledge on mouse preclinical cancer models, with a particular attention on patient-derived xenografts of non small cell lung cancer and their relevance for preclinical and biological studies.

  3. Noninvasive monitoring of early antiangiogenic therapy response in human nasopharyngeal carcinoma xenograft model using MRI with RGD-conjugated ultrasmall superparamagnetic iron oxide nanoparticles

    Directory of Open Access Journals (Sweden)

    Cui Y

    2016-11-01

    Full Text Available Yanfen Cui,1,* Caiyuan Zhang,1,* Ran Luo,1 Huanhuan Liu,1 Zhongyang Zhang,1 Tianyong Xu,2 Yong Zhang,2 Dengbin Wang11Department of Radiology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, 2MR Advanced Application and Research Center, GE Healthcare China, Shanghai, People’s Republic of China *These authors contributed equally to this workPurpose: Arginine-glycine-aspartic acid (RGD-based nanoprobes allow specific imaging of integrin αvβ3, a protein overexpressed during angiogenesis. Therefore, this study applied a novel RGD-coupled, polyacrylic acid (PAA-coated ultrasmall superparamagnetic iron oxide (USPIO (referred to as RGD-PAA-USPIO in order to detect tumor angiogenesis and assess the early response to antiangiogenic treatment in human nasopharyngeal carcinoma (NPC xenograft model by magnetic resonance imaging (MRI.Materials and methods: The binding specificity of RGD-PAA-USPIO with human umbilical vein endothelial cells (HUVECs was confirmed by Prussian blue staining and transmission electron microscopy in vitro. The tumor targeting of RGD-PAA-USPIO was evaluated in the NPC xenograft model. Later, mice bearing NPC underwent MRI at baseline and after 4 and 14 days of consecutive treatment with Endostar or phosphate-buffered saline (n=10 per group.Results: The specific uptake of the RGD-PAA-USPIO nanoparticles was mainly dependent on the interaction between RGD and integrin αvβ3 of HUVECs. The tumor targeting of RGD-PAA-USPIO was observed in the NPC xenograft model. Moreover, the T2 relaxation time of mice in the Endostar-treated group decreased significantly compared with those in the control group both on days 4 and 14, consistent with the immunofluorescence results of CD31 and CD61 (P<0.05.Conclusion: This study demonstrated that the magnetic resonance molecular nanoprobes, RGD-PAA-USPIOs, allow noninvasive in vivo imaging of tumor angiogenesis and assessment of the early response to antiangiogenic treatment in

  4. Gene expression profiling upon 212Pb-TCMC-trastuzumab treatment in the LS-174T i.p. xenograft model

    International Nuclear Information System (INIS)

    Yong, Kwon J; Milenic, Diane E; Baidoo, Kwamena E; Kim, Young-Seung; Brechbiel, Martin W

    2013-01-01

    Recent studies have demonstrated that therapy with 212 Pb-TCMC-trastuzumab resulted in (1) induction of apoptosis, (2) G2/M arrest, and (3) blockage of double-strand DNA damage repair in LS-174T i.p. (intraperitoneal) xenografts. To further understand the molecular basis of the cell killing efficacy of 212 Pb-TCMC-trastuzumab, gene expression profiling was performed with LS-174T xenografts 24 h after exposure to 212 Pb-TCMC-trastuzumab. DNA damage response genes (84) were screened using a quantitative real-time polymerase chain reaction array (qRT-PCR array). Differentially regulated genes were identified following exposure to 212 Pb-TCMC-trastuzumab. These included genes involved in apoptosis (ABL, GADD45α, GADD45γ, PCBP4, and p73), cell cycle (ATM, DDIT3, GADD45α, GTSE1, MKK6, PCBP4, and SESN1), and damaged DNA binding (DDB) and repair (ATM and BTG2). The stressful growth arrest conditions provoked by 212 Pb-TCMC-trastuzumab were found to induce genes involved in apoptosis and cell cycle arrest in the G2/M phase. The expression of genes involved in DDB and single-strand DNA breaks was also enhanced by 212 Pb-TCMC-trastuzumab while no modulation of genes involved in double-strand break repair was apparent. Furthermore, the p73/GADD45 signaling pathway mediated by p38 kinase signaling may be involved in the cellular response, as evidenced by the enhanced expression of genes and proteins of this pathway. These results further support the previously described cell killing mechanism by 212 Pb-TCMC-trastuzumab in the same LS-174T i.p. xenograft. Insight into these mechanisms could lead to improved strategies for rational application of radioimmunotherapy using α-particle emitters. The apoptotic response and associated gene modulations have not been clearly defined following exposure of cells to α-particle radioimmunotherapy (RIT). Gene expression profiling was performed with LS-174T i.p. (intraperitoneal) xenografts after exposure to 212 Pb

  5. Vorinostat, an HDAC inhibitor attenuates epidermoid squamous cell carcinoma growth by dampening mTOR signaling pathway in a human xenograft murine model

    Energy Technology Data Exchange (ETDEWEB)

    Kurundkar, Deepali; Srivastava, Ritesh K.; Chaudhary, Sandeep C. [Department of Dermatology and Skin Diseases Research Center, University of Alabama at Birmingham, 1530 3rd Avenue South, VH 509, Birmingham, AL 35294-0019 (United States); Ballestas, Mary E. [Department of Pediatrics Infectious Disease, Children' s of Alabama, School of Medicine, University of Alabama at Birmingham, AL (United States); Kopelovich, Levy [Division of Cancer Prevention, National Cancer Institute, 6130 Executive Blvd., Suite 2114, Bethesda, MD 20892 (United States); Elmets, Craig A. [Department of Dermatology and Skin Diseases Research Center, University of Alabama at Birmingham, 1530 3rd Avenue South, VH 509, Birmingham, AL 35294-0019 (United States); Athar, Mohammad, E-mail: mathar@uab.edu [Department of Dermatology and Skin Diseases Research Center, University of Alabama at Birmingham, 1530 3rd Avenue South, VH 509, Birmingham, AL 35294-0019 (United States)

    2013-01-15

    Histone deacetylase (HDAC) inhibitors are potent anticancer agents and show efficacy against various human neoplasms. Vorinostat is a potent HDAC inhibitor and has shown potential to inhibit growth of human xenograft tumors. However, its effect on the growth of skin neoplasm remains undefined. In this study, we show that vorinostat (2 μM) reduced expression of HDAC1, 2, 3, and 7 in epidermoid carcinoma A431 cells. Consistently, it increased acetylation of histone H3 and p53. Vorinostat (100 mg/kg body weight, IP) treatment reduced human xenograft tumor growth in highly immunosuppressed nu/nu mice. Histologically, the vorinostat-treated tumor showed features of well-differentiation with large necrotic areas. Based on proliferating cell nuclear antigen (PCNA) staining and expression of cyclins D1, D2, E, and A, vorinostat seems to impair proliferation by down-regulating the expression of these proteins. However, it also induced apoptosis. The mechanism by which vorinostat blocks proliferation and makes tumor cells prone to apoptosis, involved inhibition of mTOR signaling which was accompanied by reduction in cell survival AKT and extracellular-signal regulated kinase (ERK) signaling pathways. Our data provide a novel mechanism-based therapeutic intervention for cutaneous squamous cell carcinoma (SCC). Vorinostat may be utilized to cure skin neoplasms in organ transplant recipient (OTR). These patients have high morbidity and surgical removal of these lesions which frequently develop in these patients, is difficult. -- Highlights: ► Vorinostat reduces SCC growth in a xenograft murine model. ► Vorinostat dampens proliferation and induces apoptosis in tumor cells. ► Diminution in mTOR, Akt and ERK signaling underlies inhibition in proliferation. ► Vorinostat by inhibiting HDACs inhibits epithelial–mesenchymal transition.

  6. Vorinostat, an HDAC inhibitor attenuates epidermoid squamous cell carcinoma growth by dampening mTOR signaling pathway in a human xenograft murine model

    International Nuclear Information System (INIS)

    Kurundkar, Deepali; Srivastava, Ritesh K.; Chaudhary, Sandeep C.; Ballestas, Mary E.; Kopelovich, Levy; Elmets, Craig A.; Athar, Mohammad

    2013-01-01

    Histone deacetylase (HDAC) inhibitors are potent anticancer agents and show efficacy against various human neoplasms. Vorinostat is a potent HDAC inhibitor and has shown potential to inhibit growth of human xenograft tumors. However, its effect on the growth of skin neoplasm remains undefined. In this study, we show that vorinostat (2 μM) reduced expression of HDAC1, 2, 3, and 7 in epidermoid carcinoma A431 cells. Consistently, it increased acetylation of histone H3 and p53. Vorinostat (100 mg/kg body weight, IP) treatment reduced human xenograft tumor growth in highly immunosuppressed nu/nu mice. Histologically, the vorinostat-treated tumor showed features of well-differentiation with large necrotic areas. Based on proliferating cell nuclear antigen (PCNA) staining and expression of cyclins D1, D2, E, and A, vorinostat seems to impair proliferation by down-regulating the expression of these proteins. However, it also induced apoptosis. The mechanism by which vorinostat blocks proliferation and makes tumor cells prone to apoptosis, involved inhibition of mTOR signaling which was accompanied by reduction in cell survival AKT and extracellular-signal regulated kinase (ERK) signaling pathways. Our data provide a novel mechanism-based therapeutic intervention for cutaneous squamous cell carcinoma (SCC). Vorinostat may be utilized to cure skin neoplasms in organ transplant recipient (OTR). These patients have high morbidity and surgical removal of these lesions which frequently develop in these patients, is difficult. -- Highlights: ► Vorinostat reduces SCC growth in a xenograft murine model. ► Vorinostat dampens proliferation and induces apoptosis in tumor cells. ► Diminution in mTOR, Akt and ERK signaling underlies inhibition in proliferation. ► Vorinostat by inhibiting HDACs inhibits epithelial–mesenchymal transition.

  7. Achieving Value in Primary Care: The Primary Care Value Model.

    Science.gov (United States)

    Rollow, William; Cucchiara, Peter

    2016-03-01

    The patient-centered medical home (PCMH) model provides a compelling vision for primary care transformation, but studies of its impact have used insufficiently patient-centered metrics with inconsistent results. We propose a framework for defining patient-centered value and a new model for value-based primary care transformation: the primary care value model (PCVM). We advocate for use of patient-centered value when measuring the impact of primary care transformation, recognition, and performance-based payment; for financial support and research and development to better define primary care value-creating activities and their implementation; and for use of the model to support primary care organizations in transformation. © 2016 Annals of Family Medicine, Inc.

  8. [Compound K suppresses myeloid-derived suppressor cells in a mouse model bearing CT26 colorectal cancer xenograft].

    Science.gov (United States)

    Wang, Rong; Li, Yalin; Wang, Wuzhou; Zhou, Meijuan; Cao, Zhaohui

    2015-05-01

    To investigate the effect of ginseng-derived compound K (C-K) on apoptosis, immunosuppressive activity, and pro-inflammatory cytokine production of myeloid-derived suppressor cells (MDSCs) from mice bearing colorectal cancer xenograft. Flow-sorted bone marrow MDSCs from Balb/c mice bearing CT26 tumor xenograft were treated with either C-K or PBS for 96 h and examined for apoptosis with Annexin V/7-AAD, Cox-2 and Arg-1 expressions using qRT-PCR, and supernatant IL-1β, IL-6, and IL-17 levels with ELISA. C-K- or PBS-treated MDSCs were subcutaneously implanted along with CT26 tumor cells in WT Balb/c mice, and the tumor size and morphology were evaluated 21 days later. C-K treatment significantly increased the percentages of early and late apoptotic MDSCs in vitro (Pimmunosuppresive effect of MDSCs to inhibit tumor cell proliferation in mice, which suggests a new strategy of tumor therapy by targeting MDSCs.

  9. Increased COX-2 expression in epithelial and stromal cells of high mammographic density tissues and in a xenograft model of mammographic density.

    Science.gov (United States)

    Chew, G L; Huo, C W; Huang, D; Hill, P; Cawson, J; Frazer, H; Hopper, J L; Haviv, I; Henderson, M A; Britt, K; Thompson, E W

    2015-08-01

    Mammographic density (MD) adjusted for age and body mass index is one of the strongest known risk factors for breast cancer. Given the high attributable risk of MD for breast cancer, chemoprevention with a safe and available agent that reduces MD and breast cancer risk would be beneficial. Cox-2 has been implicated in MD-related breast cancer risk, and was increased in stromal cells in high MD tissues in one study. Our study assessed differential Cox-2 expression in epithelial and stromal cells in paired samples of high and low MD human breast tissue, and in a validated xenograft biochamber model of MD. We also examined the effects of endocrine treatment upon Cox-2 expression in high and low MD tissues in the MD xenograft model. Paired high and low MD human breast tissue samples were immunostained for Cox-2, then assessed for differential expression and staining intensity in epithelial and stromal cells. High and low MD human breast tissues were separately maintained in biochambers in mice treated with Tamoxifen, oestrogen or placebo implants, then assessed for percentage Cox-2 staining in epithelial and stromal cells. Percentage Cox-2 staining was greater for both epithelial (p = 0.01) and stromal cells (p tissues. In high MD biochamber tissues, percentage Cox-2 staining was greater in stromal cells of oestrogen-treated versus placebo-treated tissues (p = 0.05).

  10. Time-dependent pharmacokinetics of dexamethasone and its efficacy in human breast cancer xenograft mice: a semi-mechanism-based pharmacokinetic/pharmacodynamic model.

    Science.gov (United States)

    Li, Jian; Chen, Rong; Yao, Qing-Yu; Liu, Sheng-Jun; Tian, Xiu-Yun; Hao, Chun-Yi; Lu, Wei; Zhou, Tian-Yan

    2018-03-01

    Dexamethasone (DEX) is the substrate of CYP3A. However, the activity of CYP3A could be induced by DEX when DEX was persistently administered, resulting in auto-induction and time-dependent pharmacokinetics (pharmacokinetics with time-dependent clearance) of DEX. In this study we investigated the pharmacokinetic profiles of DEX after single or multiple doses in human breast cancer xenograft nude mice and established a semi-mechanism-based pharmacokinetic/pharmacodynamic (PK/PD) model for characterizing the time-dependent PK of DEX as well as its anti-cancer effect. The mice were orally given a single or multiple doses (8 mg/kg) of DEX, and the plasma concentrations of DEX were assessed using LC-MS/MS. Tumor volumes were recorded daily. Based on the experimental data, a two-compartment model with first order absorption and time-dependent clearance was established, and the time-dependence of clearance was modeled by a sigmoid E max equation. Moreover, a semi-mechanism-based PK/PD model was developed, in which the auto-induction effect of DEX on its metabolizing enzyme CYP3A was integrated and drug potency was described using an E max equation. The PK/PD model was further used to predict the drug efficacy when the auto-induction effect was or was not considered, which further revealed the necessity of adding the auto-induction effect into the final PK/PD model. This study established a semi-mechanism-based PK/PD model for characterizing the time-dependent pharmacokinetics of DEX and its anti-cancer effect in breast cancer xenograft mice. The model may serve as a reference for DEX dose adjustments or optimization in future preclinical or clinical studies.

  11. Effects of low-dose cyclophosphamide with piroxicam on tumour neovascularization in a canine oral malignant melanoma-xenografted mouse model.

    Science.gov (United States)

    Choisunirachon, N; Jaroensong, T; Yoshida, K; Saeki, K; Mochizuki, M; Nishimura, R; Sasaki, N; Nakagawa, T

    2015-12-01

    Low-dose cyclophosphamide (CyLD) has shown promise in the treatment of several cancers; however, the effect of CyLD on canine oral malignant melanoma has never been explored. In this study, we investigated the effects of CyLD with or without piroxicam (Px) on tumour neovascularization and vascular normalization in a canine oral malignant melanoma-xenografted mice model. After treatment with CyLD, Px or a combination of both (CyPx), the growth of the tumour in the treatment groups was significantly suppressed compared to the control group at 30 days of treatment. Proliferation index was also significantly reduced by all treatments, only CyPx significantly lowered microvessel density and vascular endothelial growth factor (VEGF) levels. Additionally, CyLD significantly reduced the proportion of normal vessels and caused an imbalance between VEGF and thrombospondin-1. These results suggested that CyPx has potent anti-angiogenic effects in terms of both the number and quality of blood vessels in xenografted canine oral malignant melanoma. © 2013 John Wiley & Sons Ltd.

  12. Orthotopic Patient-Derived Glioblastoma Xenografts in Mice.

    Science.gov (United States)

    Xu, Zhongye; Kader, Michael; Sen, Rajeev; Placantonakis, Dimitris G

    2018-01-01

    Patient-derived xenografts (PDX) provide in vivo glioblastoma (GBM) models that recapitulate actual tumors. Orthotopic tumor xenografts within the mouse brain are obtained by injection of GBM stem-like cells derived from fresh surgical specimens. These xenografts reproduce GBM's histologic complexity and hallmark biological behaviors, such as brain invasion, angiogenesis, and resistance to therapy. This method has become essential for analyzing mechanisms of tumorigenesis and testing the therapeutic effect of candidate agents in the preclinical setting. Here, we describe a protocol for establishing orthotopic tumor xenografts in the mouse brain with human GBM cells.

  13. Antitumor activity of erlotinib (OSI-774, Tarceva) alone or in combination in human non-small cell lung cancer tumor xenograft models.

    Science.gov (United States)

    Higgins, Brian; Kolinsky, Kenneth; Smith, Melissa; Beck, Gordon; Rashed, Mohammad; Adames, Violeta; Linn, Michael; Wheeldon, Eric; Gand, Laurent; Birnboeck, Herbert; Hoffmann, Gerhard

    2004-06-01

    Our objective was the preclinical assessment of the pharmacokinetics, monotherapy and combined antitumor activity of the epidermal growth factor receptor (HER1/EGFR) tyrosine kinase inhibitor erlotinib in athymic nude mice bearing non-small cell lung cancer (NSCLC) xenograft models. Immunohistochemistry determined the HER1/EGFR status of the NSCLC tumor models. Pharmacokinetic studies assessed plasma drug concentrations of erlotinib in tumor- and non-tumor-bearing athymic nude mice. These were followed by maximum tolerated dose (MTD) studies for erlotinib and each chemotherapy. Erlotinib was then assessed alone and in combination with these chemotherapies in the NSCLC xenograft models. Complete necropsies were performed on most of the animals in each study to further assess antitumor or toxic effects. Erlotinib monotherapy dose-dependently inhibited tumor growth in the H460a tumor model, correlating with circulating levels of drug. There was antitumor activity at the MTD with each agent tested in both the H460a and A549 tumor models (erlotinib 100 mg/kg: 71 and 93% tumor growth inhibition; gemcitabine 120 mg/kg: 93 and 75% tumor growth inhibition; cisplatin 6 mg/kg: 81 and 88% tumor growth inhibition). When each compound was given at a fraction of the MTD, tumor growth inhibition was suboptimal. Combinations of gemcitabine or cisplatin with erlotinib were assessed at 25% of the MTD to determine efficacy. In both NSCLC models, doses of gemcitabine (30 mg/kg) or cisplatin (1.5 mg/kg) with erlotinib (25 mg/kg) at 25% of the MTD were well tolerated. For the slow growing A549 tumor, there was significant tumor growth inhibition in the gemcitabine/erlotinib and cisplatin/erlotinib combinations (above 100 and 98%, respectively), with partial regressions. For the faster growing H460a tumor, there was significant but less remarkable tumor growth inhibition in these same combinations (86 and 53% respectively). These results show that in NSCLC xenograft tumors with similar

  14. Comparison of planar, PET and well-counter measurements of total tumor radioactivity in a mouse xenograft model

    International Nuclear Information System (INIS)

    Green, Michael V.; Seidel, Jurgen; Williams, Mark R.; Wong, Karen J.; Ton, Anita; Basuli, Falguni; Choyke, Peter L.; Jagoda, Elaine M.

    2017-01-01

    Introduction: Quantitative small animal radionuclide imaging studies are often carried out with the intention of estimating the total radioactivity content of various tissues such as the radioactivity content of mouse xenograft tumors exposed to putative diagnostic or therapeutic agents. We show that for at least one specific application, positron projection imaging (PPI) and PET yield comparable estimates of absolute total tumor activity and that both of these estimates are highly correlated with direct well-counting of these same tumors. These findings further suggest that in this particular application, PPI is a far more efficient data acquisition and processing methodology than PET. Methods: Forty-one athymic mice were implanted with PC3 human prostate cancer cells transfected with prostate-specific membrane antigen (PSMA (+)) and one additional animal (for a total of 42) with a control blank vector (PSMA (−)). All animals were injected with [ 18 F] DCFPyl, a ligand for PSMA, and imaged for total tumor radioactivity with PET and PPI. The tumors were then removed, assayed by well counting for total radioactivity and the values between these methods intercompared. Results: PET, PPI and well-counter estimates of total tumor radioactivity were highly correlated (R 2 > 0.98) with regression line slopes near unity (0.95 < slope ≤ 1.02) and intercepts near zero (−0.001 MBq ≤ intercept ≤0.004 MBq). Conclusion: Total mouse xenograft tumor radioactivity can be measured with PET or PPI with an accuracy comparable to well counting if certain experimental and pharmacokinetic conditions are met. In this particular application, PPI is significantly more efficient than PET in making these measurements.

  15. Colorectal cancer patient-derived xenografted tumors maintain characteristic features of the original tumors.

    Science.gov (United States)

    Cho, Yong Beom; Hong, Hye Kyung; Choi, Yoon-La; Oh, Ensel; Joo, Kyeung Min; Jin, Juyoun; Nam, Do-Hyun; Ko, Young-Hyeh; Lee, Woo Yong

    2014-04-01

    Despite significant improvements in colon cancer outcomes over the past few decades, preclinical development of more effective therapeutic strategies is still limited by the availability of clinically relevant animal models. To meet those clinical unmet needs, we generated a well-characterized in vivo preclinical platform for colorectal cancer using fresh surgical samples. Primary and metastatic colorectal tumor tissues (1-2 mm(3)) that originate from surgery were implanted into the subcutaneous space of nude mice and serially passaged in vivo. Mutation status, hematoxylin and eosin staining, short tandem repeat profiling, and array comparative genomic hybridization were used to validate the similarity of molecular characteristics between the patient tumors and tumors obtained from xenografts. From surgical specimens of 143 patients, 97 xenograft models were obtained in immunodeficient mice (establish rate = 67%). Thirty-nine xenograft models were serially expanded further in mice with a mean time to reach a size of 1000-1500 mm(3) of 90 ± 20 d. Histologic and immunohistochemical analyses revealed a high degree of pathologic similarity including histologic architecture and expression of CEA, CK7, and CD20 between the patient and xenograft tumors. Molecular analysis showed that genetic mutations, genomic alterations, and gene expression patterns of each patient tumor were also well conserved in the corresponding xenograft tumor. Xenograft animal models derived from fresh surgical sample maintained the key characteristic features of the original tumors, suggesting that this in vivo platform can be useful for preclinical development of novel therapeutic approaches to colorectal cancers. Copyright © 2014 Elsevier Inc. All rights reserved.

  16. Vitrification and xenografting of human ovarian tissue.

    Science.gov (United States)

    Amorim, Christiani Andrade; Dolmans, Marie-Madeleine; David, Anu; Jaeger, Jonathan; Vanacker, Julie; Camboni, Alessandra; Donnez, Jacques; Van Langendonckt, Anne

    2012-11-01

    To assess the efficiency of two vitrification protocols to cryopreserve human preantral follicles with the use of a xenografting model. Pilot study. Gynecology research unit in a university hospital. Ovarian biopsies were obtained from seven women aged 30-41 years. Ovarian tissue fragments were subjected to one of three cryopreservation protocols (slow freezing, vitrification protocol 1, and vitrification protocol 2) and xenografted for 1 week to nude mice. The number of morphologically normal follicles after cryopreservation and grafting and fibrotic surface area were determined by histologic analysis. Apoptosis was assessed by the TUNEL method. Morphometric analysis of TUNEL-positive surface area also was performed. Follicle proliferation was evaluated by immunohistochemistry. After xenografting, a difference was observed between the cryopreservation procedures applied. According to TUNEL analysis, both vitrification protocols showed better preservation of preantral follicles than the conventional freezing method. Moreover, histologic evaluation showed a significantly higher proportion of primordial follicles in vitrified (protocol 2)-warmed ovarian tissue than in frozen-thawed tissue. The proportion of growing follicles and fibrotic surface area was similar in all groups. Vitrification procedures appeared to preserve not only the morphology and survival of preantral follicles after 1 week of xenografting, but also their ability to resume folliculogenesis. In addition, vitrification protocol 2 had a positive impact on the quiescent state of primordial follicles after xenografting. Copyright © 2012 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

  17. Anti-podocalyxin antibody exerts antitumor effects via antibody-dependent cellular cytotoxicity in mouse xenograft models of oral squamous cell carcinoma.

    Science.gov (United States)

    Itai, Shunsuke; Ohishi, Tomokazu; Kaneko, Mika K; Yamada, Shinji; Abe, Shinji; Nakamura, Takuro; Yanaka, Miyuki; Chang, Yao-Wen; Ohba, Shun-Ichi; Nishioka, Yasuhiko; Kawada, Manabu; Harada, Hiroyuki; Kato, Yukinari

    2018-04-27

    Podocalyxin (PODXL) overexpression is associated with progression, metastasis, and poor outcomes in cancers. We recently produced the novel anti-PODXL monoclonal antibody (mAb) PcMab-47 (IgG 1 , kappa). Herein, we engineered PcMab-47 into 47-mG 2a , a mouse IgG 2a -type mAb, to add antibody-dependent cellular cytotoxicity (ADCC). We further developed 47-mG 2a -f, a core fucose-deficient type of 47-mG 2a to augment its ADCC. Immunohistochemical analysis of oral cancer tissues using PcMab-47 and 47-mG 2a revealed that the latter stained oral squamous cell carcinoma (OSCC) cells in a cytoplasmic pattern at a much lower concentration. PcMab-47 and 47-mG 2a detected PODXL in 163/201 (81.1%) and in 197/201 (98.0%) OSCC samples, respectively. 47-mG 2a -f also detected PODXL in OSCCs at a similar frequency as 47-mG 2a . In vitro analysis revealed that both 47-mG 2a and 47-mG 2a -f exhibited strong complement-dependent cytotoxicity (CDC) against CHO/hPODXL cells. In contrast, 47-mG 2a -f exhibited much stronger ADCC than 47-mG 2a against OSCC cells, indicating that ADCC and CDC of those anti-PODXL mAbs depend on target cells. In vivo analysis revealed that both 47-mG 2a and 47-mG 2a -f exerted antitumor activity in CHO/hPODXL xenograft models at a dose of 100 μg or 500 μg/mouse/week administered twice. 47-mG 2a -f, but not 47-mG 2a , exerted antitumor activity in SAS and HSC-2 xenograft models at a dose of 100 μg/mouse/week administered three times. Although both 47-mG 2a and 47-mG 2a -f exerted antitumor activity in HSC-2 xenograft models at a dose of 500 μg/mouse/week administered twice, 47-mG 2a -f also showed higher antitumor activity than 47-mG 2a . These results suggested that a core fucose-deficient anti-PODXL mAb could be useful for antibody-based therapy against PODXL-expressing OSCCs.

  18. Correlations of 3T DCE-MRI Quantitative Parameters with Microvessel Density in a Human-Colorectal-Cancer Xenograft Mouse Model

    International Nuclear Information System (INIS)

    Ahn, Sung Jun; An, Chan Sik; Koom, Woong Sub; Song, Ho Taek; Suh, Jin Suck

    2011-01-01

    To investigate the correlation between quantitative dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) parameters and microvascular density (MVD) in a human-colon-cancer xenograft mouse model using 3 Tesla MRI. A human-colon-cancer xenograft model was produced by subcutaneously inoculating 1 X 106 DLD-1 human-colon-cancer cells into the right hind limbs of 10 mice. The tumors were allowed to grow for two weeks and then assessed using MRI. DCE-MRI was performed by tail vein injection of 0.3 mmol/kg of gadolinium. A region of interest (ROI) was drawn at the midpoints along the z-axes of the tumors, and a Tofts model analysis was performed. The quantitative parameters (Ktrans, Kep and Ve) from the whole transverse ROI and the hotspot ROI of the tumor were calculated. Immunohistochemical microvessel staining was performed and analyzed according to Weidner's criteria at the corresponding MRI sections. Additional Hematoxylin and Eosin staining was performed to evaluate tumor necrosis. The Mann-Whitney test and Spearman's rho correlation analysis were performed to prove the existence of a correlation between the quantitative parameters, necrosis, and MVD. Whole transverse ROI of the tumor showed no significant relationship between the MVD values and quantitative DCE-MRI parameters. In the hotspot ROI, there was a difference in MVD between low and high group of Ktrans and Kep that had marginally statistical significance (ps = 0.06 and 0.07, respectively). Also, Ktrans and Kep were found to have an inverse relationship with MVD (r -0.61, p = 0.06 in Ktrans; r = -0.60, p = 0.07 in Kep). Quantitative analysis of T1-weighted DCE-MRI using hotspot ROI may provide a better histologic match than whole transverse section ROI. Within the hotspots, Ktrans and Kep tend to have a reverse correlation with MVD in this colon cancer mouse model.

  19. Correlations of 3T DCE-MRI Quantitative Parameters with Microvessel Density in a Human-Colorectal-Cancer Xenograft Mouse Model

    Energy Technology Data Exchange (ETDEWEB)

    Ahn, Sung Jun; An, Chan Sik; Koom, Woong Sub; Song, Ho Taek; Suh, Jin Suck [Yonsei University College of Medicine, Seoul (Korea, Republic of)

    2011-11-15

    To investigate the correlation between quantitative dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) parameters and microvascular density (MVD) in a human-colon-cancer xenograft mouse model using 3 Tesla MRI. A human-colon-cancer xenograft model was produced by subcutaneously inoculating 1 X 106 DLD-1 human-colon-cancer cells into the right hind limbs of 10 mice. The tumors were allowed to grow for two weeks and then assessed using MRI. DCE-MRI was performed by tail vein injection of 0.3 mmol/kg of gadolinium. A region of interest (ROI) was drawn at the midpoints along the z-axes of the tumors, and a Tofts model analysis was performed. The quantitative parameters (Ktrans, Kep and Ve) from the whole transverse ROI and the hotspot ROI of the tumor were calculated. Immunohistochemical microvessel staining was performed and analyzed according to Weidner's criteria at the corresponding MRI sections. Additional Hematoxylin and Eosin staining was performed to evaluate tumor necrosis. The Mann-Whitney test and Spearman's rho correlation analysis were performed to prove the existence of a correlation between the quantitative parameters, necrosis, and MVD. Whole transverse ROI of the tumor showed no significant relationship between the MVD values and quantitative DCE-MRI parameters. In the hotspot ROI, there was a difference in MVD between low and high group of Ktrans and Kep that had marginally statistical significance (ps = 0.06 and 0.07, respectively). Also, Ktrans and Kep were found to have an inverse relationship with MVD (r -0.61, p = 0.06 in Ktrans; r = -0.60, p = 0.07 in Kep). Quantitative analysis of T1-weighted DCE-MRI using hotspot ROI may provide a better histologic match than whole transverse section ROI. Within the hotspots, Ktrans and Kep tend to have a reverse correlation with MVD in this colon cancer mouse model.

  20. Reproducibility study of [{sup 18}F]FPP(RGD){sub 2} uptake in murine models of human tumor xenografts

    Energy Technology Data Exchange (ETDEWEB)

    Chang, Edwin; Liu, Shuangdong; Chin, Frederick; Cheng, Zhen [Stanford University, Molecular Imaging Program at Stanford, Department of Radiology, School of Medicine, Stanford, CA (United States); Gowrishankar, Gayatri; Yaghoubi, Shahriar [Stanford University, Molecular Imaging Program at Stanford, Department of Radiology, School of Medicine, Stanford, CA (United States); Stanford University, Molecular Imaging Program at Stanford, Department of Bioengineering, School of Medicine, Stanford, CA (United States); Wedgeworth, James Patrick [Stanford University, Molecular Imaging Program at Stanford, Department of Bioengineering, School of Medicine, Stanford, CA (United States); Berndorff, Dietmar; Gekeler, Volker [Bayer Schering Pharma AG, Global Drug Discovery, Berlin (Germany); Gambhir, Sanjiv S. [Stanford University, Molecular Imaging Program at Stanford, Department of Radiology, School of Medicine, Stanford, CA (United States); Stanford University, Molecular Imaging Program at Stanford, Department of Bioengineering, School of Medicine, Stanford, CA (United States); Canary Center at Stanford for Cancer Early Detection, Nuclear Medicine, Departments of Radiology and Bioengineering, Molecular Imaging Program at Stanford, Stanford, CA (United States)

    2011-04-15

    An {sup 18}F-labeled PEGylated arginine-glycine-aspartic acid (RGD) dimer [{sup 18}F]FPP(RGD){sub 2} has been used to image tumor {alpha}{sub v}{beta}{sub 3} integrin levels in preclinical and clinical studies. Serial positron emission tomography (PET) studies may be useful for monitoring antiangiogenic therapy response or for drug screening; however, the reproducibility of serial scans has not been determined for this PET probe. The purpose of this study was to determine the reproducibility of the integrin {alpha}{sub v}{beta}{sub 3}-targeted PET probe, [{sup 18}F ]FPP(RGD){sub 2} using small animal PET. Human HCT116 colon cancer xenografts were implanted into nude mice (n = 12) in the breast and scapular region and grown to mean diameters of 5-15 mm for approximately 2.5 weeks. A 3-min acquisition was performed on a small animal PET scanner approximately 1 h after administration of [{sup 18}F]FPP(RGD){sub 2} (1.9-3.8 MBq, 50-100 {mu}Ci) via the tail vein. A second small animal PET scan was performed approximately 6 h later after reinjection of the probe to assess for reproducibility. Images were analyzed by drawing an ellipsoidal region of interest (ROI) around the tumor xenograft activity. Percentage injected dose per gram (%ID/g) values were calculated from the mean or maximum activity in the ROIs. Coefficients of variation and differences in %ID/g values between studies from the same day were calculated to determine the reproducibility. The coefficient of variation (mean {+-}SD) for %ID{sub mean}/g and %ID{sub max}/g values between [{sup 18}F]FPP(RGD){sub 2} small animal PET scans performed 6 h apart on the same day were 11.1 {+-} 7.6% and 10.4 {+-} 9.3%, respectively. The corresponding differences in %ID{sub mean}/g and %ID{sub max}/g values between scans were -0.025 {+-} 0.067 and -0.039 {+-} 0.426. Immunofluorescence studies revealed a direct relationship between extent of {alpha}{sub {nu}}{beta}{sub 3} integrin expression in tumors and tumor vasculature

  1. Gleditsia Saponin C Induces A549 Cell Apoptosis via Caspase-Dependent Cascade and Suppresses Tumor Growth on Xenografts Tumor Animal Model

    Directory of Open Access Journals (Sweden)

    Ye Cheng

    2018-01-01

    Full Text Available Saponins are natural compounds and possess the most promising anti-cancer function. Here, a saponin gleditsia saponin C (GSC, extracted from gleditsiae fructus abnormalis, could induce apoptosis of lung tumor cell line A549 via caspase dependent cascade and this effect could be prevented by the caspase inhibitors. In addition, GSC induced cell death companied with an increase ratio of Bax:Bcl-2 and inhibition of ERK and Akt signaling pathways. Meanwhile, GSC suppressed TNFα inducing NF-κB activation and increased the susceptibility of lung cancer cell to TNFα induced apoptosis. Furthermore, on mouse xenograft model, GSC significantly suppressed tumor growth and induced cancer cell apoptosis, which validated the anti-tumor effect of GSC. Based on these results, GSC might be a promising drug candidate of anti-lung cancer for its potential clinical applications.

  2. Comparison of planar, PET and well-counter measurements of total tumor radioactivity in a mouse xenograft model.

    Science.gov (United States)

    Green, Michael V; Seidel, Jurgen; Williams, Mark R; Wong, Karen J; Ton, Anita; Basuli, Falguni; Choyke, Peter L; Jagoda, Elaine M

    2017-10-01

    Quantitative small animal radionuclide imaging studies are often carried out with the intention of estimating the total radioactivity content of various tissues such as the radioactivity content of mouse xenograft tumors exposed to putative diagnostic or therapeutic agents. We show that for at least one specific application, positron projection imaging (PPI) and PET yield comparable estimates of absolute total tumor activity and that both of these estimates are highly correlated with direct well-counting of these same tumors. These findings further suggest that in this particular application, PPI is a far more efficient data acquisition and processing methodology than PET. Forty-one athymic mice were implanted with PC3 human prostate cancer cells transfected with prostate-specific membrane antigen (PSMA (+)) and one additional animal (for a total of 42) with a control blank vector (PSMA (-)). All animals were injected with [ 18 F] DCFPyl, a ligand for PSMA, and imaged for total tumor radioactivity with PET and PPI. The tumors were then removed, assayed by well counting for total radioactivity and the values between these methods intercompared. PET, PPI and well-counter estimates of total tumor radioactivity were highly correlated (R 2 >0.98) with regression line slopes near unity (0.95radioactivity can be measured with PET or PPI with an accuracy comparable to well counting if certain experimental and pharmacokinetic conditions are met. In this particular application, PPI is significantly more efficient than PET in making these measurements. Copyright © 2017 Elsevier Inc. All rights reserved.

  3. The Cytolethal Distending Toxin Subunit CdtB of Helicobacter hepaticus Promotes Senescence and Endoreplication in Xenograft Mouse Models of Hepatic and Intestinal Cell Lines

    Directory of Open Access Journals (Sweden)

    Christelle Péré-Védrenne

    2017-06-01

    Full Text Available Cytolethal distending toxins (CDTs are common among pathogenic bacteria of the human and animal microbiota. CDTs exert cytopathic effets, via their active CdtB subunit. No clear description of those cytopathic effects has been reported at the cellular level in the target organs in vivo. In the present study, xenograft mouse models of colon and liver cell lines were set up to study the effects of the CdtB subunit of Helicobacter hepaticus. Conditional transgenic cell lines were established, validated in vitro and then engrafted into immunodeficient mice. After successful engraftment, mice were treated with doxycyclin to induce the expression of transgenes (red fluorescent protein, CdtB, and mutated CdtB. For both engrafted cell lines, results revealed a delayed tumor growth and a reduced tumor weight in CdtB-expressing tumors compared to controls. CdtB-derived tumors showed γ-H2AX foci formation, an increase in apoptosis, senescence, p21 and Ki-67 nuclear antigen expression. No difference in proliferating cells undergoing mitosis (phospho-histone H3 was observed. CdtB intoxication was also associated with an overexpression of cytokeratins in cells at the invasive front of the tumor as well as an increase in ploidy. All these features are hallmarks of endoreplication, as well as aggressiveness in cancer. These effects were dependent on the histidine residue at position 265 of the CdtB, underlying the importance of this residue in CdtB catalytic activity. Taken together, these data indicate that the CdtB triggers senescence and cell endoreplication leading to giant polyploid cells in these xenograft mouse models.

  4. Impact of MLH1 expression on tumor evolution after curative surgical tumor resection in a murine orthotopic xenograft model for human MSI colon cancer.

    Science.gov (United States)

    Meunier, Katy; Ferron, Marianne; Calmel, Claire; Fléjou, Jean-François; Pocard, Marc; Praz, Françoise

    2017-09-01

    Colorectal cancers (CRCs) displaying microsatellite instability (MSI) most often result from MLH1 deficiency. The aim of this study was to assess the impact of MLH1 expression per se on tumor evolution after curative surgical resection using a xenograft tumor model. Transplantable tumors established with the human MLH1-deficient HCT116 cell line and its MLH1-complemented isogenic clone, mlh1-3, were implanted onto the caecum of NOD/SCID mice. Curative surgical resection was performed at day 10 in half of the animals. The HCT116-derived tumors were more voluminous compared to the mlh1-3 ones (P = .001). Lymph node metastases and peritoneal carcinomatosis occurred significantly more often in the group of mice grafted with HCT116 (P = .007 and P = .035, respectively). Mlh1-3-grafted mice did not develop peritoneal carcinomatosis or liver metastasis. After surgical resection, lymph node metastases only arose in the group of mice implanted with HCT116 and the rate of cure was significantly lower than in the mlh1-3 group (P = .047). The murine orthotopic xenograft model based on isogenic human CRC cell lines allowed us to reveal the impact of MLH1 expression on tumor evolution in mice who underwent curative surgical resection and in mice whose tumor was left in situ. Our data indicate that the behavior of MLH1-deficient CRC is not only governed by mutations arising in genes harboring microsatellite repeated sequences but also from their defect in MLH1 as such. © 2017 Wiley Periodicals, Inc.

  5. Histologic evaluation of human benign prostatic hyperplasia treated by dutasteride: a study by xenograft model with improved severe combined immunodeficient mice.

    Science.gov (United States)

    Tsujimura, Akira; Fukuhara, Shinichiro; Soda, Tetsuji; Takezawa, Kentaro; Kiuchi, Hiroshi; Takao, Tetsuya; Miyagawa, Yasushi; Nonomura, Norio; Adachi, Shigeki; Tokita, Yoriko; Nomura, Taisei

    2015-01-01

    To evaluate histologic change in human prostate samples treated with dutasteride and to elucidate direct effects of dutasteride on human prostate tissue, the present study was conducted by using a xenograft model with improved severe combined immunodeficient (super-SCID) mice, although it is well known that dutasteride reduces prostate volume. After establishment of a xenograft model of human benign prostatic hyperplasia in morphology and function, samples implanted into super-SCID mice with and without dutasteride were evaluated pathohistologically at 2 and 6 months after initiation of dutasteride administration. The proliferative index evaluated by Ki-67 staining was significantly lower in the dutasteride group than the control at 2 and 6 months after administration. Apoptotic index evaluated by the terminal transferase TdT-mediated dUTP-biotin nick end labeling staining was higher in the dutasteride group than the control at 2 and 6 months after administration. Quick scores in the dutasteride group for staining of both cyclooxygenase-2 (Cox-2) and Ras homolog gene family, member A (RhoA) were significantly lower than those in the control group at 2 and 6 months after administration. Dutasteride inhibits cell proliferation and induces apoptosis of prostatic cells, causing a reduced prostate volume. Furthermore, decreased expression of Cox-2 and RhoA within benign prostatic hyperplasia tissue by dutasteride may induce an early effect on improvement of lower urinary tract symptoms, probably by attenuating inflammation reaction of the prostate and decreasing intraurethral pressure, other than the mechanism of reduced prostate volume. Copyright © 2015 Elsevier Inc. All rights reserved.

  6. Antitumour and antiangiogenic activities of [Pt(O,O'-acac)(γ-acac)(DMS)] in a xenograft model of human renal cell carcinoma.

    Science.gov (United States)

    Muscella, A; Vetrugno, C; Biagioni, F; Calabriso, N; Calierno, M T; Fornai, F; De Pascali, S A; Marsigliante, S; Fanizzi, F P

    2016-09-01

    It is thought that the mechanism of action of anticancer chemotherapeutic agents is mainly due to a direct inhibition of tumour cell proliferation. In tumour specimens, the endothelial cell proliferation rate increases, suggesting that the therapeutic effects of anticancer agents could also be attributed to inhibition of tumour angiogenesis. Hence, we investigated the potential effects of [Pt(O,O'-acac)(γ-acac)(DMS)] ([Pt(DMS)]), a new platinum drug for non-genomic targets, on human renal carcinoma and compared them with those of the well-established anticancer drug, cisplatin. Tumour growth, tumour cell proliferation and microvessel density were investigated in a xenograft model of renal cell carcinoma, developed by injecting Caki-1 cells into BALB/c nude mice. The antiangiogenic potential of compounds was also investigated using HUVECs. Treatment of the Caki-1 cells with cisplatin or [Pt(DMS)] resulted in a dose-dependent inhibition of cell survival, but the cytotoxicity of [Pt(DMS)] was approximately fivefold greater than that of cisplatin. [Pt(DMS)] was much more effective than cisplatin at inhibiting tumour growth, proliferation and angiogenesis in vivo, as well as migration, tube formation and MMP1, MMP2 and MMP9 secretion of endothelial cells in vitro. Whereas, cisplatin exerted a greater cytotoxic effect on HUVECs, but did not affect tube formation or the migration of endothelial cells. In addition, treatment of the xenograft mice with [Pt(DMS)] decreased VEGF, MMP1 and MMP2 expressions in tumours. The antiangiogenic and antitumour activities of [Pt(DMS)] provide a solid starting point for its validation as a suitable candidate for further pharmacological testing. © 2016 The British Pharmacological Society.

  7. Antitumour and antiangiogenic activities of [Pt(O,O′‐acac)(γ‐acac)(DMS)] in a xenograft model of human renal cell carcinoma

    Science.gov (United States)

    Vetrugno, C; Biagioni, F; Calabriso, N; Calierno, M T; Fornai, F; De Pascali, S A; Marsigliante, S; Fanizzi, F P

    2016-01-01

    Background and Purpose It is thought that the mechanism of action of anticancer chemotherapeutic agents is mainly due to a direct inhibition of tumour cell proliferation. In tumour specimens, the endothelial cell proliferation rate increases, suggesting that the therapeutic effects of anticancer agents could also be attributed to inhibition of tumour angiogenesis. Hence, we investigated the potential effects of [Pt(O,O′‐acac)(γ‐acac)(DMS)] ([Pt(DMS)]), a new platinum drug for non‐genomic targets, on human renal carcinoma and compared them with those of the well‐established anticancer drug, cisplatin. Experimental Approach Tumour growth, tumour cell proliferation and microvessel density were investigated in a xenograft model of renal cell carcinoma, developed by injecting Caki‐1 cells into BALB/c nude mice. The antiangiogenic potential of compounds was also investigated using HUVECs. Key Results Treatment of the Caki‐1 cells with cisplatin or [Pt(DMS)] resulted in a dose‐dependent inhibition of cell survival, but the cytotoxicity of [Pt(DMS)] was approximately fivefold greater than that of cisplatin. [Pt(DMS)] was much more effective than cisplatin at inhibiting tumour growth, proliferation and angiogenesis in vivo, as well as migration, tube formation and MMP1, MMP2 and MMP9 secretion of endothelial cells in vitro. Whereas, cisplatin exerted a greater cytotoxic effect on HUVECs, but did not affect tube formation or the migration of endothelial cells. In addition, treatment of the xenograft mice with [Pt(DMS)] decreased VEGF, MMP1 and MMP2 expressions in tumours. Conclusions and Implications The antiangiogenic and antitumour activities of [Pt(DMS)] provide a solid starting point for its validation as a suitable candidate for further pharmacological testing. PMID:27351124

  8. Knockdown of NF-E2-related factor 2 inhibits the proliferation and growth of U251MG human glioma cells in a mouse xenograft model.

    Science.gov (United States)

    Ji, Xiang-Jun; Chen, Sui-Hua; Zhu, Lin; Pan, Hao; Zhou, Yuan; Li, Wei; You, Wan-Chun; Gao, Chao-Chao; Zhu, Jian-Hong; Jiang, Kuan; Wang, Han-Dong

    2013-07-01

    NF-E2-related factor 2 (Nrf2) is a pivotal transcription factor of cellular responses to oxidative stress and recent evidence suggests that Nrf2 plays an important role in cancer pathobiology. However, the underlying mechanism has yet to be elucidated, particularly in glioma. In the present study, we investigated the role of Nrf2 in the clinical prognosis, cell proliferation and tumor growth of human glioblastoma multiforme (GBM). We detected overexpression of Nrf2 protein levels in GBM compared to normal brain tissues. Notably, higher protein levels of Nrf2 were significantly associated with poorer overall survival and 1-year survival for GBM patients. Furthermore, we constructed the plasmid Si-Nrf2 and transduced it into U251MG cells to downregulate the expression of Nrf2 and established stable Nrf2 knockdown cells. The downregulation of Nrf2 suppressed cell proliferation in vitro and tumor growth in mouse xenograft models. We performed immunohistochemistry staining to detect the protein levels of Nrf2, Ki-67, caspase-3 and CD31 in the xenograft tumors and found that the expression levels of Nrf2 and Ki-67 were much lower in the Si-Nrf2 group compared to the Si-control group. In addition, the number of caspase-3-positive cells was significantly increased in the Si-Nrf2 group. By analysis of microvessel density (MVD) assessed by CD31, the MVD value in the Si-Nrf2 group decreased significantly compared to the Si-control group. These findings indicate that the knockdown of Nrf2 may suppress tumor growth by inhibiting cell proliferation, increasing cell apoptosis and inhibiting angiogenesis. These results highlight the potential of Nrf2 as a candidate molecular target to control GBM cell proliferation and tumor growth.

  9. Anticancer activity using positron emission tomography-computed tomography and pharmacokinetics of β-eudesmol in human cholangiocarcinoma xenografted nude mouse model.

    Science.gov (United States)

    Plengsuriyakarn, Tullayakorn; Karbwang, Juntra; Na-Bangchang, Kesara

    2015-03-01

    Cholangiocarcinoma (CCA) is an important public health problem in several parts of South East Asia, particularly in Thailand. The limited availability of effective diagnostic tools for early stage CCA, including chemotherapeutic options, constitutes a major problem for treatment and control of CCA. The aim of the present study was to assess the anti-CCA activity and pharmacokinetics of β-eudesmol in CCA-xenografted nude mouse model and healthy mice. Positron emission tomography-computed tomography (PET-CT) with (18)F-fluorodeoxyglucose was used for detecting and monitoring tumour development, and PET-CT with technetium-99m was used to investigate its pharmacokinetics property. Results support the role of PET-CT as a potential tool for detecting and monitoring the progress of lung metastasis. Tumour size and lung metastasis were significantly inhibited by 91.6% (of baseline) and 95% (of total lung mass), respectively, following treatment with high-dose β-eudesmol (100 mg/kg body weight for 30 days). Survival time was prolonged by 64.4% compared with untreated controls. Systemic clearance of the compound was rapid, particularly during the first 60 min. The compound was distributed to the vital organs at maximum levels 2 h after oral administration and 15 min after intravenous injection. Results from the present study suggest the potential of β-eudesmol as a promising candidate for further development as an anti-CCA drug with respect to its pharmacodynamics and pharmacokinetic properties. PET-CT, with radiotracers (18)F-fluorodeoxyglucose and technetium-99m, was shown to be a reliable tool in the investigation of anti-CCA and pharmacokinetic properties of β-eudesmol in CCA-xenografted and healthy mice. © 2014 Wiley Publishing Asia Pty Ltd.

  10. Evaluation of 6-([18F] fluoroacetamido)-1-hexanoic-anilide (18F-FAHA) as imaging probe in tumor xenograft mice model

    Science.gov (United States)

    Li, Fiona; Cho, Sung Ju; Yu, Lihai; Hudson, Robert H. E.; Luyt, Leonard G.; Pin, Christopher L.; Kovacs, Michael S.; Koropatnick, James; Lee, Ting-Yim

    2016-03-01

    Alteration in genetic expression is as important as gene mutation in cancer development and proliferation. Epigenetic changes affect gene expression without altering the DNA sequence. Histone deacetylase (HDAC), an enzyme facilitating histone remodelling, can lead to silencing of tumor suppressor genes making HDAC inhibitors viable anticancer drugs against tumors with increased activity of the enzyme. In this study we evaluated 18F-fluroacetamido-1-hexanoicanilide (18F-FAHA), an artificial HDAC substrate, as imaging probe of HDAC activity of human tumor xenografts in immunocompromised host mice. Human breast and melanoma cell lines, MDA-MB-468 and MDA-MB-435 respectively, known to overexpress HDAC activity were xenografted into immunocompromised mice and HDAC activity was imaged using 18F-FAHA. The melanoma group was treated with saline, SAHA (suberoylanilide hydroxamic acid, an approved anticancer HDAC inhibitor) in DMSO, or DMSO as positive control. Tracer kinetic modelling and SUV were used to estimate HDAC activity from dynamic PET data. Both breast tumor and melanoma group showed great variability in binding rate constant (BRC) of 18F-FAHA suggesting highly variable inter- and intra-tumoral HDAC activity. For the SAHA treated melanoma group, HDAC activity, as monitored by BRC of 18F-FAHA, decreased more than the two (positive and negative) control groups but not tumor growth. Our preliminary study showed that noninvasive PET imaging with 18F-FAHA has the potential to identify patients for whom treatment with HDAC inhibitors are appropriate, to assess the effectiveness of that treatment as an early marker of target reduction, and also eliminate the need for invasive tissue biopsy to individualize treatment.

  11. Irradiation-Dependent Effects on Tumor Perfusion and Endogenous and Exogenous Hypoxia Markers in an A549 Xenograft Model

    International Nuclear Information System (INIS)

    Fokas, Emmanouil; Haenze, Joerg; Kamlah, Florentine; Eul, Bastian G.; Lang, Nico; Keil, Boris; Heverhagen, Johannes T.; Engenhart-Cabillic, Rita; An Hanxiang; Rose, Frank

    2010-01-01

    Purpose: Hypoxia is a major determinant of tumor radiosensitivity, and microenvironmental changes in response to ionizing radiation (IR) are often heterogenous. We analyzed IR-dependent changes in hypoxia and perfusion in A549 human lung adenocarcinoma xenografts. Materials and Methods: Immunohistological analysis of two exogenously added chemical hypoxic markers, pimonidazole and CCI-103F, and of the endogenous marker Glut-1 was performed time dependently after IR. Tumor vessels and apoptosis were analyzed using CD31 and caspase-3 antibodies. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and fluorescent beads (Hoechst 33342) were used to monitor vascular perfusion. Results: CCI-103F signals measuring the fraction of hypoxic areas after IR were significantly decreased by approximately 50% when compared with pimonidazole signals, representing the fraction of hypoxic areas from the same tumors before IR. Interestingly, Glut-1 signals were significantly decreased at early time point (6.5 h) after IR returning to the initial levels at 30.5 h. Vascular density showed no difference between irradiated and control groups, whereas apoptosis was significantly induced at 10.5 h post-IR. DCE-MRI indicated increased perfusion 1 h post-IR. Conclusions: The discrepancy between the hypoxic fractions of CCI-103F and Glut-1 forces us to consider the possibility that both markers reflect different metabolic alterations of tumor microenvironment. The reliability of endogenous markers such as Glut-1 to measure reoxygenation in irradiated tumors needs further consideration. Monitoring tumor microvascular response to IR by DCE-MRI and measuring tumor volume alterations should be encouraged.

  12. Development and evaluation of camptothecin loaded polymer stabilized nanoemulsion: Targeting potential in 4T1-breast tumour xenograft model.

    Science.gov (United States)

    Sugumaran, Abimanyu; Ponnusamy, Chandrasekar; Kandasamy, Palanivel; Krishnaswami, Venkateshwaran; Palanichamy, Rajaguru; Kandasamy, Ruckmani; Lakshmanan, Manikandan; Natesan, Subramanian

    2018-04-30

    Targeted delivery of anticancer agents is poised to improve cancer therapy, for which polymers can serve as targeting ligands or nanocarriers for chemotherapeutic agents. In this study, we have developed and evaluated the efficacy of a camptothecin (CPT)-loaded polymer stabilized nanoemulsion (PSNE) for the passive targeted delivery to breast cancer. Based on the pseudo-ternary phase diagrams, PSNEs were developed using capmul MCM:poloxamer 407 (4:1), solutol HS 15:simulsol P23 (1:2) and water. CPT polymer mixture was developed by solvent evaporation technique. The PSNEs were characterized for droplet size distribution, plasma protein adsorption, drug release, in-vivo targeting potential, hemolytic potential, cytotoxicity, genotoxicity, in-vivo biodistribution and CPT lactone ring stability. The developed PSNEs showed uniform droplet distribution, extended drug release (76.59±6.12% at 24h), acceptable hemolytic potential, significant cytotoxicity (IC 50 =176±4.3ng/mL) and genotoxicity against MCF-7 cancer cells but low DNA damage potential in human peripheral blood lymphocytes. The efficiency of PSNEs for the targeted delivery of CPT into the tumour regions was documented in 4T1-breast tumour xenografted BALB/c mice. In-vivo biodistribution study shows that 7105.84±568.46ng/g of CPT was passively targeted from PSNE to breast cancer tissue. About 80% of the lactone form was stable for 24h. Taken together, our study provides a promising strategy for developing PSNE-targeted drug delivery system for the breast cancer therapy. Copyright © 2017 Elsevier B.V. All rights reserved.

  13. Biodistribution and pharmacokinetics of a telodendrimer micellar paclitaxel nanoformulation in a mouse xenograft model of ovarian cancer

    Directory of Open Access Journals (Sweden)

    Xiao W

    2012-03-01

    Full Text Available Wenwu Xiao1, Juntao Luo2, Teesta Jain3, John Riggs3, Harry P Tseng1, Paul T Henderson3, Simon R Cherry4, Douglas Rowland4, Kit S Lam1,31Department of Biochemistry and Molecular Medicine, UC Davis Cancer Center, University of California Davis, Sacramento, CA; 2Department of Pharmacology, SUNY Upstate Cancer Research Institute, SUNY Upstate Medical University, Syracuse, NY; 3Department of Internal Medicine, Division of Hematology and Oncology, 4Department of Biomedical Engineering, UC Davis Cancer Center, University of California Davis, Davis, CABackground: A multifunctional telodendrimer-based micelle system was characterized for delivery of imaging and chemotherapy agents to mouse tumor xenografts. Previous optical imaging studies demonstrated qualitatively that these classes of nanoparticles, called nanomicelles, preferentially accumulate at tumor sites in mice. The research reported herein describes the detailed quantitative imaging and biodistribution profiling of nanomicelles loaded with a cargo of paclitaxel.Methods: The telodendrimer was covalently labeled with 125I and the nanomicelles were loaded with 14C-paclitaxel, which allowed measurement of pharmacokinetics and biodistribution in the mice using microSPECT/CT imaging and liquid scintillation counting, respectively.Results: The radio imaging data showed preferential accumulation of nanomicelles at the tumor site along with a slower clearance rate than paclitaxel formulated in Cremophor EL (Taxol®. Liquid scintillation counting confirmed that 14C-labeled paclitaxel sequestered in nanomicelles had increased uptake by tumor tissue and slower pharmacokinetics than Taxol.Conclusion: Overall, the results indicate that nanomicelle-formulated paclitaxel is a potentially superior formulation compared with Taxol in terms of water solubility, pharmacokinetics, and tumor accumulation, and may be clinically useful for both tumor imaging and improved chemotherapy applications

  14. Tumor-targeting Salmonella typhimurium A1-R is a highly effective general therapeutic for undifferentiated soft tissue sarcoma patient-derived orthotopic xenograft nude-mouse models.

    Science.gov (United States)

    Igarashi, Kentaro; Kawaguchi, Kei; Kiyuna, Tasuku; Miyake, Kentaro; Miyake, Masuyo; Singh, Arun S; Eckardt, Mark A; Nelson, Scott D; Russell, Tara A; Dry, Sarah M; Li, Yunfeng; Yamamoto, Norio; Hayashi, Katsuhiro; Kimura, Hiroaki; Miwa, Shinji; Tsuchiya, Hiroyuki; Singh, Shree Ram; Eilber, Fritz C; Hoffman, Robert M

    2018-03-18

    Undifferentiated soft tissue sarcoma (USTS) is a recalcitrant and heterogeneous subgroup of soft tissue sarcoma with high risk of metastasis and recurrence. Due to heterogeneity of USTS, there is no reliably effective first-line therapy. We have generated tumor-targeting Salmonella typhimurium A1-R (S. typhimurium A1-R), which previously showed strong efficacy on single patient-derived orthotopic xenograft (PDOX) models of Ewing's sarcoma and follicular dendritic cell sarcoma. In the present study, tumor resected from 4 patients with a biopsy-proven USTS (2 undifferentiated pleomorphic sarcoma [UPS], 1 undifferentiated sarcoma not otherwise specified [NOS] and 1 undifferentiated spindle cell sarcoma [USS]) were grown orthotopically in the biceps femoris muscle of mice to establish PDOX models. One USS model and one UPS model were doxorubicin (DOX) resistant. One UPS and the NOS model were partially sensitive to DOX. DOX is first-line therapy for these diseases. S. typhimurium A1-R arrested tumor growth all 4 models. In addition to arresting tumor growth in each case, S. typhimurium A1-R was significantly more efficacious than DOX in each case, thereby surpassing first-line therapy. These results suggest that S. typhimurium A1-R can be a general therapeutic for USTS and possibly sarcoma in general. Published by Elsevier Inc.

  15. Preclinical PK/PD model for combined administration of erlotinib and sunitinib in the treatment of A549 human NSCLC xenograft mice.

    Science.gov (United States)

    Li, Jing-Yun; Ren, Yu-Peng; Yuan, Yin; Ji, Shuang-Min; Zhou, Shu-Pei; Wang, Li-Jie; Mou, Zhen-Zhen; Li, Liang; Lu, Wei; Zhou, Tian-Yan

    2016-07-01

    Combined therapy of EGFR TKI and VEGFR TKI may produce a greater therapeutic benefit and overcome EGFR TKI-induced resistance. However, a previous study shows that a combination of EGFR TKI erlotinib (ER) with VEGFR TKI sunitinib (SU) did not improve the overall survival in patients with non-small-cell lung cancer (NSCLC). In this study we examined the anticancer effect of ER, SU and their combination in the treatment of A549 human NSCLC xenograft mice, and conducted PK/PD modeling and simulations to optimize the dose regimen. ER (20, 50 mg·kg(-1)·d(-1)) or SU (5, 10, 20 mg·kg(-1)·d(-1)) alone, or their combination were administered to BALB/c nude mice bearing A549 tumors for 22 days. The tumor size and body weight were recorded daily. The experimental data were used to develop PK/PD models describing the quantitative relationship between the plasma concentrations and tumor suppression in different dose regimens. The models were further evaluated and validated, and used to predict the efficacy of different combination regimens and to select the optimal regimen. The in vivo anticancer efficacy of the combination groups was much stronger than that of either drug administered alone. A PK/PD model was developed with a combination index (φ) of 4.4, revealing a strong synergistic effect between ER and SU. The model simulation predicted the tumor growth in different dosage regimens, and showed that the dose of SU played a decisive role in the combination treatment, and suggested that a lower dose of ER (≤5 mg·kg(-1)·d(-1)) and adjusting the dose of SU might yield a better dosage regimen for clinical research. The experimental data and modeling confirm synergistic anticancer effect of ER and SU in the treatment of A549 xenograft mice. The optimal dosage regimen determined by the PK/PD modeling and simulation can be used in future preclinical study and provide a reference for clinical application.

  16. Comparison of intratumoral FDG and Cu-ATSM distributions in cancer tissue originated spheroid (CTOS) xenografts, a tumor model retaining the original tumor properties

    International Nuclear Information System (INIS)

    Furukawa, Takako; Yuan, Qinghua; Jin, Zhao-Hui; Aung, Winn; Yoshii, Yukie; Hasegawa, Sumitaka; Endo, Hiroko; Inoue, Masahiro; Zhang, Ming-Rong; Fujibayashi, Yasuhisa; Saga, Tsuneo

    2014-01-01

    Introduction: The intratumoral distributions of [ 18 F]FDG and [ 64 Cu]Cu-ATSM have been reported to be similar in adenocarcinomas but different in squamous cell carcinoma (SCC) in clinical studies. In the present study, we compared the intratumoral distributions of these two tracers in cancer tissue originated spheroid (CTOS) xenografts derived from adenocarcinoma and SCC, which retain the histological characteristics of the original tumors, and in cancer cell line xenografts of corresponding origin, to investigate the underlying mechanism of the distinct FDG and Cu-ATSM distribution patterns in adenocarcinoma and SCC. Methods: CTOSs derived from colon adenocarcinoma and lung SCC and cell lines established from colon adenocarcinoma and lung SCC, which were used for comparison, were subcutaneously transplanted into immunodeficient mice. One hour after administering [ 14 C]FDG and [ 64 Cu]Cu-ATSM, the intratumoral distributions were compared in the xenografts by using dual-tracer autoradiography. Adjacent sections were evaluated for necrosis, vasculature anatomy, Ki-67 antigen, and pimonidazole adducts using hematoxylin and eosin and immunohistochemical staining. Results: There was a higher regional overlap of high FDG and Cu-ATSM accumulations in the adenocarcinoma CTOS xenografts than in the SCC CTOS xenografts, while the overlap in the adenocarcinoma cell line xenograft was lower than that observed in the SCC cell line. High FDG accumulation occurred primarily in proximity to necrotic or pimonidazole adduct positive regions, while high Cu-ATSM accumulation occurred primarily in live cell regions separate from the necrotic regions. The adenocarcinoma CTOS xenograft had the stereotypical glandular structure, resulting in more intricately mixed regions of live and necrotic cells compared to those observed in the SCC CTOS or the cell line xenografts. Conclusion: Tumor morphological characteristics, specifically the spatial distribution of live and necrotic cell

  17. Frankincense essential oil prepared from hydrodistillation of Boswellia sacra gum resins induces human pancreatic cancer cell death in cultures and in a xenograft murine model

    Science.gov (United States)

    2012-01-01

    Background Regardless of the availability of therapeutic options, the overall 5-year survival for patients diagnosed with pancreatic cancer remains less than 5%. Gum resins from Boswellia species, also known as frankincense, have been used as a major ingredient in Ayurvedic and Chinese medicine to treat a variety of health-related conditions. Both frankincense chemical extracts and essential oil prepared from Boswellia species gum resins exhibit anti-neoplastic activity, and have been investigated as potential anti-cancer agents. The goals of this study are to identify optimal condition for preparing frankincense essential oil that possesses potent anti-tumor activity, and to evaluate the activity in both cultured human pancreatic cancer cells and a xenograft mouse cancer model. Methods Boswellia sacra gum resins were hydrodistilled at 78°C; and essential oil distillate fractions were collected at different durations (Fraction I at 0–2 h, Fraction II at 8–10 h, and Fraction III at 11–12 h). Hydrodistillation of the second half of gum resins was performed at 100°C; and distillate was collected at 11–12 h (Fraction IV). Chemical compositions were identified by gas chromatography–mass spectrometry (GC-MS); and total boswellic acids contents were quantified by high-performance liquid chromatography (HPLC). Frankincense essential oil-modulated pancreatic tumor cell viability and cytotoxicity were determined by colorimetric assays. Levels of apoptotic markers, signaling molecules, and cell cycle regulators expression were characterized by Western blot analysis. A heterotopic (subcutaneous) human pancreatic cancer xenograft nude mouse model was used to evaluate anti-tumor capability of Fraction IV frankincense essential oil in vivo. Frankincense essential oil-induced tumor cytostatic and cytotoxic activities in animals were assessed by immunohistochemistry. Results Longer duration and higher temperature hydrodistillation produced more abundant high molecular

  18. Fluorescently labeled chimeric anti-CEA antibody improves detection and resection of human colon cancer in a patient-derived orthotopic xenograft (PDOX) nude mouse model.

    Science.gov (United States)

    Metildi, Cristina A; Kaushal, Sharmeela; Luiken, George A; Talamini, Mark A; Hoffman, Robert M; Bouvet, Michael

    2014-04-01

    The aim of this study was to evaluate a new fluorescently labeled chimeric anti-CEA antibody for improved detection and resection of colon cancer. Frozen tumor and normal human tissue samples were stained with chimeric and mouse antibody-fluorophore conjugates for comparison. Mice with patient-derived orthotopic xenografts (PDOX) of colon cancer underwent fluorescence-guided surgery (FGS) or bright-light surgery (BLS) 24 hr after tail vein injection of fluorophore-conjugated chimeric anti-CEA antibody. Resection completeness was assessed using postoperative images. Mice were followed for 6 months for recurrence. The fluorophore conjugation efficiency (dye/mole ratio) improved from 3-4 to >5.5 with the chimeric CEA antibody compared to mouse anti-CEA antibody. CEA-expressing tumors labeled with chimeric CEA antibody provided a brighter fluorescence signal on frozen human tumor tissues (P = 0.046) and demonstrated consistently lower fluorescence signals in normal human tissues compared to mouse antibody. Chimeric CEA antibody accurately labeled PDOX colon cancer in nude mice, enabling improved detection of tumor margins for more effective FGS. The R0 resection rate increased from 86% to 96% with FGS compared to BLS. Improved conjugating efficiency and labeling with chimeric fluorophore-conjugated antibody resulted in better detection and resection of human colon cancer in an orthotopic mouse model. © 2013 Wiley Periodicals, Inc.

  19. Administration of the optimized β-Lapachone-poloxamer-cyclodextrin ternary system induces apoptosis, DNA damage and reduces tumor growth in a human breast adenocarcinoma xenograft mouse model.

    Science.gov (United States)

    Seoane, Samuel; Díaz-Rodríguez, Patricia; Sendon-Lago, Juan; Gallego, Rosalia; Pérez-Fernández, Román; Landin, Mariana

    2013-08-01

    β-Lapachone (β-Lap) is a 1,2-orthonaphthoquinone that selectively induces cell death in human cancer cells through NAD(P)H:quinone oxidoreductase-1 (NQO1). NQO1 is overexpressed in a variety of tumors, as compared to normal adjacent tissue. However, the low solubility and non-specific distribution of β-Lap limit its suitability for clinical assays. We formulated β-Lap in an optimal random methylated-β-cyclodextrin/poloxamer 407 mixture (i.e., β-Lap ternary system) and, using human breast adenocarcinoma MCF-7 cells and immunodeficient mice, performed in vitro and in vivo evaluation of its anti-tumor effects on proliferation, cell cycle, apoptosis, DNA damage, and tumor growth. This ternary system is fluid at room temperature, gels over 29 °C, and provides a significant amount of drug, thus facilitating intratumoral delivery, in situ gelation, and the formation of a depot for time-release. Administration of β-Lap ternary system to MCF-7 cells induces an increase in apoptosis and DNA damage, while producing no changes in cell cycle. Moreover, in a mouse xenograft tumor model, intratumoral injection of the system significantly reduces tumor volume, while increasing apoptosis and DNA damage without visible toxicity to liver or kidney. These anti-tumoral effects and lack of visible toxicity make this system a promising new therapeutic agent for breast cancer treatment. Copyright © 2013 Elsevier B.V. All rights reserved.

  20. Pulsatilla saponin A, an active molecule from Pulsatilla chinensis, induces cancer cell death and inhibits tumor growth in mouse xenograft models.

    Science.gov (United States)

    Liu, Qiang; Chen, Weichang; Jiao, Yang; Hou, Jianquan; Wu, Qingyu; Liu, Yanli; Qi, Xiaofei

    2014-05-15

    Many natural compounds possess antitumor growth activities. Pulsatilla chinensis is an herb used in traditional Chinese medicine to treat infectious diseases. More recently, extracts from P chinensis have been shown to contain antitumor activities. In this study, we isolated Pulsatilla saponin A as an active compound from P chinensis extracts and tested its anticancer activity in vitro and in vivo. In cell culture, Pulsatilla saponin A significantly inhibited the growth of human hepatocellular carcinoma SMCC-7721 cells and pancreatic BXPC3 and SW1990 cancer cells. Similar inhibitory activities were observed when the compound was tested in mouse xenograft tumor models using human hepatocellular carcinoma Bel-7402 and pancreatic cancer SW1990 cells. In Comet assay and flow cytometric analysis of cell cycle distribution and annexin V expression, DNA damage, G2 arrest, and apoptosis were identified in Pulsatilla saponin A-treated cancer cells. Based on the results of Western blotting, p53 and cyclin B protein levels were higher, whereas Bcl-2 protein levels were lower in Pulsatilla saponin A-treated cancer cells than in vehicle-treated cells. Pulsatilla saponin A may exert its antitumor effect by inducing DNA damage and causing G2 arrest and apoptosis in cancer cells. Pulsatilla saponin A and its derivatives may be developed as a new class of anticancer agents. Crown Copyright © 2014. Published by Elsevier Inc. All rights reserved.

  1. C7a, a Biphosphinic Cyclopalladated Compound, Efficiently Controls the Development of a Patient-Derived Xenograft Model of Adult T Cell Leukemia/Lymphoma

    Directory of Open Access Journals (Sweden)

    Carlos R. Figueiredo

    2011-07-01

    Full Text Available Adult T-cell leukemia/lymphoma (ATLL is a highly aggressive disease that occurs in individuals infected with the human T lymphotropic virus type 1 (HTLV-1. Patients with aggressive ATLL have a poor prognosis because the leukemic cells are resistant to conventional chemotherapy. We have investigated the therapeutic efficacy of a biphosphinic cyclopalladated complex {Pd2 [S(−C2, N-dmpa]2 (μ-dppeCl2}, termed C7a, in a patient-derived xenograft model of ATLL, and investigated the mechanism of C7a action in HTLV-1-positive and negative transformed T cell lines in vitro. In vivo survival studies in immunocompromised mice inoculated with human RV-ATL cells and intraperitoneally treated with C7a led to significantly increased survival of the treated mice. We investigated the mechanism of C7a activity in vitro and found that it induced mitochondrial release of cytochrome c, caspase activation, nuclear condensation and DNA degradation. These results suggest that C7a triggers apoptotic cell death in both HTLV-1 infected and uninfected human transformed T-cell lines. Significantly, C7a was not cytotoxic to peripheral blood mononuclear cells (PBMC from healthy donors and HTLV-1-infected individuals. C7a inhibited more than 60% of the ex vivo spontaneous proliferation of PBMC from HTLV-1-infected individuals. These results support a potential therapeutic role for C7a in both ATLL and HTLV-1-negative T-cell lymphomas.

  2. Discovery of imidazo[1,2-a]-pyridine inhibitors of pan-PI3 kinases that are efficacious in a mouse xenograft model.

    Science.gov (United States)

    Han, Wooseok; Menezes, Daniel L; Xu, Yongjin; Knapp, Mark S; Elling, Robert; Burger, Matthew T; Ni, Zhi-Jie; Smith, Aaron; Lan, Jiong; Williams, Teresa E; Verhagen, Joelle; Huh, Kay; Merritt, Hanne; Chan, John; Kaufman, Susan; Voliva, Charles F; Pecchi, Sabina

    2016-02-01

    Alterations in PI3K/AKT signaling are known to be implicated with tumorigenesis. The PI3 kinases family of lipid kinases has been an attractive therapeutic target for cancer treatment. Imidazopyridine compound 1, a potent, selective, and orally available pan-PI3K inhibitor, identified by scaffold morphing of a benzothiazole hit, was further optimized in order to achieve efficacy in a PTEN-deleted A2780 ovarian cancer mouse xenograft model. With a hypothesis that a planar conformation between the core and the 6-heteroaryl ring will allow for the accommodation of larger 5'-substituents in a hydrophobic area under P-loop, SAR efforts focused on 5'-alkoxy heteroaryl rings at the 6-position of imidazopyridine and imidazopyridazine cores that have the same dihedral angle of zero degrees. 6'-Alkoxy 5'-aminopyrazines in the imidazopyridine series were identified as the most potent compounds in the A2780 cell line. Compound 14 with 1,1,1-trifluoroisopropoxy group at 6'-position demonstrated excellent potency and selectivity, good oral exposure in rats and in vivo efficacy in A2780 tumor-bearing mouse. Also, we disclose the X-ray co-crystal structure of one enantiomer of compound 14 in PI3Kα, confirming that the trifluoromethyl group fits nicely in the hydrophobic hot spot under P-loop. Copyright © 2016 Elsevier Ltd. All rights reserved.

  3. Discovery of imidazo[1,2- a ]-pyridine inhibitors of pan-PI3 kinases that are efficacious in a mouse xenograft model

    Energy Technology Data Exchange (ETDEWEB)

    Han, Wooseok; Menezes, Daniel L.; Xu, Yongjin; Knapp, Mark S.; Elling, Robert; Burger, Matthew T.; Ni, Zhi-Jie; Smith, Aaron; Lan, Jiong; Williams, Teresa E.; Verhagen, Joelle; Huh, Kay; Merritt, Hanne; Chan, John; Kaufman, Susan; Voliva, Charles F.; Pecchi, Sabina

    2016-02-01

    Alterations in PI3K/AKT signaling are known to be implicated with tumorigenesis. The PI3 kinases family of lipid kinases has been an attractive therapeutic target for cancer treatment. Imidazopyridine compound 1, a potent, selective, and orally available pan-PI3K inhibitor, identified by scaffold morphing of a benzothiazole hit, was further optimized in order to achieve efficacy in a PTEN-deleted A2780 ovarian cancer mouse xenograft model. With a hypothesis that a planar conformation between the core and the 6-heteroaryl ring will allow for the accommodation of larger 5'-substituents in a hydrophobic area under P-loop, SAR efforts focused on 5'-alkoxy heteroaryl rings at the 6-position of imidazopyridine and imidazopyridazine cores that have the same dihedral angle of zero degrees. 6'-Alkoxy 5'-aminopyrazines in the imidazopyridine series were identified as the most potent compounds in the A2780 cell line. Compound 14 with 1,1,1-trifluoroisopropoxy group at 6'-position demonstrated excellent potency and selectivity, good oral exposure in rats and in vivo efficacy in A2780 tumor-bearing mouse. Also, we disclose the X-ray co-crystal structure of one enantiomer of compound 14 in PI3Kα, confirming that the trifluoromethyl group fits nicely in the hydrophobic hot spot under P-loop.

  4. EFFICACY EVALUATION OF A MONOCLONAL ANTIBODY AGAINST THE EPIDERMAL GROWTH FACTORS RECEPTOR IN THE MODEL OF SUBCUTANEOUS XENOGRAFT IN IMMUNODEFICIENT MICE

    Directory of Open Access Journals (Sweden)

    Ya. Yu. Ustyugov

    2015-01-01

    Full Text Available This article presents the results of the comparative antitumor efficacy study of two test articles of therapeutic humanized monoclonal antibodies against epidermal growth factor receptor (EGFR manufactured by Russian biopharmaceutical company CJSC “Biocad” and the commercial drug “Erbitux®” (Merck, Germany in subcutaneous xenografts model using human epidermoid carcinoma A431NS cell line. EGFR overexpression in epithelial tumor cells is a commonly known fact that determines use of this receptor as a target for therapeutic monoclonal antibodies. The basic mechanism of action of such drugs is blocking of epithelial cells proliferation through competitive binding to EGFR. Evaluation of tumor growth dynamics in immunodeficient (Nu/Nu mice was performed during in vivo experiment using two parameters: tumor growth index and tumor growth inhibition (TGI, %. The results received with used study design show that antitumor effects of the test articles manufactured by CJSC “Biocad” and the commercial comparator drug “Erbitux®” estimated by values of TGI and tumor growth index are comparable.

  5. Styrene maleic acid-encapsulated RL71 micelles suppress tumor growth in a murine xenograft model of triple negative breast cancer.

    Science.gov (United States)

    Martey, Orleans; Nimick, Mhairi; Taurin, Sebastien; Sundararajan, Vignesh; Greish, Khaled; Rosengren, Rhonda J

    2017-01-01

    Patients with triple negative breast cancer have a poor prognosis due in part to the lack of targeted therapies. In the search for novel drugs, our laboratory has developed a second-generation curcumin derivative, 3,5-bis(3,4,5-trimethoxybenzylidene)-1-methylpiperidine-4-one (RL71), that exhibits potent in vitro cytotoxicity. To improve the clinical potential of this drug, we have encapsulated it in styrene maleic acid (SMA) micelles. SMA-RL71 showed improved biodistribution, and drug accumulation in the tumor increased 16-fold compared to control. SMA-RL71 (10 mg/kg, intravenously, two times a week for 2 weeks) also significantly suppressed tumor growth compared to control in a xenograft model of triple negative breast cancer. Free RL71 was unable to alter tumor growth. Tumors from SMA-RL71-treated mice showed a decrease in angiogenesis and an increase in apoptosis. The drug treatment also modulated various cell signaling proteins including the epidermal growth factor receptor, with the mechanisms for tumor suppression consistent with previous work with RL71 in vitro. The nanoformulation was also nontoxic as shown by normal levels of plasma markers for liver and kidney injury following weekly administration of SMA-RL71 (10 mg/kg) for 90 days. Thus, we report clinical potential following encapsulation of a novel curcumin derivative, RL71, in SMA micelles.

  6. Assessment of Hypoxia in the Stroma of Patient-Derived Pancreatic Tumor Xenografts

    Energy Technology Data Exchange (ETDEWEB)

    Lohse, Ines; Lourenco, Corey; Ibrahimov, Emin; Pintilie, Melania [Ontario Cancer Institute and Campbell Family Cancer Research Institute, Princess Margaret Cancer Center, University Health Network, 610 University Ave., Toronto, ON M5G2M9 (Canada); Tsao, Ming-Sound [Ontario Cancer Institute and Campbell Family Cancer Research Institute, Princess Margaret Cancer Center, University Health Network, 610 University Ave., Toronto, ON M5G2M9 (Canada); Department of Pathology, University Health Network, 200 Elizabeth Street, Toronto, ON M5G2C4 (Canada); Department of Laboratory Medicine and Pathobiology, 27 King’s College Circle, University of Toronto, Toronto, ON M5S1A1 (Canada); Hedley, David W., E-mail: david.hedley@uhn.ca [Ontario Cancer Institute and Campbell Family Cancer Research Institute, Princess Margaret Cancer Center, University Health Network, 610 University Ave., Toronto, ON M5G2M9 (Canada); Departments of Medical Biophysics University of Toronto, 610 University Ave., Toronto, ON M5G2M9 (Canada); Departments of Medicine, University of Toronto, 610 University Ave., Toronto, ON M5G2M9 (Canada); Department of Medical Oncology and Hematology, Princess Margaret Cancer Center, 610 University Ave., Toronto, ON M5G2M9 (Canada)

    2014-02-26

    The unusually dense stroma of pancreatic cancers is thought to play an important role in their biological aggression. The presence of hypoxia is also considered an adverse prognostic factor. Although it is usually assumed that this is the result of effects of hypoxia on the epithelial component, it is possible that hypoxia exerts indirect effects via the tumor stroma. We therefore measured hypoxia in the stroma of a series of primary pancreatic cancer xenografts. Nine patient-derived pancreatic xenografts representing a range of oxygenation levels were labeled by immunohistochemistry for EF5 and analyzed using semi-automated pattern recognition software. Hypoxia in the tumor and stroma was correlated with tumor growth and metastatic potential. The extent of hypoxia varied from 1%–39% between the different models. EF5 labeling in the stroma ranged from 0–20% between models, and was correlated with the level of hypoxia in the tumor cell area, but not microvessel density. Tumor hypoxia correlated with spontaneous metastasis formation with the exception of one hypoxic model that showed disproportionately low levels of hypoxia in the stroma and was non-metastatic. Our results demonstrate that hypoxia exists in the stroma of primary pancreatic cancer xenografts and suggest that stromal hypoxia impacts the metastatic potential.

  7. Global Conservation of Protein Status between Cell Lines and Xenografts

    Directory of Open Access Journals (Sweden)

    Julian Biau

    2016-08-01

    Full Text Available Common preclinical models for testing anticancer treatment include cultured human tumor cell lines in monolayer, and xenografts derived from these cell lines in immunodeficient mice. Our goal was to determine how similar the xenografts are compared with their original cell line and to determine whether it is possible to predict the stability of a xenograft model beforehand. We studied a selection of 89 protein markers of interest in 14 human cell cultures and respective subcutaneous xenografts using the reverse-phase protein array technology. We specifically focused on proteins and posttranslational modifications involved in DNA repair, PI3K pathway, apoptosis, tyrosine kinase signaling, stress, cell cycle, MAPK/ERK signaling, SAPK/JNK signaling, NFκB signaling, and adhesion/cytoskeleton. Using hierarchical clustering, most cell culture-xenograft pairs cluster together, suggesting a global conservation of protein signature. Particularly, Akt, NFkB, EGFR, and Vimentin showed very stable protein expression and phosphorylation levels highlighting that 4 of 10 pathways were highly correlated whatever the model. Other proteins were heterogeneously conserved depending on the cell line. Finally, cell line models with low Akt pathway activation and low levels of Vimentin gave rise to more reliable xenograft models. These results may be useful for the extrapolation of cell culture experiments to in vivo models in novel targeted drug discovery.

  8. The intriguing role of fibroblasts and c-Jun in the chemopreventive and therapeutic effect of finasteride on xenograft models of prostate cancer

    Directory of Open Access Journals (Sweden)

    Yi-Nong Niu

    2016-01-01

    Full Text Available In a large clinical trial, finasteride reduced the rate of low-grade prostate cancer (PCa while increasing the incidence of high-grade cancer. Whether finasteride promotes the development of high-grade tumors remains controversial. We demonstrated the role of fibroblasts and c-Jun in chemopreventive and therapeutic effect of finasteride on xenograft models of PCa. LNCaP (PC3 cells or recombinants of cancer cells and fibroblasts were implanted in male athymic nude mice treated with finasteride. Tumor growth, cell proliferation, apoptosis, p-Akt, and p-ERK1/2 were evaluated. In LNCaP (PC3 mono-grafted models, finasteride did not change the tumor growth. In recombinant-grafted models, fibroblasts and c-Jun promoted tumor growth; finasteride induced proliferation of LNCaP cells and repressed PC3 cell apoptosis. When c-Jun was knocked out, fibroblasts and/or finasteride did not promote the tumor growth. Finasteride inhibited p-Akt and p-ERK1/2 in mono-culture cancer cells while stimulating the same signaling molecules in the presence of fibroblasts. Reduced p-Akt and p-ERK1/2 were noted in the presence of c-Jun−/− fibroblasts. Fibroblasts and c-Jun promote PCa growth; finasteride further stimulates tumor growth with promoted proliferation, repressed apoptosis, and up-regulated pro-proliferative molecular pathway in the presence of fibroblasts and c-Jun. Stromal-epithelial interactions play critical roles in finasteride′s therapeutic effects on PCa. Our findings have preliminary implications in using finasteride as a chemopreventive or therapeutic agent for PCa patients.

  9. Pharmacologic inhibition of MLK3 kinase activity blocks the in vitro migratory capacity of breast cancer cells but has no effect on breast cancer brain metastasis in a mouse xenograft model.

    Directory of Open Access Journals (Sweden)

    Kun Hyoe Rhoo

    Full Text Available Brain metastasis of breast cancer is an important clinical problem, with few therapeutic options and a poor prognosis. Recent data have implicated mixed lineage kinase 3 (MLK3 in controlling the in vitro migratory capacity of breast cancer cells, as well as the metastasis of MDA-MB-231 breast cancer cells from the mammary fat pad to distant lymph nodes in a mouse xenograft model. We therefore set out to test whether MLK3 plays a role in brain metastasis of breast cancer cells. To address this question, we used a novel, brain penetrant, MLK3 inhibitor, URMC099. URMC099 efficiently inhibited the migration of breast cancer cells in an in vitro cell monolayer wounding assay, and an in vitro transwell migration assay, but had no effect on in vitro cell growth. We also tested the effect of URMC099 on tumor formation in a mouse xenograft model of breast cancer brain metastasis. This analysis showed that URMC099 had no effect on the either the frequency or size of breast cancer brain metastases. We conclude that pharmacologic inhibition of MLK3 by URMC099 can reduce the in vitro migratory capacity of breast cancer cells, but that it has no effect on either the frequency or size of breast cancer brain metastases, in a mouse xenograft model.

  10. EXPERIMENTAL MODEL OF THE PRIMARY MALE HYPOGONADISM

    Directory of Open Access Journals (Sweden)

    P. A. Kulikova

    2014-01-01

    Full Text Available Background: Development of the new methods of treatment of primary male hypogonadism is an urgent medical problem. Its solution requires a suitable experimental model of the disease. Aim: The creation of new experimental model of primary male hypogonadism. Materials and methods: The study was conducted on the male Wistar rats, hypogonadism was modeled by temporary ligation of the distal part of the spermatic cord. Results: It was shown that three-day ligation of the spermatic cord led to persistent disturbance of the testosterone-producing and reproductive functions. These manifestations were reversible at shorter duration of the exposure. Conclusion: The created model of primary male hypogonadism is characterized by the persistent testosterone-producing and reproductive functions disturbance, technical availability, non-toxicity to the other organs and systems. Availability of the model provides new opportunities for the development of approaches to treating diseases of the reproductive organs in men.

  11. Empirical study of 99Tcm-HYNIC-A(D) A(D) APRPG in rabbit model of inflammation and VX2 tumor xenografted

    International Nuclear Information System (INIS)

    Liu Ciyi; Song Shaoli; Xie Wenhui; Cai Xiaojia; Zhang Lihua; Huang Gang

    2011-01-01

    Objective: To investigate the uptake of 99 Tc m -hydrazinonicotinamide-D-alanine- D-alanine-alanine-proline-arginine-proline-glycine (HYNIC-A(D) A(D) APRPG) in rabbit models of inflammation and VX2 tumor xenografted, so as to evaluate its use as a new tracer for tumor angiogenesis. Methods: Ten rabbit models of xenoplanted VX2 tumor and inflammation were randomly divided into two groups which were injected with different injected tracers, 99 Tc m -HYNIC-A(D) A (D)APRPG 99 Tc m -RGD, followed by serial Gamma images at various time points. The first group underwent 18 F-FDG PET ahead of 99 Tc m -HYNICA(D)A (D) APRPG SPECT. Analysis of variance and t-test were performed with SPSS 10.0. Results: 99 Tc m -HYNIC-A(D) A (D)APRPG scan showed negative uptake at inflammation focus but positive uptake at tumor. Pathological examination confirmed high 99 Tc m -HYNIC-A(D)A(D) APRPG accumulation in tumor cells, with the highest tumor/inflammation ratio (3.25±0.171) at 2 h post-injection, which was significantly higher than that of 99 Tc m -RGD (2.37±0.076) (F = 15.63, P 99 Tc m -HYNIC-A(D)A(D)APRPG, 99 Tc m -RGD, 18 F-FDG were significantly different at 0.5, 1, 2, 3, 6 h (F=13.83∼26.41; t =23.84, 12.75; all P 99 Tc m -HYNIC-A (D) A (D)APRPG can be used as a potential tracer for tumor angiogenesis. (authors)

  12. Development of a Novel Preclinical Pancreatic Cancer Research Model: Bioluminescence Image-Guided Focal Irradiation and Tumor Monitoring of Orthotopic Xenografts1

    Science.gov (United States)

    Tuli, Richard; Surmak, Andrew; Reyes, Juvenal; Hacker-Prietz, Amy; Armour, Michael; Leubner, Ashley; Blackford, Amanda; Tryggestad, Erik; Jaffee, Elizabeth M; Wong, John; DeWeese, Theodore L; Herman, Joseph M

    2012-01-01

    PURPOSE: We report on a novel preclinical pancreatic cancer research model that uses bioluminescence imaging (BLI)-guided irradiation of orthotopic xenograft tumors, sparing of surrounding normal tissues, and quantitative, noninvasive longitudinal assessment of treatment response. MATERIALS AND METHODS: Luciferase-expressing MiaPaCa-2 pancreatic carcinoma cells were orthotopically injected in nude mice. BLI was compared to pathologic tumor volume, and photon emission was assessed over time. BLI was correlated to positron emission tomography (PET)/computed tomography (CT) to estimate tumor dimensions. BLI and cone-beam CT (CBCT) were used to compare tumor centroid location and estimate setup error. BLI and CBCT fusion was performed to guide irradiation of tumors using the small animal radiation research platform (SARRP). DNA damage was assessed by γ-H2Ax staining. BLI was used to longitudinally monitor treatment response. RESULTS: Bioluminescence predicted tumor volume (R = 0.8984) and increased linearly as a function of time up to a 10-fold increase in tumor burden. BLI correlated with PET/CT and necropsy specimen in size (P < .05). Two-dimensional BLI centroid accuracy was 3.5 mm relative to CBCT. BLI-guided irradiated pancreatic tumors stained positively for γ-H2Ax, whereas surrounding normal tissues were spared. Longitudinal assessment of irradiated tumors with BLI revealed significant tumor growth delay of 20 days relative to controls. CONCLUSIONS: We have successfully applied the SARRP to a bioluminescent, orthotopic preclinical pancreas cancer model to noninvasively: 1) allow the identification of tumor burden before therapy, 2) facilitate image-guided focal radiation therapy, and 3) allow normalization of tumor burden and longitudinal assessment of treatment response. PMID:22496923

  13. Development of a novel preclinical pancreatic cancer research model: bioluminescence image-guided focal irradiation and tumor monitoring of orthotopic xenografts.

    Science.gov (United States)

    Tuli, Richard; Surmak, Andrew; Reyes, Juvenal; Hacker-Prietz, Amy; Armour, Michael; Leubner, Ashley; Blackford, Amanda; Tryggestad, Erik; Jaffee, Elizabeth M; Wong, John; Deweese, Theodore L; Herman, Joseph M

    2012-04-01

    We report on a novel preclinical pancreatic cancer research model that uses bioluminescence imaging (BLI)-guided irradiation of orthotopic xenograft tumors, sparing of surrounding normal tissues, and quantitative, noninvasive longitudinal assessment of treatment response. Luciferase-expressing MiaPaCa-2 pancreatic carcinoma cells were orthotopically injected in nude mice. BLI was compared to pathologic tumor volume, and photon emission was assessed over time. BLI was correlated to positron emission tomography (PET)/computed tomography (CT) to estimate tumor dimensions. BLI and cone-beam CT (CBCT) were used to compare tumor centroid location and estimate setup error. BLI and CBCT fusion was performed to guide irradiation of tumors using the small animal radiation research platform (SARRP). DNA damage was assessed by γ-H2Ax staining. BLI was used to longitudinally monitor treatment response. Bioluminescence predicted tumor volume (R = 0.8984) and increased linearly as a function of time up to a 10-fold increase in tumor burden. BLI correlated with PET/CT and necropsy specimen in size (P < .05). Two-dimensional BLI centroid accuracy was 3.5 mm relative to CBCT. BLI-guided irradiated pancreatic tumors stained positively for γ-H2Ax, whereas surrounding normal tissues were spared. Longitudinal assessment of irradiated tumors with BLI revealed significant tumor growth delay of 20 days relative to controls. We have successfully applied the SARRP to a bioluminescent, orthotopic preclinical pancreas cancer model to noninvasively: 1) allow the identification of tumor burden before therapy, 2) facilitate image-guided focal radiation therapy, and 3) allow normalization of tumor burden and longitudinal assessment of treatment response.

  14. Preclinical activity of the type II CD20 antibody GA101 (obinutuzumab) compared with rituximab and ofatumumab in vitro and in xenograft models.

    Science.gov (United States)

    Herter, Sylvia; Herting, Frank; Mundigl, Olaf; Waldhauer, Inja; Weinzierl, Tina; Fauti, Tanja; Muth, Gunter; Ziegler-Landesberger, Doris; Van Puijenbroek, Erwin; Lang, Sabine; Duong, Minh Ngoc; Reslan, Lina; Gerdes, Christian A; Friess, Thomas; Baer, Ute; Burtscher, Helmut; Weidner, Michael; Dumontet, Charles; Umana, Pablo; Niederfellner, Gerhard; Bacac, Marina; Klein, Christian

    2013-10-01

    We report the first preclinical in vitro and in vivo comparison of GA101 (obinutuzumab), a novel glycoengineered type II CD20 monoclonal antibody, with rituximab and ofatumumab, the two currently approved type I CD20 antibodies. The three antibodies were compared in assays measuring direct cell death (AnnexinV/PI staining and time-lapse microscopy), complement-dependent cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cell-mediated phagocytosis (ADCP), and internalization. The models used for the comparison of their activity in vivo were SU-DHL4 and RL xenografts. GA101 was found to be superior to rituximab and ofatumumab in the induction of direct cell death (independent of mechanical manipulation required for cell aggregate disruption formed by antibody treatment), whereas it was 10 to 1,000 times less potent in mediating CDC. GA101 showed superior activity to rituximab and ofatumumab in ADCC and whole-blood B-cell depletion assays, and was comparable with these two in ADCP. GA101 also showed slower internalization rate upon binding to CD20 than rituximab and ofatumumab. In vivo, GA101 induced a strong antitumor effect, including complete tumor remission in the SU-DHL4 model and overall superior efficacy compared with both rituximab and ofatumumab. When rituximab-pretreated animals were used, second-line treatment with GA101 was still able to control tumor progression, whereas tumors escaped rituximab treatment. Taken together, the preclinical data show that the glyoengineered type II CD20 antibody GA101 is differentiated from the two approved type I CD20 antibodies rituximab and ofatumumab by its overall preclinical activity, further supporting its clinical investigation. ©2013 AACR.

  15. Prevention of EBV lymphoma development by oncolytic myxoma virus in a murine xenograft model of post-transplant lymphoproliferative disease

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Manbok, E-mail: manbok66@dankook.ac.kr [Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, FL 32610 (United States); Rahman, Masmudur M. [Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, FL 32610 (United States); Cogle, Christopher R. [Department of Hematology/Oncology, University of Florida, Gainesville, FL 32610 (United States); McFadden, Grant [Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, FL 32610 (United States)

    2015-07-10

    Epstein–Barr virus (EBV) has been associated with a variety of epithelial and hematologic malignancies, including B-, T- and NK cell-lymphomas, Hodgkin's disease (HD), post-transplant lymphoproliferative diseases (LPDs), nasopharyngeal and gastric carcinomas, smooth muscle tumors, and HIV-associated lymphomas. Currently, treatment options for EBV-associated malignancies are limited. We have previously shown that myxoma virus specifically targets various human solid tumors and leukemia cells in a variety of animal models, while sparing normal human or murine tissues. Since transplant recipients of bone marrow or solid organs often develop EBV-associated post-transplant LPDs and lymphoma, myxoma virus may be of utility to prevent EBV-associated malignancies in immunocompromised transplant patients where treatment options are frequently limited. In this report, we demonstrate the safety and efficacy of myxoma virus purging as a prophylactic strategy for preventing post-transplant EBV-transformed human lymphomas, using a highly immunosuppressed mouse xenotransplantation model. This provides support for developing myxoma virus as a potential oncolytic therapy for preventing EBV-associated LPDs following transplantation of bone marrow or solid organ allografts. - Highlights: • Myxoma virus effectively infects and purges EBV lymphoma cells in vivo. • Oncolytic myxoma virus effectively eradicates oncogenic EBV tumorigenesis. • Ex vivo pre-treatment of myxoma virus can be effective as a preventive treatment modality for post-transplant lymphoproliferative diseases.

  16. Prevention of EBV lymphoma development by oncolytic myxoma virus in a murine xenograft model of post-transplant lymphoproliferative disease

    International Nuclear Information System (INIS)

    Kim, Manbok; Rahman, Masmudur M.; Cogle, Christopher R.; McFadden, Grant

    2015-01-01

    Epstein–Barr virus (EBV) has been associated with a variety of epithelial and hematologic malignancies, including B-, T- and NK cell-lymphomas, Hodgkin's disease (HD), post-transplant lymphoproliferative diseases (LPDs), nasopharyngeal and gastric carcinomas, smooth muscle tumors, and HIV-associated lymphomas. Currently, treatment options for EBV-associated malignancies are limited. We have previously shown that myxoma virus specifically targets various human solid tumors and leukemia cells in a variety of animal models, while sparing normal human or murine tissues. Since transplant recipients of bone marrow or solid organs often develop EBV-associated post-transplant LPDs and lymphoma, myxoma virus may be of utility to prevent EBV-associated malignancies in immunocompromised transplant patients where treatment options are frequently limited. In this report, we demonstrate the safety and efficacy of myxoma virus purging as a prophylactic strategy for preventing post-transplant EBV-transformed human lymphomas, using a highly immunosuppressed mouse xenotransplantation model. This provides support for developing myxoma virus as a potential oncolytic therapy for preventing EBV-associated LPDs following transplantation of bone marrow or solid organ allografts. - Highlights: • Myxoma virus effectively infects and purges EBV lymphoma cells in vivo. • Oncolytic myxoma virus effectively eradicates oncogenic EBV tumorigenesis. • Ex vivo pre-treatment of myxoma virus can be effective as a preventive treatment modality for post-transplant lymphoproliferative diseases

  17. Inhibition of Cell Proliferation and Growth of Pancreatic Cancer by Silencing of Carbohydrate Sulfotransferase 15 In Vitro and in a Xenograft Model.

    Directory of Open Access Journals (Sweden)

    Kazuki Takakura

    Full Text Available Chondroitin sulfate E (CS-E, a highly sulfated glycosaminoglycan, is known to promote tumor invasion and metastasis. Because the presence of CS-E is detected in both tumor and stromal cells in pancreatic ductal adenocarcinoma (PDAC, multistage involvement of CS-E in the development of PDAC has been considered. However, its involvement in the early stage of PDAC progression is still not fully understood. In this study, to clarify the direct role of CS-E in tumor, but not stromal, cells of PDAC, we focused on carbohydrate sulfotransferase 15 (CHST15, a specific enzyme that biosynthesizes CS-E, and investigated the effects of the CHST15 siRNA on tumor cell proliferation in vitro and growth in vivo. CHST15 mRNA is highly expressed in the human pancreatic cancer cell lines PANC-1, MIA PaCa-2, Capan-1 and Capan-2. CHST15 siRNA significantly inhibited the expression of CHST15 mRNA in these four cells in vitro. Silencing of the CHST15 gene in the cells was associated with significant reduction of proliferation and up-regulation of the cell cycle inhibitor-related gene p21CIP1/WAF1. In a subcutaneous xenograft tumor model of PANC-1 in nude mice, a single intratumoral injection of CHST15 siRNA almost completely suppressed tumor growth. Reduced CHST15 protein signals associated with tumor necrosis were observed with the treatment with CHST15 siRNA. These results provide evidence of the direct action of CHST15 on the proliferation of pancreatic tumor cells partly through the p21CIP1/WAF1 pathway. Thus, CHST15-CS-E axis-mediated tumor cell proliferation could be a novel therapeutic target in the early stage of PDAC progression.

  18. Styrene maleic acid-encapsulated RL71 micelles suppress tumor growth in a murine xenograft model of triple negative breast cancer

    Directory of Open Access Journals (Sweden)

    Martey O

    2017-10-01

    Full Text Available Orleans Martey,1 Mhairi Nimick,1 Sebastien Taurin,1 Vignesh Sundararajan,1 Khaled Greish,2 Rhonda J Rosengren1 1Department of Pharmacology and Toxicology, University of Otago, Dunedin, New Zealand; 2Department of Molecular Medicine, College of Medicine and Medical Sciences, Arabian Gulf University, Manama, Kingdom of Bahrain Abstract: Patients with triple negative breast cancer have a poor prognosis due in part to the lack of targeted therapies. In the search for novel drugs, our laboratory has developed a second-generation curcumin derivative, 3,5-bis(3,4,5-trimethoxybenzylidene-1-methylpiperidine-4-one (RL71, that exhibits potent in vitro cytotoxicity. To improve the clinical potential of this drug, we have encapsulated it in styrene maleic acid (SMA micelles. SMA-RL71 showed improved biodistribution, and drug accumulation in the tumor increased 16-fold compared to control. SMA-RL71 (10 mg/kg, intravenously, two times a week for 2 weeks also significantly suppressed tumor growth compared to control in a xenograft model of triple negative breast cancer. Free RL71 was unable to alter tumor growth. Tumors from SMA-RL71-treated mice showed a decrease in angiogenesis and an increase in apoptosis. The drug treatment also modulated various cell signaling proteins including the epidermal growth factor receptor, with the mechanisms for tumor suppression consistent with previous work with RL71 in vitro. The nanoformulation was also nontoxic as shown by normal levels of plasma markers for liver and kidney injury following weekly administration of SMA-RL71 (10 mg/kg for 90 days. Thus, we report clinical potential following encapsulation of a novel curcumin derivative, RL71, in SMA micelles. Keywords: curcumin derivatives, nanomedicine, EGFR, biodistribution

  19. Magnetic Resonance Tracking of Endothelial Progenitor Cells Labeled with Alkyl-Polyethylenimine 2 kDa/Superparamagnetic Iron Oxide in a Mouse Lung Carcinoma Xenograft Model

    Directory of Open Access Journals (Sweden)

    Cong Chen

    2014-11-01

    Full Text Available The potential of using endothelial progenitor cells (EPCs in novel anticancer therapy and the repair of vascular injury has been increasingly recognized. In the present study, EPCs were labeled with N-alkyl-polyethylenimine 2 kDa (PEI2k-stabilized superparamagnetic iron oxide (SPIO to facilitate magnetic resonance imaging (MRI of EPCs in a mouse lung carcinoma xenograft model. EPCs derived from human peripheral blood were labeled with alkyl-PEI2k/SPIO. The viability and activity of labeled cells were evaluated using proliferation, migration, and tubulogenesis assays. Alkyl-PEI2k/SPIO-labeled EPCs were injected intravenously (group 1 or mixed and injected together with A549 cells subcutaneously (group 2 into groups of six mice with severe combined immunodeficiency. The labeling efficiency with alkyl-PEI2k/SPIO at 7 mg Fe/mL concentration was approximately 100%. Quantitative analysis of cellular iron was 6.062 ± 0.050 pg/cell. No significant effects on EPC proliferation, migration, or tubulogenesis were seen after labeling. Seventesla micro-MRI showed the presence of schistic or linear hypointense regions at the tumor margins starting from days 7 to 8 after EPC administration. This gradually extended into the inner tumor layers in group 1. In group 2, tumor growth was accompanied by dispersion of low-signal intensity regions inside the tumor. Iron-positive cells identified by Prussian blue dye were seen at the sites identified using MRI. Human CD31-positive cells and mouse CD31-positive cells were present in both groups. Labeling EPCs with alkyl-PEI2k/SPIO allows noninvasive magnetic resonance investigation of EPC involvement in tumor neovasculature and is associated with excellent biocompatibility and MRI sensitivity.

  20. Formulation, Characterization, and Antitumor Properties of Trans- and Cis-Citral in the 4T1 Breast Cancer Xenograft Mouse Model.

    Science.gov (United States)

    Zeng, San; Kapur, Arvinder; Patankar, Manish S; Xiong, May P

    2015-08-01

    Citral is composed of a random mixture of two geometric stereoisomers geranial (trans-citral) and neral (cis-citral) yet few studies have directly compared their in vivo antitumor properties. A micelle formulation was therefore developed. Geranial and neral were synthesized. Commercially-purchased citral, geranial, and neral were formulated in PEG-b-PCL (block sizes of 5000:10,000, Mw/Mn 1.26) micelles. In vitro degradation, drug release, cytotoxicity, flow cytometry, and western blot studies were conducted. The antitumor properties of drug formulations (40 and 80 mg/kg based on MTD studies) were evaluated on the 4T1 xenograft mouse model and tumor tissues were analyzed by western blot. Micelles encapsulated drugs with >50% LE at 5-40% drug to polymer (w/w), displayed sustained release (t1/2 of 8-9 h), and improved drug stability at pH 5.0. The IC50 of drug formulations against 4T1 cells ranged from 1.4 to 9.9 μM. Western blot revealed that autophagy was the main cause of cytotoxicity. Geranial at 80 mg/kg was most effective at inhibiting tumor growth. Geranial is significantly more potent than neral and citral at 80 mg/kg (p < 0.001) and western blot of tumor tissues confirms that autophagy and not apoptosis is the major mechanism of tumor growth inhibition in p53-null 4T1 cells.

  1. Blockade of the ERK pathway enhances the therapeutic efficacy of the histone deacetylase inhibitor MS-275 in human tumor xenograft models

    Energy Technology Data Exchange (ETDEWEB)

    Sakamoto, Toshiaki; Ozaki, Kei-ichi; Fujio, Kohsuke; Kajikawa, Shu-hei [Laboratory of Cell Regulation, Department of Pharmaceutical Sciences, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8521 (Japan); Uesato, Shin-ichi [Department of Biotechnology, Faculty of Engineering, Kansai University, Osaka 564-8680 (Japan); Watanabe, Kazushi [Proubase Technology Inc., Kanagawa 211-0063 (Japan); Tanimura, Susumu [Laboratory of Cell Regulation, Department of Pharmaceutical Sciences, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8521 (Japan); Koji, Takehiko [Department of Histology and Cell Biology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8523 (Japan); Kohno, Michiaki, E-mail: kohnom@nagasaki-u.ac.jp [Laboratory of Cell Regulation, Department of Pharmaceutical Sciences, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8521 (Japan); Proubase Technology Inc., Kanagawa 211-0063 (Japan); Kyoto University Graduate School of Pharmaceutical Sciences, Kyoto 606-8501 (Japan)

    2013-04-19

    Highlights: •Blockade of the ERK pathway enhances the anticancer efficacy of HDAC inhibitors. •MEK inhibitors sensitize human tumor xenografts to HDAC inhibitor cytotoxicity. •Such the enhanced efficacy is achieved by a transient blockade of the ERK pathway. •This drug combination provides a promising therapeutic strategy for cancer patients. -- Abstract: The ERK pathway is up-regulated in various human cancers and represents a prime target for mechanism-based approaches to cancer treatment. Specific blockade of the ERK pathway alone induces mostly cytostatic rather than pro-apoptotic effects, however, resulting in a limited therapeutic efficacy of the ERK kinase (MEK) inhibitors. We previously showed that MEK inhibitors markedly enhance the ability of histone deacetylase (HDAC) inhibitors to induce apoptosis in tumor cells with constitutive ERK pathway activation in vitro. To evaluate the therapeutic efficacy of such drug combinations, we administered the MEK inhibitor PD184352 or AZD6244 together with the HDAC inhibitor MS-275 in nude mice harboring HT-29 or H1650 xenografts. Co-administration of the MEK inhibitor markedly sensitized the human xenografts to MS-275 cytotoxicity. A dose of MS-275 that alone showed only moderate cytotoxicity thus suppressed the growth of tumor xenografts almost completely as well as induced a marked reduction in tumor cellularity when administered with PD184352 or AZD6244. The combination of the two types of inhibitor also induced marked oxidative stress, which appeared to result in DNA damage and massive cell death, specifically in the tumor xenografts. The enhanced therapeutic efficacy of the drug combination was achieved by a relatively transient blockade of the ERK pathway. Administration of both MEK and HDAC inhibitors represents a promising chemotherapeutic strategy with improved safety for cancer patients.

  2. Anti-tumour efficacy of etoposide alone and in combination with piroxicam against canine osteosarcoma in a xenograft model.

    Science.gov (United States)

    Ong, S M; Saeki, K; Kok, M K; Tanaka, Y; Choisunirachon, N; Yoshitake, R; Nishimura, R; Nakagawa, T

    2017-08-01

    Osteosarcoma (OSA) in dogs is locally invasive and highly malignant. Distant metastasis is the most common cause of death. To date, the survival rate in dogs with OSA remains poor. The cytotoxic effects of etoposide against canine OSA cell lines, either alone or in combination with piroxicam, have been previously demonstrated in vitro. The aim of this study was to evaluate the anti-tumour effect of etoposide alone and in combination with piroxicam on canine OSA using murine models. Etoposide single agent treatment significantly delayed tumour progression with a marked reduction in Ki-67 immunoreactivity in tumour tissue. Concomitant treatment with piroxicam did not enhance the anti-tumour efficacy of etoposide. Etoposide single agent treatment and combination treatment with piroxicam down-regulated survivin expression, but was not followed by increased apoptotic activity. These findings indicate that etoposide might be a promising novel therapeutic for canine OSA. Further investigations into its potential for clinical application in veterinary oncology are warranted. Copyright © 2017 Elsevier Ltd. All rights reserved.

  3. CGRP in human models of primary headaches

    DEFF Research Database (Denmark)

    Ashina, Håkan; Schytz, Henrik Winther; Ashina, Messoud

    2018-01-01

    experiments are likely due to assay variation; therefore, proper validation and standardization of an assay is needed. To what extent CGRP is involved in tension-type headache and cluster headache is unknown. CONCLUSION: Human models of primary headaches have elucidated the role of CGRP in headache...... pathophysiology and sparked great interest in developing new treatment strategies using CGRP antagonists and antibodies. Future studies applying more refined human experimental models should identify biomarkers of CGRP-induced primary headache and reveal whether CGRP provocation experiments could be used......OBJECTIVE: To review the role of CGRP in human models of primary headaches and to discuss methodological aspects and future directions. DISCUSSION: Provocation experiments demonstrated a heterogeneous CGRP migraine response in migraine patients. Conflicting CGRP plasma results in the provocation...

  4. Metastatic behaviour of primary human tumours in a zebrafish xenotransplantation model

    International Nuclear Information System (INIS)

    Marques, Ines J; Bagowski, Christoph P; Weiss, Frank Ulrich; Vlecken, Danielle H; Nitsche, Claudia; Bakkers, Jeroen; Lagendijk, Anne K; Partecke, Lars Ivo; Heidecke, Claus-Dieter; Lerch, Markus M

    2009-01-01

    Aberrant regulation of cell migration drives progression of many diseases, including cancer cell invasion and metastasis formation. Analysis of tumour invasion and metastasis in living organisms to date is cumbersome and involves difficult and time consuming investigative techniques. For primary human tumours we establish here a simple, fast, sensitive and cost-effective in vivo model to analyse tumour invasion and metastatic behaviour. We fluorescently labelled small explants from gastrointestinal human tumours and investigated their metastatic behaviour after transplantation into zebrafish embryos and larvae. The transparency of the zebrafish embryos allows to follow invasion, migration and micrometastasis formation in real-time. High resolution imaging was achieved through laser scanning confocal microscopy of live zebrafish. In the transparent zebrafish embryos invasion, circulation of tumour cells in blood vessels, migration and micrometastasis formation can be followed in real-time. Xenografts of primary human tumours showed invasiveness and micrometastasis formation within 24 hours after transplantation, which was absent when non-tumour tissue was implanted. Furthermore, primary human tumour cells, when organotopically implanted in the zebrafish liver, demonstrated invasiveness and metastatic behaviour, whereas primary control cells remained in the liver. Pancreatic tumour cells showed no metastatic behaviour when injected into cloche mutant embryos, which lack a functional vasculature. Our results show that the zebrafish is a useful in vivo animal model for rapid analysis of invasion and metastatic behaviour of primary human tumour specimen

  5. Adoptively transferred human lung tumor specific cytotoxic T cells can control autologous tumor growth and shape tumor phenotype in a SCID mouse xenograft model

    Directory of Open Access Journals (Sweden)

    Ferrone Soldano

    2007-06-01

    Full Text Available Abstract Background The anti-tumor efficacy of human immune effector cells, such as cytolytic T lymphocytes (CTLs, has been difficult to study in lung cancer patients in the clinical setting. Improved experimental models for the study of lung tumor-immune cell interaction as well as for evaluating the efficacy of adoptive transfer of immune effector cells are needed. Methods To address questions related to the in vivo interaction of human lung tumor cells and immune effector cells, we obtained an HLA class I + lung tumor cell line from a fresh surgical specimen, and using the infiltrating immune cells, isolated and characterized tumor antigen-specific, CD8+ CTLs. We then established a SCID mouse-human tumor xenograft model with the tumor cell line and used it to study the function of the autologous CTLs provided via adoptive transfer. Results The tumor antigen specific CTLs isolated from the tumor were found to have an activated memory phenotype and able to kill tumor cells in an antigen specific manner in vitro. Additionally, the tumor antigen-specific CTLs were fully capable of homing to and killing autologous tumors in vivo, and expressing IFN-γ, each in an antigen-dependent manner. A single injection of these CTLs was able to provide significant but temporary control of the growth of autologous tumors in vivo without the need for IL-2. The timing of injection of CTLs played an essential role in the outcome of tumor growth control. Moreover, immunohistochemical analysis of surviving tumor cells following CTL treatment indicated that the surviving tumor cells expressed reduced MHC class I antigens on their surface. Conclusion These studies confirm and extend previous studies and provide additional information regarding the characteristics of CTLs which can be found within a patient's tumor. Moreover, the in vivo model described here provides a unique window for observing events that may also occur in patients undergoing adoptive cellular

  6. A complete dynamic model of primary sedimentation.

    Science.gov (United States)

    Paraskevas, P; Kolokithas, G; Lekkas, T

    1993-11-01

    A dynamic mathematical model for the primary clarifier of a wastewater treatment plant is described, which is represented by a general tanks-in-series model, to simulate insufficient mixing. The model quantifies successfully the diurnal response of both the suspended and dissolved species. It is general enough, so that the values of the parameters can be replaced with those applicable to a specific case. The model was verified through data from the Biological Centre of Metamorfosi, in Athens, Greece, and can be used to assist in the design of new plants or in the analysis and output predictions of existing ones.

  7. Radioimmunoimaging of human breast carcinoma xenografts in nude mouse model with 111In-labeled new monoclonal antibody EBA-1 and F(ab')2 fragments

    International Nuclear Information System (INIS)

    Yemul, Shrishailam; Leon, J.A.; Pozniakoff, Ted; Esser, P.D.; Estabrook, Alison; Met-Path Inc., Teterboro, NJ

    1993-01-01

    Radioimmunoimaging characteristics of a new monoclonal antibody EBA-1 and its F(ab') 2 fragments utilizing nu/nu mice bearing human breast carcinoma xenografts are described. 111 In-DPTA conjugates of EBA-1 localized with tumor/blood ratios of 0.99 ± 0.10 (P 2 radioconjugates at 48 h. These results suggest that EBA-1 and its F(ab') 2 might be useful reagents in radioimmunoimaging and radioimmunotherapy. (author)

  8. Preclinical In Vitro and In Vivo Evaluation of [18F]FE@SUPPY for Cancer PET Imaging: Limitations of a Xenograft Model for Colorectal Cancer

    Directory of Open Access Journals (Sweden)

    T. Balber

    2018-01-01

    Full Text Available Molecular imaging probes such as PET-tracers have the potential to improve the accuracy of tumor characterization by directly visualizing the biochemical situation. Thus, molecular changes can be detected early before morphological manifestation. The A3 adenosine receptor (A3AR is described to be highly expressed in colon cancer cell lines and human colorectal cancer (CRC, suggesting this receptor as a tumor marker. The aim of this preclinical study was the evaluation of F18FE@SUPPY as a PET-tracer for CRC using in vitro imaging and in vivo PET imaging. First, affinity and selectivity of FE@SUPPY and its metabolites were determined, proving the favorable binding profile of FE@SUPPY. The human adenocarcinoma cell line HT-29 was characterized regarding its hA3AR expression and was subsequently chosen as tumor graft. Promising results regarding the potential of F18FE@SUPPY as a PET-tracer for CRC imaging were obtained by autoradiography as ≥2.3-fold higher accumulation of F18FE@SUPPY was found in CRC tissue compared to adjacent healthy colon tissue from the same patient. Nevertheless, first in vivo studies using HT-29 xenografts showed insufficient tumor uptake due to (1 poor conservation of target expression in xenografts and (2 unfavorable pharmacokinetics of F18FE@SUPPY in mice. We therefore conclude that HT-29 xenografts are not adequate to visualize hA3ARs using F18FE@SUPPY.

  9. Mesothelioma patient derived tumor xenografts with defined BAP1 mutations that mimic the molecular characteristics of human malignant mesothelioma

    International Nuclear Information System (INIS)

    Kalra, Neetu; Zhang, Jingli; Thomas, Anish; Xi, Liqiang; Cheung, Mitchell; Talarchek, Jacqueline; Burkett, Sandra; Tsokos, Maria G; Chen, Yuanbin; Raffeld, Mark; Miettinen, Markku; Pastan, Ira; Testa, Joseph R; Hassan, Raffit

    2015-01-01

    The development and evaluation of new therapeutic approaches for malignant mesothelioma has been sparse due, in part, to lack of suitable tumor models. We established primary mesothelioma cultures from pleural and ascitic fluids of five patients with advanced mesothelioma. Electron microscopy and immunohistochemistry (IHC) confirmed their mesothelial origin. Patient derived xenografts were generated by injecting the cells in nude or SCID mice, and malignant potential of the cells was analyzed by soft agar colony assay. Molecular profiles of the primary patient tumors, early passage cell cultures, and patient derived xenografts were assessed using mutational analysis, fluorescence in situ hybridization (FISH) analysis and IHC. Primary cultures from all five tumors exhibited morphologic and IHC features consistent to those of mesothelioma cells. Mutations of BAP1 and CDKN2A were each detected in four tumors. BAP1 mutation was associated with the lack of expression of BAP1 protein. Three cell cultures, all of which were derived from BAP1 mutant primary tumors, exhibited anchorage independent growth and also formed tumors in mice, suggesting that BAP1 loss may enhance tumor growth in vivo. Both early passage cell cultures and mouse xenograft tumors harbored BAP1 mutations and CDKN2A deletions identical to those found in the corresponding primary patient tumors. The mesothelioma patient derived tumor xenografts with mutational alterations that mimic those observed in patient tumors which we established can be used for preclinical development of novel drug regimens and for studying the functional aspects of BAP1 biology in mesothelioma. The online version of this article (doi:10.1186/s12885-015-1362-2) contains supplementary material, which is available to authorized users

  10. Efficacy of a non-hypercalcemic vitamin-D2 derived anti-cancer agent (MT19c and inhibition of fatty acid synthesis in an ovarian cancer xenograft model.

    Directory of Open Access Journals (Sweden)

    Richard G Moore

    Full Text Available BACKGROUND: Numerous vitamin-D analogs exhibited poor response rates, high systemic toxicities and hypercalcemia in human trials to treat cancer. We identified the first non-hypercalcemic anti-cancer vitamin D analog MT19c by altering the A-ring of ergocalciferol. This study describes the therapeutic efficacy and mechanism of action of MT19c in both in vitro and in vivo models. METHODOLOGY/PRINCIPAL FINDING: Antitumor efficacy of MT19c was evaluated in ovarian cancer cell (SKOV-3 xenografts in nude mice and a syngenic rat ovarian cancer model. Serum calcium levels of MT19c or calcitriol treated animals were measured. In-silico molecular docking simulation and a cell based VDR reporter assay revealed MT19c-VDR interaction. Genomewide mRNA analysis of MT19c treated tumors identified drug targets which were verified by immunoblotting and microscopy. Quantification of cellular malonyl CoA was carried out by HPLC-MS. A binding study with PPAR-Y receptor was performed. MT19c reduced ovarian cancer growth in xenograft and syngeneic animal models without causing hypercalcemia or acute toxicity. MT19c is a weak vitamin-D receptor (VDR antagonist that disrupted the interaction between VDR and coactivator SRC2-3. Genome-wide mRNA analysis and western blot and microscopy of MT19c treated xenograft tumors showed inhibition of fatty acid synthase (FASN activity. MT19c reduced cellular levels of malonyl CoA in SKOV-3 cells and inhibited EGFR/phosphoinositol-3kinase (PI-3K activity independently of PPAR-gamma protein. SIGNIFICANCE: Antitumor effects of non-hypercalcemic agent MT19c provide a new approach to the design of vitamin-D based anticancer molecules and a rationale for developing MT19c as a therapeutic agent for malignant ovarian tumors by targeting oncogenic de novo lipogenesis.

  11. ISSLS PRIZE IN BASIC SCIENCE 2018: Growth differentiation factor-6 attenuated pro-inflammatory molecular changes in the rabbit anular-puncture model and degenerated disc-induced pain generation in the rat xenograft radiculopathy model.

    Science.gov (United States)

    Miyazaki, Shingo; Diwan, Ashish D; Kato, Kenji; Cheng, Kevin; Bae, Won C; Sun, Yang; Yamada, Junichi; Muehleman, Carol; Lenz, Mary E; Inoue, Nozomu; Sah, Robert L; Kawakami, Mamoru; Masuda, Koichi

    2018-04-01

    To elucidate the effects of growth differentiation factor-6 (GDF6) on: (i) gene expression of inflammatory/pain-related molecules and structural integrity in the rabbit intervertebral disc (IVD) degeneration model, and (ii) sensory dysfunction and changes in pain-marker expression in dorsal nerve ganglia (DRGs) in the rat xenograft radiculopathy model. Forty-six adolescent rabbits received anular-puncture in two non-consecutive lumbar IVDs. Four weeks later, phosphate-buffered saline (PBS) or GDF6 (1, 10 or 100 µg) was injected into the nucleus pulposus (NP) of punctured discs and followed for 4 weeks for gene expression analysis and 12 weeks for structural analyses. For pain assessment, eight rabbits were sacrificed at 4 weeks post-injection and NP tissues of injected discs were transplanted onto L5 DRGs of 16 nude rats to examine mechanical allodynia. The rat DRGs were analyzed immunohistochemically. In GDF6-treated rabbit NPs, gene expressions of interleukin-6, tumor necrosis factor-α, vascular endothelial growth factor, prostaglandin-endoperoxide synthase 2, and nerve growth factor were significantly lower than those in the PBS group. GDF6 injections resulted in partial restoration of disc height and improvement of MRI disc degeneration grades with statistical significance in rabbit structural analyses. Allodynia induced by xenograft transplantation of rabbit degenerated NPs onto rat DRGs was significantly reduced by GDF6 injection. Staining intensities for ionized calcium-binding adaptor molecule-1 and calcitonin gene-related peptide in rat DRGs of the GDF6 group were significantly lower than those of the PBS group. GDF6 injection may change the pathological status of degenerative discs and attenuate degenerated IVD-induced pain.

  12. Physiologically based pharmacokinetic and pharmacodynamic modeling of an antagonist (SM-406/AT-406) of multiple inhibitor of apoptosis proteins (IAPs) in a mouse xenograft model of human breast cancer.

    Science.gov (United States)

    Zhang, Tao; Li, Yanyan; Zou, Peng; Yu, Jing-yu; McEachern, Donna; Wang, Shaomeng; Sun, Duxin

    2013-09-01

    The inhibitors of apoptosis proteins (IAPs) are a class of key apoptosis regulators overexpressed or dysregulated in cancer. SM-406/AT-406 is a potent and selective small molecule mimetic of Smac that antagonizes the inhibitor of apoptosis proteins (IAPs). A physiologically based pharmacokinetic and pharmacodynamic (PBPK-PD) model was developed to predict the tissue concentration-time profiles of SM-406, the related onco-protein levels in tumor, and the tumor growth inhibition in a mouse model bearing human breast cancer xenograft. In the whole body physiologically based pharmacokinetic (PBPK) model for pharmacokinetics characterization, a well stirred (perfusion rate-limited) model was used to describe SM-406 pharmacokinetics in the lung, heart, kidney, intestine, liver and spleen, and a diffusion rate-limited (permeability limited) model was used for tumor. Pharmacodynamic (PD) models were developed to correlate the SM-406 concentration in tumor to the cIAP1 degradation, pro-caspase 8 decrease, CL-PARP accumulation and tumor growth inhibition. The PBPK-PD model well described the experimental pharmacokinetic data, the pharmacodynamic biomarker responses and tumor growth. This model may be helpful to predict tumor and plasma SM-406 concentrations in the clinic. Copyright © 2013 John Wiley & Sons, Ltd.

  13. Experimental model of bone response to collagenized xenografts of porcine origin (OsteoBiol® mp3): a radiological and histomorphometric study.

    Science.gov (United States)

    Calvo Guirado, Jose Luis; Ramírez Fernández, Maria Piedad; Negri, Bruno; Delgado Ruiz, Rafael Arcesio; Maté Sánchez de-Val, José Eduardo; Gómez-Moreno, Gerardo

    2013-02-01

    Adequate alveolar ridges are fundamental to successful rehabilitation with implants. There are diverse techniques for reconstructing atrophied ridges, of which bone substitute grafts is one possibility. The aim of this study was to carry out radiological and histomorphometric evaluations of bone response to collagenized porcine bone xenografts over a 4-month period following their insertion in rabbits' tibiae. Twenty New Zealand rabbits were used. Twenty collagenized porcine bone xenografts (Osteobiol® mp3, Tecnoss Dental s.r.l., Torino, Italy), in granulated form of 600 to 1,000 µm, were inserted in the proximal metaphyseal area of the animals' tibiae and 20 control areas were created. Following implantation, the animals were sacrificed in four groups of five, after 1, 2, 3, and 4 months, respectively. Radiological and histomorphometric studies were made. After 4 months, radiological images revealed bone defects with a decrease in graft volume and the complete repair of the osseous defect. No healed or residual bone alterations attributable to the presence of the implants were observed. Histomorphometric analysis at 4 months found mean values for newly formed bone, residual graft material, and non-mineralized connective tissue of 25.4 ± 1.8%, 36.37 ± 3.0%, and 38.22 ± 2.5%, respectively. There were no statistical differences in the length of cortical formation with collagenized porcine xenograft (98.9 ± 1.1%) compared with the control samples (99.1 ± 0.7%) at the end of the study period. The biomaterial used proved to be biocompatible, bioabsorbable, and osteoconductive and as such, a possible bone substitute that did not interfere with the bone's normal reparative processes. © 2011 Wiley Periodicals, Inc.

  14. Celecoxib and GABA cooperatively prevent the progression of pancreatic cancer in vitro and in xenograft models of stress-free and stress-exposed mice.

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    Hussein A N Al-Wadei

    Full Text Available Pancreatic ductal adenocarcinoma (PDAC has a poor prognosis and is associated with high levels of psychological distress. We have shown that beta-adrenergic receptors (β-ARs, which are activated by stress neurotransmitters, regulate PDAC cells via cyclic AMP (cAMP-dependent signaling in vitro, that social stress promotes PDAC progression in mouse xenografts and that γ-aminobutyric acid (GABA inhibits these responses in vitro and in vivo. The targeted inhibition of stress-induced regulatory pathways may abolish the potentially negative impact of psychological stress on clinical outcomes. Our current data show that chronic exposure of PDAC cell lines Panc-1 (activating point mutations in K-ras and BXPC-3 (no mutations in K-ras in vitro to the stress neurotransmitter epinephrine at the concentration (15 nM previously measured in the serum of mice exposed to social stress significantly increased proliferation and migration. These responses were inhibited in a concentration-dependent manner by celecoxib. The effects of celecoxib alone and in combination with γ-aminobutyric acid (GABA on the progression of subcutaneous mouse xenografts from the cell line (BXPC-3 most responsive to epinephrine were then investigated in the presence and absence of social stress. Cancer-stimulating factors (VEGF & prostaglandin E(2 [PGE(2] and levels of cAMP were measured by immunoassays in blood and xenograft tissue. Phosphorylation of the signaling proteins ERK, CREB, Src, and AKT was assessed by ELISA assays and Western blotting. Expression of COX-2, 5-lipoxygenase, and p-5-LOX were determined by semi-quantitative Western blotting. Celecoxib alone significantly inhibited xenograft progression and decreased systemic and tumor VEGF, PGE2, and cAMP as well as phosphorylated signaling proteins in stress-exposed and stress-free mice. These responses were significantly enhanced by co-treatment with GABA. The celecoxib-induced downregulation of COX-2 protein and p-5-LOX

  15. Use of a conformational switching aptamer for rapid and specific ex vivo identification of central nervous system lymphoma in a xenograft model.

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    Joseph F Georges

    Full Text Available Improved tools for providing specific intraoperative diagnoses could improve patient care. In neurosurgery, intraoperatively differentiating non-operative lesions such as CNS B-cell lymphoma from operative lesions can be challenging, often necessitating immunohistochemical (IHC procedures which require up to 24-48 hours. Here, we evaluate the feasibility of generating rapid ex vivo specific labeling using a novel lymphoma-specific fluorescent switchable aptamer. Our B-cell lymphoma-specific switchable aptamer produced only low-level fluorescence in its unbound conformation and generated an 8-fold increase in fluorescence once bound to its target on CD20-positive lymphoma cells. The aptamer demonstrated strong binding to B-cell lymphoma cells within 15 minutes of incubation as observed by flow cytometry. We applied the switchable aptamer to ex vivo xenograft tissue harboring B-cell lymphoma and astrocytoma, and within one hour specific visual identification of lymphoma was routinely possible. In this proof-of-concept study in human cell culture and orthotopic xenografts, we conclude that a fluorescent switchable aptamer can provide rapid and specific labeling of B-cell lymphoma, and that developing aptamer-based labeling approaches could simplify tissue staining and drastically reduce time to histopathological diagnoses compared with IHC-based methods. We propose that switchable aptamers could enhance expeditious, accurate intraoperative decision-making.

  16. Use of a conformational switching aptamer for rapid and specific ex vivo identification of central nervous system lymphoma in a xenograft model.

    Science.gov (United States)

    Georges, Joseph F; Liu, Xiaowei; Eschbacher, Jennifer; Nichols, Joshua; Mooney, Michael A; Joy, Anna; Spetzler, Robert F; Feuerstein, Burt G; Preul, Mark C; Anderson, Trent; Yan, Hao; Nakaji, Peter

    2015-01-01

    Improved tools for providing specific intraoperative diagnoses could improve patient care. In neurosurgery, intraoperatively differentiating non-operative lesions such as CNS B-cell lymphoma from operative lesions can be challenging, often necessitating immunohistochemical (IHC) procedures which require up to 24-48 hours. Here, we evaluate the feasibility of generating rapid ex vivo specific labeling using a novel lymphoma-specific fluorescent switchable aptamer. Our B-cell lymphoma-specific switchable aptamer produced only low-level fluorescence in its unbound conformation and generated an 8-fold increase in fluorescence once bound to its target on CD20-positive lymphoma cells. The aptamer demonstrated strong binding to B-cell lymphoma cells within 15 minutes of incubation as observed by flow cytometry. We applied the switchable aptamer to ex vivo xenograft tissue harboring B-cell lymphoma and astrocytoma, and within one hour specific visual identification of lymphoma was routinely possible. In this proof-of-concept study in human cell culture and orthotopic xenografts, we conclude that a fluorescent switchable aptamer can provide rapid and specific labeling of B-cell lymphoma, and that developing aptamer-based labeling approaches could simplify tissue staining and drastically reduce time to histopathological diagnoses compared with IHC-based methods. We propose that switchable aptamers could enhance expeditious, accurate intraoperative decision-making.

  17. Use of a conformational switching aptamer for rapid and specific ex vivo identification of central nervous system lymphoma in a xenograft model

    Science.gov (United States)

    Georges, Joseph F.; Liu, Xiaowei; Eschbacher, Jennifer; Nichols, Joshua; Mooney, Michael A.; Joy, Anna; Spetzler, Robert F.; Feuerstein, Burt G.; Anderson, Trent; Preul, Mark C.; Yan, Hao; Nakaji, Peter

    2018-02-01

    Improved tools for providing specific intraoperative diagnoses could improve patient care. In neurosurgery, intraoperatively differentiating non-operative lesions can be challenging, often necessitating immunohistochemical (IHC) procedures which require up to 24-48 hours. Here, we evaluate the feasibility of generating rapid ex vivo specific labeling using a novel lymphoma-specific fluorescent switchable aptamer. Our B-cell lymphoma-specific switchable aptamer produced only low-level fluorescence in its unbound conformation and generated an 8-fold increase in fluorescence once bound to its target on CD20-positive lymphoma cells. The aptamer demonstrated strong binding to B-cell lymphoma cells within 10 minutes of incubation. We applied the switchable aptamer to ex vivo xenograft tissue harboring B-cell lymphoma and astrocytoma, and within one hour specific visual identification of lymphoma was routinely possible. In this proof-of-concept study in human cell culture and orthotopic xenografts, we conclude that a fluorescent switchable aptamer can provide rapid and specific labeling of B-cell lymphoma, and that developing aptamer-based labeling approaches could simplify tissue staining and drastically reduce time to histopathological diagnoses compared with IHC-based methods. We propose that switchable aptamers could enhance expeditious, accurate intraoperative decision-making.

  18. Vorinostat, an HDAC inhibitor attenuates epidermoid squamous cell carcinoma growth by dampening mTOR signaling pathway in a human xenograft murine model.

    Science.gov (United States)

    Kurundkar, Deepali; Srivastava, Ritesh K; Chaudhary, Sandeep C; Ballestas, Mary E; Kopelovich, Levy; Elmets, Craig A; Athar, Mohammad

    2013-01-15

    Histone deacetylase (HDAC) inhibitors are potent anticancer agents and show efficacy against various human neoplasms. Vorinostat is a potent HDAC inhibitor and has shown potential to inhibit growth of human xenograft tumors. However, its effect on the growth of skin neoplasm remains undefined. In this study, we show that vorinostat (2 μM) reduced expression of HDAC1, 2, 3, and 7 in epidermoid carcinoma A431 cells. Consistently, it increased acetylation of histone H3 and p53. Vorinostat (100mg/kg body weight, IP) treatment reduced human xenograft tumor growth in highly immunosuppressed nu/nu mice. Histologically, the vorinostat-treated tumor showed features of well-differentiation with large necrotic areas. Based on proliferating cell nuclear antigen (PCNA) staining and expression of cyclins D1, D2, E, and A, vorinostat seems to impair proliferation by down-regulating the expression of these proteins. However, it also induced apoptosis. The mechanism by which vorinostat blocks proliferation and makes tumor cells prone to apoptosis, involved inhibition of mTOR signaling which was accompanied by reduction in cell survival AKT and extracellular-signal regulated kinase (ERK) signaling pathways. Our data provide a novel mechanism-based therapeutic intervention for cutaneous squamous cell carcinoma (SCC). Vorinostat may be utilized to cure skin neoplasms in organ transplant recipient (OTR). These patients have high morbidity and surgical removal of these lesions which frequently develop in these patients, is difficult. Copyright © 2012 Elsevier Inc. All rights reserved.

  19. Simplified model of a PWR primary circuit

    International Nuclear Information System (INIS)

    Souza, A.L.; Faya, A.J.G.

    1988-07-01

    The computer program RENUR was developed to perform a very simplified simulation of a typical PWR primary circuit. The program has mathematical models for the thermal-hydraulics of the reactor core and the pressurizer, the rest of the circuit being treated as a single volume. Heat conduction in the fuel rod is analyzed by a nodal model. Average and hot channels are treated so that bulk response of the core and DNBR can be evaluated. A homogenenous model is employed in the pressurizer. Results are presented for a steady-state situation as well as for a loss of load transient. Agreement with the results of more elaborate computer codes is good with substantial reduction in computer costs. (author) [pt

  20. Targeting Tumor Cells with Anti-CD44 Antibody Triggers Macrophage-Mediated Immune Modulatory Effects in a Cancer Xenograft Model.

    Science.gov (United States)

    Maisel, Daniela; Birzele, Fabian; Voss, Edgar; Nopora, Adam; Bader, Sabine; Friess, Thomas; Goller, Bernhard; Laifenfeld, Daphna; Weigand, Stefan; Runza, Valeria

    2016-01-01

    CD44, a transmembrane receptor reported to be involved in various cellular functions, is overexpressed in several cancer types and supposed to be involved in the initiation, progression and prognosis of these cancers. Since the sequence of events following the blockage of the CD44-HA interaction has not yet been studied in detail, we profiled xenograft tumors by RNA Sequencing to elucidate the mode of action of the anti-CD44 antibody RG7356. Analysis of tumor and host gene-expression profiles led us to the hypothesis that treatment with RG7356 antibody leads to an activation of the immune system. Using cytokine measurements we further show that this activation involves the secretion of chemo-attractants necessary for the recruitment of immune cells (i.e. macrophages) to the tumor site. We finally provide evidence for antibody-dependent cellular phagocytosis (ADCP) of the malignant cells by macrophages.

  1. Targeting Tumor Cells with Anti-CD44 Antibody Triggers Macrophage-Mediated Immune Modulatory Effects in a Cancer Xenograft Model.

    Directory of Open Access Journals (Sweden)

    Daniela Maisel

    Full Text Available CD44, a transmembrane receptor reported to be involved in various cellular functions, is overexpressed in several cancer types and supposed to be involved in the initiation, progression and prognosis of these cancers. Since the sequence of events following the blockage of the CD44-HA interaction has not yet been studied in detail, we profiled xenograft tumors by RNA Sequencing to elucidate the mode of action of the anti-CD44 antibody RG7356. Analysis of tumor and host gene-expression profiles led us to the hypothesis that treatment with RG7356 antibody leads to an activation of the immune system. Using cytokine measurements we further show that this activation involves the secretion of chemo-attractants necessary for the recruitment of immune cells (i.e. macrophages to the tumor site. We finally provide evidence for antibody-dependent cellular phagocytosis (ADCP of the malignant cells by macrophages.

  2. Inhibition of COX-2 expression by topical diclofenac enhanced radiation sensitivity via enhancement of TRAIL in human prostate adenocarcinoma xenograft model

    Science.gov (United States)

    2013-01-01

    Background COX-2 inhibitors have an antitumor potential and have been verified by many researchers. Treatment of cancer cells with external stressors such as irradiation can stimulate the over-expression of COX-2 and possibly confer radiation resistance. In this study, we tested if topical diclofenac, which inhibits both COX-1 and COX-2, administration rendered prostate tumor cells sensitize to the effects of radiation. Methods LNCaP-COX-2 and LNCaP-Neo cells were treated with 0 to 1000 μM diclofenac. Next, a clonogenic assay was performed in which cells were subjected to irradiation (0 to 4 Gy) with or without diclofenac. COX-2 expression and other relevant molecules were measured by real-time PCR and immunohistochemistry after irradiation and diclofenac treatment. In addition, we assessed the tumor volumes of xenograft LNCaP-COX-2 cells treated with topical diclofenac with or without radiation therapy (RT). Results LNCaP-COX-2 and LNCaP-Neo cell lines experienced cytotoxic effects of diclofenac in a dose related manner. Clonogenic assays demonstrated that LNCaP-COX-2 cells were significantly more resistant to RT than LNCaP-Neo cells. Furthermore, the addition of diclofenac sensitized LNCaP-COX-2 not but LNCaP-Neo cells to the cytocidal effects of radiation. In LNCaP-COX-2 cells, diclofenac enhanced radiation-induced apoptosis compared with RT alone. This phenomenon might be attributed to enhancement of RT-induced TRAIL expression as demonstrated by real-time PCR analysis. Lastly, tumor volumes of LNCaP-COX-2 cells xenograft treated with diclofenac or RT alone was >4-fold higher than in mice treated with combined diclofenac and radiation (pdiclofenac enhances the effect of RT on prostate cancer cells that express COX-2. Thus, diclofenac may have potential as radiosensitizer for treatment of prostate cancer. PMID:23289871

  3. Selenite Treatment Inhibits LAPC-4 Tumor Growth and Prostate-Specific Antigen Secretion in a Xenograft Model of Human Prostate Cancer

    International Nuclear Information System (INIS)

    Bhattacharyya, Rumi S.; Husbeck, Bryan; Feldman, David; Knox, Susan J.

    2008-01-01

    Purpose: Selenium compounds have known chemopreventive effects on prostate cancer. However selenite, an inorganic form of selenium, has not been extensively studied as a treatment option for prostate cancer. Our previous studies have demonstrated the inhibition of androgen receptor expression and androgen stimulated prostate-specific antigen (PSA) expression by selenite in human prostate cancer cell lines. In this study, we investigated the in vivo effects of selenite as a therapy to treat mice with established LAPC-4 tumors. Methods and Materials: Male mice harboring androgen-dependent LAPC-4 xenograft tumors were treated with selenite (2 mg/kg intraperitoneally three times per week) or vehicle for 42 days. In addition, androgen-independent LAPC-4 xenograft tumors were generated in female mice over 4 to 6 months. Once established, androgen-independent LAPC-4 tumor fragments were passaged into female mice and were treated with selenite or vehicle for 42 days. Changes in tumor volume and serum PSA levels were assessed. Results: Selenite significantly decreased androgen-dependent LAPC-4 tumor growth in male mice over 42 days (p < 0.001). Relative tumor volume was decreased by 41% in selenite-treated animals compared with vehicle-treated animals. The inhibition of LAPC-4 tumor growth corresponded to a marked decrease in serum PSA levels (p < 0.01). In the androgen-independent LAPC-4 tumors in female mice, selenite treatment decreased tumor volume by 58% after 42 days of treatment (p < 0.001). Conclusions: These results suggest that selenite may have potential as a novel therapeutic agent to treat both androgen-dependent and androgen-independent prostate cancer

  4. Modelling the stochastic behaviour of primary nucleation.

    Science.gov (United States)

    Maggioni, Giovanni Maria; Mazzotti, Marco

    2015-01-01

    We study the stochastic nature of primary nucleation and how it manifests itself in a crystallisation process at different scales and under different operating conditions. Such characteristics of nucleation are evident in many experiments where detection times of crystals are not identical, despite identical experimental conditions, but instead are distributed around an average value. While abundant experimental evidence has been reported in the literature, a clear theoretical understanding and an appropriate modelling of this feature is still missing. In this contribution, we present two models describing a batch cooling crystallisation, where the interplay between stochastic nucleation and deterministic crystal growth is described differently in each. The nucleation and growth rates of the two models are estimated by a comprehensive set of measurements of paracetamol crystallisation from aqueous solution in a 1 mL vessel [Kadam et al., Chemical Engineering Science, 2012, 72, 10-19]. Both models are applied to the cooling crystallisation process above under different operating conditions, i.e. different volumes, initial concentrations, cooling rates. The advantages and disadvantages of the two approaches are illustrated and discussed, with particular reference to their use across scales of nucleation rate measured in very small crystallisers.

  5. Clonal selection in xenografted TAM recapitulates the evolutionary process of myeloid leukemia in Down syndrome.

    Science.gov (United States)

    Saida, Satoshi; Watanabe, Ken-ichiro; Sato-Otsubo, Aiko; Terui, Kiminori; Yoshida, Kenichi; Okuno, Yusuke; Toki, Tsutomu; Wang, RuNan; Shiraishi, Yuichi; Miyano, Satoru; Kato, Itaru; Morishima, Tatsuya; Fujino, Hisanori; Umeda, Katsutsugu; Hiramatsu, Hidefumi; Adachi, Souichi; Ito, Etsuro; Ogawa, Seishi; Ito, Mamoru; Nakahata, Tatsutoshi; Heike, Toshio

    2013-05-23

    Transient abnormal myelopoiesis (TAM) is a clonal preleukemic disorder that progresses to myeloid leukemia of Down syndrome (ML-DS) through the accumulation of genetic alterations. To investigate the mechanism of leukemogenesis in this disorder, a xenograft model of TAM was established using NOD/Shi-scid, interleukin (IL)-2Rγ(null) mice. Serial engraftment after transplantation of cells from a TAM patient who developed ML-DS a year later demonstrated their self-renewal capacity. A GATA1 mutation and no copy number alterations (CNAs) were detected in the primary patient sample by conventional genomic sequencing and CNA profiling. However, in serial transplantations, engrafted TAM-derived cells showed the emergence of divergent subclones with another GATA1 mutation and various CNAs, including a 16q deletion and 1q gain, which are clinically associated with ML-DS. Detailed genomic analysis identified minor subclones with a 16q deletion or this distinct GATA1 mutation in the primary patient sample. These results suggest that genetically heterogeneous subclones with varying leukemia-initiating potential already exist in the neonatal TAM phase, and ML-DS may develop from a pool of such minor clones through clonal selection. Our xenograft model of TAM may provide unique insight into the evolutionary process of leukemia.

  6. Integrated genomics of ovarian xenograft tumor progression and chemotherapy response

    International Nuclear Information System (INIS)

    Stuckey, Ashley; Brodsky, Alexander S; Fischer, Andrew; Miller, Daniel H; Hillenmeyer, Sara; Kim, Kyu K; Ritz, Anna; Singh, Rakesh K; Raphael, Benjamin J; Brard, Laurent

    2011-01-01

    Ovarian cancer is the most deadly gynecological cancer with a very poor prognosis. Xenograft mouse models have proven to be one very useful tool in testing candidate therapeutic agents and gene function in vivo. In this study we identify genes and gene networks important for the efficacy of a pre-clinical anti-tumor therapeutic, MT19c. In order to understand how ovarian xenograft tumors may be growing and responding to anti-tumor therapeutics, we used genome-wide mRNA expression and DNA copy number measurements to identify key genes and pathways that may be critical for SKOV-3 xenograft tumor progression. We compared SKOV-3 xenografts treated with the ergocalciferol derived, MT19c, to untreated tumors collected at multiple time points. Cell viability assays were used to test the function of the PPARγ agonist, Rosiglitazone, on SKOV-3 cell growth. These data indicate that a number of known survival and growth pathways including Notch signaling and general apoptosis factors are differentially expressed in treated vs. untreated xenografts. As tumors grow, cell cycle and DNA replication genes show increased expression, consistent with faster growth. The steroid nuclear receptor, PPARγ, was significantly up-regulated in MT19c treated xenografts. Surprisingly, stimulation of PPARγ with Rosiglitazone reduced the efficacy of MT19c and cisplatin suggesting that PPARγ is regulating a survival pathway in SKOV-3 cells. To identify which genes may be important for tumor growth and treatment response, we observed that MT19c down-regulates some high copy number genes and stimulates expression of some low copy number genes suggesting that these genes are particularly important for SKOV-3 xenograft growth and survival. We have characterized the time dependent responses of ovarian xenograft tumors to the vitamin D analog, MT19c. Our results suggest that PPARγ promotes survival for some ovarian tumor cells. We propose that a combination of regulated expression and copy number

  7. Radiosynthesis, biodistribution and imaging of [11C]YM155, a novel survivin suppressant, in a human prostate tumor-xenograft mouse model

    International Nuclear Information System (INIS)

    Murakami, Yoshihiro; Matsuya, Takahiro; Kita, Aya; Yamanaka, Kentaro; Noda, Akihiro; Mitsuoka, Keisuke; Nakahara, Takahito; Miyoshi, Sosuke; Nishimura, Shintaro

    2013-01-01

    Introduction: Sepantronium bromide (YM155) is an antitumor drug in development and is a first-in-class chemical entity, which is a survivin suppressant. We developed a radiosynthesis of [ 11 C]YM155 to non-invasively evaluate its tissue and tumor distribution in mice bearing human prostate tumor xenografts. Methods: Methods utilizing [ 11 C]acetyl chloride and [ 11 C]methyl triflate, both accessible with automated radiosynthesis boxes, were evaluated. The O-methylation of ethanolamine-alkolate with [ 11 C]methyl triflate proved to be the key development toward a rapid and efficient process. The whole-body distribution of [ 11 C]YM155 in PC-3 xenografted mice was examined using a planar positron imaging system (PPIS). Results: Sufficient quantities of radiopharmaceutical grade [ 11 C]YM155 were produced for our PET imaging and distribution studies. The decay corrected (EOB) radiochemical yield was 16–22%, within a synthesis time of 47 min. The radiochemical purity was higher than 99%, and the specific activity was 29–60 GBq/μmol (EOS). High uptake levels of radioactivity (%ID/g, mean ± SE) were observed in tumor (0.0613 ± 0.0056), kidneys (0.0513 ± 0.0092), liver (0.0368 ± 0.0043) and cecum (0.0623 ± 0.0070). The highest tumor uptake was observed at an early time point (from 10 min after) following injection. Tumor-to-blood and tumor-to-muscle uptake ratios of [ 11 C]YM155, at 40 min after injection, were 26.5 (± 2.9) and 25.6 (± 3.6), respectively. Conclusion: A rapid method for producing a radiopharmaceutical grade [ 11 C]YM155 was developed. An in vivo distribution study using PPIS showed high uptake of [ 11 C]YM155 in tumor tissue. Our methodology may facilitate the evaluation and prediction of response to YM155, when given as an anti-cancer agent

  8. Anti-metastasis activity of black rice anthocyanins against breast cancer: analyses using an ErbB2 positive breast cancer cell line and tumoral xenograft model.

    Science.gov (United States)

    Luo, Li-Ping; Han, Bin; Yu, Xiao-Ping; Chen, Xiang-Yan; Zhou, Jie; Chen, Wei; Zhu, Yan-Feng; Peng, Xiao-Li; Zou, Qiang; Li, Sui-Yan

    2014-01-01

    Increasing evidence from animal, epidemiological and clinical investigations suggest that dietary anthocyanins have potential to prevent chronic diseases, including cancers. It is also noteworthy that human epidermal growth factor receptor 2 (ErbB2) protein overexpression or ErbB2 gene amplification has been included as an indicator for metastasis and higher risk of recurrence for breast cancer. The present experiments investigated the anti-metastasis effects of black rice anthocyanins (BRACs) on ErbB2 positive breast cancer cells in vivo and in vitro. Oral administration of BRACs (150 mg/kg/day) reduced transplanted tumor growth, inhibited pulmonary metastasis, and decreased lung tumor nodules in BALB/c nude mice bearing ErbB2 positive breast cancer cell MDA-MB-453 xenografts. The capacity for migration, adhesion, motility and invasion was also inhibited by BRACs in MDA-MB-453 cells in a concentration dependent manner, accompanied by decreased activity of a transfer promoting factor, urokinase-type plasminogen activator (u-PA). Together, our results indicated that BRACs possess anti-metastasis potential against ErbB2 positive human breast cancer cells in vivo and in vitro through inhibition of metastasis promoting molecules.

  9. Overexpression of YB1 C-terminal domain inhibits proliferation, angiogenesis and tumorigenicity in a SK-BR-3 breast cancer xenograft mouse model.

    Science.gov (United States)

    Shi, Jian-Hong; Cui, Nai-Peng; Wang, Shuo; Zhao, Ming-Zhi; Wang, Bing; Wang, Ya-Nan; Chen, Bao-Ping

    2016-01-01

    Y-box-binding protein 1 (YB1) is a multifunctional transcription factor with vital roles in proliferation, differentiation and apoptosis. In this study, we have examined the role of its C-terminal domain (YB1 CTD) in proliferation, angiogenesis and tumorigenicity in breast cancer. Breast cancer cell line SK-BR-3 was infected with GFP-tagged YB1 CTD adenovirus expression vector. An 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) proliferation assay showed that YB1 CTD decreased SK-BR-3 cell proliferation, and down-regulated cyclin B1 and up-regulated p21 levels in SK-BR-3 cells. YB1 CTD overexpression changed the cytoskeletal organization and slightly inhibited the migration of SK-BR-3 cells. YB1 CTD also inhibited secreted VEGF expression in SK-BR-3 cells, which decreased SK-BR-3-induced EA.hy926 endothelial cell angiogenesis in vitro. YB1 CTD overexpression attenuated the ability of SK-BR-3 cells to form tumours in nude mice, and decreased in vivo VEGF levels and angiogenesis in the xenografts in SK-BR-3 tumour-bearing mice. Taken together, our findings demonstrate the vital role of YB1 CTD overexpression in inhibiting proliferation, angiogenesis and tumorigenicity of breast cancer cell line SK-BR-3.

  10. Evaluation of heterogeneous metabolic profile in an orthotopic human glioblastoma xenograft model using compressed sensing hyperpolarized 3D 13C magnetic resonance spectroscopic imaging.

    Science.gov (United States)

    Park, Ilwoo; Hu, Simon; Bok, Robert; Ozawa, Tomoko; Ito, Motokazu; Mukherjee, Joydeep; Phillips, Joanna J; James, C David; Pieper, Russell O; Ronen, Sabrina M; Vigneron, Daniel B; Nelson, Sarah J

    2013-07-01

    High resolution compressed sensing hyperpolarized (13)C magnetic resonance spectroscopic imaging was applied in orthotopic human glioblastoma xenografts for quantitative assessment of spatial variations in (13)C metabolic profiles and comparison with histopathology. A new compressed sensing sampling design with a factor of 3.72 acceleration was implemented to enable a factor of 4 increase in spatial resolution. Compressed sensing 3D (13)C magnetic resonance spectroscopic imaging data were acquired from a phantom and 10 tumor-bearing rats following injection of hyperpolarized [1-(13)C]-pyruvate using a 3T scanner. The (13)C metabolic profiles were compared with hematoxylin and eosin staining and carbonic anhydrase 9 staining. The high-resolution compressed sensing (13)C magnetic resonance spectroscopic imaging data enabled the differentiation of distinct (13)C metabolite patterns within abnormal tissues with high specificity in similar scan times compared to the fully sampled method. The results from pathology confirmed the different characteristics of (13)C metabolic profiles between viable, non-necrotic, nonhypoxic tumor, and necrotic, hypoxic tissue. Copyright © 2012 Wiley Periodicals, Inc.

  11. Therapeutic Silencing of Bcl-2 by Systemically Administered siRNA Nanotherapeutics Inhibits Tumor Growth by Autophagy and Apoptosis and Enhances the Efficacy of Chemotherapy in Orthotopic Xenograft Models of ER (− and ER (+ Breast Cancer

    Directory of Open Access Journals (Sweden)

    Ibrahim Tekedereli

    2013-01-01

    Full Text Available Bcl-2 is overexpressed in about a half of human cancers and 50–70% of breast cancer patients, thereby conferring resistance to conventional therapies and making it an excellent therapeutic target. Small interfering RNA (siRNA offers novel and powerful tools for specific gene silencing and molecularly targeted therapy. Here, we show that therapeutic silencing of Bcl-2 by systemically administered nanoliposomal (NL-Bcl-2 siRNA (0.15 mg siRNA/kg, intravenous twice a week leads to significant antitumor activity and suppression of growth in both estrogen receptor-negative (ER(− MDA-MB-231 and ER-positive (+ MCF7 breast tumors in orthotopic xenograft models (P < 0.05. A single intravenous injection of NL-Bcl-2-siRNA provided robust and persistent silencing of the target gene expression in xenograft tumors. NL-Bcl-2-siRNA treatment significantly increased the efficacy of chemotherapy when combined with doxorubicin in both MDA-MB-231 and MCF-7 animal models (P < 0.05. NL-Bcl-2-siRNA treatment-induced apoptosis and autophagic cell death, and inhibited cyclin D1, HIF1α and Src/Fak signaling in tumors. In conclusion, our data provide the first evidence that in vivo therapeutic targeting Bcl-2 by systemically administered nanoliposomal-siRNA significantly inhibits growth of both ER(− and ER(+ breast tumors and enhances the efficacy of chemotherapy, suggesting that therapeutic silencing of Bcl-2 by siRNA is a viable approach in breast cancers.

  12. The primary care amplification model: taking the best of primary care forward

    Directory of Open Access Journals (Sweden)

    Nicholson Caroline

    2008-12-01

    Full Text Available Abstract Background Primary care internationally is approaching a new paradigm. The change agenda implicit in this threatens to de-stabilise and challenge established general practice and primary care. Discussion The Primary Care Amplification Model offers a means to harness the change agenda by 'amplifying' the strengths of established general practices around a 'beacon' practice. Conclusion Such 'beacon' practices can provide a mustering point for an expanded scope of practice for primary care, integrated primary/secondary service delivery, interprofessional learning, relevant local clinical research, and a focus on local service innovation, enhancing rather than fragmenting the collective capacity of existing primary care.

  13. Patient-derived Hormone-naive Prostate Cancer Xenograft Models Reveal Growth Factor Receptor Bound Protein 10 as an Androgen Receptor-repressed Gene Driving the Development of Castration-resistant Prostate Cancer.

    Science.gov (United States)

    Hao, Jun; Ci, Xinpei; Xue, Hui; Wu, Rebecca; Dong, Xin; Choi, Stephen Yiu Chuen; He, Haiqing; Wang, Yu; Zhang, Fang; Qu, Sifeng; Zhang, Fan; Haegert, Anne M; Gout, Peter W; Zoubeidi, Amina; Collins, Colin; Gleave, Martin E; Lin, Dong; Wang, Yuzhuo

    2018-06-01

    Although androgen deprivation therapy is initially effective in controlling growth of hormone-naive prostate cancers (HNPCs) in patients, currently incurable castration-resistant prostate cancer (CRPC) inevitably develops. To identify CRPC driver genes that may provide new targets to enhance CRPC therapy. Patient-derived xenografts (PDXs) of HNPCs that develop CRPC following host castration were examined for changes in expression of genes at various time points after castration using transcriptome profiling analysis; particular attention was given to pre-CRPC changes in expression indicative of genes acting as potential CRPC drivers. The functionality of a potential CRPC driver was validated via its knockdown in cultured prostate cancer cells; its clinical relevance was established using data from prostate cancer patient databases. Eighty genes were found to be significantly upregulated at the CRPC stage, while seven of them also showed elevated expression prior to CRPC development. Among the latter, growth factor receptor bound protein 10 (GRB10) was the most significantly and consistently upregulated gene. Moreover, elevated GRB10 expression in clinical prostate cancer samples correlated with more aggressive tumor types and poorer patient treatment outcome. GRB10 knockdown markedly reduced prostate cancer cell proliferation and activity of AKT, a well-established CRPC mediator. A positive correlation between AKT activity and GRB10 expression was also found in clinical cohorts. GRB10 acts as a driver of CRPC and sensitizes androgen receptor pathway inhibitors, and hence GRB10 targeting provides a novel therapeutic strategy for the disease. Development of castration-resistant prostate cancer (CRPC) is a major problem in the management of the disease. Using state-of-the-art patient-derived hormone-naive prostate cancer xenograft models, we found and validated the growth factor receptor bound protein 10 gene as a driver of CRPC, indicating that it may be used as a

  14. Antitumor Efficacy of the Dual PI3K/mTOR Inhibitor PF-04691502 in a Human Xenograft Tumor Model Derived from Colorectal Cancer Stem Cells Harboring a PIK3CA Mutation.

    Directory of Open Access Journals (Sweden)

    Douglas D Fang

    Full Text Available PIK3CA (phosphoinositide-3-kinase, catalytic, alpha polypeptide mutations can help predict the antitumor activity of phosphatidylinositol-3-kinase (PI3K/mammalian target of rapamycin (mTOR pathway inhibitors in both preclinical and clinical settings. In light of the recent discovery of tumor-initiating cancer stem cells (CSCs in various tumor types, we developed an in vitro CSC model from xenograft tumors established in mice from a colorectal cancer patient tumor in which the CD133+/EpCAM+ population represented tumor-initiating cells. CD133+/EpCAM+ CSCs were enriched under stem cell culture conditions and formed 3-dimensional tumor spheroids. Tumor spheroid cells exhibited CSC properties, including the capability for differentiation and self-renewal, higher tumorigenic potential and chemo-resistance. Genetic analysis using an OncoCarta™ panel revealed a PIK3CA (H1047R mutation in these cells. Using a dual PI3K/mTOR inhibitor, PF-04691502, we then showed that blockage of the PI3K/mTOR pathway inhibited the in vitro proliferation of CSCs and in vivo xenograft tumor growth with manageable toxicity. Tumor growth inhibition in mice was accompanied by a significant reduction of phosphorylated Akt (pAKT (S473, a well-established surrogate biomarker of PI3K/mTOR signaling pathway inhibition. Collectively, our data suggest that PF-04691502 exhibits potent anticancer activity in colorectal cancer by targeting both PIK3CA (H1047R mutant CSCs and their derivatives. These results may assist in the clinical development of PF-04691502 for the treatment of a subpopulation of colorectal cancer patients with poor outcomes.

  15. Costs of health care across primary care models in Ontario.

    Science.gov (United States)

    Laberge, Maude; Wodchis, Walter P; Barnsley, Jan; Laporte, Audrey

    2017-08-01

    The purpose of this study is to analyze the relationship between newly introduced primary care models in Ontario, Canada, and patients' primary care and total health care costs. A specific focus is on the payment mechanisms for primary care physicians, i.e. fee-for-service (FFS), enhanced-FFS, and blended capitation, and whether providers practiced as part of a multidisciplinary team. Utilization data for a one year period was measured using administrative databases for a 10% sample selected at random from the Ontario adult population. Primary care and total health care costs were calculated at the individual level and included costs from physician services, hospital visits and admissions, long term care, drugs, home care, lab tests, and visits to non-medical health care providers. Generalized linear model regressions were conducted to assess the differences in costs between primary care models. Patients not enrolled with a primary care physicians were younger, more likely to be males and of lower socio-economic status. Patients in blended capitation models were healthier and wealthier than FFS and enhanced-FFS patients. Primary care and total health care costs were significantly different across Ontario primary care models. Using the traditional FFS as the reference, we found that patients in the enhanced-FFS models had the lowest total health care costs, and also the lowest primary care costs. Patients in the blended capitation models had higher primary care costs but lower total health care costs. Patients that were in multidisciplinary teams (FHT), where physicians are also paid on a blended capitation basis, had higher total health care costs than non-FHT patients but still lower than the FFS reference group. Primary care and total health care costs increased with patients' age, morbidity, and lower income quintile across all primary care payment types. The new primary care models were associated with lower total health care costs for patients compared to the

  16. Evaluation of the therapeutic efficacy of a VEGFR2-blocking antibody using sodium-iodide symporter molecular imaging in a tumor xenograft model

    Energy Technology Data Exchange (ETDEWEB)

    Cheong, Su-Jin; Lee, Chang-Moon; Kim, Eun-Mi [Department of Nuclear Medicine, Chonbuk National University Medical School, Jeonju-si, Jeonbuk 561-712 (Korea, Republic of); Research Institute of Clinical Medicine, Chonbuk National University Medical School, Jeonju-si, Jeonbuk 561-712 (Korea, Republic of); Cyclotron Research Center, Chonbuk National University Hospital, Jeonju-si, Jeonbuk 561-712 (Korea, Republic of); Uhm, Tai-Boong [Faculty of Biological Science, Chonbuk National University, Jeonju-si, jeonbuk 561-756 (Korea, Republic of); Jeong, Hwan-Jeong, E-mail: jayjeong@chonbuk.ac.k [Department of Nuclear Medicine, Chonbuk National University Medical School, Jeonju-si, Jeonbuk 561-712 (Korea, Republic of); Research Institute of Clinical Medicine, Chonbuk National University Medical School, Jeonju-si, Jeonbuk 561-712 (Korea, Republic of); Cyclotron Research Center, Chonbuk National University Hospital, Jeonju-si, Jeonbuk 561-712 (Korea, Republic of); Kim, Dong Wook; Lim, Seok Tae; Sohn, Myung-Hee [Department of Nuclear Medicine, Chonbuk National University Medical School, Jeonju-si, Jeonbuk 561-712 (Korea, Republic of); Research Institute of Clinical Medicine, Chonbuk National University Medical School, Jeonju-si, Jeonbuk 561-712 (Korea, Republic of); Cyclotron Research Center, Chonbuk National University Hospital, Jeonju-si, Jeonbuk 561-712 (Korea, Republic of)

    2011-01-15

    Purpose: Vascular endothelial growth factor receptor 2-blocking antibody (DC101) has inhibitory effects on tumor growth and angiogenesis in vivo. The human sodium/iodide symporter (hNIS) gene has been shown to be a useful molecular imaging reporter gene. Here, we investigated the evaluation of therapeutic efficacy by molecular imaging in reporter gene transfected tumor xenografts using a gamma imaging system. Methods: The hNIS gene was transfected into MDA-MB-231 cells using Lipofectamine. The correlation between the number of MDA-MB-231-hNIS cells and the uptake of {sup 99m}Tc-pertechnetate or {sup 125}I was investigated in vitro by gamma imaging and counting. MDA-MB-231-hNIS cells were injected subcutaneously into mice. When the tumor volume reached 180-200 mm{sup 3}, we randomly assigned five animals to each of three groups representing different tumor therapies; no DC101 (control), 100 {mu}g, or 150 {mu}g DC101/mouse. One week and 2 weeks after the first injection of DC101, gamma imaging was performed. Mice were sacrificed 2 weeks after the first injection of DC101. The tumor tissues were used for reverse transcriptase-polymerase chain reaction (RT-PCR) and CD31 staining. Results: Uptake of {sup 125}I and {sup 99m}Tc-pertechnetate into MDA-MB-231-hNIS cells in vitro showed correlation with the number of cells. In DC101 treatment groups, the mean tumor volume was smaller than that of the control mice. Furthermore, tumor uptake of {sup 125}I was lower than in the controls. The CD31 staining and RT-PCR assay results showed that vessel formation and expression of the hNIS gene were significantly reduced in the tumor tissues of treatment groups. Conclusion: This study demonstrated the power of molecular imaging using a gamma imaging system for evaluating the therapeutic efficacy of an antitumor treatment. Molecular imaging systems may be useful in evaluation and development of effective diagnostic and/or therapeutic antibodies for specific target molecules.

  17. 4-tert-Octylphenol stimulates the expression of cathepsins in human breast cancer cells and xenografted breast tumors of a mouse model via an estrogen receptor-mediated signaling pathway

    International Nuclear Information System (INIS)

    Lee, Hye-Rim; Choi, Kyung-Chul

    2013-01-01

    Highlights: ► Cathepsins B and D were markedly enhanced by octylphenol (OP) in MCF-7 cells. ► OP may accelerate breast cancer cell growth and cathepsins via ER-mediated signaling. ► Breast cancer cells exposed with OP to mouse model were more aggressive. ► OP can promote metastasis through the amplification of cathepsins B and D via ER-mediated signaling pathway. -- Abstract: Endocrine disrupting chemicals (EDCs) are defined as environmental compounds that modulate steroid hormone receptor-dependent responses an abnormal manner, resulting in adverse health problems for humans such as cancer growth and metastasis. Cathepsins are proteases that have been implicated in cancer progression. However, there have been few studies about the association between cathepsins and estrogenic chemicals during the cancer progression. In this study, we examined the effect(s) of 4-tert-octylphenol (OP), a potent EDC, on the expression of cathepsins B and D in human MCF-7 breast cancer cells and a xenograft mouse model. Treatment with OP significantly induced the proliferation MCF-7 cells in an MTT assay. In addition, the expression of cathepsins B and D was markedly enhanced in MCF-7 cells at both the transcriptional and the translational levels following treatment with E2 or OP up to 48 h. These results demonstrated the ability of OP to disrupt normal transcriptional regulation of cathepsins B and D in human breast cancer cells. However, the effects of OP on cell growth or overexpression of cathepsins by inhibiting ER-mediated signaling were abolished by an ER antagonist and siRNA specific for ERα. In conclusion, our findings suggest that OP at 10 −6 M, like E2, may accelerate breast cancer cell proliferation and the expression of cathepsins through an ER-mediated signaling pathway. In addition, the breast cancer cells exposed with OP to a xenograft mouse model were more aggressive according to our histological analysis and showed markedly increased expression of

  18. Genomic characterisation of small cell lung cancer patient-derived xenografts generated from endobronchial ultrasound-guided transbronchial needle aspiration specimens.

    Directory of Open Access Journals (Sweden)

    Tracy L Leong

    Full Text Available Patient-derived xenograft (PDX models generated from surgical specimens are gaining popularity as preclinical models of cancer. However, establishment of PDX lines from small cell lung cancer (SCLC patients is difficult due to very limited amount of available biopsy material. We asked whether SCLC cells obtained from endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA could generate PDX lines that maintained the phenotypic and genetic characteristics of the primary tumor. Following successful EBUS-TBNA sampling for diagnostic purposes, we obtained an extra sample for cytologic analysis and implantation into the flanks of immunodeficient mice. Animals were monitored for engraftment for up to 6 months. Histopathologic and immunohistochemical analysis, and targeted next-generation re-sequencing, were then performed in both the primary sample and the derivative PDX line. A total of 12 patients were enrolled in the study. EBUS-TBNA aspirates yielded large numbers of viable tumor cells sufficient to inject between 18,750 and 1,487,000 cells per flank, and to yield microgram quantities of high-quality DNA. Of these, samples from 10 patients generated xenografts (engraftment rate 83% with a mean latency of 104 days (range 63-188. All but one maintained a typical SCLC phenotype that closely matched the original sample. Identical mutations that are characteristic of SCLC were identified in both the primary sample and xenograft line. EBUS-TBNA has the potential to be a powerful tool in the development of new targeting strategies for SCLC patients by providing large numbers of viable tumor cells suitable for both xenografting and complex genomic analysis.

  19. A Participatory Model of the Paradox of Primary Care

    Science.gov (United States)

    Homa, Laura; Rose, Johnie; Hovmand, Peter S.; Cherng, Sarah T.; Riolo, Rick L.; Kraus, Alison; Biswas, Anindita; Burgess, Kelly; Aungst, Heide; Stange, Kurt C.; Brown, Kalanthe; Brooks-Terry, Margaret; Dec, Ellen; Jackson, Brigid; Gilliam, Jules; Kikano, George E.; Reichsman, Ann; Schaadt, Debbie; Hilfer, Jamie; Ticknor, Christine; Tyler, Carl V.; Van der Meulen, Anna; Ways, Heather; Weinberger, Richard F.; Williams, Christine

    2015-01-01

    PURPOSE The paradox of primary care is the observation that primary care is associated with apparently low levels of evidence-based care for individual diseases, but systems based on primary care have healthier populations, use fewer resources, and have less health inequality. The purpose of this article is to explore, from a complex systems perspective, mechanisms that might account for the effects of primary care beyond disease-specific care. METHODS In an 8-session, participatory group model-building process, patient, caregiver, and primary care clinician community stakeholders worked with academic investigators to develop and refine an agent-based computer simulation model to test hypotheses about mechanisms by which features of primary care could affect health and health equity. RESULTS In the resulting model, patients are at risk for acute illness, acute life-changing illness, chronic illness, and mental illness. Patients have changeable health behaviors and care-seeking tendencies that relate to their living in advantaged or disadvantaged neighborhoods. There are 2 types of care available to patients: primary and specialty. Primary care in the model is less effective than specialty care in treating single diseases, but it has the ability to treat multiple diseases at once. Primary care also can provide disease prevention visits, help patients improve their health behaviors, refer to specialty care, and develop relationships with patients that cause them to lower their threshold for seeking care. In a model run with primary care features turned off, primary care patients have poorer health. In a model run with all primary care features turned on, their conjoint effect leads to better population health for patients who seek primary care, with the primary care effect being particularly pronounced for patients who are disadvantaged and patients with multiple chronic conditions. Primary care leads to more total health care visits that are due to more disease

  20. Effect of fenhexamid and cyprodinil on the expression of cell cycle- and metastasis-related genes via an estrogen receptor-dependent pathway in cellular and xenografted ovarian cancer models

    International Nuclear Information System (INIS)

    Go, Ryeo-Eun; Kim, Cho-Won; Choi, Kyung-Chul

    2015-01-01

    ABSTRACT: Fenhexamid and cyprodinil are antifungal agents (pesticides) used for agriculture, and are present at measurable amounts in fruits and vegetables. In the current study, the effects of fenhexamid and cyprodinil on cancer cell proliferation and metastasis were examined. Additionally, the protein expression levels of cyclin D1 and cyclin E as well as cathepsin D were analyzed in BG-1 ovarian cancer cells that express estrogen receptors (ERs). The cells were cultured with 0.1% dimethyl sulfoxide (DMSO; control), 17β-estradiol (E2; 10 −9 M), and fenhexamid or cyprodinil (10 –5 –10 −7 M). Results of a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay showed that fenhexamid and cyprodinil increased BG-1 cell proliferation about 1.5 to 2 times similar to E2 (5 times) compared to the control. When the cells were co-treated with ICI 182,780 (10 −8 M), an ER antagonist, the proliferation of pesticide-treated BG-1 cells was decreased to the level of the control. A wound healing assay revealed that the pesticides reduced the disrupted area in the BG-1 cell monolayer similar to E2. Protein levels of cyclin D1 and E as well as cathepsin D were increased by fenhexamid and cyprodinil. This effect was reversed by co-treatment with ICI 182,780. In a xenograft mouse model with transplanted BG-1 cells, cyprodinil significantly increased tumor mass formation about 2 times as did E2 (6 times) compared to the vehicle (0.1% DMSO) over an 80-day period. In contrast, fenhexamid did not promote ovarian tumor formation in this mouse model. Cyprodinil also induced cell proliferation along with the expression of proliferating cell nuclear antigen (PCNA) and cathepsin D in tumor tissues similar to E2. Taken together, these results imply that fenhexamid and cyprodinil may have disruptive effects on ER-expressing cancer by altering the cell cycle- and metastasis-related gene expression via an ER-dependent pathway. - Highlights: • Fenhexamid and

  1. Eribulin regresses a doxorubicin-resistant Ewing's sarcoma with a FUS-ERG fusion and CDKN2A-deletion in a patient-derived orthotopic xenograft (PDOX) nude mouse model.

    Science.gov (United States)

    Miyake, Kentaro; Murakami, Takashi; Kiyuna, Tasuku; Igarashi, Kentaro; Kawaguchi, Kei; Li, Yunfeng; Singh, Arun S; Dry, Sarah M; Eckardt, Mark A; Hiroshima, Yukihiko; Momiyama, Masashi; Matsuyama, Ryusei; Chishima, Takashi; Endo, Itaru; Eilber, Fritz C; Hoffman, Robert M

    2018-01-01

    Ewing's sarcoma is a recalcitrant tumor greatly in need of more effective therapy. The aim of this study was to determine the efficacy of eribulin on a doxorubicin (DOX)-resistant Ewing's sarcoma patient derived orthotopic xenograft (PDOX) model. The Ewing's sarcoma PDOX model was previously established in the right chest wall of nude mice from tumor resected form the patient's right chest wall. In the previous study, the Ewing's sarcoma PDOX was resistant to doxorubicin (DOX) and sensitive to palbociclib and linsitinib. In the present study, the PDOX models were randomized into three groups when the tumor volume reached 60 mm 3 : G1, untreated control (n = 6); G2, DOX treated (n = 6), intraperitoneal (i.p.) injection, weekly, for 2 weeks); G3, Eribulin treated (n = 6, intravenous (i.v.) injection, weekly for 2 weeks). All mice were sacrificed on day 15. Changes in body weight and tumor volume were assessed two times per week. Tumor weight was measured after sacrifice. DOX did not suppress tumor growth compared to the control group (P = 0.589), consistent with the previous results in the patient and PDOX. Eribulin regressed tumor size significantly compared to G1 and G2 (P = 0.006, P = 0.017) respectively. No significant difference was observed in body weight among any group. Our results demonstrate that eribulin is a promising novel therapeutic agent for Ewing's sarcoma. © 2017 Wiley Periodicals, Inc.

  2. A review of ocean chlorophyll algorithms and primary production models

    Science.gov (United States)

    Li, Jingwen; Zhou, Song; Lv, Nan

    2015-12-01

    This paper mainly introduces the five ocean chlorophyll concentration inversion algorithm and 3 main models for computing ocean primary production based on ocean chlorophyll concentration. Through the comparison of five ocean chlorophyll inversion algorithm, sums up the advantages and disadvantages of these algorithm,and briefly analyzes the trend of ocean primary production model.

  3. Benzophenone-1 stimulated the growth of BG-1 ovarian cancer cells by cell cycle regulation via an estrogen receptor alpha-mediated signaling pathway in cellular and xenograft mouse models

    International Nuclear Information System (INIS)

    Park, Min-Ah; Hwang, Kyung-A; Lee, Hye-Rim; Yi, Bo-Rim; Jeung, Eui-Bae; Choi, Kyung-Chul

    2013-01-01

    Highlights: ► BP-1 induced cell growth was reversed by an ER antagonist in BG-1 cells. ► BP-1 up-regulated the mRNA expression of cyclin D1. ► Up-regulation of cyclin D1 by BP-1 was reversed by an ER antagonist. ► BP-1 is a potential endocrine disruptor that exerts estrogenic effects. - Abstract: 2,4-Dihydroxybenzophenone (benzophenone-1; BP-1) is an UV stabilizer primarily used to prevent polymer degradation and deterioration in quality due to UV irradiation. Recently, BP-1 has been reported to bioaccumulate in human bodies by absorption through the skin and has the potential to induce health problems including endocrine disruption. In the present study, we examined the xenoestrogenic effect of BP-1 on BG-1 human ovarian cancer cells expressing estrogen receptors (ERs) and relevant xenografted animal models in comparison with 17-β estradiol (E2). In in vitro cell viability assay, BP-1 (10 −8 –10 −5 M) significantly increased BG-1 cell growth the way E2 did. The mechanism underlying the BG-1 cell proliferation was proved to be related with the up-regulation of cyclin D1, a cell cycle progressor, by E2 or BP-1. Both BP-1 and E2 induced cell growth and up-regulation of cyclin D1 were reversed by co-treatment with ICI 182,780, an ER antagonist, suggesting that BP-1 may mediate the cancer cell proliferation via an ER-dependent pathway like E2. On the other hand, the expression of p21, a regulator of cell cycle progression at G 1 phase, was not altered by BP-1 though it was down-regulated by E2. In xenograft mouse models transplanted with BG-1 cells, BP-1 or E2 treatment significantly increased the tumor mass formation compared to a vehicle (corn oil) within 8 weeks. In histopathological analysis, the tumor sections of E2 or BP-1 group displayed extensive cell formations with high density and disordered arrangement, which were supported by the increased number of BrdUrd positive nuclei and the over-expression of cyclin D1 protein. Taken together, these

  4. Inhibition of signaling between human CXCR4 and zebrafish ligands by the small molecule IT1t impairs the formation of triple-negative breast cancer early metastases in a zebrafish xenograft model

    Directory of Open Access Journals (Sweden)

    Claudia Tulotta

    2016-02-01

    Full Text Available Triple-negative breast cancer (TNBC is a highly aggressive and recurrent type of breast carcinoma that is associated with poor patient prognosis. Because of the limited efficacy of current treatments, new therapeutic strategies need to be developed. The CXCR4-CXCL12 chemokine signaling axis guides cell migration in physiological and pathological processes, including breast cancer metastasis. Although targeted therapies to inhibit the CXCR4-CXCL12 axis are under clinical experimentation, still no effective therapeutic approaches have been established to block CXCR4 in TNBC. To unravel the role of the CXCR4-CXCL12 axis in the formation of TNBC early metastases, we used the zebrafish xenograft model. Importantly, we demonstrate that cross-communication between the zebrafish and human ligands and receptors takes place and human tumor cells expressing CXCR4 initiate early metastatic events by sensing zebrafish cognate ligands at the metastatic site. Taking advantage of the conserved intercommunication between human tumor cells and the zebrafish host, we blocked TNBC early metastatic events by chemical and genetic inhibition of CXCR4 signaling. We used IT1t, a potent CXCR4 antagonist, and show for the first time its promising anti-tumor effects. In conclusion, we confirm the validity of the zebrafish as a xenotransplantation model and propose a pharmacological approach to target CXCR4 in TNBC.

  5. Models for Primary Eye Care Services in India

    Directory of Open Access Journals (Sweden)

    Vasundhra Misra

    2015-01-01

    In the current situation, an integrated health care system with primary eye care promoted by government of India is apparently the best answer. This model is both cost effective and practical for the prevention and control of blindness among the underprivileged population. Other models functioning with the newer technology of tele-ophthalmology or mobile clinics also add to the positive outcome in providing primary eye care services. This review highlights the strengths and weaknesses of various models presently functioning in the country with the idea of providing useful inputs for eye care providers and enabling them to identify and adopt an appropriate model for primary eye care services.

  6. Costs of health care across primary care models in Ontario

    OpenAIRE

    Laberge, Maude; Wodchis, Walter P; Barnsley, Jan; Laporte, Audrey

    2017-01-01

    Background The purpose of this study is to analyze the relationship between newly introduced primary care models in Ontario, Canada, and patients? primary care and total health care costs. A specific focus is on the payment mechanisms for primary care physicians, i.e. fee-for-service (FFS), enhanced-FFS, and blended capitation, and whether providers practiced as part of a multidisciplinary team. Methods Utilization data for a one year period was measured using administrative databases for a 1...

  7. The irony of highly-effective bacterial therapy of a patient-derived orthotopic xenograft (PDOX) model of Ewing's sarcoma, which was blocked by Ewing himself 80 years ago.

    Science.gov (United States)

    Murakami, Takashi; Kiyuna, Tasuku; Kawaguchi, Kei; Igarashi, Kentaro; Singh, Arun S; Hiroshima, Yukihiko; Zhang, Yong; Zhao, Ming; Miyake, Kentaro; Nelson, Scott D; Dry, Sarah M; Li, Yunfeng; DeLong, Jonathan C; Lwin, Thinzar M; Chishima, Takashi; Tanaka, Kuniya; Bouvet, Michael; Endo, Itaru; Eilber, Fritz C; Hoffman, Robert M

    2017-06-03

    William B. Coley developed bacterial therapy of cancer more than 100 years ago and had clinical success. James Ewing, a very famous cancer pathologist for whom the Ewing sarcoma is named, was Coley's boss at Memorial Hospital in New York and terminated Coley's bacterial therapy of cancer. A tumor from a patient with soft-tissue Ewing's sarcoma, who failed doxorubicin (DOX) therapy, was previously implanted in nude mice to establish a patient-derived orthotopic xenograft (PDOX) model. In the present study, the Ewing's sarcoma PDOX was treated with tumor-targeting S. typhimurium A1-R expressing green fluorescent (GFP), alone and in combination with DOX. S. typhimurium A1-R-GFP was detected in the tumors after intratumor (i.t.) or intravenous (i.v.) injection. The combination of S. typhimurium A1-R and DOX significantly reduced tumor weight (37.8 ± 15.6 mg) compared to the untreated control (73.8 ± 10.1 mg, P Ewing's sarcoma had in the patient. S. typhimurium A1-R converted the Ewing's sarcoma from DOX resistant to sensitive. One can only wonder how bacterial therapy and immunotherapy of cancer would have developed over the past 80 years if Ewing did not stop Coley.

  8. Consulting Psychiatry within an Integrated Primary Care Model

    Science.gov (United States)

    Schreiter, Elizabeth A. Zeidler; Pandhi, Nancy; Fondow, Meghan D. M.; Thomas, Chantelle; Vonk, Jantina; Reardon, Claudia L.; Serrano, Neftali

    2014-01-01

    Summary After implementation of an integrated consulting psychiatry model and psychology services within primary care at a federally qualified health center, patients have increased access to needed mental health services, and primary care clinicians receive the support and collaboration needed to meet the psychiatric needs of the population. PMID:24185149

  9. Effective molecular targeting of CDK4/6 and IGF-1R in a rare FUS-ERG fusion CDKN2A-deletion doxorubicin-resistant Ewing's sarcoma patient-derived orthotopic xenograft (PDOX) nude-mouse model.

    Science.gov (United States)

    Murakami, Takashi; Singh, Arun S; Kiyuna, Tasuku; Dry, Sarah M; Li, Yunfeng; James, Aaron W; Igarashi, Kentaro; Kawaguchi, Kei; DeLong, Jonathan C; Zhang, Yong; Hiroshima, Yukihiko; Russell, Tara; Eckardt, Mark A; Yanagawa, Jane; Federman, Noah; Matsuyama, Ryusei; Chishima, Takashi; Tanaka, Kuniya; Bouvet, Michael; Endo, Itaru; Eilber, Fritz C; Hoffman, Robert M

    2016-07-26

    Ewing's sarcoma is a rare and aggressive malignancy. In the present study, tumor from a patient with a Ewing's sarcoma with cyclin-dependent kinase inhibitor 2A/B (CDKN2A/B) loss and FUS-ERG fusion was implanted in the right chest wall of nude mice to establish a patient-derived orthotopic xenograft (PDOX) model. The aim of the present study was to determine efficacy of cyclin-dependent kinase 4/6 (CDK4/6) and insulin-like growth factor-1 receptor (IGF-1R) inhibitors on the Ewing's sarcoma PDOX. The PDOX models were randomized into the following groups when tumor volume reached 50 mm3: G1, untreated control; G2, doxorubicin (DOX) (intraperitoneal (i.p.) injection, weekly, for 2 weeks); G3, CDK4/6 inhibitor (palbociclib, PD0332991, per oral (p.o.), daily, for 14 days); G4, IGF-1R inhibitor (linsitinib, OSI-906, p.o., daily, for 14 days). Tumor growth was significantly suppressed both in G3 (palbociclib) and in G4 (linsitinib) compared to G1 (untreated control) at all measured time points. In contrast, DOX did not inhibit tumor growth at any time point, which is consistent with the failure of DOX to control tumor growth in the patient. The results of the present study demonstrate the power of the PDOX model to identify effective targeted molecular therapy of a recalcitrant DOX-resistant Ewing's sarcoma with specific genetic alterations. The results of this study suggest the potential of PDOX models for individually-tailored, effective targeted therapy for recalcitrant cancer.

  10. Pharmacokinetic-Pharmacodynamic Modeling of the Anti-Tumor Effect of Sunitinib Combined with Dopamine in the Human Non-Small Cell Lung Cancer Xenograft.

    Science.gov (United States)

    Hao, Fangran; Wang, Siyuan; Zhu, Xiao; Xue, Junsheng; Li, Jingyun; Wang, Lijie; Li, Jian; Lu, Wei; Zhou, Tianyan

    2017-02-01

    To investigate the anti-tumor effect of sunitinib in combination with dopamine in the treatment of nu/nu nude mice bearing non-small cell lung cancer (NSCLC) A549 cells and to develop the combination PK/PD model. Further, simulations were conducted to optimize the administration regimens. A PK/PD model was developed based on our preclinical experiment to explore the relationship between plasma concentration and drug effect quantitatively. Further, the model was evaluated and validated. By fixing the parameters obtained from the PK/PD model, simulations were built to predict the tumor suppression under various regimens. The synergistic effect was observed between sunitinib and dopamine in the study, which was confirmed by the effect constant (GAMA, estimated as 2.49). The enhanced potency of dopamine on sunitinib was exerted by on/off effect in the PK/PD model. The optimal dose regimen was selected as sunitinib (120 mg/kg, q3d) in combination with dopamine (2 mg/kg, q3d) based on the simulation study. The synergistic effect of sunitinib and dopamine was demonstrated by the preclinical experiment and confirmed by the developed PK/PD model. In addition, the regimens were optimized by means of modeling as well as simulation, which may be conducive to clinical study.

  11. Xenograft survival in two species combinations using total-lymphoid irradiation and cyclosporine

    International Nuclear Information System (INIS)

    Knechtle, S.J.; Halperin, E.C.; Bollinger, R.R.

    1987-01-01

    Total lymphoid irradiation (TLI) has profound immunosuppressive actions and has been applied successfully to allotransplantation but not xenotransplantation. Cyclosporine (CsA) has not generally permitted successful xenotransplantation of organs but has not been used in combination with TLI. TLI and CsA were given alone and in combination to rats that were recipients of hamster or rabbit cardiac xenografts. Combined TLI and CsA prolonged survival of hamster-to-rat cardiac xenografts from three days in untreated controls to greater than 100 days in most recipients. TLI alone significantly prolonged rabbit to rat xenograft survival with doubling of survival time. However, combined treatment did not significantly prolong rabbit-to-rat cardiac xenograft survival compared with TLI alone. The hamster and rat are phylogenetically closely related. Transplants from hamsters to rat are concordant xenografts since the time course of unmodified rejection is similar to first-set rejection of allografts. Although the rabbit-to-rat transplant is also between concordant species (average survival of untreated controls: 3.2 days) the rabbit and rat are more distantly related. These results suggest that TLI is an effective immunosuppressant when applied to cardiac xenotransplants in these animal models; that the choice of species critically affects xenograft survival when TLI and/or CsA are used for immunosuppression; and that the closely related species combination tested has markedly prolonged (greater than 100 days) survival using combined TLI and CsA

  12. Role of DNA Methylation in Altering Gene Expression During the Early Stages of Human Breast Cancer Progression in the MCF10AT Xenograft Model

    National Research Council Canada - National Science Library

    Christman, Judith

    2004-01-01

    ...) Collect microdissected tissue representative of each of the morphologically different stages of early breast cancer progression in the MCFlOAT model to obtain RNA and DNA for miroarray analysis...

  13. Modeling and Control of Primary Parallel Isolated Boost Converter

    DEFF Research Database (Denmark)

    Mira Albert, Maria del Carmen; Hernandez Botella, Juan Carlos; Sen, Gökhan

    2012-01-01

    In this paper state space modeling and closed loop controlled operation have been presented for primary parallel isolated boost converter (PPIBC) topology as a battery charging unit. Parasitic resistances have been included to have an accurate dynamic model. The accuracy of the model has been...

  14. Fast Appearance Modeling for Automatic Primary Video Object Segmentation.

    Science.gov (United States)

    Yang, Jiong; Price, Brian; Shen, Xiaohui; Lin, Zhe; Yuan, Junsong

    2016-02-01

    Automatic segmentation of the primary object in a video clip is a challenging problem as there is no prior knowledge of the primary object. Most existing techniques thus adapt an iterative approach for foreground and background appearance modeling, i.e., fix the appearance model while optimizing the segmentation and fix the segmentation while optimizing the appearance model. However, these approaches may rely on good initialization and can be easily trapped in local optimal. In addition, they are usually time consuming for analyzing videos. To address these limitations, we propose a novel and efficient appearance modeling technique for automatic primary video object segmentation in the Markov random field (MRF) framework. It embeds the appearance constraint as auxiliary nodes and edges in the MRF structure, and can optimize both the segmentation and appearance model parameters simultaneously in one graph cut. The extensive experimental evaluations validate the superiority of the proposed approach over the state-of-the-art methods, in both efficiency and effectiveness.

  15. Conjugated nanoliposome with the HER2/neu-derived peptide GP2 as an effective vaccine against breast cancer in mice xenograft model.

    Directory of Open Access Journals (Sweden)

    Atefeh Razazan

    Full Text Available One of the challenging issues in vaccine development is peptide and adjuvant delivery into target cells. In this study, we developed a vaccine and therapeutic delivery system to increase cytotoxic T lymphocyte (CTL response against a breast cancer model overexpressing HER2/neu. Gp2, a HER2/neu-derived peptide, was conjugated to Maleimide-mPEG2000-DSPE micelles and post inserted into liposomes composed of DMPC, DMPG phospholipids, and fusogenic lipid dioleoylphosphatidylethanolamine (DOPE containing monophosphoryl lipid A (MPL adjuvant (DMPC-DMPG-DOPE-MPL-Gp2. BALB/c mice were immunized with different formulations and the immune response was evaluated in vitro and in vivo. ELISpot and intracellular cytokine analysis by flow cytometry showed that the mice vaccinated with Lip-DOPE-MPL-GP2 incited the highest number of IFN-γ+ in CD8+ cells and CTL response. The immunization led to lower tumor sizes and longer survival time compared to the other groups of mice immunized and treated with the Lip-DOPE-MPL-GP2 formulation in both prophylactic and therapeutic experiments. These results showed that co-formulation of DOPE and MPL conjugated with GP2 peptide not only induces high antitumor immunity but also enhances therapeutic efficacy in TUBO mice model. Lip-DOPE-MPL-GP2 formulation could be a promising vaccine and a therapeutic delivery system against HER2 positive cancers and merits further investigation.

  16. Novel Tc-99m labeled ELR-containing 6-mer peptides for tumor imaging in epidermoid carcinoma xenografts model. A pilot study

    International Nuclear Information System (INIS)

    Kim, Dae-Weung; Kim, Woo-Hyoung; Kim, Myoung-Hyoun; Kim, Chang-Guhn

    2013-01-01

    ELR-containing peptides targeting CXCR2 could be the excellent candidate for targeting ligand of molecular tumor imaging. In this study, we had developed two ELR-containing 6-mer peptides and evaluated the diagnostic performance of Tc-99m labeled 6-mer peptides as a molecular imaging agent in murine models bearing KB epidermoid carcinoma. Peptides were synthesized using Fmoc solid phase peptide synthesis. Radiolabeling efficiency with Tc-99m was evaluated using instant thin-layer chromatography. In KB epidermoid cancer-bearing mice, gamma images had acquired and tumor-to-muscle uptake ratio was calculated. Competition and biodistribution studies had performed. Two 6-mer peptides, ELR-ECG and ECG-ELR were successfully synthesized. After radiolabeling procedures with Tc-99m, the complex Tc-99m ELR-ECG and Tc-99m ECG-ELR were prepared in high yield. In the gamma camera imaging of murine model, Tc-99m ELR-ECG was substantially accumulated in the subcutaneously engrafted tumor and tumor uptake had been suppressed by the free ELR co-injection. However, Tc-99m ECG-ELR was minimally accumulated in the tumor. Two ELR-containing 6-mer peptides, ELR-ECG and ECG-ELR, were developed as a molecular imaging agent to target CXCR2 of epidermoid carcinoma. Tc-99m ELR-ECG had showed significant uptake in tumor and it was good candidate for a tumor imaging. (author)

  17. A comparison of targeting of neuroblastoma with mIBG and anti L1-CAM antibody mAb chCE7: therapeutic efficacy in a neuroblastoma xenograft model and imaging of neuroblastoma patients

    NARCIS (Netherlands)

    Hoefnagel, C. A.; Rutgers, M.; Buitenhuis, C. K.; Smets, L. A.; de Kraker, J.; Meli, M.; Carrel, F.; Amstutz, H.; Schubiger, P. A.; Novak-Hofer, I.

    2001-01-01

    Iodine-131 labelled anti L1-CAM antibody mAb chCE7 was compared with the effective neuroblastoma-seeking agent 131I-labelled metaiodobenzylguanidine (MIBG) with regard to (a) its therapeutic efficacy in treating nude mice with neuroblastoma xenografts and (b) its tumour targeting ability in

  18. Comparison of [(11)C]Choline ([(11)C]CHO) and [(18)F]Bombesin (BAY 86-4367) as Imaging Probes for Prostate Cancer in a PC-3 Prostate Cancer Xenograft Model.

    Science.gov (United States)

    Schwarzenböck, Sarah Marie; Schmeja, Philipp; Kurth, Jens; Souvatzoglou, Michael; Nawroth, Roman; Treiber, Uwe; Kundt, Guenther; Berndt, Sandra; Graham, Keith; Senekowitsch-Schmidtke, Reingard; Schwaiger, Markus; Ziegler, Sibylle I; Dinkelborg, Ludger; Wester, Hans-Jürgen; Krause, Bernd Joachim

    2016-06-01

    Carbon-11- and fluorine-18-labeled choline derivatives are commonly used in prostate cancer imaging in the clinical setting for staging and re-staging of prostate cancer. Due to a limited detection rate of established positron emission tomography (PET) tracers, there is a clinical need for innovative tumor-specific PET compounds addressing new imaging targets. The aim of this study was to compare the properties of [(18)F]Bombesin (BAY 86-4367) as an innovative biomarker for prostate cancer imaging targeting the gastrin-releasing peptide receptor and [(11)C]Choline ([(11)C]CHO) in a human prostate tumor mouse xenograft model by small animal PET/X-ray computed tomography (CT). We carried out a dual-tracer small animal PET/CT study comparing [(18)F]Bombesin and [(11)C]CHO. The androgen-independent human prostate tumor cell line PC-3 was implanted subcutaneously in the flanks of nu/nu NMRI mice (n = 10) (PET/CT measurements of two [(11)C]Choline mice could not be analyzed due to technical reasons). [(18)F]Bombesin and [(11)C]CHO PET/CT imaging was performed about 3-4 weeks after the implantation of PC-3 cells on two separate days. After the intravenous tail vein injection of 14 MBq [(18)F]Bombesin and 37 MBq [(11)C]CHO, respectively, a dynamic study over 60 min was acquired in list mode using an Inveon animal PET/CT scanner (Siemens Medical Solutions). The sequence of [(18)F]Bombesin and [(11)C]CHO was randomized. Image analysis was performed using summed images as well as dynamic data. To calculate static and dynamic tumor-to-muscle (T/M), tumor-to-blood (T/B), liver-to-blood (L/B), and kidney-to-blood (K/B) ratios, 4 × 4 × 4 mm(3) volumes of interest (VOIs) of tumor, muscle (thigh), liver, kidney, and blood derived from transversal slices were used. The mean T/M ratio of [(18)F]Bombesin and [(11)C]CHO was 6.54 ± 2.49 and 1.35 ± 0.30, respectively. The mean T/B ratio was 1.83 ± 0.79 for [(18)F]Bombesin and 0.55 ± 0.10 for [(11)C

  19. Inhibition of Tumor Growth of Human Hepatocellular Carcinoma HepG2 Cells in a Nude Mouse Xenograft Model by the Total Flavonoids from Arachniodes exilis

    Directory of Open Access Journals (Sweden)

    Huimin Li

    2017-01-01

    Full Text Available A tumor growth model of human hepatocellular carcinoma HepG2 cells in nude mice was employed to investigate the antitumor activity of the total flavonoids extracted from Arachniodes exilis (TFAE in vivo. Several biochemical assays including hematoxylin-eosin (HE staining, immunohistochemistry, and Western blot were performed to elucidate the mechanism of action of total flavonoids extracted from Arachniodes exilis (TFAE. The results showed that TFAE effectively inhibited the tumor growth of hepatocellular carcinoma in nude mice and had no significant effect on body weight, blood system, and functions of liver and kidney. Expression levels of proapoptotic proteins Bax and cleaved caspase-3 remarkably increased while the expressions of Bcl-2, HIF-1α, and VEGF were suppressed by TFAE. These results suggested that the antitumor potential of TFEA was implied by the apoptosis of tumor cells and the inhibition of angiogenesis in tumor tissue.

  20. [68Ga]pentixafor for CXCR4 imaging in a PC-3 prostate cancer xenograft model - comparison with [18F]FDG PET/CT, MRI and ex vivo receptor expression.

    Science.gov (United States)

    Schwarzenböck, Sarah M; Stenzel, Jan; Otto, Thomas; Helldorff, Heike V; Bergner, Carina; Kurth, Jens; Polei, Stefan; Lindner, Tobias; Rauer, Romina; Hohn, Alexander; Hakenberg, Oliver W; Wester, Hans J; Vollmar, Brigitte; Krause, Bernd J

    2017-11-10

    The aim was to characterize the properties of [ 68 Ga]Pentixafor as tracer for prostate cancer imaging in a PC-3 prostate cancer xenograft mouse model and to investigate its correlation with [ 18 F]FDG PET/CT, magnetic resonance imaging (MRI) and ex vivo analyses. Static [ 68 Ga]Pentixafor and [ 18 F]FDG PET as well as morphological/ diffusion weighted MRI and 1 H MR spectroscopy was performed. Imaging data were correlated with ex vivo biodistribution and CXCR4 expression in PC-3 tumors (immunohistochemistry (IHC), mRNA analysis). Flow cytometry was performed for evaluation of localization of CXCR4 receptors ( in vitro PC-3 cell experiments). Tumor uptake of [ 68 Ga]Pentixafor was significantly lower compared to [ 18 F]FDG. Ex vivo CXCR4 mRNA expression of tumors was shown by PCR. Only faint tumor CXCR4 expression was shown by IHC (immuno reactive score of 3). Accordingly, flow cytometry of PC-3 cells revealed only a faint signal, cell membrane permeabilisation showed a slight signal increase. There was no significant correlation of [ 68 Ga]Pentixafor tumor uptake and ex vivo receptor expression. Spectroscopy showed typical spectra of prostate cancer. PC-3 tumor uptake of [ 68 Ga]Pentixafor was existent but lower compared to [ 18 F]FDG. No significant correlation of ex vivo tumor CXCR4 receptor expression and [ 68 Ga]Pentixafor tumor uptake was shown. CXCR4 receptor expression on the surface of PC-3 cells was existent but rather low possibly explaining the limited [ 68 Ga]Pentixafor tumor uptake; receptor localization in the interior of PC-3 cells is presumable as shown by cell membrane permeabilisation. Further studies are necessary to define the role of [ 68 Ga]Pentixafor in prostate cancer imaging.

  1. Day/Night Cycle: Mental Models of Primary School Children

    Science.gov (United States)

    Chiras, Andreas

    2008-01-01

    The study investigated the mental models of primary school children related to the day/night cycle. Semi-structure interviews were conducted with 40 fourth-grade and 40 sixth-grade children. Qualitative and quantitative analysis of the data indicated that the majority of the children were classified as having geocentric models. The results also…

  2. Assessment of Primary 5 Students' Mathematical Modelling Competencies

    Science.gov (United States)

    Chan, Chun Ming Eric; Ng, Kit Ee Dawn; Widjaja, Wanty; Seto, Cynthia

    2012-01-01

    Mathematical modelling is increasingly becoming part of an instructional approach deemed to develop students with competencies to function as 21st century learners and problem solvers. As mathematical modelling is a relatively new domain in the Singapore primary school mathematics curriculum, many teachers may not be aware of the learning outcomes…

  3. Imaging biomarkers to monitor response to the hypoxia-activated prodrug TH-302 in the MiaPaCa2 flank xenograft model.

    Science.gov (United States)

    Cárdenas-Rodríguez, Julio; Li, Yuguo; Galons, Jean-Philippe; Cornnell, Heather; Gillies, Robert J; Pagel, Mark D; Baker, Amanda F

    2012-09-01

    TH-302, a hypoxia-activated anticancer prodrug, was evaluated for antitumor activity and changes in dynamic contrast-enhanced (DCE) and diffusion-weighted (DW) magnetic resonance imaging (MRI) in a mouse model of pancreatic cancer. TH-302 monotherapy resulted in a significant delay in tumor growth compared to vehicle-treated controls. TH-302 treatment was also associated with a significant decrease in the volume transfer constant (K(trans)) compared to vehicle-treated controls 1 day following the first dose measured using DCE-MRI. This early decrease in K(trans) following the first dose as measured is consistent with selective killing of the hypoxic fraction of cells which are associated with enhanced expression of hypoxia inducible transcription factor-1 alpha that regulates expression of permeability and perfusion factors including vascular endothelial growth factor-A. No changes were observed in DW-MRI following treatment with TH-302, which may indicate that this technique is not sensitive enough to detect changes in small hypoxic fractions of the tumor targeted by TH-302. These results suggest that changes in tumor permeability and/or perfusion may be an early imaging biomarker for response to TH-302 therapy. Copyright © 2012 Elsevier Inc. All rights reserved.

  4. Synthesis and characterization of a porphyrazine-Gd(III) MRI contrast agent and in vivo imaging of a breast cancer xenograft model.

    Science.gov (United States)

    Trivedi, Evan R; Ma, Zhidong; Waters, Emily A; Macrenaris, Keith W; Subramanian, Rohit; Barrett, Anthony G M; Meade, Thomas J; Hoffman, Brian M

    2014-01-01

    Porphyrazines (Pz), or tetraazaporphyrins, are being studied for their potential use in detection and treatment of cancer. Here, an amphiphilic Cu-Pz-Gd(III) conjugate has been prepared via azide-alkyne Huisgen cycloaddition or 'click' chemistry between an azide functionalized Pz and alkyne functionalized DOTA-Gd(III) analog for use as an MRI contrast agent. This agent, Cu-Pz-Gd(III), is synthesized in good yield and exhibits solution-phase ionic relaxivity (r1  = 11.5 mM(-1) s(-1)) that is approximately four times higher than that of a clinically used monomeric Gd(III) contrast agent, DOTA-Gd(III). Breast tumor cells (MDA-MB-231) associate with Cu-Pz-Gd(III) in vitro, where significant contrast enhancement (9.336 ± 0.335 contrast-to-noise ratio) is observed in phantom cell pellet MR images. This novel contrast agent was administered in vivo to an orthotopic breast tumor model in athymic nude mice and MR images were collected. The average T1 of tumor regions in mice treated with 50 mg kg(-1) Cu-Pz-Gd(III) decreased relative to saline-treated controls. Furthermore, the decrease in T1 was persistent relative to mice treated with the monomeric Gd(III) contrast agent. An ex vivo biodistribution study confirmed that Cu-Pz-Gd(III) accumulates in the tumors and is rapidly cleared, primarily through the kidneys. Differential accumulation and T1 enhancement by Cu-Pz-Gd(III) in the tumor's core relative to the periphery offer preliminary evidence that this agent would find application in the imaging of necrotic tissue. Copyright © 2014 John Wiley & Sons, Ltd.

  5. Volumetrical and morphological responses of human laryngeal squamous cell carcinoma xenografts treated with fractionated irradiation

    International Nuclear Information System (INIS)

    Hoogenhout, J.; Gasteren, H. van; Jerusalem, C.R.; Kal, H.B.

    1988-01-01

    Xenografts of both primary human laryngeal squamous cell carcinoma and its metastases were irradiated with five daily fractions of 5.0 Gy. Tumor volume changes, morphology, mitotic index and mitotic figures were studied. Primary xenografts disappeared within 17±3 days. Grafts of metastases showed complete regression within 26±5 days, or regrowth after a delay period. Mitotic activity was higher in the grafts of metastases. The number of mitotic figures decreased and ceased within 14 days in the primary tumor, while some were still occasionally noted in the grafts of metastases. Telophase stages were practically absent after the first fraction. This study suggests that the response of metastases to radiation therapy is lower than the response of the primary tumor. (orig.) [de

  6. Evaluating topic model interpretability from a primary care physician perspective.

    Science.gov (United States)

    Arnold, Corey W; Oh, Andrea; Chen, Shawn; Speier, William

    2016-02-01

    Probabilistic topic models provide an unsupervised method for analyzing unstructured text. These models discover semantically coherent combinations of words (topics) that could be integrated in a clinical automatic summarization system for primary care physicians performing chart review. However, the human interpretability of topics discovered from clinical reports is unknown. Our objective is to assess the coherence of topics and their ability to represent the contents of clinical reports from a primary care physician's point of view. Three latent Dirichlet allocation models (50 topics, 100 topics, and 150 topics) were fit to a large collection of clinical reports. Topics were manually evaluated by primary care physicians and graduate students. Wilcoxon Signed-Rank Tests for Paired Samples were used to evaluate differences between different topic models, while differences in performance between students and primary care physicians (PCPs) were tested using Mann-Whitney U tests for each of the tasks. While the 150-topic model produced the best log likelihood, participants were most accurate at identifying words that did not belong in topics learned by the 100-topic model, suggesting that 100 topics provides better relative granularity of discovered semantic themes for the data set used in this study. Models were comparable in their ability to represent the contents of documents. Primary care physicians significantly outperformed students in both tasks. This work establishes a baseline of interpretability for topic models trained with clinical reports, and provides insights on the appropriateness of using topic models for informatics applications. Our results indicate that PCPs find discovered topics more coherent and representative of clinical reports relative to students, warranting further research into their use for automatic summarization. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  7. The AKT inhibitor AZD5363 is selectively active in PI3KCA mutant gastric cancer, and sensitizes a patient-derived gastric cancer xenograft model with PTEN loss to Taxotere.

    Science.gov (United States)

    Li, Jing; Davies, Barry R; Han, Sufang; Zhou, Minhua; Bai, Yu; Zhang, Jingchuan; Xu, Yan; Tang, Lily; Wang, Huiying; Liu, Yuan Jie; Yin, Xiaolu; Ji, Qunsheng; Yu, De-Hua

    2013-10-02

    Activation of the PI3K/AKT pathway is a common phenomenon in cancer due to multiple mechanisms, including mutation of PI3KCA, loss or mutation of PTEN, or over-expression of receptor tyrosine kinases. We recently developed a novel AKT kinase inhibitor, AZD5363, and demonstrated that HGC27, a cell line harboring both PI3KCA mutation and PTEN loss, displayed the greatest sensitivity to this AKT inhibitor in vitro and in vivo. To further elucidate the correlation between AZD5363 response and genetic alterations in gastric cancer (GC) and identify GC patients with both PI3KCA mutations and PTEN loss, we investigated the effects of pharmacological inhibition of AKT on a panel of 20 GC cell lines and genetic aberrations in tumor samples from a cohort of Chinese GC patients. We demonstrated that GC cells with PI3KCA mutations were selectively sensitive to AZD5363. Disease linkage studies showed that PI3KCA activating mutations or PTEN loss were found in 2.7% (4/150) and 23% (14/61) of Chinese GC patients respectively. To further dissect the role of PI3KCA mutation and PTEN loss in response to AKT inhibition, we tested the antitumor activity of AZD5363 in two patient-derived GC xenograft (PDGCX) models harboring either PI3KCA mutation or PTEN loss. Our data indicated that AZD5363 monotherapy treatment led to a moderate response in the PI3KCA mutant PDGCX model. Whilst monotherapy AZD5363 or Taxotere were ineffective in the PTEN negative PDGCX model, significant anti-tumor activity was observed when AZD5363 was combined with Taxotere. Our results indicated that PI3KCA mutation is an important determinant of response to AKT inhibition in GC and combination with AZD5363 can overcome innate resistance to Taxotere in a PTEN loss PDGCX model. It is suggested that AKT inhibitor is an attractive option for treatment of a new segment of GC patients with aberrant PI3K/AKT signaling.

  8. Dynamic Modelling with "MLE-Energy Dynamic" for Primary School

    Science.gov (United States)

    Giliberti, Enrico; Corni, Federico

    During the recent years simulation and modelling are growing instances in science education. In primary school, however, the main use of software is the simulation, due to the lack of modelling software tools specially designed to fit/accomplish the needs of primary education. In particular primary school teachers need to use simulation in a framework that is both consistent and simple enough to be understandable by children [2]. One of the possible area to approach modelling is about the construction of the concept of energy, in particular for what concerns the relations among substance, potential, power [3]. Following the previous initial research results with this approach [2], and with the static version of the software MLE Energy [1], we suggest the design and the experimentation of a dynamic modelling software—MLE dynamic-capable to represent dynamically the relations occurring when two substance-like quantities exchange energy, modifying their potential. By means of this software the user can graphically choose the dependent and independent variables and leave the other parameters fixed. The software has been initially evaluated, during a course of science education with a group of primary school teachers-to-be, to test the ability of the software to improve teachers' way of thinking in terms of substance-like quantities and their effects (graphical representation of the extensive, intensive variables and their mutual relations); moreover, the software has been tested with a group of primary school teachers, asking their opinion about the software didactical relevance in the class work.

  9. Matrigel alters the pathophysiology of orthotopic human breast adenocarcinoma xenografts with implications for nanomedicine evaluation.

    Science.gov (United States)

    Shuhendler, Adam J; Prasad, Preethy; Cai, Ping; Hui, Kelvin K W; Henderson, Jeffrey T; Rauth, Andrew M; Wu, Xiao Yu

    2013-08-01

    Matrigel, a mouse sarcoma-derived basement membrane protein mixture, is frequently used to facilitate human tumor xenograft growth in rodents. Despite its known effects on tumor growth and metastasis, its impact on tumor pathophysiology and preclinical evaluation of nanomedicines in tumor xenografts has not been reported previously. Herein bilateral MDA435 tumors were established orthotopically with (Mat+) or without (Mat-) co-injection of Matrigel. Tumor perfusion, morphology and nanoparticle retention were evaluated. As compared to Mat- tumors, Mat+tumors exhibited enhanced vascular perfusion and lymphatic flow, greater blood vessel and lymphatic growth within the tumor core, and more deformation and collapse of lymphatics in tumor-associated lymph nodes. These changes were accompanied by reduced nanoparticle retention in Mat+tumors. The results suggest that Matrigel is not a passive medium for tumor growth, but rather significantly alters long-term tumor architecture. These findings have significant implications for the evaluation of therapeutic nanomedicine in xenograft mouse models. Matrigel is utilized in facilitating human tumor xenograft growth in rodents. The authors demonstrate that Matrigel is not a passive medium for tumor growth; instead it significantly alters long-term tumor architecture, with major implications in the evaluation of therapeutic nanomedicine in xenograft mouse models. Copyright © 2013 Elsevier Inc. All rights reserved.

  10. Establishment and characterization of 7 novel hepatocellular carcinoma cell lines from patient-derived tumor xenografts.

    Directory of Open Access Journals (Sweden)

    Hong Xin

    Full Text Available Hepatocellular carcinoma (HCC is a common cancer with poor prognosis worldwide and the molecular mechanism is not well understood. This study aimed to establish a collection of human HCC cell lines from patient-derived xenograft (PDX models. From the 20 surgical HCC sample collections, 7 tumors were successfully developed in immunodeficient mice and further established 7 novel HCC cell lines (LIXC002, LIXC003, LIXC004, LIXC006, LIXC011, LIXC012 and CPL0903 by primary culture. The characterization of cell lines was defined by morphology, growth kinetics, cell cycle, chromosome analysis, short tandem repeat (STR analysis, molecular profile, and tumorigenicity. Additionally, response to clinical chemotherapeutics was validated both in vitro and in vivo. STR analysis indicated that all cell lines were unique cells different from known cell lines and free of contamination by bacteria or mycoplasma. The other findings were quite heterogeneous between individual lines. Chromosome aberration could be found in all cell lines. Alpha-fetoprotein was overexpressed only in 3 out of 7 cell lines. 4 cell lines expressed high level of vimentin. Ki67 was strongly stained in all cell lines. mRNA level of retinoic acid induced protein 3 (RAI3 was decreased in all cell lines. The 7 novel cell lines showed variable sensitivity to 8 tested compounds. LIXC011 and CPL0903 possessed multiple drug resistance property. Sorafenib inhibited xenograft tumor growth of LIXC006, but not of LIXC012. Our results indicated that the 7 novel cell lines with low passage maintaining their clinical and pathological characters could be good tools for further exploring the molecular mechanism of HCC and anti-cancer drug screening.

  11. Implementation strategies for collaborative primary care-mental health models.

    Science.gov (United States)

    Franx, Gerdien; Dixon, Lisa; Wensing, Michel; Pincus, Harold

    2013-09-01

    Extensive research exists that collaborative primary care-mental health models can improve care and outcomes for patients. These programs are currently being implemented throughout the United States and beyond. The purpose of this study is to review the literature and to generate an overview of strategies currently used to implement such models in daily practice. Six overlapping strategies to implement collaborative primary care-mental health models were described in 18 selected studies. We identified interactive educational strategies, quality improvement change processes, technological support tools, stakeholder engagement in the design and execution of implementation plans, organizational changes in terms of expanding the task of nurses and financial strategies such as additional collaboration fees and pay for performance incentives. Considering the overwhelming evidence about the effectiveness of primary care-mental health models, there is a lack of good studies focusing on their implementation strategies. In practice, these strategies are multifaceted and locally defined, as a result of intensive and required stakeholder engagement. Although many barriers still exist, the implementation of collaborative models could have a chance to succeed in the United States, where new service delivery and payment models, such as the Patient-Centered Medical Home, the Health Home and the Accountable Care Organization, are being promoted.

  12. Aortic valve replacement with the Biocor PSB stentless xenograft.

    Science.gov (United States)

    Bertolini, P; Luciani, G B; Vecchi, B; Pugliese, P; Mazzucco, A

    1998-08-01

    The midterm clinical results after aortic valve replacement with the Biocor PSB stentless xenograft on all patients operated between October 1992 and October 1996 were reviewed. One hundred six patients, aged 70+/-6 years, had aortic valve replacement for aortic stenosis (67%), regurgitation (11%), or both (22%). Associated procedures were done in 49 patients (46%), including coronary artery bypass in 30 patients, mitral valve repair/replacement in 16, and ascending aorta replacement in 5 patients. Aortic cross-clamp and cardiopulmonary bypass times were 96+/-24 and 129+/-31 minutes, respectively. There were 3 (3%) early deaths due to low output (2 patients) and cerebrovascular accident (1 patient). Follow-up of survivors ranged from 6 to 66 months (mean, 39+/-14 months). Survival was 94%+/-2% and 90%+/-3% at 1 and 5 years. There were 5 late deaths due to cardiac cause (2), cancer (2), and pulmonary embolism (1 patient). No patient had structural valve deterioration, whereas 100% and 95%+/-3% were free from valve-related events at 1 and 5 years. There were two reoperations due to narrowing of the left coronary ostium and endocarditis, with an actuarial freedom from reoperation of 99%+/-1% and 98+/-1% at 1 and 5 years, respectively. Functional results demonstrated a mean peak transprosthetic gradient of 16+/-12 mm Hg, with only 1 patient (1%) with a 55 mm Hg gradient. No cases of valve regurgitation greater than mild were recorded at follow-up. Assessment of New York Heart Association functional class demonstrated a significant improvement (2.9+/-0.6 versus 1.4+/-0.7; p=0.01). All patients were free from anticoagulation. Aortic valve replacement using the Biocor PSB stentless xenograft offers excellent midterm survival, negligible valve deterioration, and a very low rate of valve-related events, which are comparable to estimates reported with other models of stentless xenografts and currently available stented xenografts. Hemodynamic performance is favorable and

  13. Diabetes care: model for the future of primary care.

    Science.gov (United States)

    Posey, L Michael; Tanzi, Maria G

    2010-01-01

    To review relevant trends threatening primary care and the evidence supporting use of nonphysicians in primary and chronic care of patients with diabetes. Current medical and pharmacy literature as selected by authors. The care needed by patients with diabetes does not fit well into our current medical model for primary care, and an adequate supply of physicians is not likely to be available for primary care roles in coming years. Patients with diabetes who are placed on evidence-based regimens, are educated about their disease, are coached in ways that motivate them to lose weight and adopt other therapeutic lifestyle changes, and are adhering to and persisting with therapy will soon have improved clinical parameters. These quickly translate into fewer hospitalizations and emergency department visits. A growing body of literature supports the use of pharmacists and other nonphysicians in meeting the needs of patients with diabetes. Pharmacists should join nurse practitioners, specially trained nurses, and physician assistants as integral members of the health care team in providing care to patients with diabetes and, by logical extension, other chronic conditions. Demand for primary care is likely to outstrip the available supply of generalist physicians in the coming years. In addition to nurse practitioners and physician assistants, pharmacists should be considered for key roles in future interdisciplinary teams that triage and provide direct care to patients, including those with diabetes and other chronic conditions.

  14. Human pancreatic cancer xenografts recapitulate key aspects of cancer cachexia.

    Science.gov (United States)

    Delitto, Daniel; Judge, Sarah M; Delitto, Andrea E; Nosacka, Rachel L; Rocha, Fernanda G; DiVita, Bayli B; Gerber, Michael H; George, Thomas J; Behrns, Kevin E; Hughes, Steven J; Wallet, Shannon M; Judge, Andrew R; Trevino, Jose G

    2017-01-03

    Cancer cachexia represents a debilitating syndrome that diminishes quality of life and augments the toxicities of conventional treatments. Cancer cachexia is particularly debilitating in patients with pancreatic cancer (PC). Mechanisms responsible for cancer cachexia are under investigation and are largely derived from observations in syngeneic murine models of cancer which are limited in PC. We evaluate the effect of human PC cells on both muscle wasting and the systemic inflammatory milieu potentially contributing to PC-associated cachexia. Specifically, human PC xenografts were generated by implantation of pancreatic cancer cells, L3.6pl and PANC-1, either in the flank or orthotopically within the pancreas. Mice bearing orthotopic xenografts demonstrated significant muscle wasting and atrophy-associated gene expression changes compared to controls. Further, despite the absence of adaptive immunity, splenic tissue from orthotopically engrafted mice demonstrated elevations in several pro-inflammatory cytokines associated with cancer cachexia, including TNFα, IL1β, IL6 and KC (murine IL8 homologue), when compared to controls. Therefore, data presented here support further investigation into the complexity of cancer cachexia in PC to identify potential targets for this debilitating syndrome.

  15. Towards a model for integrative medicine in Swedish primary care

    Directory of Open Access Journals (Sweden)

    Falkenberg Torkel

    2007-07-01

    Full Text Available Abstract Background Collaboration between providers of conventional care and complementary therapies (CTs has gained in popularity but there is a lack of conceptualised models for delivering such care, i.e. integrative medicine (IM. The aim of this paper is to describe some key findings relevant to the development and implementation of a proposed model for IM adapted to Swedish primary care. Methods Investigative procedures involved research group and key informant meetings with multiple stakeholders including general practitioners, CT providers, medical specialists, primary care administrators and county council representatives. Data collection included meeting notes which were fed back within the research group and used as ongoing working documents. Data analysis was made by immersion/crystallisation and research group consensus. Results were categorised within a public health systems framework of structures, processes and outcomes. Results The outcome was an IM model that aimed for a patient-centered, interdisciplinary, non-hierarchical mix of conventional and complementary medical solutions to individual case management of patients with pain in the lower back and/or neck. The IM model case management adhered to standard clinical practice including active partnership between a gate-keeping general practitioner, collaborating with a team of CT providers in a consensus case conference model of care. CTs with an emerging evidence base included Swedish massage therapy, manual therapy/naprapathy, shiatsu, acupuncture and qigong. Conclusion Despite identified barriers such as no formal recognition of CT professions in Sweden, it was possible to develop a model for IM adapted to Swedish primary care. The IM model calls for testing and refinement in a pragmatic randomised controlled trial to explore its clinical effectiveness.

  16. Modeling of Food and Nutrition Surveillance in Primary Health Care

    Directory of Open Access Journals (Sweden)

    Santuzza Arreguy Silva VITORINO

    Full Text Available ABSTRACT Objective: To describe the modeling stages of food and nutrition surveillance in the Primary Health Care of the Unified Health Care System, considering its activities, objectives, and goals Methods: Document analysis and semi-structured interviews were used for identifying the components, describe the intervention, and identify potential assessment users. Results: The results include identification of the objectives and goals of the intervention, the required inputs, activities, and expected effects. The intervention was then modeled based on these data. The use of the theoretical logic model optimizes times, resources, definition of the indicators that require monitoring, and the aspects that require assessment, identifying more clearly the contribution of the intervention to the results Conclusion: Modeling enabled the description of food and nutrition surveillance based on its components and may guide the development of viable plans to monitor food and nutrition surveillance actions so that modeling can be established as a local intersectoral planning instrument.

  17. Comparing Intrinsic Connectivity Models for the Primary Auditory Cortices

    Science.gov (United States)

    Hamid, Khairiah Abdul; Yusoff, Ahmad Nazlim; Mohamad, Mazlyfarina; Hamid, Aini Ismafairus Abd; Manan, Hanani Abd

    2010-07-01

    This fMRI study is about modeling the intrinsic connectivity between Heschl' gyrus (HG) and superior temporal gyrus (STG) in human primary auditory cortices. Ten healthy male subjects participated and required to listen to white noise stimulus during the fMRI scans. Two intrinsic connectivity models comprising bilateral HG and STG were constructed using statistical parametric mapping (SPM) and dynamic causal modeling (DCM). Group Bayes factor (GBF), positive evidence ratio (PER) and Bayesian model selection (BMS) for group studies were used in model comparison. Group results indicated significant bilateral asymmetrical activation (puncorr < 0.001) in HG and STG. Comparison results showed strong evidence of Model 2 as the preferred model (STG as the input center) with GBF value of 5.77 × 1073 The model is preferred by 6 out of 10 subjects. The results were supported by BMS results for group studies. One-sample t-test on connection values obtained from Model 2 indicates unidirectional parallel connections from STG to bilateral HG (p<0.05). Model 2 was determined to be the most probable intrinsic connectivity model between bilateral HG and STG when listening to white noise.

  18. Activity of MM-398, nanoliposomal irinotecan (nal-IRI), in Ewing's family tumor xenografts is associated with high exposure of tumor to drug and high SLFN11 expression.

    Science.gov (United States)

    Kang, Min H; Wang, Jing; Makena, Monish R; Lee, Joo-Sang; Paz, Nancy; Hall, Connor P; Song, Michael M; Calderon, Ruben I; Cruz, Riza E; Hindle, Ashly; Ko, Winford; Fitzgerald, Jonathan B; Drummond, Daryl C; Triche, Timothy J; Reynolds, C Patrick

    2015-03-01

    To determine the pharmacokinetics and the antitumor activity in pediatric cancer models of MM-398, a nanoliposomal irinotecan (nal-IRI). Mouse plasma and tissue pharmacokinetics of nal-IRI and the current clinical formulation of irinotecan were characterized. In vivo activity of irinotecan and nal-IRI was compared in xenograft models (3 each in nu/nu mice) of Ewing's sarcoma family of tumors (EFT), neuroblastoma (NB), and rhabdomyosarcoma (RMS). SLFN11 expression was assessed by Affymetrix HuEx arrays, Taqman RT-PCR, and immunoblotting. Plasma and tumor concentrations of irinotecan and SN-38 (active metabolite) were approximately 10-fold higher for nal-IRI than for irinotecan. Two doses of NAL-IRI (10 mg/kg/dose) achieved complete responses maintained for >100 days in 24 of 27 EFT-xenografted mice. Event-free survival for mice with RMS and NB was significantly shorter than for EFT. High SLFN11 expression has been reported to correlate with sensitivity to DNA damaging agents; median SLFN11 mRNA expression was >100-fold greater in both EFT cell lines and primary tumors compared with NB or RMS cell lines or primary tumors. Cytotoxicity of SN-38 inversely correlated with SLFN11 mRNA expression in 20 EFT cell lines. In pediatric solid tumor xenografts, nal-IRI demonstrated higher systemic and tumor exposures to SN-38 and improved antitumor activity compared with the current clinical formulation of irinotecan. Clinical studies of nal-IRI in pediatric solid tumors (especially EFT) and correlative studies to determine if SLFN11 expression can serve as a biomarker to predict nal-IRI clinical activity are warranted. ©2015 American Association for Cancer Research.

  19. Antitumor activity of ZD6126, a novel vascular-targeting agent, is enhanced when combined with ZD1839, an epidermal growth factor receptor tyrosine kinase inhibitor, and potentiates the effects of radiation in a human non-small cell lung cancer xenograft model.

    Science.gov (United States)

    Raben, David; Bianco, Cataldo; Damiano, Vincenzo; Bianco, Roberto; Melisi, Davide; Mignogna, Chiara; D'Armiento, Francesco Paolo; Cionini, Luca; Bianco, A Raffaele; Tortora, Giampaolo; Ciardiello, Fortunato; Bunn, Paul

    2004-08-01

    Targeting the tumor vasculature may offer an alternative or complementary therapeutic approach to targeting growth factor signaling in lung cancer. The aim of these studies was to evaluate the antitumor effects in vivo of the combination of ZD6126, a tumor-selective vascular-targeting agent; ZD1839 (gefitinib, Iressa), an epidermal growth factor receptor tyrosine kinase inhibitor; and ionizing radiation in the treatment of non-small cell lung cancer xenograft model. Athymic nude mice with established flank A549 human non-small cell lung cancer xenograft model xenografts were treated with fractionated radiation therapy, ZD6126, ZD1839, or combinations of each treatment. ZD6126 (150 mg/kg) was given i.p. the day after each course of radiation. Animals treated with ZD1839 received 100 mg/kg per dose per animal, 5 or 7 days/wk for 2 weeks. Immunohistochemistry was done to evaluate the effects on tumor growth using an anti-Ki67 monoclonal antibody. Effects on tumor-induced vascularization were quantified using an anti-factor VIII-related antigen monoclonal antibody. ZD6126 attenuated the growth of human A549 flank xenografts compared with untreated animals. Marked antitumor effects were observed when animals were treated with a combination of ZD6126 and fractionated radiation therapy with protracted tumor regression. ZD6126 + ZD1839 resulted in a greater tumor growth delay than either agent alone. Similar additive effects were seen with ZD1839 + fractionated radiation. Finally, the addition of ZD6126 to ZD1839 and radiation therapy seemed to further improve tumor growth control, with a significant tumor growth delay compared with animals treated with single agent or with double combinations. Immunohistochemistry showed that ZD1839 induced a marked reduction in A549 tumor cell proliferation. Both ZD1839 and ZD6126 treatment substantially reduced tumor-induced angiogenesis. ZD6126 caused marked vessel destruction through loss of endothelial cells and thrombosis

  20. Interrogating open issues in cancer precision medicine with patient-derived xenografts

    NARCIS (Netherlands)

    Byrne, Annette T; Alférez, Denis G; Amant, Frédéric; Annibali, Daniela; Arribas, Joaquín; Biankin, Andrew V; Bruna, Alejandra; Budinská, Eva; Caldas, Carlos; Chang, David K; Clarke, Robert B; Clevers, Hans; Coukos, George; Dangles-Marie, Virginie; Eckhardt, S Gail; Gonzalez-Suarez, Eva; Hermans, Els; Hidalgo, Manuel; Jarzabek, Monika A; de Jong, Steven; Jonkers, Jos; Kemper, Kristel; Lanfrancone, Luisa; Mælandsmo, Gunhild Mari; Marangoni, Elisabetta; Marine, Jean-Christophe; Medico, Enzo; Norum, Jens Henrik; Palmer, Héctor G; Peeper, Daniel S; Pelicci, Pier Giuseppe; Piris-Gimenez, Alejandro; Roman-Roman, Sergio; Rueda, Oscar M; Seoane, Joan; Serra, Violeta; Soucek, Laura; Vanhecke, Dominique; Villanueva, Alberto; Vinolo, Emilie; Bertotti, Andrea; Trusolino, Livio

    Patient-derived xenografts (PDXs) have emerged as an important platform to elucidate new treatments and biomarkers in oncology. PDX models are used to address clinically relevant questions, including the contribution of tumour heterogeneity to therapeutic responsiveness, the patterns of cancer

  1. Interrogating open issues in cancer precision medicine with patient-derived xenografts

    NARCIS (Netherlands)

    Byrne, Annette T.; Alférez, Denis G.; Amant, Frédéric; Annibali, Daniela; Arribas, Joaquín; Biankin, Andrew V.; Bruna, Alejandra; Budinská, Eva; Caldas, Carlos; Chang, David K.; Clarke, Robert B.; Clevers, Hans; Coukos, George; Dangles-Marie, Virginie; Eckhardt, S. Gail; Gonzalez-Suarez, Eva; Hermans, Els; Hidalgo, Manuel; Jarzabek, Monika A.; de Jong, Steven; Jonkers, Jos; Kemper, Kristel; Lanfrancone, Luisa; Mælandsmo, Gunhild Mari; Marangoni, Elisabetta; Marine, Jean-Christophe; Medico, Enzo; Norum, Jens Henrik; Palmer, Héctor G.; Peeper, Daniel S.; Pelicci, Pier Giuseppe; Piris-Gimenez, Alejandro; Roman-Roman, Sergio; Rueda, Oscar M.; Seoane, Joan; Serra, Violeta; Soucek, Laura; Vanhecke, Dominique; Villanueva, Alberto; Vinolo, Emilie; Bertotti, Andrea; Trusolino, Livio

    2017-01-01

    Patient-derived xenografts (PDXs) have emerged as an important platform to elucidate new treatments and biomarkers in oncology. PDX models are used to address clinically relevant questions, including the contribution of tumour heterogeneity to therapeutic responsiveness, the patterns of cancer

  2. Ultimate load model test for Sizewell 'B' primary containment

    International Nuclear Information System (INIS)

    Crowder, R.

    1988-01-01

    This paper considers the factors influencing the adoption of an ultimate load factor for the Sizewell 'B' PWR primary containment structure. As part of the validation process for the ultimate load analysis method, a proposal has been made by Nuclear Design Associates to build and test a 1/10th scale model of the containment structure, which would proceed following the granting of section 2 consent for Sizewell 'B'. The modelling principles, construction method and test proposals are examined in some detail. The proposal is currently being considered by the CEGB's Project Management Team. (author)

  3. An integrated analysis of miRNA and gene copy numbers in xenografts of Ewing's sarcoma

    Directory of Open Access Journals (Sweden)

    Mosakhani Neda

    2012-03-01

    Full Text Available Abstract Background Xenografts have been shown to provide a suitable source of tumor tissue for molecular analysis in the absence of primary tumor material. We utilized ES xenograft series for integrated microarray analyses to identify novel biomarkers. Method Microarray technology (array comparative genomic hybridization (aCGH and micro RNA arrays was used to screen and identify copy number changes and differentially expressed miRNAs of 34 and 14 passages, respectively. Incubated cells used for xenografting (Passage 0 were considered to represent the primary tumor. Four important differentially expressed miRNAs (miR-31, miR-31*, miR-145, miR-106 were selected for further validation by real time polymerase chain reaction (RT-PCR. Integrated analysis of aCGH and miRNA data was performed on 14 xenograft passages by bioinformatic methods. Results The most frequent losses and gains of DNA copy number were detected at 9p21.3, 16q and at 8, 15, 17q21.32-qter, 1q21.1-qter, respectively. The presence of these alterations was consistent in all tumor passages. aCGH profiles of xenograft passages of each series resembled their corresponding primary tumors (passage 0. MiR-21, miR-31, miR-31*, miR-106b, miR-145, miR-150*, miR-371-5p, miR-557 and miR-598 showed recurrently altered expression. These miRNAS were predicted to regulate many ES-associated genes, such as genes of the IGF1 pathway, EWSR1, FLI1 and their fusion gene (EWS-FLI1. Twenty differentially expressed miRNAs were pinpointed in regions carrying altered copy numbers. Conclusion In the present study, ES xenografts were successfully applied for integrated microarray analyses. Our findings showed expression changes of miRNAs that were predicted to regulate many ES associated genes, such as IGF1 pathway genes, FLI1, EWSR1, and the EWS-FLI1 fusion genes.

  4. Rituximab Treatment Prevents Lymphoma Onset in Gastric Cancer Patient-Derived Xenografts

    Directory of Open Access Journals (Sweden)

    Simona Corso

    2018-05-01

    Full Text Available Patient-Derived Xenografts (PDXs, entailing implantation of cancer specimens in immunocompromised mice, are emerging as a valuable translational model that could help validate biologically relevant targets and assist the clinical development of novel therapeutic strategies for gastric cancer.More than 30% of PDXs generated from gastric carcinoma samples developed human B-cell lymphomas instead of gastric cancer. These lymphomas were monoclonal, Epstein Barr Virus (EBV positive, originated tumorigenic cell cultures and displayed a mutational burden and an expression profile distinct from gastric adenocarcinomas. The ability of grafted samples to develop lymphomas did not correlate with patient outcome, nor with the histotype, the lymphocyte infiltration level, or the EBV status of the original gastric tumor, impeding from foreseeing lymphoma onset. Interestingly, lymphoma development was significantly more frequent when primary rather than metastatic samples were grafted.Notably, the development of such lympho-proliferative disease could be prevented by a short rituximab treatment upon mice implant, without negatively affecting gastric carcinoma engraftment.Due to the high frequency of human lymphoma onset, our data show that a careful histologic analysis is mandatory when generating gastric cancer PDXs. Such care would avoid misleading results that could occur if testing of putative gastric cancer therapies is performed in lymphoma PDXs. We propose rituximab treatment of mice to prevent lymphoma development in PDX models, averting the loss of human-derived samples.

  5. Simplified model of a PWR primary coolant circuit

    International Nuclear Information System (INIS)

    Souza, A.L. de; Faya, A.J.G.

    1988-01-01

    The computer program RENUR was developed to perform a very simplified simulation of a typical PWR primary circuit. The program has mathematical models for the thermal-hydraulics of the reactor core and the pressurizer, the rest of the circuit being treated as a single volume. Heat conduction in the fuel rod is analysed by a nodal model. Average and hot channels are treated so that the bulk response of the core and DNBR can be evaluated. A Homogenenous model is employed in the pressurizer. Results are presented for a steady-state situation as well as for a loss of load transient. Agreement with the results of more elaborate computer codes is good with substantial reduction in computer costs. (author) [pt

  6. Developing a Model of Teaching English to Primary School Students

    Directory of Open Access Journals (Sweden)

    Suwarsih Madya

    2004-01-01

    Full Text Available Under the auspices of the Centre for Curriculum Decelopment, a three-cycle action research study was carried out in three primary schools in Yogyakarta with the aim of developing a model of teaching English to primary school students. The model consists of five parts: Opening, Content Focus, Language Focus, Communication Focus, and Closing. The model, requiring that learning tasks involve active participation of students, both physically and mentally, supported by the use of media suitable for young learners, was developmentally fully implemented. The results showed that efforts were mostly made to establish teacher-student rapport in the first cycle, in which success in classroom management was gradually reached. This led to the easier second cycle, which was characterized by increasing teacher talk (classroom English, the use of interesting media, and more active students' participation in the tasks involving various games which successfully elicited students' English. All of this was solidified in the third cycle. The conclusion is that with the three aspects being focused successively, teacher-student good rapport being established, various media being used, and competing and cooperative tasks being assigned in balance, joyful and effective learning is likely to occur.

  7. A micro-epidemic model for primary dengue infection

    Science.gov (United States)

    Mishra, Arti; Gakkhar, Sunita

    2017-06-01

    In this paper, a micro-epidemic non-linear dynamical model has been proposed and analyzed for primary dengue infection. The model incorporates the effects of T cells immune response as well as humoral response during pathogenesis of dengue infection. The time delay has been accounted for production of antibodies from B cells. The basic reproduction number (R0) has been computed. Three equilibrium states are obtained. The existence and stability conditions for infection-free and ineffective cellular immune response state have been discussed. The conditions for existence of endemic state have been obtained. Further, the parametric region is obtained where system exhibits complex behavior. The threshold value of time delay has been computed which is critical for change in stability of endemic state. A threshold level for antibodies production rate has been obtained over which the infection will die out even though R0 > 1. The model is in line with the clinical observation that viral load decreases within 7-14 days from the onset of primary infection.

  8. Toward a Unified Integration Approach: Uniting Diverse Primary Care Strategies Under the Primary Care Behavioral Health (PCBH) Model.

    Science.gov (United States)

    Sandoval, Brian E; Bell, Jennifer; Khatri, Parinda; Robinson, Patricia J

    2017-12-12

    Primary care continues to be at the center of health care transformation. The Primary Care Behavioral Health (PCBH) model of service delivery includes patient-centered care delivery strategies that can improve clinical outcomes, cost, and patient and primary care provider satisfaction with services. This article reviews the link between the PCBH model of service delivery and health care services quality improvement, and provides guidance for initiating PCBH model clinical pathways for patients facing depression, chronic pain, alcohol misuse, obesity, insomnia, and social barriers to health.

  9. Anti-EGFR therapy radiosensitizes human lung adenocarcinoma xenograft in nude mouse

    International Nuclear Information System (INIS)

    Wang Hui; Li Tianran; Tian Jiahe; Qu Baolin; Zhu Hui

    2008-01-01

    Objective: To investigate the effect of Gefitinib on radiosensitivity of human lung adenocarcinoma xenograft in nude mouse. Methods: Human lung adenocarcinoma cell line A549 was used to establish nude mouse xenograft tumor model. The mice were derided into 4 groups: control, irradiation alone, Gefinitib alone and radiation combined with Genifitib. Radiation schedule was 3 fractions of 5 Gy, once daily. Gefitinib was daily administered by gavage at 100 mg/(kg·day -1 ) for 14 days. In the combination group, radiotherapy was performed 2 hours after Gefitinib administration. Tumor diameter was measured every other day. Percentage of tumor growth inhibition, growth delay time and regrowth delay time were evaluated. Results: For A549 xenografts in radiation alone, gefitinib alone and combination therapy groups, the percentage of tumor growth inhibition was 22.7%, 12.4% and 38.2%, respectively (F=25.75, P=0.000). Tumor growth delay time was 6.0, 7.8 and 21.6 days, respectively (F=70.49, P=0.000). Tumor regrowth delay time in combination therapy and irradiation alone groups was 23.4 and 10.2 days. (F=174.24, P= 0.000). Sensitizing enhancement ratio of combination group was 1.5 in growth and 1.7 in regrowth. Conclusions: Anti-EGFR therapy enhances the radiosensitivity of human lung adenocarcinoma xenograft in nude mouse. (authors)

  10. Primary circuit iodine model addition to IMPAIR-3

    Energy Technology Data Exchange (ETDEWEB)

    Osetek, D J; Louie, D L.Y. [Los Alamos Technical Associates, Inc., Albuquerque, NM (United States); Guntay, S; Cripps, R [Paul Scherrer Inst. (PSI), Villigen (Switzerland)

    1996-12-01

    As part of a continuing effort to provide the U.S. Department of Energy (DOE) Advanced Reactor Severe Accident Program (ARSAP) with complete iodine analysis capability, a task was undertaken to expand the modeling of IMPAIR-3, an iodine chemistry code. The expanded code will enable the DOE to include detailed iodine behavior in the assessment of severe accident source terms used in the licensing of U.S. Advanced Light Water Reactors (ALWRs). IMPAIR-3 was developed at the Paul Scherrer Institute (PSI), Switzerland, and has been used by ARSAP for the past two years to analyze containment iodine chemistry for ALWR source term analyses. IMPAIR-3 is primarily a containment code but the iodine chemistry inside the primary circuit (the Reactor Coolant System or RCS) may influence the iodine species released into the the containment; therefore, a RCS iodine chemistry model must be implemented in IMPAIR-3 to ensure thorough source term analysis. The ARSAP source term team and the PSI IMPAIR-3 developers are working together to accomplish this task. This cooperation is divided into two phases. Phase I, taking place in 1996, involves developing a stand-alone RCS iodine chemistry program called IMPRCS (IMPAIR -Reactor Coolant System). This program models a number of the chemical and physical processes of iodine that are thought to be important at conditions of high temperature and pressure in the RCS. In Phase II, which is tentatively scheduled for 1997, IMPRCS will be implemented as a subroutine in IMPAIR-3. To ensure an efficient calculation, an interface/tracking system will be developed to control the use of the RCS model from the containment model. These two models will be interfaced in such a way that once the iodine is released from the RCS, it will no longer be tracked by the RCS model but will be tracked by the containment model. All RCS thermal-hydraulic parameters will be provided by other codes. (author) figs., tabs., refs.

  11. NOSH–aspirin (NBS-1120), a novel nitric oxide- and hydrogen sulfide-releasing hybrid is a potent inhibitor of colon cancer cell growth in vitro and in a xenograft mouse model

    International Nuclear Information System (INIS)

    Chattopadhyay, Mitali; Kodela, Ravinder; Olson, Kenneth R.; Kashfi, Khosrow

    2012-01-01

    Highlights: ► NOSH–aspirin is the first dual acting NO and H 2 S releasing hybrid. ► Its IC 50 for cell growth inhibition is in the low nano-molar range. ► Structure–activity studies show that the sum of the parts does not equal the whole. ► NOSH–aspirin reduced tumor growth by 85% in mice bearing a colon cancer xenograft. -- Abstract: Nonsteroidal anti-inflammatory drugs (NSAIDs) are prototypical anti-cancer agents. However, their long-term use is associated with adverse gastrointestinal effects. Recognition that endogenous gaseous mediators, nitric oxide (NO) and hydrogen sulfide (H 2 S) can increase mucosal defense mechanisms has led to the development of NO- and H 2 S-releasing NSAIDs with increased safety profiles. Here we report on a new hybrid, NOSH–aspirin, which is an NO- and H 2 S-releasing agent. NOSH–aspirin inhibited HT-29 colon cancer growth with IC 50 s of 45.5 ± 2.5, 19.7 ± 3.3, and 7.7 ± 2.2 nM at 24, 48, and 72 h, respectively. This is the first NSAID based agent with such high degree of potency. NOSH–aspirin inhibited cell proliferation, induced apoptosis, and caused G 0 /G 1 cell cycle block. Reconstitution and structure–activity studies representing a fairly close approximation to the intact molecule showed that NOSH–aspirin was 9000-fold more potent than the sum of its parts towards growth inhibition. NOSH–aspirin inhibited ovine COX-1 more than ovine COX-2. NOSH–ASA treatment of mice bearing a human colon cancer xenograft caused a reduction in volume of 85%. Taken together, these results demonstrate that NOSH–aspirin has strong anti-cancer potential and merits further evaluation.

  12. Modelling the cost effectiveness of antidepressant treatment in primary care.

    Science.gov (United States)

    Revicki, D A; Brown, R E; Palmer, W; Bakish, D; Rosser, W W; Anton, S F; Feeny, D

    1995-12-01

    The aim of this study was to estimate the cost effectiveness of nefazodone compared with imipramine or fluoxetine in treating women with major depressive disorder. Clinical decision analysis and a Markov state-transition model were used to estimate the lifetime health outcomes and medical costs of 3 antidepressant treatments. The model, which represents ideal primary care practice, compares treatment with nefazodone to treatment with either imipramine or fluoxetine. The economic analysis was based on the healthcare system of the Canadian province of Ontario, and considered only direct medical costs. Health outcomes were expressed as quality-adjusted life years (QALYs) and costs were in 1993 Canadian dollars ($Can; $Can1 = $US0.75, September 1995). Incremental cost-utility ratios were calculated comparing the relative lifetime discounted medical costs and QALYs associated with nefazodone with those of imipramine or fluoxetine. Data for constructing the model and estimating necessary parameters were derived from the medical literature, clinical trial data, and physician judgement. Data included information on: Ontario primary care physicians' clinical management of major depression; medical resource use and costs; probabilities of recurrence of depression; suicide rates; compliance rates; and health utilities. Estimates of utilities for depression-related hypothetical health states were obtained from patients with major depression (n = 70). Medical costs and QALYs were discounted to present value using a 5% rate. Sensitivity analyses tested the assumptions of the model by varying the discount rate, depression recurrence rates, compliance rates, and the duration of the model. The base case analysis found that nefazodone treatment costs $Can1447 less per patient than imipramine treatment (discounted lifetime medical costs were $Can50,664 vs $Can52,111) and increases the number of QALYs by 0.72 (13.90 vs 13.18). Nefazodone treatment costs $Can14 less than fluoxetine

  13. Inhibition of Stromal PlGF Suppresses the Growth of Prostate Cancer Xenografts

    Directory of Open Access Journals (Sweden)

    Dietmar Abraham

    2013-09-01

    Full Text Available The growth and vascularization of prostate cancer is dependent on interactions between cancer cells and supporting stromal cells. The primary stromal cell type found in prostate tumors is the carcinoma-associated fibroblast, which produces placental growth factor (PlGF. PlGF is a member of the vascular endothelial growth factor (VEGF family of angiogenic molecules and PlGF mRNA levels increase after androgen deprivation therapy in prostate cancer. In this study, we show that PlGF has a direct dose-dependent proliferative effect on human PC-3 prostate cancer cells in vitro and fibroblast-derived PlGF increases PC-3 proliferation in co-culture. In xenograft tumor models, intratumoral administration of murine PlGF siRNA reduced stromal-derived PlGF expression, reduced tumor burden and decreased the number of Ki-67 positive proliferating cells associated with reduced vascular density. These data show that targeting stromal PlGF expression may represent a therapeutic target for the treatment of prostate cancer.

  14. Modeling primary energy substitution in the Asia Pacific

    International Nuclear Information System (INIS)

    Aguilera, Roberto F.; Ripple, Ronald D.

    2013-01-01

    Highlights: • We model the market shares (i.e. energy mix) of gases, liquids and solids in the Asia Pacific. • The model matches the historical energy mix and projects three scenarios of the future mix to 2030. • We then model the past and future hydrogen to carbon ratio (a proxy for environmental quality). • Importance of natural gas in the region could increase significantly, depending on policy and tech progress. - Abstract: A Global Energy Market model (GEM) is used to analyze the market shares (i.e. the primary energy mix) of gases, liquids and solids in the Asia Pacific. The model is successful in matching the historical energy mix from 1850 to 2009. The model also provides a good match of the hydrogen to carbon ratio, which is a proxy for environmental quality. Given these validations, the GEM is then used to present scenarios of the Asia Pacific energy mix and hydrogen to carbon ratio until the year 2030. Three energy mix scenarios are presented – reference case; alternative case 1; alternative case 2. The reference case assumes limited divergence from current policies and technologies. It indicates that Asia Pacific energy needs will be met by approximately 46% solids, 34% liquids, and 20% gases by 2030. Alternative cases 1 and 2 represent policies and technologies that either encourage or discourage the use of gases. The good matches observed for historical data suggest the GEM can be used cautiously for evaluating outcomes and opportunities in the region. Although the model can be used for projecting far into the future, it is currently calibrated to what we consider a reasonable time horizon – until the year 2030. Given appropriate energy policies and sufficient technological advancement, the importance of natural gas in the region could increase significantly

  15. Establishing Prostate Cancer Patient Derived Xenografts: Lessons Learned From Older Studies

    OpenAIRE

    Russell, Pamela J; Russell, Peter; Rudduck, Christina; Tse, Brian W-C; Williams, Elizabeth D; Raghavan, Derek

    2015-01-01

    Background Understanding the progression of prostate cancer to androgen-independence/castrate resistance and development of preclinical testing models are important for developing new prostate cancer therapies. This report describes studies performed 30 years ago, which demonstrate utility and shortfalls of xenografting to preclinical modeling. Methods We subcutaneously implanted male nude mice with small prostate cancer fragments from transurethral resection of the prostate (TURP) from 29 pa...

  16. NOSH-aspirin (NBS-1120), a novel nitric oxide- and hydrogen sulfide-releasing hybrid is a potent inhibitor of colon cancer cell growth in vitro and in a xenograft mouse model

    Energy Technology Data Exchange (ETDEWEB)

    Chattopadhyay, Mitali; Kodela, Ravinder [Department of Physiology, Pharmacology, and Neuroscience, Sophie Davis School of Biomedical Education, City University of New York Medical School, New York, NY 10031 (United States); Olson, Kenneth R. [Department of Physiology, Indiana University School of Medicine, South Bend, IN 46617 (United States); Kashfi, Khosrow, E-mail: kashfi@med.cuny.edu [Department of Physiology, Pharmacology, and Neuroscience, Sophie Davis School of Biomedical Education, City University of New York Medical School, New York, NY 10031 (United States)

    2012-03-16

    Highlights: Black-Right-Pointing-Pointer NOSH-aspirin is the first dual acting NO and H{sub 2}S releasing hybrid. Black-Right-Pointing-Pointer Its IC{sub 50} for cell growth inhibition is in the low nano-molar range. Black-Right-Pointing-Pointer Structure-activity studies show that the sum of the parts does not equal the whole. Black-Right-Pointing-Pointer NOSH-aspirin reduced tumor growth by 85% in mice bearing a colon cancer xenograft. -- Abstract: Nonsteroidal anti-inflammatory drugs (NSAIDs) are prototypical anti-cancer agents. However, their long-term use is associated with adverse gastrointestinal effects. Recognition that endogenous gaseous mediators, nitric oxide (NO) and hydrogen sulfide (H{sub 2}S) can increase mucosal defense mechanisms has led to the development of NO- and H{sub 2}S-releasing NSAIDs with increased safety profiles. Here we report on a new hybrid, NOSH-aspirin, which is an NO- and H{sub 2}S-releasing agent. NOSH-aspirin inhibited HT-29 colon cancer growth with IC{sub 50}s of 45.5 {+-} 2.5, 19.7 {+-} 3.3, and 7.7 {+-} 2.2 nM at 24, 48, and 72 h, respectively. This is the first NSAID based agent with such high degree of potency. NOSH-aspirin inhibited cell proliferation, induced apoptosis, and caused G{sub 0}/G{sub 1} cell cycle block. Reconstitution and structure-activity studies representing a fairly close approximation to the intact molecule showed that NOSH-aspirin was 9000-fold more potent than the sum of its parts towards growth inhibition. NOSH-aspirin inhibited ovine COX-1 more than ovine COX-2. NOSH-ASA treatment of mice bearing a human colon cancer xenograft caused a reduction in volume of 85%. Taken together, these results demonstrate that NOSH-aspirin has strong anti-cancer potential and merits further evaluation.

  17. A hybrid model of primary radiation damage in crystals

    International Nuclear Information System (INIS)

    Samarin, S.I.; Dremov, V.V.

    2009-01-01

    The paper offers a hybrid model which combines molecular dynamics and Monte Carlo (MD+MC) methods to describe primary radiation damage in crystals, caused by particles whose energies are no higher than several tens of keV. The particles are tracked in accord with equations of motion with account for pair interaction. The model also considers particle interaction with the mean-field potential (MFP) of the crystal. Only particles involved in cascading are tracked. Equations of motion for these particles include dissipative forces which describe energy exchange between cascade particles and electrons. New particles - the atoms of the crystal in the cascade region - have stochastic parameters (phase coordinates); they are sampled by the Monte Carlo method from the distribution that describes the classic canonical ensemble of non-interacting particles subjected to the external MFP. The introduction of particle interaction with the MFP helps avoid difficulties related to crystal stability and the choice of an adequate interparticle interaction potential in the traditional MD methods. Our technique is many times as fast as the traditional MD methods because we consider only particles which are involved in cascading and apply special methods to speedup the calculation of forces by accounting for the short-range pair potential used

  18. Physicochemical characterization of two deproteinized bovine xenografts

    Directory of Open Access Journals (Sweden)

    Thais Accorsi-Mendonça

    2008-03-01

    Full Text Available Calcium phosphate salts, or more specifically hydroxyapatite, are products of great interest in the fields of medical and dental science due to their biocompatibility and osteoconduction property. Deproteinized xenografts are primarily constituted of natural apatites, sintered or not. Variations in the industrial process may affect physicochemical properties and, therefore, the biological outcome. The purpose of this work was to characterize the physical and chemical properties of deproteinized xenogenic biomaterials, Bio-Oss (Geistlich Biomaterials, Wolhuser, Switzerland and Gen-Ox (Baumer S.A., Brazil, widely used as bone grafts. Scanning electron microscopy, infrared region spectroscopy, X-ray diffraction, thermogravimetry and degradation analysis were conducted. The results show that both materials presented porous granules, composed of crystalline hydroxyapatite without apparent presence of other phases. Bio-Oss presented greater dissolution in Tris-HCl than Gen-Ox in the degradation test, possibly due to the low crystallinity and the presence of organic residues. In conclusion, both commercial materials are hydroxyapatite compounds, Bio-Oss being less crystalline than Gen-Ox and, therefore, more prone to degradation.

  19. Pharmacologic modeling of primary mitochondrial respiratory chain dysfunction in zebrafish.

    Science.gov (United States)

    Byrnes, James; Ganetzky, Rebecca; Lightfoot, Richard; Tzeng, Michael; Nakamaru-Ogiso, Eiko; Seiler, Christoph; Falk, Marni J

    2017-07-18

    Mitochondrial respiratory chain (RC) disease is a heterogeneous and highly morbid group of energy deficiency disorders for which no proven effective therapies exist. Robust vertebrate animal models of primary RC dysfunction are needed to explore the effects of variation in RC disease subtypes, tissue-specific manifestations, and major pathogenic factors contributing to each disorder, as well as their pre-clinical response to therapeutic candidates. We have developed a series of zebrafish (Danio rerio) models that inhibit, to variable degrees, distinct aspects of RC function, and enable quantification of animal development, survival, behaviors, and organ-level treatment effects as well as effects on mitochondrial biochemistry and physiology. Here, we characterize four pharmacologic inhibitor models of mitochondrial RC dysfunction in early larval zebrafish, including rotenone (complex I inhibitor), azide (complex IV inhibitor), oligomycin (complex V inhibitor), and chloramphenicol (mitochondrial translation inhibitor that leads to multiple RC complex dysfunction). A range of concentrations and exposure times of each RC inhibitor were systematically evaluated on early larval development, animal survival, integrated behaviors (touch and startle responses), organ physiology (brain death, neurologic tone, heart rate), and fluorescence-based analyses of mitochondrial physiology in zebrafish skeletal muscle. Pharmacologic RC inhibitor effects were validated by spectrophotometric analysis of Complex I, II and IV enzyme activities, or relative quantitation of ATP levels in larvae. Outcomes were prioritized that utilize in vivo animal imaging and quantitative behavioral assessments, as may optimally inform the translational potential of pre-clinical drug screens for future clinical study in human mitochondrial disease subjects. The RC complex inhibitors each delayed early embryo development, with short-term exposures of these three agents or chloramphenicol from 5 to 7 days

  20. NOSH-aspirin (NBS-1120), a novel nitric oxide- and hydrogen sulfide-releasing hybrid is a potent inhibitor of colon cancer cell growth in vitro and in a xenograft mouse model.

    Science.gov (United States)

    Chattopadhyay, Mitali; Kodela, Ravinder; Olson, Kenneth R; Kashfi, Khosrow

    2012-03-16

    Nonsteroidal anti-inflammatory drugs (NSAIDs) are prototypical anti-cancer agents. However, their long-term use is associated with adverse gastrointestinal effects. Recognition that endogenous gaseous mediators, nitric oxide (NO) and hydrogen sulfide (H(2)S) can increase mucosal defense mechanisms has led to the development of NO- and H(2)S-releasing NSAIDs with increased safety profiles. Here we report on a new hybrid, NOSH-aspirin, which is an NO- and H(2)S-releasing agent. NOSH-aspirin inhibited HT-29 colon cancer growth with IC(50)s of 45.5 ± 2.5, 19.7 ± 3.3, and 7.7 ± 2.2 nM at 24, 48, and 72 h, respectively. This is the first NSAID based agent with such high degree of potency. NOSH-aspirin inhibited cell proliferation, induced apoptosis, and caused G(0)/G(1) cell cycle block. Reconstitution and structure-activity studies representing a fairly close approximation to the intact molecule showed that NOSH-aspirin was 9000-fold more potent than the sum of its parts towards growth inhibition. NOSH-aspirin inhibited ovine COX-1 more than ovine COX-2. NOSH-ASA treatment of mice bearing a human colon cancer xenograft caused a reduction in volume of 85%. Taken together, these results demonstrate that NOSH-aspirin has strong anti-cancer potential and merits further evaluation. Copyright © 2012 Elsevier Inc. All rights reserved.

  1. Biodistribution of 99mTc-labeled anti-human epidermal growth factor receptor (EGF-R) humanized monoclonal antibody h-R3 in a xenograft model of human lung adenocarcinoma

    International Nuclear Information System (INIS)

    Morales-Morales, Alejo; Duconge, Jorge; Caballero-Torres, Idania; Nunez-Gandolff, Gilda; Fernandez, Eduardo; Iznaga-Escobar, Normando

    1999-01-01

    The anti-human epidermal growth factor receptor (EGF-R) humanized monoclonal antibody (MAb) h-R3 is an (IgG 1 ), which binds to an extracellular domain of EGF-R. It was used to evaluate the biodistribution on nude mice xenografted with H-125 human lung adenocarcinoma cell line. Results were compared with its murine version of the MAb ior-egf/r3. Twenty-one athymic female 4NMRI nu/nu mice were injected intraperitoneally with 10 μg/100 μCi of 99m Tc-labeled MAbs. Immunoreactivity of 99m Tc-labeled MAbs were measured by enzyme-linked immunosorbent assay (ELISA) on H-125 cell line and the immunoreactive fractions was determined by the Lindmo method. Among all organs, significant accumulation was found in serum (27.05 ± 2.08 %ID/g) and tumor (3.903 ± 0.89 %ID/g) at 4 h after injection. These values decreased to 5.03 ± 0.50 %ID/g and 2.19 ± 0.56 %ID/g for serum and tumor, respectively. The immunoreactive fraction was found to be 0.70, with a correlation coefficient r=0.9984. With the good biodistribution and tumor uptake of the 99m Tc-labeled humanized antibody h-R3, a phase I diagnostic clinical trial of tumor with epithelial origin should be pursued

  2. Biodistribution of {sup 99m}Tc-labeled anti-human epidermal growth factor receptor (EGF-R) humanized monoclonal antibody h-R3 in a xenograft model of human lung adenocarcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Morales-Morales, Alejo; Duconge, Jorge; Caballero-Torres, Idania; Nunez-Gandolff, Gilda; Fernandez, Eduardo; Iznaga-Escobar, Normando E-mail: normando@ict.cim.sld.cu

    1999-04-01

    The anti-human epidermal growth factor receptor (EGF-R) humanized monoclonal antibody (MAb) h-R3 is an (IgG{sub 1}), which binds to an extracellular domain of EGF-R. It was used to evaluate the biodistribution on nude mice xenografted with H-125 human lung adenocarcinoma cell line. Results were compared with its murine version of the MAb ior-egf/r3. Twenty-one athymic female 4NMRI nu/nu mice were injected intraperitoneally with 10 {mu}g/100 {mu}Ci of {sup 99m}Tc-labeled MAbs. Immunoreactivity of {sup 99m}Tc-labeled MAbs were measured by enzyme-linked immunosorbent assay (ELISA) on H-125 cell line and the immunoreactive fractions was determined by the Lindmo method. Among all organs, significant accumulation was found in serum (27.05 {+-} 2.08 %ID/g) and tumor (3.903 {+-} 0.89 %ID/g) at 4 h after injection. These values decreased to 5.03 {+-} 0.50 %ID/g and 2.19 {+-} 0.56 %ID/g for serum and tumor, respectively. The immunoreactive fraction was found to be 0.70, with a correlation coefficient r=0.9984. With the good biodistribution and tumor uptake of the {sup 99m}Tc-labeled humanized antibody h-R3, a phase I diagnostic clinical trial of tumor with epithelial origin should be pursued.

  3. High-degree Gravity Models from GRAIL Primary Mission Data

    Science.gov (United States)

    Lemoine, Frank G.; Goossens, Sander J.; Sabaka, Terence J.; Nicholas, Joseph B.; Mazarico, Erwan; Rowlands, David D.; Loomis, Bryant D.; Chinn, Douglas S.; Caprette, Douglas S.; Neumann, Gregory A.; hide

    2013-01-01

    We have analyzed Ka?band range rate (KBRR) and Deep Space Network (DSN) data from the Gravity Recovery and Interior Laboratory (GRAIL) primary mission (1 March to 29 May 2012) to derive gravity models of the Moon to degree 420, 540, and 660 in spherical harmonics. For these models, GRGM420A, GRGM540A, and GRGM660PRIM, a Kaula constraint was applied only beyond degree 330. Variance?component estimation (VCE) was used to adjust the a priori weights and obtain a calibrated error covariance. The global root?mean?square error in the gravity anomalies computed from the error covariance to 320×320 is 0.77 mGal, compared to 29.0 mGal with the pre?GRAIL model derived with the SELENE mission data, SGM150J, only to 140×140. The global correlations with the Lunar Orbiter Laser Altimeter?derived topography are larger than 0.985 between l = 120 and 330. The free?air gravity anomalies, especially over the lunar farside, display a dramatic increase in detail compared to the pre?GRAIL models (SGM150J and LP150Q) and, through degree 320, are free of the orbit?track?related artifacts present in the earlier models. For GRAIL, we obtain an a posteriori fit to the S?band DSN data of 0.13 mm/s. The a posteriori fits to the KBRR data range from 0.08 to 1.5 micrometers/s for GRGM420A and from 0.03 to 0.06 micrometers/s for GRGM660PRIM. Using the GRAIL data, we obtain solutions for the degree 2 Love numbers, k20=0.024615+/-0.0000914, k21=0.023915+/-0.0000132, and k22=0.024852+/-0.0000167, and a preliminary solution for the k30 Love number of k30=0.00734+/-0.0015, where the Love number error sigmas are those obtained with VCE.

  4. Development and Exemplification of a Model for Teacher Assessment in Primary Science

    Science.gov (United States)

    Davies, D. J.; Earle, S.; McMahon, K.; Howe, A.; Collier, C.

    2017-01-01

    The Teacher Assessment in Primary Science project is funded by the Primary Science Teaching Trust and based at Bath Spa University. The study aims to develop a whole-school model of valid, reliable and manageable teacher assessment to inform practice and make a positive impact on primary-aged children's learning in science. The model is based on a…

  5. Morphological Features of the Porcine Lacrimal Gland and Its Compatibility for Human Lacrimal Gland Xenografting

    OpenAIRE

    Henker, Robert; Scholz, Michael; Gaffling, Simone; Asano, Nagayoshi; Hampel, Ulrike; Garreis, Fabian; Hornegger, Joachim; Paulsen, Friedrich

    2013-01-01

    In this study, we present first data concerning the anatomical structure, blood supply and location of the lacrimal gland of the pig. Our data indicate that the porcine lacrimal gland may serve as a potential xenograft candidate in humans or as an animal model for engineering of a bioartificial lacrimal gland tissue construct for clinical application. For this purpose, we used different macroscopic preparation techniques and digital reconstruction of the histological gland morphology to gain ...

  6. A comprehensive patient-derived xenograft collection representing the heterogeneity of melanoma

    OpenAIRE

    Krepler, Clemens; Sproesser, Katrin; Brafford, Patricia; Beqiri, Marilda; Garman, Bradley; Xiao, Min; Shannan, Batool; Watters, Andrea; Perego, Michela; Zhang, Gao; Vultur, Adina; Yin, Xiangfan; Liu, Qin; Anastopoulos, Ioannis N; Wubbenhorst, Bradley

    2017-01-01

    Summary: Therapy of advanced melanoma is changing dramatically. Following mutational and biological subclassification of this heterogeneous cancer, several targeted and immune therapies were approved and increased survival significantly. To facilitate further advancements through pre-clinical in vivo modeling, we have established 459 patient-derived xenografts (PDX) and live tissue samples from 384 patients representing the full spectrum of clinical, therapeutic, mutational, and biological he...

  7. Prevention of Human Lymphoproliferative Tumor Formation in Ovarian Cancer Patient-Derived Xenografts

    Directory of Open Access Journals (Sweden)

    Kristina A. Butler

    2017-08-01

    Full Text Available Interest in preclinical drug development for ovarian cancer has stimulated development of patient-derived xenograft (PDX or tumorgraft models. However, the unintended formation of human lymphoma in severe combined immunodeficiency (SCID mice from Epstein-Barr virus (EBV–infected human lymphocytes can be problematic. In this study, we have characterized ovarian cancer PDXs which developed human lymphomas and explore methods to suppress lymphoproliferative growth. Fresh human ovarian tumors from 568 patients were transplanted intraperitoneally in SCID mice. A subset of PDX models demonstrated atypical patterns of dissemination with mediastinal masses, hepatosplenomegaly, and CD45-positive lymphoblastic atypia without ovarian tumor engraftment. Expression of human CD20 but not CD3 supported a B-cell lineage, and EBV genomes were detected in all lymphoproliferative tumors. Immunophenotyping confirmed monoclonal gene rearrangements consistent with B-cell lymphoma, and global gene expression patterns correlated well with other human lymphomas. The ability of rituximab, an anti-CD20 antibody, to suppress human lymphoproliferation from a patient's ovarian tumor in SCID mice and prevent growth of an established lymphoma led to a practice change with a goal to reduce the incidence of lymphomas. A single dose of rituximab during the primary tumor heterotransplantation process reduced the incidence of CD45-positive cells in subsequent PDX lines from 86.3% (n = 117 without rituximab to 5.6% (n = 160 with rituximab, and the lymphoma rate declined from 11.1% to 1.88%. Taken together, investigators utilizing PDX models for research should routinely monitor for lymphoproliferative tumors and consider implementing methods to suppress their growth.

  8. The Child Anxiety Prevention Study: intervention model and primary outcomes.

    Science.gov (United States)

    Ginsburg, Golda S

    2009-06-01

    The article presents the intervention model and primary outcomes of a preventive intervention designed to reduce anxiety symptoms and prevent the onset of anxiety disorders in the offspring of parents with anxiety disorders. Participants were 40 volunteer children (mean age = 8.94 years; 45% girls; 90% Caucasian) whose parents met criteria for a broad range of anxiety disorders. Families were randomly assigned to an 8-week cognitive-behavioral intervention, the Coping and Promoting Strength program (CAPS; n = 20) or a wait list control condition (WL; n = 20). Independent evaluators (IEs) conducted diagnostic interviews, and children and parents completed measures of anxiety symptoms. Assessments were conducted pre- and postintervention and 6 and 12 months after the postintervention assessment. On the basis of intent to treat analyses, 30% of the children in the WL group developed an anxiety disorder by the 1-year follow-up compared with 0% in the CAPS group. IE and parent-reported (but not child-reported) levels of anxiety showed significant decreases from the preintervention assessment to the 1-year follow-up assessment in the CAPS but not the WL group. Parental satisfaction with the intervention was high. Findings suggest that a family-based intervention may prevent the onset of anxiety disorders in the offspring of parents with anxiety disorders. Copyright 2009 APA

  9. Classification Model That Predicts Medical Students' Choices of Primary Care or Non-Primary Care Specialties.

    Science.gov (United States)

    Fincher, Ruth-Marie E.; And Others

    1992-01-01

    This study identified factors in graduating medical students' choice of primary versus nonprimary care specialty. Subjects were 509 students at the Medical College of Georgia in 1988-90. Students could be classified by such factors as desire for longitudinal patient care opportunities, monetary rewards, perception of lifestyle, and perception of…

  10. Pancreatic Adenocarcinoma Therapeutic Targets Revealed by Tumor-Stroma Cross-Talk Analyses in Patient-Derived Xenografts

    Directory of Open Access Journals (Sweden)

    Rémy Nicolle

    2017-11-01

    Full Text Available Preclinical models based on patient-derived xenografts have remarkable specificity in distinguishing transformed human tumor cells from non-transformed murine stromal cells computationally. We obtained 29 pancreatic ductal adenocarcinoma (PDAC xenografts from either resectable or non-resectable patients (surgery and endoscopic ultrasound-guided fine-needle aspirate, respectively. Extensive multiomic profiling revealed two subtypes with distinct clinical outcomes. These subtypes uncovered specific alterations in DNA methylation and transcription as well as in signaling pathways involved in tumor-stromal cross-talk. The analysis of these pathways indicates therapeutic opportunities for targeting both compartments and their interactions. In particular, we show that inhibiting NPC1L1 with Ezetimibe, a clinically available drug, might be an efficient approach for treating pancreatic cancers. These findings uncover the complex and diverse interplay between PDAC tumors and the stroma and demonstrate the pivotal role of xenografts for drug discovery and relevance to PDAC.

  11. Tumor Repression of VCaP Xenografts by a Pyrrole-Imidazole Polyamide.

    Directory of Open Access Journals (Sweden)

    Amanda E Hargrove

    Full Text Available Pyrrole-imidazole (Py-Im polyamides are high affinity DNA-binding small molecules that can inhibit protein-DNA interactions. In VCaP cells, a human prostate cancer cell line overexpressing both AR and the TMPRSS2-ERG gene fusion, an androgen response element (ARE-targeted Py-Im polyamide significantly downregulates AR driven gene expression. Polyamide exposure to VCaP cells reduced proliferation without causing DNA damage. Py-Im polyamide treatment also reduced tumor growth in a VCaP mouse xenograft model. In addition to the effects on AR regulated transcription, RNA-seq analysis revealed inhibition of topoisomerase-DNA binding as a potential mechanism that contributes to the antitumor effects of polyamides in cell culture and in xenografts. These studies support the therapeutic potential of Py-Im polyamides to target multiple aspects of transcriptional regulation in prostate cancers without genotoxic stress.

  12. Model of affective assessment of primary school students

    Directory of Open Access Journals (Sweden)

    Amir Syamsudin

    2016-06-01

    Full Text Available This study aims to develop an instrument of affective assessment to measure the social competence of elementary school students in the learning process in schools. This study used the development model of Borg & Gall’s approach which was modified into five phases, including the need analyses, developing draft of the product conducted by experts, developing an affective assessment instrument, trying out the affective assessment instrument conducted by teachers of primary education in Yogyakarta, and the dissemination and implementation of the developed affective assessment instrument. The subjects were elementary school students whose school implemented Curriculum 2013 in the academic year of 2013/2014. The validity and reliability of each construct of the affective instrument were established using the PLS SEM Wrap PLS 3.0 analysis program. The study finds the following results. First, the construct of Honesty, Discipline, Responsibility, Decency, Care, and Self-Confidence in the limited, main, and extended testing has been supported by empirical data. Second, the validity of Honesty, Discipline, Responsibility, Decency, Care, and Self-Confidence in the limited, main, and extended testing meets the criteria above 0.70 for each indicator of the loading factor and the criteria below 0.50 for each indicator score of the cross-loading factor. Third, the reliability of Honesty, Discipline, Responsibility, Decency, Care, and Self-Confidence in limited, main, and extended testing meets the criteria above 0.70 for both composite reliability and Cronbach’s alpha scores. Fourth, the number of indicators at preresearch was 53, and 10 indicators were rejected in the limited testing, and four indicators were rejected in the main testing, and one indicator was rejected in the extended testing.

  13. A Comprehensive Patient-Derived Xenograft Collection Representing the Heterogeneity of Melanoma

    Directory of Open Access Journals (Sweden)

    Clemens Krepler

    2017-11-01

    Full Text Available Summary: Therapy of advanced melanoma is changing dramatically. Following mutational and biological subclassification of this heterogeneous cancer, several targeted and immune therapies were approved and increased survival significantly. To facilitate further advancements through pre-clinical in vivo modeling, we have established 459 patient-derived xenografts (PDX and live tissue samples from 384 patients representing the full spectrum of clinical, therapeutic, mutational, and biological heterogeneity of melanoma. PDX have been characterized using targeted sequencing and protein arrays and are clinically annotated. This exhaustive live tissue resource includes PDX from 57 samples resistant to targeted therapy, 61 samples from responders and non-responders to immune checkpoint blockade, and 31 samples from brain metastasis. Uveal, mucosal, and acral subtypes are represented as well. We show examples of pre-clinical trials that highlight how the PDX collection can be used to develop and optimize precision therapies, biomarkers of response, and the targeting of rare genetic subgroups. : Krepler et al. have established a collection of melanoma patient-derived xenografts (PDX. Melanoma is a very heterogeneous cancer, and this large collection includes even rare subtypes and genetic aberrations in sufficient numbers. Multiple PDX from therapy-resistant patients are characterized and tested in pre-clinical trials for second line therapies. Keywords: melanoma, patient-derived xenografts, targeted therapy, immune checkpoint blockade, melanoma brain metastasis, in vivo models, BRAF inhibitor resistance, ERK inhibitor, MDM2 inhibitor, PI3K beta inhibitor

  14. Inhibitory effect of Dendrobium officinale polysaccharide on human gastric cancer cell xenografts in nude mice

    Directory of Open Access Journals (Sweden)

    Liying ZHANG

    2017-10-01

    Full Text Available Abstract This study investigated the inhibitory effect of Dendrobium officinale polysaccharide (DOPA on human gastric cancer cell SGC-7901 xenografts in nude mice. The nude mice with SGC-7901 xenografts were randomly divided into model, 5-fluorouracil (5-Fu, low-dose DOPA, middle-dose DOPA and high-dose DOPA group. The later four groups were intragastrically administrated with 100, 200 and 400 mg·kg–1·day–1 DOPA, 400 mg·kg–1·day–1 5-Fu and normal saline, respectively. After treatment for 20 days, the tumor inhibition rate of in high-dose DOPA group was basically equivalent to 5-Fu group. Compared with 5-Fu, DOPA had no obvious toxic side effect on spleen or thymus indexes, routine blood indexes or liver and kidney functions of nude mice. Compared with model group, the serum tumor necrosis factor-α and interleukin-2 levels in middle- and high-dose DOPA group were significantly increased (P < 0.05, Bax protein expression was significantly increased (P < 0.05, and Bcl-2 protein expression was significantly decreased (P < 0.05. DOPA can inhibit the growth of SGC-7901 cell xenografts in nude mice. The mechanism may be related to its increase of serum TNF-α and IL-2 levels, up-regulation of Bax protein expression and down-regulation of Bcl-2 protein expression.

  15. Radiation responses of human bladder cancer assessed in vitro or as xenografts in immune-deprived mice

    International Nuclear Information System (INIS)

    Tannock, I.; Choo, B.; Buick, R.

    1984-01-01

    The response to radiation of cells derived from transitional cell carcinoma (TCC) of the human bladder has been studied. In vitro radiation survival curves for two established cell lines, RT-4 and MGH-U1, and for a cell line HB-10 derived recently from biopsy of a metastatic lymph node were characterized by values of D 0 and anti n in the range of 1.1-1.5 Gy and 2-7 respectively. The oxygen enhancement ratio of HB-10 cells was 2.8. Xenografts derived from the line HB-10 were irradiated in vivo under both aerobic and hypoxic conditions and cell survival was assessed in agar. Both aerobic and hypoxic survival curves were similar to that obtained for irradiation of hypoxic HB-10 cells in culture. Another tumor line, HB-15, derived from a cystoscopic biopsy of primary TCC, was maintained by transplantation of xenografts. Regrowth curves for HB-15 xenografts after radiation doses of 10 or 20 Gy were parallel to the growth curve for untreated controls but with volume reduced by factors of about 5 and 20 respectively. Cells derived from TCC of the human bladder exhibit parameters of radiation survival similar to those of other mammalian cells, and that xenografts derived from such cells contain a high proportion of hypoxic cells

  16. Vascular abnormalities associated with acute hypoxia in human melanoma xenografts

    International Nuclear Information System (INIS)

    Simonsen, Trude G.; Gaustad, Jon-Vidar; Leinaas, Marit N.; Rofstad, Einar K.

    2012-01-01

    Background and purpose: The fraction of hypoxic cells has been shown to differ substantially among human tumors of the same histological type. In this study, a window chamber model was used to identify possible mechanisms leading to the development of highly different hypoxic fractions in A-07 and R-18 human melanoma xenografts. Materials and methods: Chronic and acute hypoxia was assessed in intradermal tumors using an immunohistochemical and a radiobiological assay. Functional and morphological parameters of the vascular networks of tumors growing in dorsal window chambers were assessed with intravital microscopy. Results: R-18 tumors showed significantly higher hypoxic fractions than A-07 tumors, and the difference was mostly due to acute hypoxia. Compared to A-07 tumors, R-18 tumors showed low vascular densities, low vessel diameters, long vessel segments, low blood flow velocities, frequent fluctuations in blood flow, and a high fraction of narrow vessels with absent or very low and varying flux of red blood cells. Conclusion: The high fraction of acute hypoxia in R-18 tumors was a consequence of frequent fluctuations in blood flow and red blood cell flux combined with low vascular density. The fluctuations were most likely caused by high geometric resistance to blood flow in the tumor microvasculature.

  17. The Implementation of Character Education Model Based on Empowerment Theatre for Primary School Students

    Science.gov (United States)

    Anggraini, Purwati; Kusniarti, Tuti

    2016-01-01

    This study aimed at constructing character education model implemented in primary school. The research method was qualitative with five samples in total, comprising primary schools in Malang city/regency and one school as a pilot model. The pilot model was instructed by theatre coach teacher, parents, and school society. The result showed that…

  18. Modeling tissue contamination to improve molecular identification of the primary tumor site of metastases

    DEFF Research Database (Denmark)

    Vincent, Martin; Perell, Katharina; Nielsen, Finn Cilius

    2014-01-01

    with any predictor model. The usability of the model is illustrated on primary tumor site identification of liver biopsies, specifically, on a human dataset consisting of microRNA expression measurements of primary tumor samples, benign liver samples and liver metastases. For a predictor trained on primary...... tumor and benign liver samples, the contamination model decreased the test error on biopsies from liver metastases from 77 to 45%. A further reduction to 34% was obtained by including biopsies in the training data....

  19. Sulforaphane suppresses the growth of glioblastoma cells, glioblastoma stem cell-like spheroids, and tumor xenografts through multiple cell signaling pathways.

    Science.gov (United States)

    Bijangi-Vishehsaraei, Khadijeh; Reza Saadatzadeh, M; Wang, Haiyan; Nguyen, Angie; Kamocka, Malgorzata M; Cai, Wenjing; Cohen-Gadol, Aaron A; Halum, Stacey L; Sarkaria, Jann N; Pollok, Karen E; Safa, Ahmad R

    2017-12-01

    OBJECTIVE Defects in the apoptotic machinery and augmented survival signals contribute to drug resistance in glioblastoma (GBM). Moreover, another complexity related to GBM treatment is the concept that GBM development and recurrence may arise from the expression of GBM stem cells (GSCs). Therefore, the use of a multifaceted approach or multitargeted agents that affect specific tumor cell characteristics will likely be necessary to successfully eradicate GBM. The objective of this study was to investigate the usefulness of sulforaphane (SFN)-a constituent of cruciferous vegetables with a multitargeted effect-as a therapeutic agent for GBM. METHODS The inhibitory effects of SFN on established cell lines, early primary cultures, CD133-positive GSCs, GSC-derived spheroids, and GBM xenografts were evaluated using various methods, including GSC isolation and the sphere-forming assay, analysis of reactive oxygen species (ROS) and apoptosis, cell growth inhibition assay, comet assays for assessing SFN-triggered DNA damage, confocal microscopy, Western blot analysis, and the determination of in vivo efficacy as assessed in human GBM xenograft models. RESULTS SFN triggered the significant inhibition of cell survival and induced apoptotic cell death, which was associated with caspase 3 and caspase 7 activation. Moreover, SFN triggered the formation of mitochondrial ROS, and SFN-triggered cell death was ROS dependent. Comet assays revealed that SFN increased single- and double-strand DNA breaks in GBM. Compared with the vehicle control cells, a significantly higher amount of γ-H2AX foci correlated with an increase in DNA double-strand breaks in the SFN-treated samples. Furthermore, SFN robustly inhibited the growth of GBM cell-induced cell death in established cell cultures and early-passage primary cultures and, most importantly, was effective in eliminating GSCs, which play a major role in drug resistance and disease recurrence. In vivo studies revealed that SFN

  20. Optimization, biological evaluation and microPET imaging of copper-64-labeled bombesin agonists, [64Cu-NO2A-(X)-BBN(7-14)NH2], in a prostate tumor xenografted mouse model

    International Nuclear Information System (INIS)

    Lane, Stephanie R.; Nanda, Prasanta; Rold, Tammy L.; Sieckman, Gary L.; Figueroa, Said D.; Hoffman, Timothy J.; Jurisson, Silvia S.; Smith, Charles J.

    2010-01-01

    Gastrin-releasing peptide receptors (GRPr) are a member of the bombesin (BBN) receptor family. GRPr are expressed in high numbers on specific human cancers, including human prostate cancer. Therefore, copper-64 ( 64 Cu) radiolabeled BBN(7-14)NH 2 conjugates could have potential for diagnosis of human prostate cancer via positron-emission tomography (PET). The aim of this study was to produce [ 64 Cu-NO2A-(X)-BBN(7-14)NH 2 ] conjugates for prostate cancer imaging, where X=pharmacokinetic modifier (beta-alanine, 5-aminovaleric acid, 6-aminohexanoic acid, 8-aminooctanoic acid, 9-aminonanoic acid or para-aminobenzoic acid) and NO2A=1,4,7-triazacyclononane-1,4-diacetic acid [a derivative of NOTA (1,4,7-triazacyclononane-1,4,7-triacetic acid)]. Methods: [(X)-BBN(7-14)NH 2 ] Conjugates were synthesized by solid-phase peptide synthesis (SPPS), after which NOTA was added via manual conjugation. The new peptide conjugates were radiolabeled with 64 Cu radionuclide. The receptor-binding affinity was determined in human prostate PC-3 cells, and tumor-targeting efficacy was determined in PC-3 tumor-bearing severely combined immunodeficient (SCID) mice. Whole-body maximum intensity microPET/CT images of PC-3 tumor-bearing SCID mice were obtained 18 h postinjection (pi). Results: Competitive binding assays in PC-3 cells indicated high receptor-binding affinity for the [NO2A-(X)-BBN(7-14)NH 2 ] and [ nat Cu-NO2A-(X)-BBN(7-14)NH 2 ] conjugates. In vivo biodistribution studies of the [ 64 Cu-NO2A-(X)-BBN(7-14)NH 2 ] conjugates at 1, 4 and 24 h pi showed very high uptake of the tracer in GRPr-positive tissue with little accumulation and retention in nontarget tissues. High-quality, high-contrast microPET images were obtained, with xenografted tumors being clearly visible at 18 h pi. Conclusions: NO2A chelator sufficiently stabilizes copper(II) radiometal under in vivo conditions, producing conjugates with very high uptake and retention in targeted GRPr. Preclinical evaluation of these

  1. A comparison of targetting of neuroblastoma with MIBG and anti L1-CAM antibody mAb chCE7: therapeutic efficacy in a neuroblastoma xenograft model and imaging of neuroblastoma patients

    International Nuclear Information System (INIS)

    Hoefnagel, C.A.; Rutgers, M.; Buitenhuis, C.K.M.; Smets, L.A.; Kraker, J. de; Meli, M.; Carrel, F.; Schubiger, P.A.; Novak-Hofer, I.; Amstutz, H.

    2001-01-01

    Modine-131 labelled anti L1-CAM antibody mAb chCE7 was compared with the effective neuroblastoma-seeking agent 131 I-labelled metaiodobenzylguanidine (MIBG) with regard to (a) its therapeutic efficacy in treating nude mice with neuroblastoma xenografts and (b) its tumour targetting ability in neuroblastoma patients. The SK-N-SH tumour cells used in the mouse experiments show good MIBG uptake and provide a relatively low number of 6,300 binding sites/cell for mAb chCE7. Tumours were treated with single injections of 131 I-MIBG (110 MBq) and with 131 I-labelled mAb chCE7 (17 MBq) and both agents showed antitumour activity. After therapy with 131 I-chCE7, the subcutaneous tumours nearly disappeared; treatment with 131 I-MIBG was somewhat less effective, resulting in a 70% reduction in tumour volume. A calculated tumour regrowth delay of 9 days occurred with a radioactivity dose of 17 MBq of an irrelevant control antibody mAb 35, which does not bind to SK-N-SH cells, compared with a regrowth delay of 34 days with 131 I-mAb chCE7 and of 24 days with 131 I-MIBG. General toxicity appeared to be mild, as assessed by a transient, approximate 10% maximum decrease in body weight during the treatments. The superior growth inhibition achieved by 131 I-chCE7 compared with 131 I-MIBG can be explained by its prolonged retention in the tumours, due to slower normal tissue and plasma clearance. Cross-reaction of mAb chCE7 with L1-CAM present in normal human tissues was investigated by direct binding of radioiodinated mAb to frozen tissue sections. Results showed a strong reaction with normal human brain tissue and weak but detectable binding to normal adult kidney sections. Seven patients with recurrent neuroblastoma were sequentially imaged with 131 I-MIBG and 131 I-chCE7. The results underlined the heterogeneity of neuroblastoma and showed the two imaging modalities to be complementary. 131 I-chCE7 scintigraphy may have clinical utility in detecting metastases which do not

  2. Effects of curcumin on growth of human cervical cancer xenograft in nude mice and underlying mechanism

    Directory of Open Access Journals (Sweden)

    Aixue LIU

    Full Text Available Abstract The present study investigated the effects of curcumin (Cur on growth of human cervical cancer xenograft in nude mice and underlying mechanism. The nude mice modeled with human cervical cancer HeLa cell xenograft were treated with normal saline (control, 3 mg/kg Cisplatin, 50, 100 and 200 mg/kg Cur, respectively. The animal body weight and growth of tumor were measured. The expressions of Bax, Bcl-2, p53, p21, HIF-1α, VEGF and MIF protein in tumor tissue were determined. Results showed that, after treatment for 20 days, the tumor mass and tumor volume in 100 and 200 mg/kg Cur group were significantly lower than control group (P < 0.05. The expressions of Bax, p53 and p21 protein in tumor tissue in 200 mg/kg Cur group were significantly higher than control group (P < 0.05, and the expressions of Bcl-2, HIF-1α, VEGF and MIF protein in tumor tissue in 200 mg/kg Cur group were significantly lower than control group (P < 0.05. Cur can inhibit the growth of HeLa cell xenograft in nude mice. The possible mechanism may be related to its up-regulation of Bax, p53 and p21 protein expression in tumor tissue, and down-regulation of Bcl-2, HIF-1α, VEGF and MIF protein expression.

  3. Allografts versus Equine Xenografts in Calcaneal Fracture Repair.

    Science.gov (United States)

    Sonmez, Mehmet Mesut; Armagan, Raffi; Ugurlar, Meric; Eren, Tugrul

    Displaced intra-articular calcaneal fractures are difficult to treat. We determined the functional results and complications of using allografts or equine xenografts in treating these fractures. We reviewed patients seen at our center from May 2011 to December 2014 with Sanders type III or IV unilateral calcaneal fractures treated with locking plates and an additional bone allograft or equine xenograft. A minimum of 1 year after surgery, a history of infection and functional outcomes were assessed using the American Orthopaedic Foot and Ankle Society clinical rating system. Changes in the Gissane angle (GA) and Böhler angle were assessed from radiographs. Of the 91 eligible patients, 15 were lost to follow-up, leaving a sample of 76 patients (42 males): 45 received allografts (19 for type III and 26 for type IV fractures) and 31 received xenografts (20 for type III and 11 for type IV fractures). The mean age was about 40 years in both groups. After ≥1 year of follow-up, the proportion of patients in the American Orthopaedic Foot and Ankle Society scoring categories did not differ significantly between the 2 groups (mean ankle score, 86.5 in the allograft group and 85.1 in the xenograft group), and the American Orthopaedic Foot and Ankle Society functional outcomes were good or excellent in 69% and 68%, respectively (p = .986). The groups did not differ in the incidence of superficial or deep infection (p = 1.000). The Böhler angles were significantly decreased in the xenograft group. Xenografts might be preferred for repairing intra-articular calcaneal fractures because they can perform as well as allografts, avoid donor site morbidities, and are more available and less expensive than allografts. Copyright © 2017 American College of Foot and Ankle Surgeons. Published by Elsevier Inc. All rights reserved.

  4. [Inhibitory effect of Biejiajian pills on HepG2 cell xenograft growth and expression of β-catenin and Tbx3 in nude mice].

    Science.gov (United States)

    Wen, Bin; Sun, Hai-Tao; He, Song-Qi; LA, Lei; An, Hai-Yan; Pang, Jie

    2016-02-01

    To explore the molecular mechanism by which Biejiajian pills inhibit hepatocellular carcinoma in a nude mouse model bearing HepG2 cell xenograft. The inhibitory effect of Biejiajian pills on the growth of HepG2 cell xenograft in nude mice was observed. Immunohistochemical method was used to examine proliferating cell nuclear antigen (PCNA) expression in HepG2 cell xenograft, and TUNEL method was employed to detect the cell apoptosis; the expression levels of β-catenin and Tbx3 were measured by Western blotting. Biejiajian pills significantly suppressed the growth of HepG2 cell xenograft in nude mice. The tumor-bearing mice treated with a high and a moderate dose of Biejiajian pills showed significantly increased apoptosis rate of the tumor cells [(22.9±1.220)% and (14.7±0.50)%, respectively] compared with the control group [(5.5±0.90)%, Ppills significantly decreased the expressions of PNCA, β-catenin, and Tbx3 in the cell xenograft (Ppills can inhibit the growth of HepG2 cell xenograft in nude mice and promote tumor cell apoptosis possibly by inhibiting PNCA expression and the Wnt/β-catenin signaling pathway.

  5. An Effect of the Co-Operative Network Model for Students' Quality in Thai Primary Schools

    Science.gov (United States)

    Khanthaphum, Udomsin; Tesaputa, Kowat; Weangsamoot, Visoot

    2016-01-01

    This research aimed: 1) to study the current and desirable states of the co-operative network in developing the learners' quality in Thai primary schools, 2) to develop a model of the co-operative network in developing the learners' quality, and 3) to examine the results of implementation of the co-operative network model in the primary school.…

  6. ISMS: A New Model for Improving Student Motivation and Self-Esteem in Primary Education

    Science.gov (United States)

    Ghilay, Yaron; Ghilay, Ruth

    2015-01-01

    In this study we introduce a new model for primary education called ISMS: Improving Student Motivation and Self-esteem. Following a two-year study undertaken in a primary school (n = 67), the new model was found to be successful. Students who participated in the research, reported that a course based on ISMS principles was very helpful for…

  7. A reproducible brain tumour model established from human glioblastoma biopsies

    International Nuclear Information System (INIS)

    Wang, Jian; Chekenya, Martha; Bjerkvig, Rolf; Enger, Per Ø; Miletic, Hrvoje; Sakariassen, Per Ø; Huszthy, Peter C; Jacobsen, Hege; Brekkå, Narve; Li, Xingang; Zhao, Peng; Mørk, Sverre

    2009-01-01

    Establishing clinically relevant animal models of glioblastoma multiforme (GBM) remains a challenge, and many commonly used cell line-based models do not recapitulate the invasive growth patterns of patient GBMs. Previously, we have reported the formation of highly invasive tumour xenografts in nude rats from human GBMs. However, implementing tumour models based on primary tissue requires that these models can be sufficiently standardised with consistently high take rates. In this work, we collected data on growth kinetics from a material of 29 biopsies xenografted in nude rats, and characterised this model with an emphasis on neuropathological and radiological features. The tumour take rate for xenografted GBM biopsies were 96% and remained close to 100% at subsequent passages in vivo, whereas only one of four lower grade tumours engrafted. Average time from transplantation to the onset of symptoms was 125 days ± 11.5 SEM. Histologically, the primary xenografts recapitulated the invasive features of the parent tumours while endothelial cell proliferations and necrosis were mostly absent. After 4-5 in vivo passages, the tumours became more vascular with necrotic areas, but also appeared more circumscribed. MRI typically revealed changes related to tumour growth, several months prior to the onset of symptoms. In vivo passaging of patient GBM biopsies produced tumours representative of the patient tumours, with high take rates and a reproducible disease course. The model provides combinations of angiogenic and invasive phenotypes and represents a good alternative to in vitro propagated cell lines for dissecting mechanisms of brain tumour progression

  8. Radiosensitivity of drug-resistant human tumour xenografts

    International Nuclear Information System (INIS)

    Mattern, J.; Bak, M. Jr.; Volm, M.; Hoever, K.H.

    1989-01-01

    The radiosensitivity of three drug-resistant sublines of a human epidermoid lung carcinoma growing as xenografts in nude mice was investigated. Drug resistance to vincristine, actinomycin D and cisplatin was developed in vivo by repeated drug treatment. It was found that all three drug-resistant tumour lines were not cross-resistant to irradiation. (orig.) [de

  9. Cryopreservation of human colorectal carcinomas prior to xenografting

    International Nuclear Information System (INIS)

    Linnebacher, Michael; Maletzki, Claudia; Ostwald, Christiane; Klier, Ulrike; Krohn, Mathias; Klar, Ernst; Prall, Friedrich

    2010-01-01

    Molecular heterogeneity of colorectal carcinoma (CRC) is well recognized, forming the rationale for molecular tests required before administration of some of the novel targeted therapies that now are rapidly entering the clinics. For clinical research at least, but possibly even for future individualized tumor treatment on a routine basis, propagation of patients' CRC tissue may be highly desirable for detailed molecular, biochemical or functional analyses. However, complex logistics requiring close liaison between surgery, pathology, laboratory researchers and animal care facilities are a major drawback in this. We here describe and evaluate a very simple cryopreservation procedure for colorectal carcinoma tissue prior to xenografting that will considerably reduce this logistic complexity. Fourty-eight CRC collected ad hoc were xenografted subcutaneously into immunodeficient mice either fresh from surgery (N = 23) or after cryopreservation (N = 31; up to 643 days). Take rates after cryopreservation were satisfactory (71%) though somewhat lower than with tumor tissues fresh from surgery (74%), but this difference was not statistically significant. Re-transplantation of cryopreserved established xenografts (N = 11) was always successful. Of note, in this series, all of the major molecular types of CRC were xenografted successfully, even after cryopreservation. Our procedure facilitates collection, long-time storage and propagation of clinical CRC specimens (even from different centres) for (pre)clinical studies of novel therapies or for basic research

  10. Exosomal secretion of cytoplasmic prostate cancer xenograft-derived proteins

    NARCIS (Netherlands)

    F.H. Jansen (Flip); J. Krijgsveld (Jeroen); A.L. Rijswijk (Angelique); G.J.C.M. van den Bemd (Gert-Jan); M.S. van den Berg (Mirella); W.M. van Weerden (Wytske); R. Willemsen (Rob); L.J.M. Dekker (Lennard); T.M. Luider (Theo); G.W. Jenster (Guido)

    2009-01-01

    textabstractNovel markers for prostate cancer (PCa) are needed because current established markers such as prostate-specific antigen lack diagnostic specificity and prognostic value. Proteomics analysis of serum from mice grafted with human PCa xenografts resulted in the identification of 44

  11. Mental models of audit and feedback in primary care settings.

    Science.gov (United States)

    Hysong, Sylvia J; Smitham, Kristen; SoRelle, Richard; Amspoker, Amber; Hughes, Ashley M; Haidet, Paul

    2018-05-30

    Audit and feedback has been shown to be instrumental in improving quality of care, particularly in outpatient settings. The mental model individuals and organizations hold regarding audit and feedback can moderate its effectiveness, yet this has received limited study in the quality improvement literature. In this study we sought to uncover patterns in mental models of current feedback practices within high- and low-performing healthcare facilities. We purposively sampled 16 geographically dispersed VA hospitals based on high and low performance on a set of chronic and preventive care measures. We interviewed up to 4 personnel from each location (n = 48) to determine the facility's receptivity to audit and feedback practices. Interview transcripts were analyzed via content and framework analysis to identify emergent themes. We found high variability in the mental models of audit and feedback, which we organized into positive and negative themes. We were unable to associate mental models of audit and feedback with clinical performance due to high variance in facility performance over time. Positive mental models exhibit perceived utility of audit and feedback practices in improving performance; whereas, negative mental models did not. Results speak to the variability of mental models of feedback, highlighting how facilities perceive current audit and feedback practices. Findings are consistent with prior research  in that variability in feedback mental models is associated with lower performance.; Future research should seek to empirically link mental models revealed in this paper to high and low levels of clinical performance.

  12. Modelling primary branch growth based on a multilevel nonlinear ...

    African Journals Online (AJOL)

    In addition to random effects, various time series correlation structures were evaluated to account for residual autocorrelation, and the AR(1) and ARMA(1,1) structures were selected for the branch diameter and length growth models, respectively. Model validation results using an independent data set confirmed that ...

  13. Primary skin fibroblasts as a model of Parkinson's disease

    NARCIS (Netherlands)

    Auburger, G.; Klinkenberg, M.; Droste, J.A.H.; Marcus, K.; Morales-Gordo, B.; Kunz, W.S.; Brandt, U.; Broccoli, V.; Reichmann, H.; Gispert, S.; Jendrach, M.

    2012-01-01

    Parkinson's disease is the second most frequent neurodegenerative disorder. While most cases occur sporadic mutations in a growing number of genes including Parkin (PARK2) and PINK1 (PARK6) have been associated with the disease. Different animal models and cell models like patient skin fibroblasts

  14. Development of CANDU 6 Primary Heat Transport System Modeling Program

    International Nuclear Information System (INIS)

    Seo, Hyung-beom; Kim, Sung-min; Park, Joong-woo; Kim, Kwang-su; Ko, Dae-hack; Han, Bong-seob

    2007-01-01

    NUCIRC is a steady-state thermal-hydraulic code used for design and performance analyses of CANDU Heat Transport System. The code is used to build PHT model in Wolsong NPP and to calculate channel flow distribution. Wolsong NPP has to calculate channel flow distribution and quality of coolant at the ROH header after every outage by OPP (Operating Policy and Principal). PHT modeling work is time consuming which need a lot of operation experience and specialty. It is very difficult to build PHT model as plant operator in two weeks which is obligate for plant operation after every outage. That is why Wolsong NPP develop NUMODEL (NUcirc MODELing) with many-years experience and a know-how of using NUCIRC code. NUMODEL is computer program which is used to create PHT model based on utilizing NUCIRC code

  15. External Validation of Prediction Models for Pneumonia in Primary Care Patients with Lower Respiratory Tract Infection

    DEFF Research Database (Denmark)

    Schierenberg, Alwin; Minnaard, Margaretha C; Hopstaken, Rogier M

    2016-01-01

    BACKGROUND: Pneumonia remains difficult to diagnose in primary care. Prediction models based on signs and symptoms (S&S) serve to minimize the diagnostic uncertainty. External validation of these models is essential before implementation into routine practice. In this study all published S&S mode...... discriminative accuracy coupled with reasonable to good calibration across the IPD of different study populations. This model is therefore the main candidate for primary care use....

  16. Development of affective modelling competencies in primary school learners

    Directory of Open Access Journals (Sweden)

    Piera Biccard

    2011-09-01

    Full Text Available Learner affect and beliefs about mathematics are complex and multifaceted aspects of mathematical learning. Traditional teaching and learning approaches in mathematics education often result in problematic beliefs about mathematics. Since beliefs influence what learners learn and how they deal with learning mathematics, it is essential that the roles of beliefs and affect in mathematics classrooms are carefully examined. In solving modelling problems, learners and teachers take on new roles in the classroom: learners are placed in an active, self-directing situation in which they solve real-world problems. When learners engage in modelling tasks, they display and integrate cognitive, meta-cognitive and affective competencies. A modelling approach therefore allows one to detect learner beliefs in an authentic learning environment. Will this environment lead to students having more positive and productive dispositions towards mathematics? This article presents partial results of a study documenting the development of modelling competencies in learners working in groups over a period of 12 weeks. Through a design research approach, 12 learners working in groups solved three modelling problems, and transcriptions of learner interactions, questionnaires and informal interviews revealed that learner beliefs improved over this short period when exposed to modelling tasks. The results are encouraging, and may provide mathematics education with an avenue to develop more positive learner beliefs in mathematics.

  17. Primary care clinicians' recognition and management of depression: a model of depression care in real-world primary care practice.

    Science.gov (United States)

    Baik, Seong-Yi; Crabtree, Benjamin F; Gonzales, Junius J

    2013-11-01

    Depression is prevalent in primary care (PC) practices and poses a considerable public health burden in the United States. Despite nearly four decades of efforts to improve depression care quality in PC practices, a gap remains between desired treatment outcomes and the reality of how depression care is delivered. This article presents a real-world PC practice model of depression care, elucidating the processes and their influencing conditions. Grounded theory methodology was used for the data collection and analysis to develop a depression care model. Data were collected from 70 individual interviews (60 to 70 min each), three focus group interviews (n = 24, 2 h each), two surveys per clinician, and investigators' field notes on practice environments. Interviews were audiotaped and transcribed for analysis. Surveys and field notes complemented interview data. Seventy primary care clinicians from 52 PC offices in the Midwest: 28 general internists, 28 family physicians, and 14 nurse practitioners. A depression care model was developed that illustrates how real-world conditions infuse complexity into each step of the depression care process. Depression care in PC settings is mediated through clinicians' interactions with patients, practice, and the local community. A clinician's interactional familiarity ("familiarity capital") was a powerful facilitator for depression care. For the recognition of depression, three previously reported processes and three conditions were confirmed. For the management of depression, 13 processes and 11 conditions were identified. Empowering the patient was a parallel process to the management of depression. The clinician's ability to develop and utilize interactional relationships and resources needed to recognize and treat a person with depression is key to depression care in primary care settings. The interactional context of depression care makes empowering the patient central to depression care delivery.

  18. Human Sulfatase 2 inhibits in vivo tumor growth of MDA-MB-231 human breast cancer xenografts

    International Nuclear Information System (INIS)

    Peterson, Sarah M; Concino, Michael F; Liaw, Lucy; Martini, Paolo GV; Iskenderian, Andrea; Cook, Lynette; Romashko, Alla; Tobin, Kristen; Jones, Michael; Norton, Angela; Gómez-Yafal, Alicia; Heartlein, Michael W

    2010-01-01

    Extracellular human sulfatases modulate growth factor signaling by alteration of the heparin/heparan sulfate proteoglycan (HSPG) 6-O-sulfation state. HSPGs bind to numerous growth factor ligands including fibroblast growth factors (FGF), epidermal growth factors (EGF), and vascular endothelial growth factors (VEGF), and are critically important in the context of cancer cell growth, invasion, and metastasis. We hypothesized that sulfatase activity in the tumor microenvironment would regulate tumor growth in vivo. We established a model of stable expression of sulfatases in the human breast cancer cell line MDA-MB-231 and purified recombinant human Sulfatase 2 (rhSulf2) for exogenous administration. In vitro studies were performed to measure effects on breast cancer cell invasion and proliferation, and groups were statistically compared using Student's t-test. The effects of hSulf2 on tumor progression were tested using in vivo xenografts with two methods. First, MDA-MB-231 cells stably expressing hSulf1, hSulf2, or both hSulf1/hSulf2 were grown as xenografts and the resulting tumor growth and vascularization was compared to controls. Secondly, wild type MDA-MB-231 xenografts were treated by short-term intratumoral injection with rhSulf2 or vehicle during tumor growth. Ultrasound analysis was also used to complement caliper measurement to monitor tumor growth. In vivo studies were statistically analyzed using Student's t test. In vitro, stable expression of hSulf2 or administration of rhSulf2 in breast cancer cells decreased cell proliferation and invasion, corresponding to an inhibition of ERK activation. Stable expression of the sulfatases in xenografts significantly suppressed tumor growth, with complete regression of tumors expressing both hSulf1 and hSulf2 and significantly smaller tumor volumes in groups expressing hSulf1 or hSulf2 compared to control xenografts. Despite significant suppression of tumor volume, sulfatases did not affect vascular

  19. Primary continuous unilateral headaches: a nosologic model for hemicrania continua.

    Science.gov (United States)

    Pareja, Juan A; Cuadrado, María-Luz; Fernández-de-las-Peñas, César; Montojo, Teresa; Álvarez, Mónica; López-de-Silanes, Carlos

    2012-04-01

    Hemicrania continua was originally described as a strictly unilateral, continuous headache with an absolute response to indomethacin. Recognition of an increasing number of patients with the same clinical features except for a lack of response to indomethacin has generated controversy about whether the responsive/non-responsive phenotypes belong to the same disorder. We suggest that the non-responsive phenotype should be differentiated from the original concept of hemicrania continua, because it probably indicates a separate type of headache of undetermined nature, i.e. hemicrania incerta. However, differentiating hemicrania incerta from hemicrania continua does not imply that the two headaches are unrelated. Both hemicranias may outline a continuum, giving rise to a broader diagnostic field. There seems to be a syndrome of 'primary continuous unilateral headache' with at least two distinctive categories: hemicrania continua and hemicrania incerta, which are differentiated by their respective response to indomethacin. This division means plurality but adds precision, and allows a clear-cut diagnosis of some controversial cases.

  20. Analyzing the mechanisms of cell killing by ionizing radiation in monolayer, spheroids and xenografted tumours

    International Nuclear Information System (INIS)

    Horas, J.A.; Olguín, O.R.; Rizzotto, M.G.

    2017-01-01

    A relationship between oxygen enhancement ratio (OER) and parameters of Linear Quadratic (LQ) model in hypoxic and aerobic conditions in several cell lines grown as monolayer, spheroids and transplanted tumors (xenograft) is tested. By considering this relationship, the two mechanisms of cell death by radiation appear. Surviving Fraction (SF) fits are compared in both oxygenation conditions by using the LQ. The data are obtained from literature. The existence of such mechanisms and their implications in the different systems studied is shown. The validity of one or other mechanism in each case is determined and the OER dependence with dose. (authors) [es

  1. Examining the Mathematical Modeling Processes of Primary School 4th-Grade Students: Shopping Problem

    Science.gov (United States)

    Ulu, Mustafa

    2017-01-01

    The purpose of this study is to identify primary school students' thinking processes within the mathematical modeling process and the challenges they encounter, if any. This is a basic qualitative research study conducted in a primary school in the city of Kütahya in the academic year of 2015-2016. The study group of the research was composed of…

  2. A Sexual Assault Primary Prevention Model with Diverse Urban Youth

    Science.gov (United States)

    Smothers, Melissa Kraemer; Smothers, D. Brian

    2011-01-01

    In this study, a nonprofit community mental health clinic developed a socioecological model of sexual abuse prevention that was implemented in a public school. The goal of the program was to promote and create community change within individuals and the school community by reducing tolerance of sexual violence and sexual harassment. Participants…

  3. Ovarian and cervical cancer patient derived xenografts: The past, present, and future.

    Science.gov (United States)

    Boone, Jonathan D; Dobbin, Zachary C; Straughn, J Michael; Buchsbaum, Donald J

    2015-08-01

    Preclinical research in gynecologic malignancies has largely relied upon cloned cancer-derived cell lines and tumor xenografts derived from these cell lines. Unfortunately, the use of cell lines for translational research has disadvantages because genetic and phenotypic alterations from serial passaging have resulted in expression profiles that are different from the original patient tumors. The patient-derived xenograft (PDX) model derived from human tumor not previously cultured has shown better representation of the heterogeneity of gynecologic malignancies and the human tumor microenvironment with preservation of cytogenetics, cellular complexity, and vascular and stromal tumor architecture. Studies have shown promise with these models to analyze tumor development and adaptation, test drug efficacy, and predict clinical outcomes. Their ultimate value may be seen with preclinical drug screening including novel targeted therapies, biomarker identification, and the development of individualized treatment plans. This article reviews PDX model development, current studies testing chemotherapeutics and targeted therapies, and limitations of the PDX model in gynecologic malignancies. Copyright © 2015 Elsevier Inc. All rights reserved.

  4. Remote sensing of oceanic primary production: Computations using a spectral model

    Digital Repository Service at National Institute of Oceanography (India)

    Sathyendranath, S.; Platt, T.; Caverhill, C.M.; Warnock, R.E.; Lewis, M.R.

    A spectral model of underwater irradiance is coupled with a spectral version of the photosynthesis-light relationship to compute oceanic primary production. The results are shown to be significantly different from those obtained using...

  5. Published diagnostic models safely excluded colorectal cancer in an independent primary care validation study

    NARCIS (Netherlands)

    Elias, Sjoerd G; Kok, Liselotte; Witteman, Ben J M; Goedhard, Jelle G; Romberg-Camps, Mariëlle J L; Muris, Jean W M; de Wit, Niek J; Moons, Karel G M

    OBJECTIVE: To validate published diagnostic models for their ability to safely reduce unnecessary endoscopy referrals in primary care patients suspected of significant colorectal disease. STUDY DESIGN AND SETTING: Following a systematic literature search, we independently validated the identified

  6. Examination of models of knee in primary cosmic ray spectrum using gamma-hadron families

    International Nuclear Information System (INIS)

    Sveshnikova, L.G.; Managadze, A.K.; Roganova, T.M.; Mukhamedshin, R.A.

    2005-01-01

    Four models for describing the primary cosmic radiation (PCR) spectrum are proposed/ The examination of the PCR spectra models is carried out from the viewpoint of their consistency with the data on the gamma-hadron families for the threshold energies of 100 and 500 TeV. The maximum possible contribution of the superfamilies, originating from the primary nuclei, but not from the protons, is calculated [ru

  7. Exploration of funding models to support hybridisation of Australian primary health care organisations.

    Science.gov (United States)

    Reddy, Sandeep

    2017-09-01

    Primary Health Care (PHC) funding in Australia is complex and fragmented. The focus of PHC funding in Australia has been on volume rather than comprehensive primary care and continuous quality improvement. As PHC in Australia is increasingly delivered by hybrid style organisations, an appropriate funding model that matches this set-up while addressing current issues with PHC funding is required. This article discusses and proposes an appropriate funding model for hybrid PHC organisations.

  8. Primary School Pre-Service Mathematics Teachers' Views on Mathematical Modeling

    Science.gov (United States)

    Karali, Diren; Durmus, Soner

    2015-01-01

    The current study aimed to identify the views of pre-service teachers, who attended a primary school mathematics teaching department but did not take mathematical modeling courses. The mathematical modeling activity used by the pre-service teachers was developed with regards to the modeling activities utilized by Lesh and Doerr (2003) in their…

  9. The primary demand for beer in the Netherlands; an application of ARMAX model specification

    OpenAIRE

    Franses, Philip Hans

    1991-01-01

    textabstractThe central issue in the application of econometric and time series analysis (ETS) to market response models is the model-building process. The author proposes a specification strategy for ETS modeling and applies it to the primary demand for beer in The Netherlands.

  10. Modelling the radiolysis of RSG-GAS primary cooling water

    Science.gov (United States)

    Butarbutar, S. L.; Kusumastuti, R.; Subekti, M.; Sunaryo, G. R.

    2018-02-01

    Water chemistry control for light water coolant reactor required a reliable understanding of radiolysis effect in mitigating corrosion and degradation of reactor structure material. It is known that oxidator products can promote the corrosion, cracking and hydrogen pickup both in the core and in the associated piping components of the reactor. The objective of this work is to provide the radiolysis model of RSG GAS cooling water and further more to predict the oxidator concentration which can lead to corrosion of reactor material. Direct observations or measurements of the chemistry in and around the high-flux core region of a nuclear reactor are difficult due to the extreme conditions of high temperature, pressure, and mixed radiation fields. For this reason, chemical models and computer simulations of the radiolysis of water under these conditions are an important route of investigation. FACSIMILE were used to calculate the concentration of O2 formed at relatively long-time by the pure water γ and neutron irradiation (pH=7) at temperature between 25 and 50 °C. This simulation method is based on a complex chemical reaction kinetic. In this present work, 300 MeV-proton were used to mimic γ-rays radiolysis and 2 MeV fast neutrons. Concentration of O2 were calculated at 10-6 - 106 s time scale.

  11. Modelling size-fractionated primary production in the Atlantic Ocean from remote sensing

    Science.gov (United States)

    Brewin, Robert J. W.; Tilstone, Gavin H.; Jackson, Thomas; Cain, Terry; Miller, Peter I.; Lange, Priscila K.; Misra, Ankita; Airs, Ruth L.

    2017-11-01

    Marine primary production influences the transfer of carbon dioxide between the ocean and atmosphere, and the availability of energy for the pelagic food web. Both the rate and the fate of organic carbon from primary production are dependent on phytoplankton size. A key aim of the Atlantic Meridional Transect (AMT) programme has been to quantify biological carbon cycling in the Atlantic Ocean and measurements of total primary production have been routinely made on AMT cruises, as well as additional measurements of size-fractionated primary production on some cruises. Measurements of total primary production collected on the AMT have been used to evaluate remote-sensing techniques capable of producing basin-scale estimates of primary production. Though models exist to estimate size-fractionated primary production from satellite data, these have not been well validated in the Atlantic Ocean, and have been parameterised using measurements of phytoplankton pigments rather than direct measurements of phytoplankton size structure. Here, we re-tune a remote-sensing primary production model to estimate production in three size fractions of phytoplankton (10 μm) in the Atlantic Ocean, using measurements of size-fractionated chlorophyll and size-fractionated photosynthesis-irradiance experiments conducted on AMT 22 and 23 using sequential filtration-based methods. The performance of the remote-sensing technique was evaluated using: (i) independent estimates of size-fractionated primary production collected on a number of AMT cruises using 14C on-deck incubation experiments and (ii) Monte Carlo simulations. Considering uncertainty in the satellite inputs and model parameters, we estimate an average model error of between 0.27 and 0.63 for log10-transformed size-fractionated production, with lower errors for the small size class (10 μm), and errors generally higher in oligotrophic waters. Application to satellite data in 2007 suggests the contribution of cells 2 μm to total

  12. Positron Emission Tomography Based Analysis of Long-Circulating Cross-Linked Triblock Polymeric Micelles in a U87MG Mouse Xenograft Model and Comparison of DOTA and CB-TE2A as Chelators of Copper-64

    DEFF Research Database (Denmark)

    Jensen, Andreas Tue Ingemann; Binderup, Tina; Ek, Pramod Kumar

    2014-01-01

    Copolymers of ABC-type (PEG-PHEMA-PCMA) architecture were prepared by atom transfer radical polymerization and formulated as micelles with functionalizable primary alcohols in the shell-region (PHEMA-block) to which the metal-ion chelators DOTA or CB-TE2A were conjugated. Using this micelle system...... we compared the in vivo stabilities of DOTA and CB-TE2A as chelators of 64Cu in micelle nanoparticles. The coumarin polymer (PCMA-block) micelle core was cross-linked by UV irradiation at 2 W/cm2 for 30 min. The cross-linked micelles were labeled with 64Cu at room temperature for 2 h (DOTA) or 80 °C...... for 3 h (CB-TE2A), giving labeling efficiencies of 60–76% (DOTA) and 40–47% (CB-TE2A). 64Cu-micelles were injected into tumor-bearing mice (8 mg/kg) and PET/CT scans were carried out at 1, 22, and 46 h postinjection. The micelles showed good blood stability (T1/2: 20–26 h) and tumor uptake...

  13. Reversal of multidrug resistance by magnetic Fe3O4 nanoparticle copolymerizating daunorubicin and 5-bromotetrandrine in xenograft nude-mice

    OpenAIRE

    Chen, Baoan; Cheng, Jian; Wu, Yanan; Gao, Feng; Xu, Wenlin; Shen, Huilin; Ding, Jiahua; Gao, Chong; Sun, Qian; Sun, Xinchen; Cheng, Hongyan; Li, Guohong; Chen, Wenji; Chen, Ningna; Liu, Lijie

    2009-01-01

    In this paper we establish the xenograft leukemia model with stable multidrug resistance in nude mice and to investigate the reversal effect of 5-bromotetrandrine (5-BrTet) and magnetic nanoparticle of Fe3O4 (MNP-Fe3O4) combined with daunorubicin (DNR) in vivo. Two subclones of K562 and K562/A02 cells were inoculated subcutaneously into the back of athymic nude mice (1 × 107 cells/each) respectively to establish leukemia xenograft models. Drug-resistant and sensitive tumor-bearing nude mice w...

  14. Survivin inhibitor YM155 suppresses gastric cancer xenograft growth in mice without affecting normal tissues.

    Science.gov (United States)

    Cheng, Xiao Jiao; Lin, Jia Cheng; Ding, Yan Fei; Zhu, Liming; Ye, Jing; Tu, Shui Ping

    2016-02-09

    Survivin overexpression is associated with poor prognosis of human gastric cancer, and is a target for gastric cancer therapy. YM155 is originally identified as a specific inhibitor of survivin. In this study, we investigated the antitumor effect of YM155 on human gastric cancer. Our results showed that YM155 treatment significantly inhibited cell proliferation, reduced colony formation and induced apoptosis of gastric cancer cells in a dose-dependent manner. Accordingly, YM155 treatment significantly decreased survivin expression without affecting XIAP expression and increased the cleavage of apoptosis-associated proteins caspase 3, 7, 8, 9. YM155 significantly inhibited sphere formation of gastric cancer cells, suppressed expansion and growth of the formed spheres (cancer stem cell-like cells, CSCs) and downregulated the protein levels of β-catenin, c-Myc, Cyclin D1 and CD44 in gastric cancer cells. YM155 infusion at 5 mg/kg/day for 7 days markedly inhibited growth of gastric cancer xenograft in a nude mouse model. Immunohistochemistry staining and Western Blot showed that YM155 treatment inhibited expression of survivin and CD44, induced apoptosis and reduced CD44+ CSCs in xenograft tumor tissues in vivo. No obvious pathological changes were observed in organs (e.g. heart, liver, lung and kidney) in YM155-treated mice. Our results demonstrated that YM155 inhibits cell proliferation, induces cell apoptosis, reduces cancer stem cell expansion, and inhibits xenograft tumor growth in gastric cancer cells. Our results elucidate a new mechanism by which YM155 inhibits gastric cancer growth by inhibition of CSCs. YM155 may be a promising agent for gastric cancer treatment.

  15. A model of regional primary production for use with coarse resolution satellite data

    Science.gov (United States)

    Prince, S. D.

    1991-01-01

    A model of crop primary production, which was originally developed to relate the amount of absorbed photosynthetically active radiation (APAR) to net production in field studies, is discussed in the context of coarse resolution regional remote sensing of primary production. The model depends on an approximately linear relationship between APAR and the normalized difference vegetation index. A more comprehensive form of the conventional model is shown to be necessary when different physiological types of plants or heterogeneous vegetation types occur within the study area. The predicted variable in the new model is total assimilation (net production plus respiration) rather than net production alone or harvest yield.

  16. Experimental system model of a primary active fluid

    International Nuclear Information System (INIS)

    Deseigne, Julien

    2010-01-01

    Collective motion, such as flocks of birds or shoals of fish, is ubiquitous in nature. Such fundamentally out-of-equilibrium phenomena may be described with the new conceptual background of polar active matter, a system of polar particles which enables to use provided energy in order to move in their own directions. A 2D experimental system of vibrated polar disks that interact only by contact has been set up. These disks behave as random walkers, whose trajectories are characterized by a persistence length greater than their size and controlled by the angular fluctuations of their polarity. The interplay between the hard-core repulsion and the persistence of the motion leads to complex alignment modes. For instance, only 10 pc of the binary collisions correspond to an effective ferromagnetic alignment. Yet, spontaneous collective motion inside the system characterized by giant fluctuations of density have been observed. These results reveal the robustness of the polar order observed in theoretical and numerical models of 2D polar active matter on substrate

  17. Temporal morphologic changes in human colorectal carcinomas following xenografting.

    Science.gov (United States)

    Barkla, D H; Tutton, P J

    1983-03-01

    The temporal morphologic changes of human colorectal carcinomas following xenografting into immunosuppressed mice were investigated by the use of light and transmission electron microscopy. The results show that colorectal carcinomas undergo a series of morphologic changes during the initial 30-day period following transplantation. During the initial 1-5-day period the majority of tumor cells die, and during the following 5-10-day period the necrotic debris created during the 1-5-day period is removed by host-supplied inflammatory cells. Only small groups of peripherally placed tumor cells survived at the end of the first 10 days. During the 10-20-day period the tumor cell populations of xenografts were reestablished by a morphologically heterogeneous population of tumor cells, and during the 20-30 day period consolidation of this process continued and some xenografts showed macroscopic evidence of growth. The authors hypothesize that human colorectal carcinomas, like the antecedent epithelium, contain subpopulations of undifferentiated cells that give rise to populations of more-differentiated cells.

  18. Positron emission tomography based analysis of long-circulating cross-linked triblock polymeric micelles in a U87MG mouse xenograft model and comparison of DOTA and CB-TE2A as chelators of copper-64.

    Science.gov (United States)

    Jensen, Andreas I; Binderup, Tina; Kumar EK, Pramod; Kjær, Andreas; Rasmussen, Palle H; Andresen, Thomas L

    2014-05-12

    Copolymers of ABC-type (PEG-PHEMA-PCMA) architecture were prepared by atom transfer radical polymerization and formulated as micelles with functionalizable primary alcohols in the shell-region (PHEMA-block) to which the metal-ion chelators DOTA or CB-TE2A were conjugated. Using this micelle system we compared the in vivo stabilities of DOTA and CB-TE2A as chelators of (64)Cu in micelle nanoparticles. The coumarin polymer (PCMA-block) micelle core was cross-linked by UV irradiation at 2 W/cm(2) for 30 min. The cross-linked micelles were labeled with (64)Cu at room temperature for 2 h (DOTA) or 80 °C for 3 h (CB-TE2A), giving labeling efficiencies of 60-76% (DOTA) and 40-47% (CB-TE2A). (64)Cu-micelles were injected into tumor-bearing mice (8 mg/kg) and PET/CT scans were carried out at 1, 22, and 46 h postinjection. The micelles showed good blood stability (T1/2: 20-26 h) and tumor uptake that was comparable with other nanoparticle systems. The DOTA micelles showed a biodistribution similar to the CB-TE2A micelles and the tumor uptake was comparable for both micelle types at 1 h (1.9% ID/g) and 22 h (3.9% ID/g) but diverged at 46 h with 3.6% ID/g (DOTA) and 4.9% ID/g (CB-TE2A). On the basis of our data, we conclude that cross-linked PEG-PHEMA-PCMA micelles have long circulating properties resulting in tumor accumulation and that DOTA and CB-TE2A (64)Cu-chelates show similar in vivo stability for the studied micelle system.

  19. BC047440 antisense eukaryotic expression vectors inhibited HepG2 cell proliferation and suppressed xenograft tumorigenicity

    International Nuclear Information System (INIS)

    Lu, Zheng; Ping, Liang; JianBo, Zhou; XiaoBing, Huang; Yu, Wen; Zheng, Wang; Jing, Li

    2012-01-01

    The biological functions of the BC047440 gene highly expressed by hepatocellular carcinoma (HCC) are unknown. The objective of this study was to reconstruct antisense eukaryotic expression vectors of the gene for inhibiting HepG 2 cell proliferation and suppressing their xenograft tumorigenicity. The full-length BC047440 cDNA was cloned from human primary HCC by RT-PCR. BC047440 gene fragments were ligated with pMD18-T simple vectors and subsequent pcDNA3.1(+) plasmids to construct the recombinant antisense eukaryotic vector pcDNA3.1(+)BC047440AS. The endogenous BC047440 mRNA abundance in target gene-transfected, vector-transfected and naive HepG 2 cells was semiquantitatively analyzed by RT-PCR and cell proliferation was measured by the MTT assay. Cell cycle distribution and apoptosis were profiled by flow cytometry. The in vivo xenograft experiment was performed on nude mice to examine the effects of antisense vector on tumorigenicity. BC047440 cDNA fragments were reversely inserted into pcDNA3.1(+) plasmids. The antisense vector significantly reduced the endogenous BC047440 mRNA abundance by 41% in HepG 2 cells and inhibited their proliferation in vitro (P < 0.01). More cells were arrested by the antisense vector at the G 1 phase in an apoptosis-independent manner (P = 0.014). Additionally, transfection with pcDNA3.1(+) BC047440AS significantly reduced the xenograft tumorigenicity in nude mice. As a novel cell cycle regulator associated with HCC, the BC047440 gene was involved in cell proliferation in vitro and xenograft tumorigenicity in vivo through apoptosis-independent mechanisms

  20. Modeling the electrochemistry of the primary circuits of light water reactors

    International Nuclear Information System (INIS)

    Bertuch, A.; Macdonald, D.D.; Pang, J.; Kriksunov, L.; Arioka, K.

    1994-01-01

    To model the corrosion behaviors of the heat transport circuits of light water reactors, a mixed potential model (NTM) has been developed and applied to both boiling water reactors (BWRs) and pressurized water reactors (PWRs). Using the data generated by the GE/UKEA-Harwell radiolysis model, electrochemical potentials (ECPs) have been calculated for the heat transport circuits of eight BWRs operating under hydrogen water chemistry (HWC). By modeling the corrosion behaviors of these reactors, the effectiveness of HWC at limiting IGSCC and IASCC can be determined. For simulating PWR primary circuits, a chemical-radiolysis model (developed by the authors) was used to generate input parameters for the MPM. Corrosion potentials of Type 304 and 316 SSs in PWR primary environments were calculated using the NTM and were found to be in good agreement with the corrosion potentials measured in the laboratory for simulated PWR primary environments

  1. CO_2 emission trends of China's primary aluminum industry: A scenario analysis using system dynamics model

    International Nuclear Information System (INIS)

    Li, Qiang; Zhang, Wenjuan; Li, Huiquan; He, Peng

    2017-01-01

    China announced its promise on CO_2 emission peak. When and what level of CO_2 emission peak China's primary aluminum industry will reach is in suspense. In this paper, a system dynamic model is established, with five subsystems of economy development, primary aluminum production, secondary aluminum production, CO_2 emission intensity and policies making involved. The model is applied to examine potential CO_2 emission trends of China's primary aluminum industry in next fifteen years with three scenarios of “no new policies”, “13th five-year plan” and “additional policies”. Simulation results imply that: merely relying on rapid expansion of domestic scarps recycling and reuse could not mitigate CO_2 emission continuously. Combination of energy-saving technology application and electrolytic technology innovation, as well as promoting hydropower utilization in primary aluminum industry are necessary for long term low-carbon development. From a global prospective, enhancing international cooperation on new primary aluminum capacity construction in other countries, especially with rich low-carbon energy, could bring about essential CO_2 emission for both China's and global primary aluminum industry. - Highlights: • A system dynamic model is established for future CO_2 emission trend of China's primary aluminum industry. • Three potential policy scenarios are simulated. • The impacts of potential policies implication on the CO_2 emission trend are discussed.

  2. Genetic and Genomic Characterization of 462 Melanoma Patient-Derived Xenografts, Tumor Biopsies, and Cell Lines

    Directory of Open Access Journals (Sweden)

    Bradley Garman

    2017-11-01

    Full Text Available Summary: Tumor-sequencing studies have revealed the widespread genetic diversity of melanoma. Sequencing of 108 genes previously implicated in melanomagenesis was performed on 462 patient-derived xenografts (PDXs, cell lines, and tumors to identify mutational and copy number aberrations. Samples came from 371 unique individuals: 263 were naive to treatment, and 108 were previously treated with targeted therapy (34, immunotherapy (54, or both (20. Models of all previously reported major melanoma subtypes (BRAF, NRAS, NF1, KIT, and WT/WT/WT were identified. Multiple minor melanoma subtypes were also recapitulated, including melanomas with multiple activating mutations in the MAPK-signaling pathway and chromatin-remodeling gene mutations. These well-characterized melanoma PDXs and cell lines can be used not only as reagents for a large array of biological studies but also as pre-clinical models to facilitate drug development. : Garman et al. have characterized melanoma PDXs and cell lines described in Krepler et al. (see the related paper in this issue of Cell Reports, identifying major and minor subtypes, some of which were previously not well defined, targeted and immunotherapy resistance, and tumor heterogeneity, creating a set of reagents for future drug discovery and biological studies. Keywords: melanoma, patient-derived xenografts, massively parallel sequencing, cell lines

  3. A new O6-alkylguanine-DNA alkyltransferase inhibitor associated with a nitrosourea (cystemustine) validates a strategy of melanoma-targeted therapy in murine B16 and human-resistant M4Beu melanoma xenograft models.

    Science.gov (United States)

    Rapp, Maryse; Maurizis, Jean C; Papon, Janine; Labarre, Pierre; Wu, Ting-Di; Croisy, Alain; Guerquin-Kern, Jean L; Madelmont, Jean C; Mounetou, Emmanuelle

    2008-07-01

    Chemoresistance to O(6)-alkylating agents is a major barrier to successful treatment of melanoma. It is mainly due to a DNA repair suicide protein, O(6)-alkylguanine-DNA alkyltransferase (AGT). Although AGT inactivation is a powerful clinical strategy for restoring tumor chemosensitivity, it was limited by increased toxicity to nontumoral cells resulting from a lack of tumor selectivity. Achieving enhanced chemosensitization via AGT inhibition preferably in the tumor should protect normal tissue. To this end, we have developed a strategy to target AGT inhibitors. In this study, we tested a new potential melanoma-directed AGT inhibitor [2-amino-6-(4-iodobenzyloxy)-9-[4-(diethylamino) ethylcarbamoylbenzyl] purine; IBgBZ] designed as a conjugate of O(6)-(4-iododbenzyl)guanine (IBg) as the AGT inactivator and a N,N-diethylaminoethylenebenzamido (BZ) moiety as the carrier to the malignant melanocytes. IBgBZ demonstrated AGT inactivation ability and potentiation of O(6)-alkylating agents (cystemustine, a chloroethylnitrosourea) in M4Beu highly chemoresistant human melanoma cells both in vitro and in tumor models. The biodisposition study on mice bearing B16 melanoma, the standard model for the evaluation of melanoma-directed agents, and the secondary ion mass spectrometry imaging confirmed the concentration of IBgBZ in the tumor and in particular in the intracytoplasmic melanosomes. These results validate the potential of IBgBZ as a new, more tumor-selective, AGT inhibitor in a strategy of melanoma-targeted therapy.

  4. Family-centred care delivery: comparing models of primary care service delivery in Ontario.

    Science.gov (United States)

    Mayo-Bruinsma, Liesha; Hogg, William; Taljaard, Monica; Dahrouge, Simone

    2013-11-01

    To determine whether models of primary care service delivery differ in their provision of family-centred care (FCC) and to identify practice characteristics associated with FCC. Cross-sectional study. Primary care practices in Ontario (ie, 35 salaried community health centres, 35 fee-for-service practices, 32 capitation-based health service organizations, and 35 blended remuneration family health networks) that belong to 4 models of primary care service delivery. A total of 137 practices, 363 providers, and 5144 patients. Measures of FCC in patient and provider surveys were based on the Primary Care Assessment Tool. Statistical analyses were conducted using linear mixed regression models and generalized estimating equations. Patient-reported FCC scores were high and did not vary significantly by primary care model. Larger panel size in a practice was associated with lower odds of patients reporting FCC. Provider-reported FCC scores were significantly higher in community health centres than in family health networks (P = .035). A larger number of nurse practitioners and clinical services on-site were both associated with higher FCC scores, while scores decreased as the number of family physicians in a practice increased and if practices were more rural. Based on provider and patient reports, primary care reform strategies that encourage larger practices and more patients per family physician might compromise the provision of FCC, while strategies that encourage multidisciplinary practices and a range of services might increase FCC.

  5. Do new and traditional models of primary care differ with regard to access?: Canadian QUALICOPC study.

    Science.gov (United States)

    Miedema, Baukje; Easley, Julie; Thompson, Ashley E; Boivin, Antoine; Aubrey-Bassler, Kris; Katz, Alan; Hogg, William E; Breton, Mylaine; Francoeur, Danièle; Wong, Sabrina T; Wodchis, Walter P

    2016-01-01

    To examine access to primary care in new and traditional models using 2 dimensions of the concept of patient-centred access. An international survey examining the quality and costs of primary health care (the QUALICOPC study) was conducted in 2013 in Canada. This study adopted a descriptive cross-sectional survey method using data from practices across Canada. Each participating practice filled out the Family Physician Survey and the Practice Survey, and patients in each participating practice were asked to complete the Patient Experiences Survey. All 10 Canadian provinces. A total of 759 practices and 7172 patients. Independent t tests were conducted to examine differences between new and traditional models of care in terms of availability and accommodation, and affordability of care. Of the 759 practices, 407 were identified as having new models of care and 352 were identified as traditional. New models of care were distinct with respect to payment structure, opening hours, and having an interdisciplinary work force. Most participating practices were from large cities or suburban areas. There were few differences between new and traditional models of care regarding accessibility and accommodation in primary care. Patients under new models of care reported easier access to other physicians in the same practice, while patients from traditional models reported seeing their regular family physicians more frequently. There was no difference between the new and traditional models of care with regard to affordability of primary care. Patients attending clinics with new models of care reported that their physicians were more involved with them as a whole person than patients attending clinics based on traditional models did. Primary care access issues do not differ strongly between traditional and new models of care; however, patients in the new models of care believed that their physicians were more involved with them as people.

  6. The combination of temozolomide-irinotecan regresses a doxorubicin-resistant patient-derived orthotopic xenograft (PDOX) nude-mouse model of recurrent Ewing's sarcoma with a FUS-ERG fusion and CDKN2A deletion: Direction for third-line patient therapy.

    Science.gov (United States)

    Miyake, Kentaro; Murakami, Takashi; Kiyuna, Tasuku; Igarashi, Kentaro; Kawaguchi, Kei; Miyake, Masuyo; Li, Yunfeng; Nelson, Scott D; Dry, Sarah M; Bouvet, Michael; Elliott, Irmina A; Russell, Tara A; Singh, Arun S; Eckardt, Mark A; Hiroshima, Yukihiko; Momiyama, Masashi; Matsuyama, Ryusei; Chishima, Takashi; Endo, Itaru; Eilber, Fritz C; Hoffman, Robert M

    2017-11-28

    The aim of the present study was to determine the usefulness of a patient-derived orthotopic xenograft (PDOX) nude-mouse model of a doxorubicin-resistant metastatic Ewing's sarcoma, with a unique combination of a FUS-ERG fusion and CDKN2A deletion, to identify effective drugs for third-line chemotherapy of the patient. Our previous study showed that cyclin-dependent kinase 4/6 (CDK4/6) and insulin-like growth factor-1 receptor (IGF-1R) inhibitors were effective on the Ewing's sarcoma PDOX, but not doxorubicin, similar to the patient's resistance to doxorubicin. The results of the previous PDOX study were successfully used for second-line therapy of the patiend. In the present study, the PDOX mice established with the Ewing's sarcoma in the right chest wall were randomized into 5 groups when the tumor volume reached 60 mm 3 : untreated control; gemcitabine combined with docetaxel (intraperitoneal [i.p.] injection, weekly, for 2 weeks); irinotecan combined with temozolomide (irinotecan: i.p. injection; temozolomide: oral administration, daily, for 2 weeks); pazopanib (oral administration, daily, for 2 weeks); yondelis (intravenous injection, weekly, for 2 weeks). All mice were sacrificed on day 15. Body weight and tumor volume were assessed 2 times per week. Tumor weight was measured after sacrifice. Irinotecan combined with temozolomide was the most effective regimen compared to the untreated control group (p=0.022). Gemcitabine combined with docetaxel was also effective (p=0.026). Pazopanib and yondelis did not have significant efficacy compared to the untreated control (p=0.130, p=0.818). These results could be obtained within two months after the physician's request and were used for third-line therapy of the patient.

  7. Model of Supervision Based on Primary School Teacher Professional Competency in Tematic Learning in Curriculum 2013

    Directory of Open Access Journals (Sweden)

    Meilani Hartono

    2017-08-01

    Full Text Available This study aims to find the Supervision Model Based on Primary Teacher Professional Competence which effective on integrated learning. This study use research and development with qualitative approach which will be carried out in the Palmerah, West Jakarta. The techniques used to collect data are interviews, questionnaires, observation and documentation. Data v alidity is tested with credibility, transferability, dependability, and comfortability. The model developed will be validated using the Delphi technique. The result of this research is the discovery of the model and device-based supervision model of professional competence of primary teachers in integrated learning. The long-term goal of this research is to improve the teachers’ competence and the supervision quality for primary teachers in integrated learning

  8. TRANSFoRm: a flexible zone model of a data privacy framework for Primary Care research.

    NARCIS (Netherlands)

    Kuchinke, W.; Veen, E.B. van; Delaney, B.C.; Verheij, R.; Taweel, A.; Ohmann, C.

    2011-01-01

    As part of the TRANSFoRm project a flexible zone model for data privacy in Primary Care research was developed. The model applies different privacy generating methods to different aspects of the research data flow and allows in this way for only minimal hindrance of research activities. This is

  9. Pairwise comparison of 89Zr- and 124I-labeled cG250 based on positron emission tomography imaging and nonlinear immunokinetic modeling: in vivo carbonic anhydrase IX receptor binding and internalization in mouse xenografts of clear-cell renal cell carcinoma

    International Nuclear Information System (INIS)

    Cheal, Sarah M.; Punzalan, Blesida; Doran, Michael G.; Osborne, Joseph R.; Evans, Michael J.; Lewis, Jason S.; Zanzonico, Pat; Larson, Steven M.

    2014-01-01

    The PET tracer, 124 I-cG250, directed against carbonic anhydrase IX (CAIX) shows promise for presurgical diagnosis of clear-cell renal cell carcinoma (ccRCC) (Divgi et al. in Lancet Oncol 8:304-310, 2007; Divgi et al. in J Clin Oncol 31:187-194, 2013). The radiometal 89 Zr, however, may offer advantages as a surrogate PET nuclide over 124 I in terms of greater tumor uptake and retention (Rice et al. in Semin Nucl Med 41:265-282, 2011). We have developed a nonlinear immunokinetic model to facilitate a quantitative comparison of absolute uptake and antibody turnover between 124 I-cG250 and 89 Zr-cG250 using a human ccRCC xenograft tumor model in mice. We believe that this unique model better relates quantitative imaging data to the salient biological features of tumor antibody-antigen binding and turnover. We conducted experiments with 89 Zr-cG250 and 124 I-cG250 using a human ccRCC cell line (SK-RC-38) to characterize the binding affinity and internalization kinetics of the two tracers in vitro. Serial PET imaging was performed in mice bearing subcutaneous ccRCC tumors to simultaneously detect and quantify time-dependent tumor uptake in vivo. Using the known specific activities of the two tracers, the equilibrium rates of antibody internalization and turnover in the tumors were derived from the PET images using nonlinear compartmental modeling. The two tracers demonstrated virtually identical tumor cell binding and internalization but showed markedly different retentions in vitro. Superior PET images were obtained using 89 Zr-cG250, owing to the more prolonged trapping of the radiolabel in the tumor and simultaneous washout from normal tissues. Estimates of cG250/CAIX complex turnover were 1.35 - 5.51 x 10 12 molecules per hour per gram of tumor (20 % of receptors internalized per hour), and the ratio of 124 I/ 89 Zr atoms released per unit time by tumor was 17.5. Pairwise evaluation of 89 Zr-cG250 and 124 I-cG250 provided the basis for a nonlinear immunokinetic

  10. Pairwise comparison of {sup 89}Zr- and {sup 124}I-labeled cG250 based on positron emission tomography imaging and nonlinear immunokinetic modeling: in vivo carbonic anhydrase IX receptor binding and internalization in mouse xenografts of clear-cell renal cell carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Cheal, Sarah M.; Punzalan, Blesida; Doran, Michael G.; Osborne, Joseph R. [Memorial Sloan-Kettering Cancer Center, Department of Radiology, New York, NY (United States); Evans, Michael J. [Memorial Sloan-Kettering Cancer Center, Human Oncology and Pathogenesis Program, New York, NY (United States); Lewis, Jason S. [Memorial Sloan-Kettering Cancer Center, Department of Radiology, New York, NY (United States); Memorial Sloan-Kettering Cancer Center, Program in Molecular Pharmacology and Chemistry, New York, NY (United States); Memorial Sloan-Kettering Cancer Center, Radiochemistry and Imaging Sciences Service, New York, NY (United States); Zanzonico, Pat [Memorial Sloan-Kettering Cancer Center, Department of Radiology, New York, NY (United States); Memorial Sloan-Kettering Cancer Center, Molecular Pharmacology and Therapy Service, New York, NY (United States); Memorial-Sloan Kettering Cancer Center, New York, NY (United States); Larson, Steven M. [Memorial Sloan-Kettering Cancer Center, Department of Radiology, New York, NY (United States); Memorial Sloan-Kettering Cancer Center, Program in Molecular Pharmacology and Chemistry, New York, NY (United States); Memorial Sloan-Kettering Cancer Center, Molecular Pharmacology and Therapy Service, New York, NY (United States)

    2014-05-15

    The PET tracer, {sup 124}I-cG250, directed against carbonic anhydrase IX (CAIX) shows promise for presurgical diagnosis of clear-cell renal cell carcinoma (ccRCC) (Divgi et al. in Lancet Oncol 8:304-310, 2007; Divgi et al. in J Clin Oncol 31:187-194, 2013). The radiometal {sup 89}Zr, however, may offer advantages as a surrogate PET nuclide over {sup 124}I in terms of greater tumor uptake and retention (Rice et al. in Semin Nucl Med 41:265-282, 2011). We have developed a nonlinear immunokinetic model to facilitate a quantitative comparison of absolute uptake and antibody turnover between {sup 124}I-cG250 and {sup 89}Zr-cG250 using a human ccRCC xenograft tumor model in mice. We believe that this unique model better relates quantitative imaging data to the salient biological features of tumor antibody-antigen binding and turnover. We conducted experiments with {sup 89}Zr-cG250 and {sup 124}I-cG250 using a human ccRCC cell line (SK-RC-38) to characterize the binding affinity and internalization kinetics of the two tracers in vitro. Serial PET imaging was performed in mice bearing subcutaneous ccRCC tumors to simultaneously detect and quantify time-dependent tumor uptake in vivo. Using the known specific activities of the two tracers, the equilibrium rates of antibody internalization and turnover in the tumors were derived from the PET images using nonlinear compartmental modeling. The two tracers demonstrated virtually identical tumor cell binding and internalization but showed markedly different retentions in vitro. Superior PET images were obtained using {sup 89}Zr-cG250, owing to the more prolonged trapping of the radiolabel in the tumor and simultaneous washout from normal tissues. Estimates of cG250/CAIX complex turnover were 1.35 - 5.51 x 10{sup 12} molecules per hour per gram of tumor (20 % of receptors internalized per hour), and the ratio of {sup 124}I/{sup 89}Zr atoms released per unit time by tumor was 17.5. Pairwise evaluation of {sup 89}Zr-cG250 and {sup

  11. Morphological features of the porcine lacrimal gland and its compatibility for human lacrimal gland xenografting.

    Science.gov (United States)

    Henker, Robert; Scholz, Michael; Gaffling, Simone; Asano, Nagayoshi; Hampel, Ulrike; Garreis, Fabian; Hornegger, Joachim; Paulsen, Friedrich

    2013-01-01

    In this study, we present first data concerning the anatomical structure, blood supply and location of the lacrimal gland of the pig. Our data indicate that the porcine lacrimal gland may serve as a potential xenograft candidate in humans or as an animal model for engineering of a bioartificial lacrimal gland tissue construct for clinical application. For this purpose, we used different macroscopic preparation techniques and digital reconstruction of the histological gland morphology to gain new insights and important information concerning the feasibility of a lacrimal gland transplantation from pig to humans in general. Our results show that the lacrimal gland of the pig reveals a lot of morphological similarities to the analogous human lacrimal gland and thus might be regarded as a xenograft in the future. This is true for a similar anatomical location within the orbit as well as for the feeding artery supply to the organ. Functional differences concerning the composition of the tear fluid, due to a different secretory unit distribution within the gland tissue will, however, be a challenge in future investigations.

  12. Morphological features of the porcine lacrimal gland and its compatibility for human lacrimal gland xenografting.

    Directory of Open Access Journals (Sweden)

    Robert Henker

    Full Text Available In this study, we present first data concerning the anatomical structure, blood supply and location of the lacrimal gland of the pig. Our data indicate that the porcine lacrimal gland may serve as a potential xenograft candidate in humans or as an animal model for engineering of a bioartificial lacrimal gland tissue construct for clinical application. For this purpose, we used different macroscopic preparation techniques and digital reconstruction of the histological gland morphology to gain new insights and important information concerning the feasibility of a lacrimal gland transplantation from pig to humans in general. Our results show that the lacrimal gland of the pig reveals a lot of morphological similarities to the analogous human lacrimal gland and thus might be regarded as a xenograft in the future. This is true for a similar anatomical location within the orbit as well as for the feeding artery supply to the organ. Functional differences concerning the composition of the tear fluid, due to a different secretory unit distribution within the gland tissue will, however, be a challenge in future investigations.

  13. Spectral CT evaluation of interstitial brachytherapy in pancreatic carcinoma xenografts: preliminary animal experience

    Energy Technology Data Exchange (ETDEWEB)

    Hu, Shudong [Jiangsu University, Department of Radiology, The Affiliated Renmin Hospital, Zhenjiang, Jiangsu (China); Shanghai Jiao tong University, School of Medicine, Department of Radiology, Ruijin Hospital, Shanghai (China); Huang, Wei; Song, Qi; Lin, Xiaozhu; Wang, Zhongmin; Chen, Kemin [Shanghai Jiao tong University, School of Medicine, Department of Radiology, Ruijin Hospital, Shanghai (China); Chen, Yerong [Jiangsu University, Department of Radiology, The Affiliated Renmin Hospital, Zhenjiang, Jiangsu (China)

    2014-09-15

    We sought to evaluate the capability of spectral CT to detect the therapeutic response to {sup 125}I interstitial brachytherapy in a pancreatic carcinoma xenograft nude mouse model. Twenty mice bearing SWl990 human pancreatic cancer cell xenografts were randomly separated into two groups: experimental (n = 10; 1.0 mCi) and control (n = 10; 0 mCi). After a two-week treatment, spectral CT was performed. Contrast-to-noise ratio (CNR) and iodine concentration (IC) in the lesions were measured and normalized to the muscle tissue, and nIC CD31 immunohistochemistry was used to measure microvessel density (MVD). The relationships between the nIC and MVD of the tumours were analysed. The nIC of the experimental group was significantly lower than that of the control group during the multiphase examination. A significant difference in the MVD was observed between the two groups (P <0.001). The nIC values of the three-phase scans have a certain positive correlation with MVD (r = 0.57, p < 0.0001; r = 0.48, p = 0.002; r = 0.63, p = 0.0017 in the 10, 25, and 60 s phase, respectively). Spectral CT can be a useful non-invasive imaging modality in evaluating the therapeutic effect of {sup 125}I interstitial brachytherapy to a pancreatic carcinoma. (orig.)

  14. Effects of antineoplastic agents and ionizing irradiation on a human testicular cancer xenograft

    International Nuclear Information System (INIS)

    Osieka, R.; Pfeiffer, R.; Glatte, P.; Schmidt, C.G.; Bamberg, M.; Scherer, E.

    1985-01-01

    Chemotherapy has afforded a high percentage of definitive cures in advanced testicular cancer. Nevertheless some patients with large tumor burden still succumb to chemorefractory disease. Therefore preclinical and clinical evaluation of new drugs and agents not primarily used against this type of disease are still mandatory. For preclinical drug screening purposes heterotransplantation of specific human tumors yields a model with high validity for tumor markers and drug response. Heterotransplantation of a human embryonal testicular cancer was used for simultaneous testing of established agents such as cisplatin, melphalan, bleomycin, vinblastine, etoposide and adriamycin and some newer derivatives such as PHM or mafosfamide. Furthermore agents such as procarbazine, dacarbazine and methyl-CCNU that cross the blood-brain-barrier displayed some interesting activity. The results hint at a unique chemosensitivity pattern of the xenograft line, with some accordance between clinical response to vinblastine and bleomycin and good response of the xenografts to bleomycin but not to vinblastine. Radiotherapy was also effective against this tumor line, but there was not much difference in response when the schedule of fractionation was changed. It is concluded that a combined modality approach might salvage patients with residual, chemorefractory disease. (orig.) [de

  15. Utility of Glioblastoma Patient-Derived Orthotopic Xenografts in Drug Discovery and Personalized Therapy

    Directory of Open Access Journals (Sweden)

    Michele Patrizii

    2018-02-01

    Full Text Available Despite substantial effort and resources dedicated to drug discovery and development, new anticancer agents often fail in clinical trials. Among many reasons, the lack of reliable predictive preclinical cancer models is a fundamental one. For decades, immortalized cancer cell cultures have been used to lay the groundwork for cancer biology and the quest for therapeutic responses. However, cell lines do not usually recapitulate cancer heterogeneity or reveal therapeutic resistance cues. With the rapidly evolving exploration of cancer “omics,” the scientific community is increasingly investigating whether the employment of short-term patient-derived tumor cell cultures (two- and three-dimensional and/or patient-derived xenograft models might provide a more representative delineation of the cancer core and its therapeutic response. Patient-derived cancer models allow the integration of genomic with drug sensitivity data on a personalized basis and currently represent the ultimate approach for preclinical drug development and biomarker discovery. The proper use of these patient-derived cancer models might soon influence clinical outcomes and allow the implementation of tailored personalized therapy. When assessing drug efficacy for the treatment of glioblastoma multiforme (GBM, currently, the most reliable models are generated through direct injection of patient-derived cells or more frequently the isolation of glioblastoma cells endowed with stem-like features and orthotopically injecting these cells into the cerebrum of immunodeficient mice. Herein, we present the key strengths, weaknesses, and potential applications of cell- and animal-based models of GBM, highlighting our experience with the glioblastoma stem-like patient cell-derived xenograft model and its utility in drug discovery.

  16. ISMS: A New Model for Improving Student Motivation and Self-esteem in Primary Education

    Directory of Open Access Journals (Sweden)

    Yaron GHILAY

    2015-06-01

    Full Text Available In this study we introduce a new model for primary education called ISMS: Improving Student Motivation and Self-esteem. Following a two-year study undertaken in a primary school (n=67, the new model was found to be successful. Students who participated in the research, reported that a course based on ISMS principles was very helpful for strengthening their perceived ability and their motivation to make an effort. They became more enthusiastic, responsible, self-confident, optimistic and determined to succeed. The meaning of such findings is that it is possible to improve key variables having vital influence on student learning and academic performance. The ISMS model was found to be applicable to primary education, in particular, but it may be suitable to secondary schools as well.

  17. Modeling PWR systems for monitoring primary-to-secondary leakage using tritium tracer

    International Nuclear Information System (INIS)

    Peiffer, D.G.

    1992-01-01

    This paper discusses several techniques available for monitoring primary to secondary leakage, focusing on the advantages and disadvantages of each. A mathematical model of Millstone 2 describes the behavior of tritium activity in the secondary plant water when a leak exists. Real data from Millstone 2 illustrate the accuracy and reliability of the model and use of the model to measure the mass of water in the secondary system

  18. Targeting of human glioma xenografts in vivo utilizing radiolabeled antibodies

    International Nuclear Information System (INIS)

    Williams, J.A.; Wessels, B.W.; Wharam, M.D.; Order, S.E.; Wanek, P.M.; Poggenburg, J.K.; Klein, J.L.

    1990-01-01

    Radiolabeled antibodies provide a potential basis for selective radiotherapy of human gliomas. We have measured tumor targeting by radiolabeled monoclonal and polyclonal antibodies directed against neuroectodermal and tumor-associated antigens in nude mice bearing human glioma xenografts. Monoclonal P96.5, a mouse IgG2a immunoglobulin, defines an epitope of a human melanoma cell surface protein, and specifically binds the U-251 human glioma as measured by immunoperoxidase histochemistry. 111In-radiolabeled P96.5 specifically targets the U-251 human glioma xenograft and yields 87.0 microCuries (microCi) of tumor activity per gram per 100 microCi injected activity compared to 4.5 microCi following administration of radiolabeled irrelevant monoclonal antibody. Calculations of targeting ratios demonstrate deposited dose to be 11.6 times greater with radiolabeled P96.5 administration compared to irrelevant monoclonal antibody. The proportion of tumor dose found in normal organs is less than 10%, further supporting specific targeting of the human glioma xenograft by this antibody. Monoclonal antibody ZME018, which defines a second melanoma-associated antigen, and polyclonal rabbit antiferritin, which defines a tumor-associated antigen, demonstrate positive immunoperoxidase staining of the tumor, but comparatively decreased targeting. When compared to the 111In-radiolabeled antibody, 90Y-radiolabeled P96.5 demonstrates comparable tumor targeting and percentages of tumor dose found in normal organs. To test the therapeutic potential of 90Y-radiolabeled P96.5, tumors and normal sites were implanted with miniature thermoluminescent dosimeters (TLD). Seven days following administration of 100 microCi 90Y-radiolabeled P96.5, average absorbed doses of 3770, 980, 353, and 274 cGy were observed in tumor, liver, contralateral control site, and total body, respectively

  19. The Study of Role of Transactional Model Constructs in Yazd Teachers of Primary School by Using of Structural Equation Model

    Directory of Open Access Journals (Sweden)

    M. Mohammadi

    2014-12-01

    Full Text Available Background: By considering, transactional model is one of the most comprehensive model for reduction of stress, this study was determined the role of Transactional Model constructs in Yazd teachers of Primary school by using of Structural Equation Model. Methods: This research was a descriptive- analytical. Categorized approach was applied for sampling. A standard questionnaire and the questionnaire planned based on Transactional Model were applied for data collection. Validity (CVR=0.85 and reliability (α=0.87 of instrument confirmed by experts. SPSS15 and LISREL8.8 software were used for data analysis. Results: In this research 200 Yazd teachers of primary schools (average age of 41.70±5.69 were participated. The results of this study showed the effect of stress on secondary appraisal and primary appraisal was -0.87 and 0.84, respectively. Our results also showed an inverse relationship between perceived stress and secondary appraisal also between primary appraisal and coping effort. Also, the results were confirmed validity and good fitness of model, because of the RMSEA=0.0329 and index χ2/df were less than 3. Conclusion: Since the constructs of this model had a significant effect on the stress, it suggests the policies and plans for improvement of these factors.

  20. Primary care models for treating opioid use disorders: What actually works? A systematic review.

    Directory of Open Access Journals (Sweden)

    Pooja Lagisetty

    Full Text Available Primary care-based models for Medication-Assisted Treatment (MAT have been shown to reduce mortality for Opioid Use Disorder (OUD and have equivalent efficacy to MAT in specialty substance treatment facilities.The objective of this study is to systematically analyze current evidence-based, primary care OUD MAT interventions and identify program structures and processes associated with improved patient outcomes in order to guide future policy and implementation in primary care settings.PubMed, EMBASE, CINAHL, and PsychInfo.We included randomized controlled or quasi experimental trials and observational studies evaluating OUD treatment in primary care settings treating adult patient populations and assessed structural domains using an established systems engineering framework.We included 35 interventions (10 RCTs and 25 quasi-experimental interventions that all tested MAT, buprenorphine or methadone, in primary care settings across 8 countries. Most included interventions used joint multi-disciplinary (specialty addiction services combined with primary care and coordinated care by physician and non-physician provider delivery models to provide MAT. Despite large variability in reported patient outcomes, processes, and tasks/tools used, similar key design factors arose among successful programs including integrated clinical teams with support staff who were often advanced practice clinicians (nurses and pharmacists as clinical care managers, incorporating patient "agreements," and using home inductions to make treatment more convenient for patients and providers.The findings suggest that multidisciplinary and coordinated care delivery models are an effective strategy to implement OUD treatment and increase MAT access in primary care, but research directly comparing specific structures and processes of care models is still needed.

  1. Comparison between remote sensing and a dynamic vegetation model for estimating terrestrial primary production of Africa.

    Science.gov (United States)

    Ardö, Jonas

    2015-12-01

    Africa is an important part of the global carbon cycle. It is also a continent facing potential problems due to increasing resource demand in combination with climate change-induced changes in resource supply. Quantifying the pools and fluxes constituting the terrestrial African carbon cycle is a challenge, because of uncertainties in meteorological driver data, lack of validation data, and potentially uncertain representation of important processes in major ecosystems. In this paper, terrestrial primary production estimates derived from remote sensing and a dynamic vegetation model are compared and quantified for major African land cover types. Continental gross primary production estimates derived from remote sensing were higher than corresponding estimates derived from a dynamic vegetation model. However, estimates of continental net primary production from remote sensing were lower than corresponding estimates from the dynamic vegetation model. Variation was found among land cover classes, and the largest differences in gross primary production were found in the evergreen broadleaf forest. Average carbon use efficiency (NPP/GPP) was 0.58 for the vegetation model and 0.46 for the remote sensing method. Validation versus in situ data of aboveground net primary production revealed significant positive relationships for both methods. A combination of the remote sensing method with the dynamic vegetation model did not strongly affect this relationship. Observed significant differences in estimated vegetation productivity may have several causes, including model design and temperature sensitivity. Differences in carbon use efficiency reflect underlying model assumptions. Integrating the realistic process representation of dynamic vegetation models with the high resolution observational strength of remote sensing may support realistic estimation of components of the carbon cycle and enhance resource monitoring, providing suitable validation data is available.

  2. The TCD50 and regrowth delay assay in human tumor xenografts: Differences and implications

    International Nuclear Information System (INIS)

    Budach, W.; Budach, V.; Stuschke, M.; Dinges, S.; Sack, H.

    1993-01-01

    The response to irradiation of five human xenograft cell lines - a malignant paraganglioma, a neurogenic sarcoma, a malignant histiocytoma, a primary lymphoma of the brain, and a squamous cell carcinoma - were tested in nude mice. All mice underwent 5 Gy whole body irradiation prior to xenotransplantation to minimize the residual immune response. The subcutaneous tumors were irradiated at a tumor volume of 120 mm 3 under acutely hypoxic conditions with single doses between 8 Gy and 80 Gy depending on the expected radiation sensitivity of the tumor line. Endpoints of the study were the tumor control dose 50% (TCD 50 ) and the regrowth delay endpoints growth delay, specific growth delay, and the tumor bed effect corrected specific growth delay. Specific growth delay and corrected specific growth delay at 76% of the TCD 50 was used in order to compare the data to previously published data from spheroids. The lowest TCD 50 was found in the lymphoma with 24.9 Gy, whereas the TCD 50 of the soft tissue sarcomas and the squamous cell carcinoma ranged from 57.8 Gy to 65.6 Gy. The isoeffective dose levels for the induction of 30 days growth delay, a specific growth delay of 3, and a corrected specific growth delay of 3 ranged from 15.5 Gy (ECL1) to 37.1 Gy (FADU), from 7.2 Gy (ENE2) to 45.6 Gy (EPG1) and from 9.2 Gy (ENE2) to 37.6 Gy (EPG1), respectively. The corrected specific growth delay at 76% of the TCD 50 was correlated with the number of tumor rescue units per 100 cells in spheroids, which was available for three tumor lines, and with the tumor doubling time in xenografts (n = 5). The TCD 50 values corresponded better to the clinical experience than the regrowth delay data. There was no correlation between TCD 50 and any of the regrowth delay endpoints. This missing correlation was most likely a result of large differences in the number of tumor rescue units in human xenografts of the same size

  3. Combinatorial Drug Testing in 3D Microtumors Derived from GBM Patient-Derived Xenografts Reveals Cytotoxic Synergy in Pharmacokinomics-informed Pathway Interactions.

    Science.gov (United States)

    Gilbert, Ashley N; Anderson, Joshua C; Duarte, Christine W; Shevin, Rachael S; Langford, Catherine P; Singh, Raj; Gillespie, G Yancey; Willey, Christopher D

    2018-05-30

    Glioblastoma multiforme (GBM), the most common form of primary malignant brain cancer in adults, is a devastating disease for which effective treatment has remained elusive for over 75 years. One reason for the minimal progress during this time is the lack of accurate preclinical models to represent the patient's tumor's in vivo environment, causing a disconnect in drug therapy effectiveness between the laboratory and clinic. While patient-derived xenografts (PDX's or xenolines) are excellent human tumor representations, they are not amenable to high throughput testing. Therefore, we developed a miniaturized xenoline system (microtumors) for drug testing. Nineteen GBM xenolines were profiled for global kinase (kinomic) activity revealing actionable kinase targets associated with intracranial tumor growth rate. Kinase inhibitors for these targets (WP1066, selumetinib, crizotinib, and cediranib) were selected for single and combination therapy using a fully human-derived three-dimensional (3D) microtumor model of GBM xenoline cells embedded in HuBiogel for subsequent molecular and phenotype assays. GBM microtumors closely resembled orthotopically-implanted tumors based on immunohistochemical analysis and displayed kinomic and morphological diversity. Drug response testing could be reproducibly performed in a 96-well format identifying several synergistic combinations. Our findings indicate that 3D microtumors can provide a suitable high-throughput model for combination drug testing.

  4. Nurse Practitioner-Physician Comanagement: A Theoretical Model to Alleviate Primary Care Strain.

    Science.gov (United States)

    Norful, Allison A; de Jacq, Krystyna; Carlino, Richard; Poghosyan, Lusine

    2018-05-01

    Various models of care delivery have been investigated to meet the increasing demands in primary care. One proposed model is comanagement of patients by more than 1 primary care clinician. Comanagement has been investigated in acute care with surgical teams and in outpatient settings with primary care physicians and specialists. Because nurse practitioners are increasingly managing patient care as independent clinicians, our study objective was to propose a model of nurse practitioner-physician comanagement. We conducted a literature search using the following key words: comanagement; primary care; nurse practitioner OR advanced practice nurse. From 156 studies, we extracted information about nurse practitioner-physician comanagement antecedents, attributes, and consequences. A systematic review of the findings helped determine effects of nurse practitioner-physician comanagement on patient care. Then, we performed 26 interviews with nurse practitioners and physicians to obtain their perspectives on nurse practitioner-physician comanagement. Results were compiled to create our conceptual nurse practitioner-physician comanagement model. Our model of nurse practitioner-physician comanagement has 3 elements: effective communication; mutual respect and trust; and clinical alignment/shared philosophy of care. Interviews indicated that successful comanagement can alleviate individual workload, prevent burnout, improve patient care quality, and lead to increased patient access to care. Legal and organizational barriers, however, inhibit the ability of nurse practitioners to practice autonomously or with equal care management resources as primary care physicians. Future research should focus on developing instruments to measure and further assess nurse practitioner-physician comanagement in the primary care practice setting. © 2018 Annals of Family Medicine, Inc.

  5. MicroRNA signature characterizes primary tumors that metastasize in an esophageal adenocarcinoma rat model.

    Directory of Open Access Journals (Sweden)

    Ali H Zaidi

    Full Text Available To establish a miRNA signature for metastasis in an animal model of esophageal adenocarcinoma (EAC.The incidence of esophageal adenocarcinoma (EAC has dramatically increased and esophageal cancer is now the sixth leading cause of cancer deaths worldwide. Mortality rates remain high among patients with advanced stage disease and esophagectomy is associated with high complication rates. Hence, early identification of potentially metastatic disease would better guide treatment strategies.The modified Levrat's surgery was performed to induce EAC in Sprague-Dawley rats. Primary EAC and distant metastatic sites were confirmed via histology and immunofluorescence. miRNA profiling was performed on primary tumors with or without metastasis. A unique subset of miRNAs expressed in primary tumors and metastases was identified with Ingenuity Pathway Analysis (IPA along with upstream and downstream targets. miRNA-linked gene expression analysis was performed on a secondary cohort of metastasis positive (n=5 and metastasis negative (n=28 primary tumors.The epithelial origin of distant metastasis was established by IF using villin (VIL1 and mucin 5AC (MUC5AC antibodies. miRNome analysis identified four down-regulated miRNAs in metastasis positive primary tumors compared to metastasis negative tumors: miR-92a-3p (p=0.0001, miR-141-3p (p=0.0022, miR-451-1a (p=0.0181 and miR133a-3p (p=0.0304. Six target genes identified in the top scoring networks by IPA were validated as significantly, differentially expressed in metastasis positive primary tumors: Ago2, Akt1, Kras, Bcl2L11, CDKN1B and Zeb2.In vivo metastasis was confirmed in the modified Levrat's model. Analysis of the primary tumor identified a distinctive miRNA signature for primary tumors that metastasized.

  6. Anatomical manifestations of primary blast ocular trauma observed in a postmortem porcine model.

    Science.gov (United States)

    Sherwood, Daniel; Sponsel, William E; Lund, Brian J; Gray, Walt; Watson, Richard; Groth, Sylvia L; Thoe, Kimberly; Glickman, Randolph D; Reilly, Matthew A

    2014-02-24

    We qualitatively describe the anatomic features of primary blast ocular injury observed using a postmortem porcine eye model. Porcine eyes were exposed to various levels of blast energy to determine the optimal conditions for future testing. We studied 53 enucleated porcine eyes: 13 controls and 40 exposed to a range of primary blast energy levels. Eyes were preassessed with B-scan and ultrasound biomicroscopy (UBM) ultrasonography, photographed, mounted in gelatin within acrylic orbits, and monitored with high-speed videography during blast-tube impulse exposure. Postimpact photography, ultrasonography, and histopathology were performed, and ocular damage was assessed. Evidence for primary blast injury was obtained. While some of the same damage was observed in the control eyes, the incidence and severity of this damage in exposed eyes increased with impulse and peak pressure, suggesting that primary blast exacerbated these injuries. Common findings included angle recession, internal scleral delamination, cyclodialysis, peripheral chorioretinal detachments, and radial peripapillary retinal detachments. No full-thickness openings of the eyewall were observed in any of the eyes tested. Scleral damage demonstrated the strongest associative tendency for increasing likelihood of injury with increased overpressure. These data provide evidence that primary blast alone (in the absence of particle impact) can produce clinically relevant ocular damage in a postmortem model. The blast parameters derived from this study are being used currently in an in vivo model. We also propose a new Cumulative Injury Score indicating the clinical relevance of observed injuries.

  7. Designing Excellence and Quality Model for Training Centers of Primary Health Care: A Delphi Method Study.

    Science.gov (United States)

    Tabrizi, Jafar-Sadegh; Farahbakhsh, Mostafa; Shahgoli, Javad; Rahbar, Mohammad Reza; Naghavi-Behzad, Mohammad; Ahadi, Hamid-Reza; Azami-Aghdash, Saber

    2015-10-01

    Excellence and quality models are comprehensive methods for improving the quality of healthcare. The aim of this study was to design excellence and quality model for training centers of primary health care using Delphi method. In this study, Delphi method was used. First, comprehensive information were collected using literature review. In extracted references, 39 models were identified from 34 countries and related sub-criteria and standards were extracted from 34 models (from primary 39 models). Then primary pattern including 8 criteria, 55 sub-criteria, and 236 standards was developed as a Delphi questionnaire and evaluated in four stages by 9 specialists of health care system in Tabriz and 50 specialists from all around the country. Designed primary model (8 criteria, 55 sub-criteria, and 236 standards) were concluded with 8 criteria, 45 sub-criteria, and 192 standards after 4 stages of evaluations by specialists. Major criteria of the model are leadership, strategic and operational planning, resource management, information analysis, human resources management, process management, costumer results, and functional results, where the top score was assigned as 1000 by specialists. Functional results had the maximum score of 195 whereas planning had the minimum score of 60. Furthermore the most and the least sub-criteria was for leadership with 10 sub-criteria and strategic planning with 3 sub-criteria, respectively. The model that introduced in this research has been designed following 34 reference models of the world. This model could provide a proper frame for managers of health system in improving quality.

  8. Tumor-targeting Salmonella typhimurium A1-R combined with recombinant methioninase and cisplatinum eradicates an osteosarcoma cisplatinum-resistant lung metastasis in a patient-derived orthotopic xenograft (PDOX) mouse model: decoy, trap and kill chemotherapy moves toward the clinic.

    Science.gov (United States)

    Igarashi, Kentaro; Kawaguchi, Kei; Kiyuna, Tasuku; Miyake, Kentaro; Miyake, Masuyo; Li, Shukuan; Han, Qinghong; Tan, Yuying; Zhao, Ming; Li, Yunfeng; Nelson, Scott D; Dry, Sarah M; Singh, Arun S; Elliott, Irmina A; Russell, Tara A; Eckardt, Mark A; Yamamoto, Norio; Hayashi, Katsuhiro; Kimura, Hiroaki; Miwa, Shinji; Tsuchiya, Hiroyuki; Eilber, Fritz C; Hoffman, Robert M

    2018-04-10

    In the present study, a patient-derived orthotopic xenograft (PDOX) model of recurrent cisplatinum (CDDP)-resistant metastatic osteosarcoma was treated with Salmonella typhimurium A1-R (S. typhimurium A1-R), which decoys chemoresistant quiescent cancer cells to cycle, and recombinant methioninase (rMETase), which selectively traps cancer cells in late S/G 2 , and chemotherapy. The PDOX models were randomized into the following groups 14 days after implantation: G1, control without treatment; G2, CDDP (6 mg/kg, intraperitoneal (i.p.) injection, weekly, for 2 weeks); G3, rMETase (100 unit/mouse, i.p., daily, for 2 weeks). G4, S. typhimurium A1-R (5 × 10 7 CFU/100 μl, i.v., weekly, for 2 weeks); G5, S. typhimurium A1-R (5 × 10 7 CFU/100 μl, i.v., weekly, for 2 weeks) combined with rMETase (100 unit/mouse, i.p., daily, for 2 weeks); G6, S. typhimurium A1-R (5 × 10 7 CFU/100 μl, i.v., weekly, for 2 weeks) combined with rMETase (100 unit/mouse, i.p., daily, for 2 weeks) and CDDP (6 mg/kg, i.p. injection, weekly, for 2 weeks). On day 14 after initiation, all treatments except CDDP alone, significantly inhibited tumor growth compared to untreated control: (CDDP: p = 0.586; rMETase: p = 0.002; S. typhimurium A1-R: p = 0.002; S. typhimurium A1-R combined with rMETase: p = 0.0004; rMETase combined with both S. typhimurium A1-R and CDDP: p = 0.0001). The decoy, trap and kill combination of S. typhimurium A1-R, rMETase and CDDP was the most effective of all therapies and was able to eradicate the metastatic osteosarcoma PDOX.

  9. Improving Image Segmentation with Adaptive, Recurrent, Spiking Neural Network Models of the Primary Visual Cortex

    Science.gov (United States)

    2017-05-19

    Vijay Singh, Martin Tchernookov, Rebecca Butterfield, Ilya Nemenman, Rongrong Ji. Director Field Model of the Primary Visual Cortex for Contour...FTE Equivalent: Total Number: DISCIPLINE Vijay Singh 40 Physics 0.40 1 PERCENT_SUPPORTEDNAME FTE Equivalent: Total Number: Martin Tchernookov 0.20

  10. A Professional Experience Model for Primary Pre-Service Teachers Specialising in Mathematics

    Science.gov (United States)

    McMaster, Heather; Cavanagh, Michael

    2016-01-01

    Many primary pre-service teachers (PSTs) who are enthused by tertiary courses that espouse and model a socio-constructivist approach to teaching mathematics, revert to a traditional approach when they encounter mathematics teaching during professional experience. An intervention was designed to translate the initial pedagogical intent of four…

  11. Kinetic analyses and mathematical modeling of primary photochemical and photoelectrochemical processes in plant photosystems

    NARCIS (Netherlands)

    Vredenberg, W.J.

    2011-01-01

    In this paper the model and simulation of primary photochemical and photo-electrochemical reactions in dark-adapted intact plant leaves is presented. A descriptive algorithm has been derived from analyses of variable chlorophyll a fluorescence and P700 oxidation kinetics upon excitation with

  12. Modeling the Factors Associated with Children's Mental Health Difficulties in Primary School: A Multilevel Study

    Science.gov (United States)

    Humphrey, Neil; Wigelsworth, Michael

    2012-01-01

    The current study explores some of the factors associated with children's mental health difficulties in primary school. Multilevel modeling with data from 628 children from 36 schools was used to determine how much variation in mental health difficulties exists between and within schools, and to identify characteristics at the school and…

  13. Measures of Model Uncertainty in the Assessment of Primary Stresses in Ship Structures

    DEFF Research Database (Denmark)

    Östergaard, Carsten; Dogliani, Mario; Guedes Soares, Carlos

    1996-01-01

    The paper considers various models and methods commonly used for linear elastic stress analysis and assesses the uncertainty involved in their application to the analysis of the distribution of primary stresses in the hull of a containership example, through statistical evaluations of the results...

  14. Interfacing polymeric scaffolds with primary pancreatic ductal adenocarcinoma cells to develop 3D cancer models

    NARCIS (Netherlands)

    Ricci, C.; Mota, C.M.; Moscato, S.; D' Alessandro, D.; Ugel, S.; Sartoris, S.; Bronte, V.; Boggi, U.; Campani, D.; Funel, N.; Moroni, Lorenzo; Danti, S.

    2014-01-01

    We analyzed the interactions between human primary cells from pancreatic ductal adenocarcinoma (PDAC) and polymeric scaffolds to develop 3D cancer models useful for mimicking the biology of this tumor. Three scaffold types based on two biocompatible polymeric formulations, such as poly(vinyl

  15. Using an Empowerment Professional Development Model to Support Beginning Primary Mathematics Teachers

    Science.gov (United States)

    Sparrow, Len; Frid, Sandra

    2003-01-01

    This is a case study report from a larger study that focused on how an empowerment professional development model influenced the mathematics pedagogical practices and beliefs of Australian primary school teachers during their first year of teaching. The research used an interpretive approach for analysis of data from interviews, observations,…

  16. Vegetation-specific model parameters are not required for estimating gross primary production

    Czech Academy of Sciences Publication Activity Database

    Yuan, W.; Cai, W.; Liu, S.; Dong, W.; Chen, J.; Altaf Arain, M.; Blanken, P. D.; Cescatti, A.; Wohlfahrt, G.; Georgiadis, T.; Genesio, L.; Gianelle, D.; Grelle, A.; Kiely, G.; Knohl, A.; Liu, D.; Marek, Michal V.; Merbold, L.; Montagnani, L.; Panferov, O.; Peltoniemi, M.; Rambal, S.; Raschi, A.; Varlagin, A.; Xia, J.

    2014-01-01

    Roč. 292, NOV 24 2014 (2014), s. 1-10 ISSN 0304-3800 Institutional support: RVO:67179843 Keywords : light use efficiency * gross primary production * model parameters Subject RIV: EH - Ecology, Behaviour Impact factor: 2.321, year: 2014

  17. Does a Socio-Ecological School Model Promote Resilience in Primary Schools?

    Science.gov (United States)

    Lee, Patricia C.; Stewart, Donald E.

    2013-01-01

    Background: This research investigates the extent to which the holistic, multistrategy "health-promoting school" (HPS) model using a resilience intervention can lead to improved resilience among students. Methods: A quasi-experimental design using a study cohort selected from 20 primary schools in Queensland, Australia was employed. Ten…

  18. A rheological model for elastohydrodynamic contacts based on primary laboratory data

    Science.gov (United States)

    Bair, S.; Winer, W. O.

    1979-01-01

    A shear rheological model based on primary laboratory data is proposed for concentrated contact lubrication. The model is a Maxwell model modified with a limiting shear stress. Three material properties are required: Low shear stress viscosity, limiting elastic shear modulus, and the limiting shear stress the material can withstand. All three are functions of temperature and pressure. In applying the model to EHD contacts the predicted response possesses the characteristics expected from several experiments reported in the literature and, in one specific case where direct comparison could be made, good numerical agreement is shown.

  19. Lacustrine-humate model for primary uranium ore deposits, Grants Uranium Region, New Mexico

    International Nuclear Information System (INIS)

    Turner-Peterson, C.E.

    1985-01-01

    Two generations of uranium ore, primary and redistributed, occur in fluvial sandstones of the Upper Jurassic Morrison Formation in the San Juan basin; the two stages of ore formation can be related to the hydrologic history of the basin. Primary ore formed soon after Morrison deposition, in the Late Jurassic to Early Cretaceous, and a model, the lacustrine-humate model, is offered that views primary mineralization as a diagenetic event related to early pore fluid evolution. The basic premise is that the humate, a pore-filling organic material closely associated with primary ore, originated as humic acids dissolved in pore waters of greenish-gray lacustrine mudstones deposited in the mud-flat facies of the Brushy Basin Member and similar K shale beds in the Westwater Canyon Member. During compaction associated with early burial, formation water expelled from lacustrine mudstone units carried these humic acids into adjacent sandstone beds where the organics precipitated, forming the humate deposits that concentrated uranium. During the Tertiary, much later in the hydrologic history of the basin, when Jurassic sediments were largely compacted, oxygenated ground water flowed basinward from uplifted basin margins. This invasion of Morrison sandstone beds by oxidizing ground waters redistributed uranium from primary ores along redox boundaries, forming ore deposits that resemble roll-front-type uranium ores. 11 figures

  20. Children's health care assistance according to their families: a comparison between models of Primary Care

    Directory of Open Access Journals (Sweden)

    Vanessa Bertoglio Comassetto Antunes de Oliveira

    2015-02-01

    Full Text Available OBJECTIVE To compare the health assistance models of Basic Traditional Units (UBS with the Family Health Strategy (ESF units for presence and extent of attributes of Primary Health Care (APS, specifically in the care of children. METHOD A cross-sectional study of a quantitative approach with families of children attended by the Public Health Service of Colombo, Paraná. The Primary Care Assessment Tool (PCA-Tool was applied to parents of 482 children, 235 ESF units and 247 UBS units covering all primary care units of the municipality, between June and July 2012. The results were analyzed according to the PCA-Tool manual. RESULTS ESF units reached a borderline overall score for primary health care standards. However, they fared better in their attributes of Affiliation, Integration of care coordination, Comprehensiveness, Family Centeredness and Accessibility of use, while the attributes of Community Guidance/Orientation, Coordination of Information Systems, Longitudinality and Access attributes were rated as insufficient for APS. UBS units had low scores on all attributes. CONCLUSION The ESF units are closer to the principles of APS (Primary Health Care, but there is need to review actions of child care aimed at the attributes of APS in both care models, corroborating similar studies from other regions of Brazil.

  1. Combined constraints on global ocean primary production using observations and models

    Science.gov (United States)

    Buitenhuis, Erik T.; Hashioka, Taketo; Quéré, Corinne Le

    2013-09-01

    production is at the base of the marine food web and plays a central role for global biogeochemical cycles. Yet global ocean primary production is known to only a factor of 2, with previous estimates ranging from 38 to 65 Pg C yr-1 and no formal uncertainty analysis. Here, we present an improved global ocean biogeochemistry model that includes a mechanistic representation of photosynthesis and a new observational database of net primary production (NPP) in the ocean. We combine the model and observations to constrain particulate NPP in the ocean with statistical metrics. The PlankTOM5.3 model includes a new photosynthesis formulation with a dynamic representation of iron-light colimitation, which leads to a considerable improvement of the interannual variability of surface chlorophyll. The database includes a consistent set of 50,050 measurements of 14C primary production. The model best reproduces observations when global NPP is 58 ± 7 Pg C yr-1, with a most probable value of 56 Pg C yr-1. The most probable value is robust to the model used. The uncertainty represents 95% confidence intervals. It considers all random errors in the model and observations, but not potential biases in the observations. We show that tropical regions (23°S-23°N) contribute half of the global NPP, while NPPs in the Northern and Southern Hemispheres are approximately equal in spite of the larger ocean area in the South.

  2. Intraductal delivery of adenoviruses targets pancreatic tumors in transgenic Ela-myc mice and orthotopic xenografts.

    Science.gov (United States)

    José, Anabel; Sobrevals, Luciano; Miguel Camacho-Sánchez, Juan; Huch, Meritxell; Andreu, Núria; Ayuso, Eduard; Navarro, Pilar; Alemany, Ramon; Fillat, Cristina

    2013-01-01

    Gene-based anticancer therapies delivered by adenoviruses are limited by the poor viral distribution into the tumor. In the current work we have explored the feasibility of targeting pancreatic tumors through a loco-regional route. We have taken advantage of the ductal network in the pancreas to retrogradelly inject adenoviruses through the common bile duct in two different mouse models of pancreatic carcinogenesis: The transgenic Ela-myc mice that develop mixed neoplasms displaying both acinar-like and duct-like neoplastic cells affecting the whole pancreas; and mice bearing PANC-1 and BxPC-3 orthotopic xenografts that constitute a model of localized human neoplastic tumors. We studied tumor targeting and the anticancer effects of newly thymidine kinase-engineered adenoviruses both in vitro and in vivo, and conducted comparative studies between intraductal or intravenous administration. Our data indicate that the intraductal delivery of adenovirus efficiently targets pancreatic tumors in the two mouse models. The in vivo application of AduPARTKT plus ganciclovir (GCV) treatment induced tumor regression in Ela-myc mice. Moreover, the intraductal injection of ICOVIR15-TKT oncolytic adenoviruses significantly improved mean survival of mice bearing PANC-1 and BxPC-3 pancreatic xenografts from 30 to 52 days and from 20 to 68 days respectively (p less than 0.0001) when combined with GCV. Of notice, both AduPARTKT and ICOVIR15-TKT antitumoral responses were stronger by ductal viral application than intravenously, in line with the 38-fold increase in pancreas transduction observed upon ductal administration. In summary our data show that cytotoxic adenoviruses retrogradelly injected to the pancreas can be a feasible approach to treat localized pancreatic tumors.

  3. Heterotypic mouse models of canine osteosarcoma recapitulate tumor heterogeneity and biological behavior

    Directory of Open Access Journals (Sweden)

    Milcah C. Scott

    2016-12-01

    Full Text Available Osteosarcoma (OS is a heterogeneous and rare disease with a disproportionate impact because it mainly affects children and adolescents. Lamentably, more than half of patients with OS succumb to metastatic disease. Clarification of the etiology of the disease, development of better strategies to manage progression, and methods to guide personalized treatments are among the unmet health needs for OS patients. Progress in managing the disease has been hindered by the extreme heterogeneity of OS; thus, better models that accurately recapitulate the natural heterogeneity of the disease are needed. For this study, we used cell lines derived from two spontaneous canine OS tumors with distinctly different biological behavior (OS-1 and OS-2 for heterotypic in vivo modeling that recapitulates the heterogeneous biology and behavior of this disease. Both cell lines demonstrated stability of the transcriptome when grown as orthotopic xenografts in athymic nude mice. Consistent with the behavior of the original tumors, OS-2 xenografts grew more rapidly at the primary site and had greater propensity to disseminate to lung and establish microscopic metastasis. Moreover, OS-2 promoted formation of a different tumor-associated stromal environment than OS-1 xenografts. OS-2-derived tumors comprised a larger percentage of the xenograft tumors than OS-1-derived tumors. In addition, a robust pro-inflammatory population dominated the stromal cell infiltrates in OS-2 xenografts, whereas a mesenchymal population with a gene signature reflecting myogenic signaling dominated those in the OS-1 xenografts. Our studies show that canine OS cell lines maintain intrinsic features of the tumors from which they were derived and recapitulate the heterogeneous biology and behavior of bone cancer in mouse models. This system provides a resource to understand essential interactions between tumor cells and the stromal environment that drive the progression and metastatic propensity of

  4. Heterotypic mouse models of canine osteosarcoma recapitulate tumor heterogeneity and biological behavior.

    Science.gov (United States)

    Scott, Milcah C; Tomiyasu, Hirotaka; Garbe, John R; Cornax, Ingrid; Amaya, Clarissa; O'Sullivan, M Gerard; Subramanian, Subbaya; Bryan, Brad A; Modiano, Jaime F

    2016-12-01

    Osteosarcoma (OS) is a heterogeneous and rare disease with a disproportionate impact because it mainly affects children and adolescents. Lamentably, more than half of patients with OS succumb to metastatic disease. Clarification of the etiology of the disease, development of better strategies to manage progression, and methods to guide personalized treatments are among the unmet health needs for OS patients. Progress in managing the disease has been hindered by the extreme heterogeneity of OS; thus, better models that accurately recapitulate the natural heterogeneity of the disease are needed. For this study, we used cell lines derived from two spontaneous canine OS tumors with distinctly different biological behavior (OS-1 and OS-2) for heterotypic in vivo modeling that recapitulates the heterogeneous biology and behavior of this disease. Both cell lines demonstrated stability of the transcriptome when grown as orthotopic xenografts in athymic nude mice. Consistent with the behavior of the original tumors, OS-2 xenografts grew more rapidly at the primary site and had greater propensity to disseminate to lung and establish microscopic metastasis. Moreover, OS-2 promoted formation of a different tumor-associated stromal environment than OS-1 xenografts. OS-2-derived tumors comprised a larger percentage of the xenograft tumors than OS-1-derived tumors. In addition, a robust pro-inflammatory population dominated the stromal cell infiltrates in OS-2 xenografts, whereas a mesenchymal population with a gene signature reflecting myogenic signaling dominated those in the OS-1 xenografts. Our studies show that canine OS cell lines maintain intrinsic features of the tumors from which they were derived and recapitulate the heterogeneous biology and behavior of bone cancer in mouse models. This system provides a resource to understand essential interactions between tumor cells and the stromal environment that drive the progression and metastatic propensity of OS. © 2016

  5. Physical models and primary design of reactor based slow positron source at CMRR

    Science.gov (United States)

    Wang, Guanbo; Li, Rundong; Qian, Dazhi; Yang, Xin

    2018-07-01

    Slow positron facilities are widely used in material science. A high intensity slow positron source is now at the design stage based on the China Mianyang Research Reactor (CMRR). This paper describes the physical models and our primary design. We use different computer programs or mathematical formula to simulate different physical process, and validate them by proper experiments. Considering the feasibility, we propose a primary design, containing a cadmium shield, a honeycomb arranged W tubes assembly, electrical lenses, and a solenoid. It is planned to be vertically inserted in the Si-doping channel. And the beam intensity is expected to be 5 ×109

  6. MODELING AND FORECASTING THE GROSS ENROLLMENT RATIO IN ROMANIAN PRIMARY SCHOOL

    Directory of Open Access Journals (Sweden)

    MARINOIU CRISTIAN

    2014-06-01

    Full Text Available The gross enrollment ratio in primary school is one of the basic indicators used in order to evaluate the proposed objectives of the educational system. Knowing its evolution allows a more rigorous substantiation of the strategies and of the human resources politics not only from the educational field but also from the economic one. In this paper we propose an econometric model in order to describe the gross enrollment ratio in Romanian primary school and we achieve its prediction for the next years, having as a guide the Box-Jenkins’s methodology. The obtained results indicate the continuous decrease of this rate for the next years.

  7. Legislative and Policy Developments and Imperatives for Advancing the Primary Care Behavioral Health (PCBH) Model.

    Science.gov (United States)

    Freeman, Dennis S; Hudgins, Cathy; Hornberger, Joel

    2018-03-05

    The Primary Care Behavioral Health (PCBH) practice model continues to gain converts among primary care and behavioral health professionals as the evidence supporting its effectiveness continues to accumulate. Despite a growing number of practices and organizations using the model effectively, widespread implementation has been hampered by outmoded policies and regulatory barriers. As policymakers and legislators begin to recognize the contributions that PCBH model services make to the care of complex patients and the expansion of access to those in need of behavioral health interventions, some encouraging policy initiatives are emerging and the policy environment is becoming more favorable to implementation of the PCBH model. This article outlines the necessity for policy change, exposing the policy issues and barriers that serve to limit the practice of the PCBH model; highlights innovative approaches some states are taking to foster integrated practice; and discusses the compatibility of the PCBH model with the nation's health care reform agenda. Psychologists have emerged as leaders in the design and implementation of PCBH model integration and are encouraged to continue to advance the model through the demonstration of efficient and effective clinical practice, participation in the expansion of an appropriately trained workforce, and advocacy for the inclusion of this practice model in emerging healthcare systems and value-based payment methodologies.

  8. Development and exemplification of a model for Teacher Assessment in Primary Science

    Science.gov (United States)

    Davies, D. J.; Earle, S.; McMahon, K.; Howe, A.; Collier, C.

    2017-09-01

    The Teacher Assessment in Primary Science project is funded by the Primary Science Teaching Trust and based at Bath Spa University. The study aims to develop a whole-school model of valid, reliable and manageable teacher assessment to inform practice and make a positive impact on primary-aged children's learning in science. The model is based on a data-flow 'pyramid' (analogous to the flow of energy through an ecosystem), whereby the rich formative assessment evidence gathered in the classroom is summarised for monitoring, reporting and evaluation purposes [Nuffield Foundation. (2012). Developing policy, principles and practice in primary school science assessment. London: Nuffield Foundation]. Using a design-based research (DBR) methodology, the authors worked in collaboration with teachers from project schools and other expert groups to refine, elaborate, validate and operationalise the data-flow 'pyramid' model, resulting in the development of a whole-school self-evaluation tool. In this paper, we argue that a DBR approach to theory-building and school improvement drawing upon teacher expertise has led to the identification, adaptation and successful scaling up of a promising approach to school self-evaluation in relation to assessment in science.

  9. Internal stress model for pre-primary stage of low-stress creep

    International Nuclear Information System (INIS)

    Kloc, L

    2010-01-01

    Initial transient stage in low-stress creep experiments was observed in all such experiments. Recently, evidences were presented that this stage cannot be considered as a normal creep primary stage, though the shape of the creep curve is similar. The strain reached during this so called pre-primary stage is fully recoverable upon unloading; the internal stresses must play important role in the effect. Model of standard linear anelastic solid was modified by introduction of creeping body instead of viscous dashpot. Both power law and hyperbolic sine creep law were used to fit observed creep curves of model and structural materials. Mainly the model using hyeprbolic sine creep law provides good fit to individual creep curves and sets of creep curves at different stresses.

  10. Xylem formation can be modeled statistically as a function of primary growth and cambium activity.

    Science.gov (United States)

    Huang, Jian-Guo; Deslauriers, Annie; Rossi, Sergio

    2014-08-01

    Primary (budburst, foliage and shoot) growth and secondary (cambium and xylem) growth of plants play a vital role in sequestering atmospheric carbon. However, their potential relationships have never been mathematically quantified and the underlying physiological mechanisms are unclear. We monitored primary and secondary growth in Picea mariana and Abies balsamea on a weekly basis from 2010 to 2013 at four sites over an altitudinal gradient (25-900 m) in the eastern Canadian boreal forest. We determined the timings of onset and termination through the fitted functions and their first derivative. We quantified the potential relationships between primary growth and secondary growth using the mixed-effects model. We found that xylem formation of boreal conifers can be modeled as a function of cambium activity, bud phenology, and shoot and needle growth, as well as species- and site-specific factors. Our model reveals that there may be an optimal mechanism to simultaneously allocate the photosynthetic products and stored nonstructural carbon to growth of different organs at different times in the growing season. This mathematical link can bridge phenological modeling, forest ecosystem productivity and carbon cycle modeling, which will certainly contribute to an improved prediction of ecosystem productivity and carbon equilibrium. © 2014 The Authors. New Phytologist © 2014 New Phytologist Trust.

  11. Development of model pump for establishing hydraulic design of primary sodium pumps in PFBR

    International Nuclear Information System (INIS)

    Chougule, R.J.; Sahasrabudhe, H.G.; Rao, A.S.L.K.; Balchander, K.; Kale, R.D.

    1994-01-01

    Indira Gandhi Centre for Atomic Research, Kalpakkam indicated requirement of indigenous development of primary sodium pump, handling liquid sodium as coolant in Fast Breeder Reactor. The primary sodium pump concept selected in its preliminary design is a vertical, single stage, with single suction impeller, suction facing downwards. The pump is having diffuser, discharge casing and discharge collector. The 1/3 rd size model pump is developed to establish the hydraulic performance of the prototype primary sodium pump. The main objectives were to verify the hydraulic design to operate on low net positive suction head available (NPSHA), no evidence of visible cavitation at available NPSHA, the pump should be designed with a diffuser etc. The model pump PSP 250/40 was designed and successfully developed by Research and Development Division of M/s Kirloskar Brothers Ltd., Kirloskarvadi. The performance testing using model pump was successfully carried out on a closed circuit test rig. The performance of a model pump at three different speeds 1900 rpm, 1456 rpm and 975 rpm was established. The values of hydraulic axial thrust with and without balancing holes on impeller at 1900 rpm was measured. Visual cavitation study at 1900 rpm was carried out to establish the NPSH at bubble free operation of the pump. The tested performance of the model pump is converted to the full scale prototype pump. The predicted performance of prototype pump at 700 rpm was found to be meeting fully with the expected duties. (author). 6 figs., 3 tabs

  12. Modeling a full-scale primary sedimentation tank using artificial neural networks.

    Science.gov (United States)

    Gamal El-Din, A; Smith, D W

    2002-05-01

    Modeling the performance of full-scale primary sedimentation tanks has been commonly done using regression-based models, which are empirical relationships derived strictly from observed daily average influent and effluent data. Another approach to model a sedimentation tank is using a hydraulic efficiency model that utilizes tracer studies to characterize the performance of model sedimentation tanks based on eddy diffusion. However, the use of hydraulic efficiency models to predict the dynamic behavior of a full-scale sedimentation tank is very difficult as the development of such models has been done using controlled studies of model tanks. In this paper, another type of model, namely artificial neural network modeling approach, is used to predict the dynamic response of a full-scale primary sedimentation tank. The neuralmodel consists of two separate networks, one uses flow and influent total suspended solids data in order to predict the effluent total suspended solids from the tank, and the other makes predictions of the effluent chemical oxygen demand using data of the flow and influent chemical oxygen demand as inputs. An extensive sampling program was conducted in order to collect a data set to be used in training and validating the networks. A systematic approach was used in the building process of the model which allowed the identification of a parsimonious neural model that is able to learn (and not memorize) from past data and generalize very well to unseen data that were used to validate the model. Theresults seem very promising. The potential of using the model as part of a real-time process control system isalso discussed.

  13. Characteristics of Indigenous primary health care service delivery models: a systematic scoping review.

    Science.gov (United States)

    Harfield, Stephen G; Davy, Carol; McArthur, Alexa; Munn, Zachary; Brown, Alex; Brown, Ngiare

    2018-01-25

    Indigenous populations have poorer health outcomes compared to their non-Indigenous counterparts. The evolution of Indigenous primary health care services arose from mainstream health services being unable to adequately meet the needs of Indigenous communities and Indigenous peoples often being excluded and marginalised from mainstream health services. Part of the solution has been to establish Indigenous specific primary health care services, for and managed by Indigenous peoples. There are a number of reasons why Indigenous primary health care services are more likely than mainstream services to improve the health of Indigenous communities. Their success is partly due to the fact that they often provide comprehensive programs that incorporate treatment and management, prevention and health promotion, as well as addressing the social determinants of health. However, there are gaps in the evidence base including the characteristics that contribute to the success of Indigenous primary health care services in providing comprehensive primary health care. This systematic scoping review aims to identify the characteristics of Indigenous primary health care service delivery models. This systematic scoping review was led by an Aboriginal researcher, using the Joanna Briggs Institute Scoping Review Methodology. All published peer-reviewed and grey literature indexed in PubMed, EBSCO CINAHL, Embase, Informit, Mednar, and Trove databases from September 1978 to May 2015 were reviewed for inclusion. Studies were included if they describe the characteristics of service delivery models implemented within an Indigenous primary health care service. Sixty-two studies met the inclusion criteria. Data were extracted and then thematically analysed to identify the characteristics of Indigenous PHC service delivery models. Culture was the most prominent characteristic underpinning all of the other seven characteristics which were identified - accessible health services, community

  14. Effect of total lymphoid irradiation on pancreatic islet xenograft survival in rats

    International Nuclear Information System (INIS)

    Nakajima, Y.; Lie, T.S.; Nakauo, H.; Nakagawa, K.; Segawa, M.

    1984-01-01

    Before transplantation of Syrian hamster pancreatic islet xenografts to diabetic rats the recipients received total lymphatic system irradiation and cyclosporin A treatment after transplantation for immunosuppression. The xenograft survival times were measured and the rat anti-hamster lymphocytotoxic titers were determined by 51 Cr release assay

  15. Effect of total lymphoid irradiation on pancreatic islet xenograft survival in rats

    Energy Technology Data Exchange (ETDEWEB)

    Nakajima, Y; Lie, T S [Bonn Univ. (Germany, F.R.). Chirurgische Klinik und Poliklinik; Nakauo, H; Nakagawa, K; Segawa, M [Nara Women' s Univ. (Japan). Dept. of Physics

    1984-01-01

    Before transplantation of Syrian hamster pancreatic islet xenografts to diabetic rats the recipients received total lymphatic system irradiation and cyclosporin A treatment after transplantation for immunosuppression. The xenograft survival times were measured and the rat anti-hamster lymphocytotoxic titers were determined by /sup 51/Cr release assay.

  16. [A new approach to the creation of heart valve xenograft bioprostheses resistant to calcification].

    Science.gov (United States)

    Zhuravleva, I Iu; Dobrova, N B; Novikova, S P; Derkach, G M; Kosterina, L D

    1989-01-01

    The calcium binding activity of xenograft tissue in stages of modification with papain, diphosphonates, and heparin was studied on a model of accelerated calcification in subcutaneous implantation of cusps of pig's aortic bioprostheses to 42 rats. In immobilization of 3-amino-1-oxypropylidendiphosphonic acid and xydiphon the amount of calcium in the implants reduced 50 times as compared to the control. The first stage of ion-covalent heparin immobilization--treatment with albumin--increased the calcium-binding activity of the biomaterial, but subsequent heparinization reduced again the calcium content in the cusp tissue to the level attained in the stage of diphosphonate immobilization. The results of the chemical analysis correlated with the findings of morphological examination. Besides, the new method of treatment made it possible to increase the strength of the biological tissue by 20%. This method of storage of bioprostheses is promising for clinical approbation.

  17. Pediatric primary care to help prevent child maltreatment: the Safe Environment for Every Kid (SEEK) Model.

    Science.gov (United States)

    Dubowitz, Howard; Feigelman, Susan; Lane, Wendy; Kim, Jeongeun

    2009-03-01

    Effective strategies for preventing child maltreatment are needed. Few primary care-based programs have been developed, and most have not been well evaluated. Our goal was to evaluate the efficacy of the Safe Environment for Every Kid model of pediatric primary care in reducing the occurrence of child maltreatment. A randomized trial was conducted from June 2002 to November 2005 in a university-based resident continuity clinic in Baltimore, Maryland. The study population consisted of English-speaking parents of children (0-5 years) brought in for child health supervision. Of the 1118 participants approached, 729 agreed to participate, and 558 of them completed the study protocol. Resident continuity clinics were cluster randomized by day of the week to the model (intervention) or standard care (control) groups. Model care consisted of (1) residents who received special training, (2) the Parent Screening Questionnaire, and (3) a social worker. Risk factors for child maltreatment were identified and addressed by the resident physician and/or social worker. Standard care involved routine pediatric primary care. A subset of the clinic population was sampled for the evaluation. Child maltreatment was measured in 3 ways: (1) child protective services reports using state agency data; (2) medical chart documentation of possible abuse or neglect; and (3) parental report of harsh punishment via the Parent-Child Conflict Tactics scale. Model care resulted in significantly lower rates of child maltreatment in all the outcome measures: fewer child protective services reports, fewer instances of possible medical neglect documented as treatment nonadherence, fewer children with delayed immunizations, and less harsh punishment reported by parents. One-tailed testing was conducted in accordance with the study hypothesis. The Safe Environment for Every Kid (SEEK) model of pediatric primary care seems promising as a practical strategy for helping prevent child maltreatment

  18. Modeling the transport of hydrogen in the primary coolant of pressurized heavy water reactors

    International Nuclear Information System (INIS)

    Subramanian, H.; Velmurugan, S.; Narasimhan, S.V.; Jain, A.K.; Dash, S.C.

    2008-01-01

    Heavy water (D 2 O) is used in primary heat transport systems of PHWRs. To suppress the radiolysis of heavy water and to control oxygen, hydrogen is added at regular intervals to the primary heat transport system. The added hydrogen finds it way to the heavy water storage tank after passing through the bleed condenser. Owing to the different temperatures and two phase region present in these systems, hydrogen gets redistributed. It is important to know the concentration of dissolved hydrogen in these regions in order to ensure a steady state dissolved hydrogen concentration in the primary system. Different power stations report variations in the frequency and quantity of hydrogen added to achieve the prescribed steady state level. This paper makes an attempt to account for the inventory of hydrogen and model its transport in PHT system. (author)

  19. Modeling of primary production of phytoplankton in the wetland Jaboque, Bogotá D.C.

    Directory of Open Access Journals (Sweden)

    Julio Eduardo Beltrán Vargas

    2016-02-01

    Full Text Available A dynamic simulation model is presented to explain the general behavior of the  primary production of phytoplankton in the wetland Jaboque - Bogota, Colombia, in three sections with differential physical and chemical characteristics. The model takes into account the physicochemical variables, the basin area, depth, annual rainfall, water temperature, pH and concentration of chlorophyll _a. The dynamic modeling is based on differential equations and the Euler integration method is used, the modeling was developed using Stella 9.1® computer program. The model allows quantifying the primary production of phytoplankton in wetland Jaboque from chlorophyll _a monthly average concentration for each section. The results of the Ppf modeling show that Ppf concentration variations  in each section of the wetland follow a reverse pattern to the bimodal behavior of precipitation. A high degree of correspondence between the values of chlorophyll_a Ppf field and modeled in the following manner r2 = 0.86 for the first section and r2 = 0.86 and r2 = 0.79 for the remaining sections was found. Error determination was 0,57 relative to the first section and 0,35; 0,46, indicating that the results are not overstated. The model shows in general terms the functional aspects of behavior Ppf and its relation to the process of eutrophication, and it allows recommendations for the management and restoration of wetlands.

  20. Modelling DW-MRI data from primary and metastatic ovarian tumours

    Energy Technology Data Exchange (ETDEWEB)

    Winfield, Jessica M. [Institute of Cancer Research, CRUK and EPSRC Cancer Imaging Centre, Division of Radiotherapy and Imaging, Surrey (United Kingdom); Royal Marsden NHS Foundation Trust, Surrey (United Kingdom); Institute of Cancer Research and Royal Marsden Hospital, MRI Unit, Surrey (United Kingdom); DeSouza, Nandita M.; Collins, David J. [Institute of Cancer Research, CRUK and EPSRC Cancer Imaging Centre, Division of Radiotherapy and Imaging, Surrey (United Kingdom); Royal Marsden NHS Foundation Trust, Surrey (United Kingdom); Priest, Andrew N.; Hodgkin, Charlotte; Freeman, Susan [University of Cambridge, Department of Radiology, Addenbrooke' s Hospital, Cambridge (United Kingdom); Wakefield, Jennifer C.; Orton, Matthew R. [Institute of Cancer Research, CRUK and EPSRC Cancer Imaging Centre, Division of Radiotherapy and Imaging, Surrey (United Kingdom)

    2015-07-15

    To assess goodness-of-fit and repeatability of mono-exponential, stretched exponential and bi-exponential models of diffusion-weighted MRI (DW-MRI) data in primary and metastatic ovarian cancer. Thirty-nine primary and metastatic lesions from thirty-one patients with stage III or IV ovarian cancer were examined before and after chemotherapy using DW-MRI with ten diffusion-weightings. The data were fitted with (a) a mono-exponential model to give the apparent diffusion coefficient (ADC), (b) a stretched exponential model to give the distributed diffusion coefficient (DDC) and stretching parameter (α), and (c) a bi-exponential model to give the diffusion coefficient (D), perfusion fraction (f) and pseudodiffusion coefficient (D*). Coefficients of variation, established from repeated baseline measurements, were: ADC 3.1 %, DDC 4.3 %, α 7.0 %, D 13.2 %, f 44.0 %, D* 165.1 %. The bi-exponential model was unsuitable in these data owing to poor repeatability. After excluding the bi-exponential model, analysis using Akaike Information Criteria showed that the stretched exponential model provided the better fit to the majority of pixels in 64 % of lesions. The stretched exponential model provides the optimal fit to DW-MRI data from ovarian, omental and peritoneal lesions and lymph nodes in pre-treatment and post-treatment measurements with good repeatability. (orig.)

  1. Mathematical modelling for magnetite (crude removal from primary heat transfer loop by ion-exchange resins

    Directory of Open Access Journals (Sweden)

    Zeeshan Nawaz

    2009-04-01

    Full Text Available The present research focuses to develop mathematical model for the removal of iron (magnetite by ion-exchange resin from primary heat transfer loop of process industries. This mathematical model is based on operating capacities (that’s provide more effective design as compared to loading capacity from static laboratory tests. Results showed non-steady state distribution of external Fe2+ and limitations imposed on operating conditions, these conditions includes; loading and elution cycle time, flow rate, concentration of both loading and removal, volume of resin required. Number of generalized assumptions was made under shortcut modeling techniques to overcome the gap of theoretical and actual process design.

  2. Activity transport models for PWR primary circuits; PWR-ydinvoimalaitoksen primaeaeripiirin aktiivisuuskulkeutumismallit

    Energy Technology Data Exchange (ETDEWEB)

    Tanner, V; Rosenberg, R [VTT Chemical Technology, Otaniemi (Finland)

    1995-03-01

    The corrosion products activated in the primary circuit form a major source of occupational radiation dose in the PWR reactors. Transport of corrosion activity is a complex process including chemistry, reactor physics, thermodynamics and hydrodynamics. All the mechanisms involved are not known and there is no comprehensive theory for the process, so experimental test loops and plant data are very important in research efforts. Several activity transport modelling attempts have been made to improve the water chemistry control and to minimise corrosion in PWR`s. In this research report some of these models are reviewed with special emphasis on models designed for Soviet VVER type reactors. (51 refs., 16 figs., 4 tabs.).

  3. Androgen regulated genes in human prostate xenografts in mice: relation to BPH and prostate cancer.

    Directory of Open Access Journals (Sweden)

    Harold D Love

    2009-12-01

    Full Text Available Benign prostatic hyperplasia (BPH and prostate carcinoma (CaP are linked to aging and the presence of androgens, suggesting that androgen regulated genes play a major role in these common diseases. Androgen regulation of prostate growth and development depends on the presence of intact epithelial-stromal interactions. Further, the prostatic stroma is implicated in BPH. This suggests that epithelial cell lines are inadequate to identify androgen regulated genes that could contribute to BPH and CaP and which could serve as potential clinical biomarkers. In this study, we used a human prostate xenograft model to define a profile of genes regulated in vivo by androgens, with an emphasis on identifying candidate biomarkers. Benign transition zone (TZ human prostate tissue from radical prostatectomies was grafted to the sub-renal capsule site of intact or castrated male immunodeficient mice, followed by the removal or addition of androgens, respectively. Microarray analysis of RNA from these tissues was used to identify genes that were; 1 highly expressed in prostate, 2 had significant expression changes in response to androgens, and, 3 encode extracellular proteins. A total of 95 genes meeting these criteria were selected for analysis and validation of expression in patient prostate tissues using quantitative real-time PCR. Expression levels of these genes were measured in pooled RNAs from human prostate tissues with varying severity of BPH pathologic changes and CaP of varying Gleason score. A number of androgen regulated genes were identified. Additionally, a subset of these genes were over-expressed in RNA from clinical BPH tissues, and the levels of many were found to correlate with disease status. Our results demonstrate the feasibility, and some of the problems, of using a mouse xenograft model to characterize the androgen regulated expression profiles of intact human prostate tissues.

  4. Thermal modeling of radiation and convection sections of primary reformer of ammonia plant

    International Nuclear Information System (INIS)

    Sanaye, Sepehr; Baheri, Ehsan

    2007-01-01

    The primary reformer is basically a furnace containing burners and tubes packed with supported nickel catalyst. Due to the strongly endothermic nature of the process, a large amount of heat is supplied by fuel burning (commonly natural gas) in the furnace chamber. Accordingly, selection of primary reformer operating parameters has an important influence on reduction of operating costs and increasing the reactor performance (conversion efficiency). In this paper, the radiation and convection sections of primary reformer are investigated. The effects of key parameters on reformer performance are studied and the related developed software program is presented. The stirred-reactor furnace model which was used to simulate the radiation section of primary reformer was found to make substantially correct predictions of the overall heat transfer process in the furnace. Comparison of the numerical data obtained from the simulation program with the measured data collected from primary reformer of Razi petrochemical plant showed a mean difference of 0.23% in estimating produced hydrogen mole fraction, as well as 1.7% and 7.25% in computing the outlet temperature of process fluids and induced draft fan (ID) speed, respectively

  5. Primary Cilia in the Murine Cerebellum and in Mutant Models of Medulloblastoma.

    Science.gov (United States)

    Di Pietro, Chiara; Marazziti, Daniela; La Sala, Gina; Abbaszadeh, Zeinab; Golini, Elisabetta; Matteoni, Rafaele; Tocchini-Valentini, Glauco P

    2017-01-01

    Cellular primary cilia crucially sense and transduce extracellular physicochemical stimuli. Cilium-mediated developmental signaling is tissue and cell type specific. Primary cilia are required for cerebellar differentiation and sonic hedgehog (Shh)-dependent proliferation of neuronal granule precursors. The mammalian G-protein-coupled receptor 37-like 1 is specifically expressed in cerebellar Bergmann glia astrocytes and participates in regulating postnatal cerebellar granule neuron proliferation/differentiation and Bergmann glia and Purkinje neuron maturation. The mouse receptor protein interacts with the patched 1 component of the cilium-associated Shh receptor complex. Mice heterozygous for patched homolog 1 mutations, like heterozygous patched 1 humans, have a higher incidence of Shh subgroup medulloblastoma (MB) and other tumors. Cerebellar cells bearing primary cilia were identified during postnatal development and in adulthood in two mouse strains with altered Shh signaling: a G-protein-coupled receptor 37-like 1 null mutant and an MB-susceptible, heterozygous patched homolog 1 mutant. In addition to granule and Purkinje neurons, primary cilia were also expressed by Bergmann glia astrocytes in both wild-type and mutant animals, from birth to adulthood. Variations in ciliary number and length were related to the different levels of neuronal and glial cell proliferation and maturation, during postnatal cerebellar development. Primary cilia were also detected in pre-neoplastic MB lesions in heterozygous patched homolog 1 mutant mice and they could represent specific markers for the development and analysis of novel cerebellar oncogenic models.

  6. Doxorubicin increases the effectiveness of Apo2L/TRAIL for tumor growth inhibition of prostate cancer xenografts

    International Nuclear Information System (INIS)

    El-Zawahry, Ahmed; McKillop, John; Voelkel-Johnson, Christina

    2005-01-01

    Prostate cancer is a significant health problem among American men. Treatment strategies for androgen-independent cancer are currently not available. Tumor necrosis factor-related apoptosis-inducing ligand (Apo2L/TRAIL) is a death receptor ligand that can induce apoptosis in a variety of cancer cell lines, including androgen-independent PC3 prostate carcinoma cells. In vitro, TRAIL-mediated apoptosis of prostate cancer cell lines can be enhanced by doxorubicin and correlates with the downregulation of the anti-apoptotic protein c-FLIP. This study evaluated the effects of doxorubicin on c-FLIP expression and tumor growth in combination with Apo2L/TRAIL in a xenograft model. In vitro cytotoxic effects of TRAIL were measured using a MTS-based viability assay. For in vivo studies, PC3 prostate carcinoma cells were grown subcutaneously in athymic nude mice and tumor growth was measured following treatment with doxorubicin and/or Apo2L/TRAIL. c-FLIP expression was determined by western blot analysis. Apoptosis in xenografts was detected using TUNEL. Statistical analysis was performed using the student t-test. In vitro experiments show that PC3 cells are partially susceptible to Apo2L/TRAIL and that susceptibility is enhanced by doxorubicin. In mice, doxorubicin did not significantly affect the growth of PC3 xenografts but reduced c-FLIP expression in tumors. Expression of c-FLIP in mouse heart was decreased only at the high doxorubicin concentration (8 mg/kg). Combination of doxorubicin with Apo2L/TRAIL resulted in more apoptotic cell death and tumor growth inhibition than Apo2L/TRAIL alone. Combination of doxorubicin and Apo2L/TRAIL is more effective in growth inhibition of PC3 xenografts in vivo than either agent alone and could present a novel treatment strategy against hormone-refractory prostate cancer. The intracellular mechanism by which doxorubicin enhances the effect of Apo2L/TRAIL on PC3 xenografts may be by reducing expression of c-FLIP

  7. Reversal of multidrug resistance by magnetic Fe3O4 nanoparticle copolymerizating daunorubicin and 5-bromotetrandrine in xenograft nude-mice.

    Science.gov (United States)

    Chen, Baoan; Cheng, Jian; Wu, Yanan; Gao, Feng; Xu, Wenlin; Shen, Huilin; Ding, Jiahua; Gao, Chong; Sun, Qian; Sun, Xinchen; Cheng, Hongyan; Li, Guohong; Chen, Wenji; Chen, Ningna; Liu, Lijie; Li, Xiaomao; Wang, Xuemei

    2009-01-01

    In this paper we establish the xenograft leukemia model with stable multidrug resistance in nude mice and to investigate the reversal effect of 5-bromotetrandrine (5-BrTet) and magnetic nanoparticle of Fe(3)O(4) (MNP-Fe(3)O(4)) combined with daunorubicin (DNR) in vivo. Two subclones of K562 and K562/A02 cells were inoculated subcutaneously into the back of athymic nude mice (1 x 10(7) cells/each) respectively to establish leukemia xenograft models. Drug-resistant and sensitive tumor-bearing nude mice were assigned randomly into five groups which were treated with normal saline; DNR; NP-Fe(3)O(4) combined with DNR; 5-BrTet combined with DNR; 5-BrTet and MNP-Fe(3)O(4) combined with DNR, respectively. The incidence of formation, growth characteristics, weight, and volume of tumors were observed. The histopathologic examination of tumors and organs were detected. For resistant tumors, the protein levels of Bcl-2, and BAX were detected by Western blot. Bcl-2, BAX, and caspase-3 genes were also detected. For K562/A02 cells xenograft tumors, 5-BrTet and MNP-Fe(3)O(4) combined with DNR significantly suppressed growth of tumor. A histopathologic examination of tumors clearly showed necrosis of the tumors. Application of 5-BrTet and MNP-Fe(3)O(4) inhibited the expression of Bcl-2 protein and upregulated the expression of BAX and caspase-3 proteins in K562/A02 cells xenograft tumor. It is concluded that 5-BrTet and MNP-Fe(3)O(4) combined with DNR had a significant tumor-suppressing effect on a MDR leukemia cells xenograft model.

  8. Reversal of multidrug resistance in xenograft nude-mice by magnetic Fe(3)O(4) nanoparticles combined with daunorubicin and 5-bromotetrandrine.

    Science.gov (United States)

    Wu, Ya-Nan; Chen, Bao-An; Cheng, Jian; Gao, Feng; Xu, Wen-Lin; Ding, Jia-Hua; Gao, Chong; Sun, Xin-Chen; Li, Guo-Hong; Chen, Wen-Ji; Liu, Li-Jie; Li, Xiao-Mao; Wang, Xue-Mei

    2009-02-01

    This study was aimed to investigate the reversal effect of 5-bromotetrandrine (5-BrTet) and magnetic nanoparticle of Fe(3)O(4) (Fe(3)O(4)-MNPs) combined with DNR in vivo. The xenograft leukemia model with stable multiple drug resistance in nude mice was established. The two sub-clones of K562 and K562/A02 cells were respectively inoculated subcutaneously into back of athymic nude mice (1 x 10(7) cells/each) to establish the leukemia xenograft models. Drug resistant and the sensitive tumor-bearing nude mice were both assigned randomly into 5 groups: group A was treated with NS; group B was treated with DNR; group C was treated with nanoparticle of Fe(3)O(4) combined with DNR; group D was treated with 5-BrTet combined with DNR; group E was treated with 5-bromotetrandrine and magnetic nanoparticle of Fe(3)O(4) combined with DNR. The incidence of tumor formation, growth characteristics, weight and volume of tumor were observed. The histopathologic examination of tumors and organs were carried out. The protein levels of BCL-2, BAX, and Caspase-3 in resistant tumors were detected by Western blot. The results indicated that 5-BrTet and magnetic nanoparticle of Fe(3)O(4) combined with DNR significantly suppressed growth of K562/A02 cell xenograft tumor, histopathologic examination of tumors showed the tumors necrosis obviously. Application of 5-BrTet and magnetic nanoparticle of Fe(3)O(4) inhibited the expression of BCL-2 protein and up-regulated the expression of BAX, and Caspase-3 protein in K562/A02 cell xenograft tumor. It is concluded that 5-bromotetrandrine and magnetic nanoparticle of Fe(3)O(4) combined with DNR have significant tumor-suppressing effect on MDR leukemia cell xenograft model.

  9. Estimating Net Primary Production of Swedish Forest Landscapes by Combining Mechanistic Modeling and Remote Sensing

    DEFF Research Database (Denmark)

    Tagesson, Håkan Torbern; Smith, Benjamin; Løfgren, Anders

    2009-01-01

    and the Beer-Lambert law. LAI estimates were compared with satellite-extrapolated field estimates of LAI, and the results were generally acceptable. NPP estimates directly from the dynamic vegetation model and estimates obtained by combining the model estimates with remote sensing information were, on average......The aim of this study was to investigate a combination of satellite images of leaf area index (LAI) with processbased vegetation modeling for the accurate assessment of the carbon balances of Swedish forest ecosystems at the scale of a landscape. Monthly climatologic data were used as inputs...... in a dynamic vegetation model, the Lund Potsdam Jena-General Ecosystem Simulator. Model estimates of net primary production (NPP) and the fraction of absorbed photosynthetic active radiation were constrained by combining them with satellite-based LAI images using a general light use efficiency (LUE) model...

  10. Mathematical modeling of atmospheric fine particle-associated primary organic compound concentrations

    Science.gov (United States)

    Rogge, Wolfgang F.; Hildemann, Lynn M.; Mazurek, Monica A.; Cass, Glen R.; Simoneit, Bernd R. T.

    1996-08-01

    An atmospheric transport model has been used to explore the relationship between source emissions and ambient air quality for individual particle phase organic compounds present in primary aerosol source emissions. An inventory of fine particulate organic compound emissions was assembled for the Los Angeles area in the year 1982. Sources characterized included noncatalyst- and catalyst-equipped autos, diesel trucks, paved road dust, tire wear, brake lining dust, meat cooking operations, industrial oil-fired boilers, roofing tar pots, natural gas combustion in residential homes, cigarette smoke, fireplaces burning oak and pine wood, and plant leaf abrasion products. These primary fine particle source emissions were supplied to a computer-based model that simulates atmospheric transport, dispersion, and dry deposition based on the time series of hourly wind observations and mixing depths. Monthly average fine particle organic compound concentrations that would prevail if the primary organic aerosol were transported without chemical reaction were computed for more than 100 organic compounds within an 80 km × 80 km modeling area centered over Los Angeles. The monthly average compound concentrations predicted by the transport model were compared to atmospheric measurements made at monitoring sites within the study area during 1982. The predicted seasonal variation and absolute values of the concentrations of the more stable compounds are found to be in reasonable agreement with the ambient observations. While model predictions for the higher molecular weight polycyclic aromatic hydrocarbons (PAH) are in agreement with ambient observations, lower molecular weight PAH show much higher predicted than measured atmospheric concentrations in the particle phase, indicating atmospheric decay by chemical reactions or evaporation from the particle phase. The atmospheric concentrations of dicarboxylic acids and aromatic polycarboxylic acids greatly exceed the contributions that

  11. Instructional Technology and School Ethos: A Primary School Model in Southwest England

    Directory of Open Access Journals (Sweden)

    Erik Jon Byker

    2014-04-01

    Full Text Available The way in which information and communication technology (ICT enhances the dimensions of teaching and student learning is not well understood. As a result, schools and teacher often integrate ICT with little thought to how it could be educationally profitable or pedagogically meaningful. The literature calls for models of primary school ICT integration. This paper reports on a case study of a primary school (or elementary school model of technology integration. Specifically, the case study investigates a public, primary school located in rural Southwest England. In particular, the paper describes how ICT is integrated in a Grade Six classroom in this primary school. Using a mixed-methods research methodology, the study’s data is drawn from 60 participants (n=60, including the school’s teachers and students. The analyses of this study uncovered a strong link between successful ICT integration and school ethos. Furthermore, the study found that along with school ethos the teacher leadership fostered an environment where the integration of ICT can flourish and students are motivated to learn.

  12. Unmasking feigned sanity: a neurobiological model of emotion processing in primary psychopathy.

    Science.gov (United States)

    van Honk, Jack; Schutter, Dennis J L G

    2006-05-01

    The neurobiological basis of primary psychopathy, an emotional disorder characterised by a lack of fear and empathy, on the one hand, and extremely violent, antisocial tendencies, on the other, is relatively unknown. Nevertheless, theoretical models that emphasise the role of fearlessness, imbalanced motivation, defective somatic markers, and dysfunctional violence inhibition mechanisms have complementary proposals regarding motivations and brain mechanisms involved. Presently, incorporating the heuristic value of these models and further theorising on the basis of recent data from neuropsychology, neuroendocrinology, neuroimaging, and repetitive transcranial magnetic stimulation (rTMS), an attempt is made to construct a neurobiological framework of emotion processing in primary psychopathy with clinical applicability. According to this framework, defective emotional processing in primary psychopathy results from bottom-up hormone-mediated imbalances at: (1) the subcortical level; (2) in subcortico-cortical "cross-talk"; that end up in an instrumental stance at the cortical level (3). An endocrine dual-system approach for the fine-tuned restoration of these hormone-mediated imbalances is proposed as a possible clinical application. This application may be capable of laying a neurobiological foundation for more successful sociotherapeutic interventions in primary psychopathy.

  13. Modeling strategy to identify patients with primary immunodeficiency utilizing risk management and outcome measurement.

    Science.gov (United States)

    Modell, Vicki; Quinn, Jessica; Ginsberg, Grant; Gladue, Ron; Orange, Jordan; Modell, Fred

    2017-06-01

    This study seeks to generate analytic insights into risk management and probability of an identifiable primary immunodeficiency defect. The Jeffrey Modell Centers Network database, Jeffrey Modell Foundation's 10 Warning Signs, the 4 Stages of Testing Algorithm, physician-reported clinical outcomes, programs of physician education and public awareness, the SPIRIT® Analyzer, and newborn screening, taken together, generates P values of less than 0.05%. This indicates that the data results do not occur by chance, and that there is a better than 95% probability that the data are valid. The objectives are to improve patients' quality of life, while generating significant reduction of costs. The advances of the world's experts aligned with these JMF programs can generate analytic insights as to risk management and probability of an identifiable primary immunodeficiency defect. This strategy reduces the uncertainties related to primary immunodeficiency risks, as we can screen, test, identify, and treat undiagnosed patients. We can also address regional differences and prevalence, age, gender, treatment modalities, and sites of care, as well as economic benefits. These tools support high net benefits, substantial financial savings, and significant reduction of costs. All stakeholders, including patients, clinicians, pharmaceutical companies, third party payers, and government healthcare agencies, must address the earliest possible precise diagnosis, appropriate intervention and treatment, as well as stringent control of healthcare costs through risk assessment and outcome measurement. An affected patient is entitled to nothing less, and stakeholders are responsible to utilize tools currently available. Implementation offers a significant challenge to the entire primary immunodeficiency community.

  14. [Family Health Teams in Ontario: Ideas for Germany from a Canadian Primary Care Model].

    Science.gov (United States)

    Ulrich, Lisa-R; Pham, Thuy-Nga Tia; Gerlach, Ferdinand M; Erler, Antje

    2017-07-11

    The German healthcare system is struggling with fragmentation of care in the face of an increasing shortage of general practitioners and allied health professionals, and the time-demanding healthcare needs of an aging, multimorbid patient population. Innovative interprofessional, intersectoral models of care are required to ensure adequate access to primary care across a variety of rural and urban settings into the foreseeable future. A team approach to care of the complex multimorbid patient population appears particularly suitable in attracting and retaining the next generation of healthcare professionals, including general practitioners. In 2014, the German Advisory Council on the Assessment of Developments in the Health Care System highlighted the importance of regional, integrated care with community-based primary care centres at its core, providing comprehensive, population-based, patient-centred primary care with adequate access to general practitioners for a given geographical area. Such centres exist already in Ontario, Canada; within Family Health Teams (FHT), family physicians work hand-in-hand with pharmacists, nurses, nurse practitioners, social workers, and other allied health professionals. In this article, the Canadian model of FHT will be introduced and we will discuss which components could be adapted to suit the German primary care system. © Georg Thieme Verlag KG Stuttgart · New York.

  15. Modelling in Primary School: Constructing Conceptual Models and Making Sense of Fractions

    Science.gov (United States)

    Shahbari, Juhaina Awawdeh; Peled, Irit

    2017-01-01

    This article describes sixth-grade students' engagement in two model-eliciting activities offering students the opportunity to construct mathematical models. The findings show that students utilized their knowledge of fractions including conceptual and procedural knowledge in constructing mathematical models for the given situations. Some students…

  16. Interprofessional practice in primary care: development of a tailored process model

    Directory of Open Access Journals (Sweden)

    Stans SEA

    2013-04-01

    Full Text Available Steffy EA Stans, JG Anita Stevens, Anna JHM Beurskens Research Center of Autonomy and Participation for Persons with a Chronic Illness, Zuyd University of Applied Sciences, Heerlen, The Netherlands Purpose: This study investigated the improvement of interprofessional practice in primary care by performing the first three steps of the implementation model described by Grol et al. This article describes the targets for improvement in a setting for children with complex care needs (step 1, the identification of barriers and facilitators influencing interprofessional practice (step 2, and the development of a tailored interprofessional process model (step 3. Methods: In step 2, thirteen qualitative semistructured interviews were held with several stakeholders, including parents of children, an occupational therapist, a speech and language therapist, a physical therapist, the manager of the team, two general practitioners, a psychologist, and a primary school teacher. The data were analyzed using directed content analysis and using the domains of the Chronic Care Model as a framework. In step 3, a project group was formed to develop helpful strategies, including the development of an interprofessional process through process mapping. Results: In step 2, it was found that the most important barriers to implementing interprofessional practice related to the lack of structure in the care process. A process model for interprofessional primary care was developed for the target group. Conclusion: The lack of a shared view of what is involved in the process of interprofessional practice was the most important barrier to its successful implementation. It is suggested that the tailored process developed, supported with the appropriate tools, may provide both professional staff and their clients, in this setting but also in other areas of primary care, with insight to the care process and a clear representation of "who should do what, when, and how." Keywords

  17. A comprehensive model for intimate partner violence in South African primary care: action research

    Directory of Open Access Journals (Sweden)

    Joyner Kate

    2012-11-01

    Full Text Available Abstract Background Despite extensive evidence on the magnitude of intimate partner violence (IPV as a public health problem worldwide, insubstantial progress has been made in the development and implementation of sufficiently comprehensive health services. This study aimed to implement, evaluate and adapt a published protocol for the screening and management of IPV and to recommend a model of care that could be taken to scale in our underdeveloped South African primary health care system. Methods Professional action research utilised a co-operative inquiry group that consisted of four nurses, one doctor and a qualitative researcher. The inquiry group implemented the protocol in two urban and three rural primary care facilities. Over a period of 14 months the group reflected on their experience, modified the protocol and developed recommendations on a practical but comprehensive model of care. Results The original protocol had to be adapted in terms of its expectations of the primary care providers, overly forensic orientation, lack of depth in terms of mental health, validity of the danger assessment and safety planning process, and need for ongoing empowerment and support. A three-tier model resulted: case finding and clinical care provision by primary care providers; psychological, social and legal assistance by ‘IPV champions’ followed by a group empowerment process; and then ongoing community-based support groups. Conclusion The inquiry process led to a model of comprehensive and intersectoral care that is integrated at the facility level and which is now being piloted in the Western Cape, South Africa.

  18. Evaluation of bone loss due to primary occlusal trauma in two experimental models of occlusal overload

    OpenAIRE

    LOPES, Ana Cristina Távora de Albuquerque; TÉO, Mirela Anne Quartaroli; CORRÊA, Mônica Grazieli; ISHIKIRIAMA, Bella Luna Colombini; CAMPOS, Mirella Lindoso Gomes

    2016-01-01

    Abstract Introduction Primary occlusal trauma (OT) is an injury of the periodontium with normal height as a result of occlusal forces which exceed their adaptive capacity. Objective To evaluate, histometrically, the alveolar bone loss in the furcation region of rats experimentally submitted to 2 models of occlusal overload. Material and method 45 animals randomly divided into 3 groups: Occlusal Interference (OI, n = 15) - fixing an orthodontic wire segment on the occlusal surface of the fi...

  19. Cost-effectiveness of screening for HIV in primary care: a health economics modelling analysis

    OpenAIRE

    Baggaley, R. F.; Irvine, M. A.; Leber, W.; Cambiano, V.; Figueroa, J.; McMullen, H.; Anderson, J.; Santos, A. C.; Terris-Prestholt, F.; Miners, A.; Hollingsworth, T. D.; Griffiths, C. J.

    2017-01-01

    BACKGROUND: Early HIV diagnosis reduces morbidity, mortality, the probability of onward transmission, and their associated costs, but might increase cost because of earlier initiation of antiretroviral treatment (ART). We investigated this trade-off by estimating the cost-effectiveness of HIV screening in primary care. METHODS: We modelled the effect of the four-times higher diagnosis rate observed in the intervention arm of the RHIVA2 randomised controlled trial done in Hackney, London (UK),...

  20. Cost-effectiveness of screening for HIV in primary care: a health economics modelling analysis

    OpenAIRE

    Baggaley, Rebecca F; Irvine, Michael A; Leber, Werner; Cambiano, Valentina; Figueroa, Jose; McMullen, Heather; Anderson, Jane; Santos, Andreia C; Terris-Prestholt, Fern; Miners, Alec; Hollingsworth, T Déirdre; Griffiths, Chris J

    2017-01-01

    Summary Background Early HIV diagnosis reduces morbidity, mortality, the probability of onward transmission, and their associated costs, but might increase cost because of earlier initiation of antiretroviral treatment (ART). We investigated this trade-off by estimating the cost-effectiveness of HIV screening in primary care. Methods We modelled the effect of the four-times higher diagnosis rate observed in the intervention arm of the RHIVA2 randomised controlled trial done in Hackney, London...

  1. Spatial extrapolation of light use efficiency model parameters to predict gross primary production

    Directory of Open Access Journals (Sweden)

    Karsten Schulz

    2011-12-01

    Full Text Available To capture the spatial and temporal variability of the gross primary production as a key component of the global carbon cycle, the light use efficiency modeling approach in combination with remote sensing data has shown to be well suited. Typically, the model parameters, such as the maximum light use efficiency, are either set to a universal constant or to land class dependent values stored in look-up tables. In this study, we employ the machine learning technique support vector regression to explicitly relate the model parameters of a light use efficiency model calibrated at several FLUXNET sites to site-specific characteristics obtained by meteorological measurements, ecological estimations and remote sensing data. A feature selection algorithm extracts the relevant site characteristics in a cross-validation, and leads to an individual set of characteristic attributes for each parameter. With this set of attributes, the model parameters can be estimated at sites where a parameter calibration is not possible due to the absence of eddy covariance flux measurement data. This will finally allow a spatially continuous model application. The performance of the spatial extrapolation scheme is evaluated with a cross-validation approach, which shows the methodology to be well suited to recapture the variability of gross primary production across the study sites.

  2. A mathematical model of a lithium/thionyl chloride primary cell

    Science.gov (United States)

    Evans, T. I.; Nguyen, T. V.; White, R. E.

    1987-08-01

    A 1-D mathematical model for the lithium/thionyl chloride primary cell was developed to investigate methods of improving its performance and safety. The model includes many of the components of a typical lithium/thionyl chloride cell such as the porous lithium chloride film which forms on the lithium anode surface. The governing equations are formulated from fundamental conservation laws using porous electrode theory and concentrated solution theory. The model is used to predict 1-D, time dependent profiles of concentration, porosity, current, and potential as well as cell temperature and voltage. When a certain discharge rate is required, the model can be used to determine the design criteria and operating variables which yield high cell capacities. Model predictions can be used to establish operational and design limits within which the thermal runaway problem, inherent in these cells, can be avoided.

  3. Immunological considerations of modern animal models of malignant primary brain tumors

    Directory of Open Access Journals (Sweden)

    James C David

    2009-10-01

    Full Text Available Abstract Recent advances in animal models of glioma have facilitated a better understanding of biological mechanisms underlying gliomagenesis and glioma progression. The limitations of existing therapy, including surgery, chemotherapy, and radiotherapy, have prompted numerous investigators to search for new therapeutic approaches to improve quantity and quality of survival from these aggressive lesions. One of these approaches involves triggering a tumor specific immune response. However, a difficulty in this approach is the the scarcity of animal models of primary CNS neoplasms which faithfully recapitulate these tumors and their interaction with the host's immune system. In this article, we review the existing methods utilized to date for modeling gliomas in rodents, with a focus on the known as well as potential immunological aspects of these models. As this review demonstrates, many of these models have inherent immune system limitations, and the impact of these limitations on studies on the influence of pre-clinical therapeutics testing warrants further attention.

  4. Facilitators and barriers of implementing the chronic care model in primary care: a systematic review.

    Science.gov (United States)

    Kadu, Mudathira K; Stolee, Paul

    2015-02-06

    The Chronic Care Model (CCM) is a framework developed to redesign care delivery for individuals living with chronic diseases in primary care. The CCM and its various components have been widely adopted and evaluated, however, little is known about different primary care experiences with its implementation, and the factors that influence its successful uptake. The purpose of this review is to synthesize findings of studies that implemented the CCM in primary care, in order to identify facilitators and barriers encountered during implementation. This study identified English-language, peer-reviewed research articles, describing the CCM in primary care settings. Searches were performed in three data bases: Web of Knowledge, Pubmed and Scopus. Article abstracts and titles were read based on whether they met the following inclusion criteria: 1) studies published after 2003 that described or evaluated the implementation of the CCM; 2) the care setting was primary care; 3) the target population of the study was adults over the age of 18 with chronic conditions. Studies were categorized by reference, study design and methods, participants and setting, study objective, CCM components used, and description of the intervention. The next stage of data abstraction involved qualitative analysis of cited barriers and facilitators using the Consolidating Framework for Research Implementation. This review identified barriers and facilitators of implementation across various primary care settings in 22 studies. The major emerging themes were those related to the inner setting of the organization, the process of implementation and characteristics of the individual healthcare providers. These included: organizational culture, its structural characteristics, networks and communication, implementation climate and readiness, presence of supportive leadership, and provider attitudes and beliefs. These findings highlight the importance of assessing organizational capacity and needs prior

  5. A multiprofessional information model for Brazilian primary care: Defining a consensus model towards an interoperable electronic health record.

    Science.gov (United States)

    Braga, Renata Dutra

    2016-06-01

    To develop a multiprofessional information model to be used in the decision-making process in primary care in Brazil. This was an observational study with a descriptive and exploratory approach, using action research associated with the Delphi method. A group of 13 health professionals made up a panel of experts that, through individual and group meetings, drew up a preliminary health information records model. The questionnaire used to validate this model included four questions based on a Likert scale. These questions evaluated the completeness and relevance of information on each of the four pillars that composed the model. The changes suggested in each round of evaluation were included when accepted by the majority (≥ 50%). This process was repeated as many times as necessary to obtain the desirable and recommended consensus level (> 50%), and the final version became the consensus model. Multidisciplinary health training of the panel of experts allowed a consensus model to be obtained based on four categories of health information, called pillars: Data Collection, Diagnosis, Care Plan and Evaluation. The obtained consensus model was considered valid by the experts and can contribute to the collection and recording of multidisciplinary information in primary care, as well as the identification of relevant concepts for defining electronic health records at this level of complexity in health care. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  6. Model for Physical Education Content Standards at Early Stages of Primary Education in the Republic of Macedonia

    OpenAIRE

    Klincarov, Ilija; Popeska, Biljana

    2011-01-01

    The aim of this article is to propose a model for designing national physical education content standards in early stages of primary education in the Republic of Macedonia. Proposed model is based on the findings about motor structure of children at the early stage of primary education obtained in researches realized in 5 primary schools in Skopje, the Republic of Macedonia, in relation with Macedonian PE curriculum, and overarching standards for children at this age in California, USA,chosen...

  7. Academic retainer medicine: an innovative business model for cross-subsidizing primary care.

    Science.gov (United States)

    Lucier, David J; Frisch, Nicholas B; Cohen, Brian J; Wagner, Michael; Salem, Deeb; Fairchild, David G

    2010-06-01

    Retainer-medicine primary care practices, commonly referred to as "luxury" or "concierge" practices, provide enhanced services to patients beyond those available in traditional practices for a yearly retainer fee. Adoption of retainer practices has been largely absent in academic health centers (AHCs). Reasons for this trend stem primarily from ethical concerns, such as the potential for patient abandonment when physicians downsize from larger, traditional practices to smaller, retainer-medicine practices.In 2004, the Department of Medicine at Tufts Medical Center developed an academic retainer-medicine primary care practice within the Division of General Medicine that not only generates financial support for the division but also incorporates a clinical and business model that is aligned with the mission and ethics of an academic institution.In contrast to private retainer-medicine practices, this unique business model addresses several of the ethical issues associated with traditional retainer practices-it does not restrict net access to care and it neutralizes concerns about patient abandonment. Addressing the growing primary care shortage, the model also presents the opportunity for a retainer practice to cross-subsidize the expansion of general medicine in an academic medical setting. The authors elucidate the benefits, as well as the inherent challenges, of embedding an academic retainer-medicine practice within an AHC.

  8. Effect of bevacizumab on angiogenesis and growth of canine osteosarcoma cells xenografted in athymic mice.

    Science.gov (United States)

    Scharf, Valery F; Farese, James P; Coomer, Alastair R; Milner, Rowan J; Taylor, David P; Salute, Marc E; Chang, Myron N; Neal, Dan; Siemann, Dietmar W

    2013-05-01

    Objective-To investigate the effects of bevacizumab, a human monoclonal antibody against vascular endothelial growth factor, on the angiogenesis and growth of canine osteosarcoma cells xenografted in mice. Animals-27 athymic nude mice. Procedures-To each mouse, highly metastasizing parent osteosarcoma cells of canine origin were injected into the left gastrocnemius muscle. Each mouse was then randomly allocated to 1 of 3 treatment groups: high-dose bevacizumab (4 mg/kg, IP), low-dose bevacizumab (2 mg/kg, IP), or control (no treatment). Tumor growth (the number of days required for the tumor to grow from 8 to 13 mm), vasculature, histomorphology, necrosis, and pulmonary metastasis were evaluated. Results-Mice in the high-dose bevacizumab group had significantly delayed tumor growth (mean ± SD, 13.4 ± 3.8 days; range, 9 to 21 days), compared with that for mice in the low-dose bevacizumab group (mean ± SD, 9.4 ± 1.5 days; range, 7 to 11 days) or control group (mean ± SD, 7. 2 ± 1.5 days; range, 4 to 9 days). Mice in the low-dose bevacizumab group also had significantly delayed tumor growth, compared with that for mice in the control group. Conclusions and Clinical Relevance-Results indicated that bevacizumab inhibited growth of canine osteosarcoma cells xenografted in mice, which suggested that vascular endothelial growth factor inhibitors may be clinically useful for the treatment of osteosarcoma in dogs. Impact for Human Medicine-Canine osteosarcoma is used as a research model for human osteosarcoma; therefore, bevacizumab may be clinically beneficial for the treatment of osteosarcoma in humans.

  9. Computer model predicting breakthrough febrile urinary tract infection in children with primary vesicoureteral reflux.

    Science.gov (United States)

    Arlen, Angela M; Alexander, Siobhan E; Wald, Moshe; Cooper, Christopher S

    2016-10-01

    Factors influencing the decision to surgically correct vesicoureteral reflux (VUR) include risk of breakthrough febrile urinary tract infection (fUTI) or renal scarring, and decreased likelihood of spontaneous resolution. Improved identification of children at risk for recurrent fUTI may impact management decisions, and allow for more individualized VUR management. We have developed and investigated the accuracy of a multivariable computational model to predict probability of breakthrough fUTI in children with primary VUR. Children with primary VUR and detailed clinical and voiding cystourethrogram (VCUG) data were identified. Patient demographics, VCUG findings including grade, laterality, and bladder volume at onset of VUR, UTI history, presence of bladder-bowel dysfunction (BBD), and breakthrough fUTI were assessed. The VCUG dataset was randomized into a training set of 288 with a separate representational cross-validation set of 96. Various model types and architectures were investigated using neUROn++, a set of C++ programs. Two hundred fifty-five children (208 girls, 47 boys) diagnosed with primary VUR at a mean age of 3.1 years (±2.6) met all inclusion criteria. A total 384 VCUGs were analyzed. Median follow-up was 24 months (interquartile range 12-52 months). Sixty-eight children (26.7%) experienced 90 breakthrough fUTI events. Dilating VUR, reflux occurring at low bladder volumes, BBD, and history of multiple infections/fUTI were associated with breakthrough fUTI (Table). A 2-hidden node neural network model had the best fit with a receiver operating characteristic curve area of 0.755 for predicting breakthrough fUTI. The risk of recurrent febrile infections, renal parenchymal scarring, and likelihood of spontaneous resolution, as well as parental preference all influence management of primary VUR. The genesis of UTI is multifactorial, making precise prediction of an individual child's risk of breakthrough fUTI challenging. Demonstrated risk factors for

  10. Dose rates modeling of pressurized water reactor primary loop components with SCALE6.0

    International Nuclear Information System (INIS)

    Matijević, Mario; Pevec, Dubravko; Trontl, Krešimir

    2015-01-01

    Highlights: • Shielding analysis of the typical PWR primary loop components was performed. • FW-CADIS methodology was thoroughly investigated using SCALE6.0 code package. • Versatile ability of SCALE6.0/FW-CADIS for deep penetration models was proved. • The adjoint source with focus on specific material can improve MC modeling. - Abstract: The SCALE6.0 simulation model of a typical PWR primary loop components for effective dose rates calculation based on hybrid deterministic–stochastic methodology was created. The criticality sequence CSAS6/KENO-VI of the SCALE6.0 code package, which includes KENO-VI Monte Carlo code, was used for criticality calculations, while neutron and gamma dose rates distributions were determined by MAVRIC/Monaco shielding sequence. A detailed model of a combinatorial geometry, materials and characteristics of a generic two loop PWR facility is based on best available input data. The sources of ionizing radiation in PWR primary loop components included neutrons and photons originating from critical core and photons from activated coolant in two primary loops. Detailed calculations of the reactor pressure vessel and the upper reactor head have been performed. The efficiency of particle transport for obtaining global Monte Carlo dose rates was further examined and quantified with a flexible adjoint source positioning in phase-space. It was demonstrated that generation of an accurate importance map (VR parameters) is a paramount step which enabled obtaining Monaco dose rates with fairly uniform uncertainties. Computer memory consumption by the S N part of hybrid methodology represents main obstacle when using meshes with large number of cells together with high S N /P N parameters. Detailed voxelization (homogenization) process in Denovo together with high S N /P N parameters is essential for precise VR parameters generation which will result in optimized MC distributions. Shielding calculations were also performed for the reduced PWR

  11. An Innovative Model of Professional Development to Enhance the Teaching and Learning of Primary Science in Irish Schools

    Science.gov (United States)

    Smith, Greg

    2014-01-01

    This study investigates the influence of a two-year professional development programme on primary teachers' attitudes towards primary science, their confidence and competence in teaching science, and pupils' attitudes towards school science. Unlike the traditional "one-size-fits all" model of professional development, the model developed…

  12. Information processing occurs via critical avalanches in a model of the primary visual cortex

    International Nuclear Information System (INIS)

    Bortolotto, G. S.; Girardi-Schappo, M.; Gonsalves, J. J.; Tragtenberg, M. H. R.; Pinto, L. T.

    2016-01-01

    We study a new biologically motivated model for the Macaque monkey primary visual cortex which presents power-law avalanches after a visual stimulus. The signal propagates through all the layers of the model via avalanches that depend on network structure and synaptic parameter. We identify four different avalanche profiles as a function of the excitatory postsynaptic potential. The avalanches follow a size-duration scaling relation and present critical exponents that match experiments. The structure of the network gives rise to a regime of two characteristic spatial scales, one of which vanishes in the thermodynamic limit. (paper)

  13. Primary Cilia Negatively Regulate Melanogenesis in Melanocytes and Pigmentation in a Human Skin Model.

    Science.gov (United States)

    Choi, Hyunjung; Shin, Ji Hyun; Kim, Eun Sung; Park, So Jung; Bae, Il-Hong; Jo, Yoon Kyung; Jeong, In Young; Kim, Hyoung-June; Lee, Youngjin; Park, Hea Chul; Jeon, Hong Bae; Kim, Ki Woo; Lee, Tae Ryong; Cho, Dong-Hyung

    2016-01-01

    The primary cilium is an organelle protruding from the cell body that senses external stimuli including chemical, mechanical, light, osmotic, fluid flow, and gravitational signals. Skin is always exposed to the external environment and responds to external stimuli. Therefore, it is possible that primary cilia have an important role in skin. Ciliogenesis was reported to be involved in developmental processes in skin, such as keratinocyte differentiation and hair formation. However, the relation between skin pigmentation and primary cilia is largely unknown. Here, we observed that increased melanogenesis in melanocytes treated with a melanogenic inducer was inhibited by a ciliogenesis inducer, cytochalasin D, and serum-free culture. However, these inhibitory effects disappeared in GLI2 knockdown cells. In addition, activation of sonic hedgehog (SHH)-smoothened (Smo) signaling pathway by a Smo agonist, SAG inhibited melanin synthesis in melanocytes and pigmentation in a human skin model. On the contrary, an inhibitor of primary cilium formation, ciliobrevin A1, activated melanogenesis in melanocytes. These results suggest that skin pigmentation may be regulated partly by the induction of ciliogenesis through Smo-GLI2 signaling.

  14. Primary Cilia Negatively Regulate Melanogenesis in Melanocytes and Pigmentation in a Human Skin Model.

    Directory of Open Access Journals (Sweden)

    Hyunjung Choi

    Full Text Available The primary cilium is an organelle protruding from the cell body that senses external stimuli including chemical, mechanical, light, osmotic, fluid flow, and gravitational signals. Skin is always exposed to the external environment and responds to external stimuli. Therefore, it is possible that primary cilia have an important role in skin. Ciliogenesis was reported to be involved in developmental processes in skin, such as keratinocyte differentiation and hair formation. However, the relation between skin pigmentation and primary cilia is largely unknown. Here, we observed that increased melanogenesis in melanocytes treated with a melanogenic inducer was inhibited by a ciliogenesis inducer, cytochalasin D, and serum-free culture. However, these inhibitory effects disappeared in GLI2 knockdown cells. In addition, activation of sonic hedgehog (SHH-smoothened (Smo signaling pathway by a Smo agonist, SAG inhibited melanin synthesis in melanocytes and pigmentation in a human skin model. On the contrary, an inhibitor of primary cilium formation, ciliobrevin A1, activated melanogenesis in melanocytes. These results suggest that skin pigmentation may be regulated partly by the induction of ciliogenesis through Smo-GLI2 signaling.

  15. The use of lyophilised bovine bone xenograft in mandibular reconstructive surgery - an animal experimental surgery

    International Nuclear Information System (INIS)

    Samsudin, A.R.; Meor Kamal, M. Z.; Afifi Abu Bakar

    1999-01-01

    The aim of this study is to look at the effectiveness of using lyophillised bovine bone xenograft in mandibular reconstructive surgery. Six adult merino sheep underwent bilateral marginal block resection of the mandible under general anaesthesia. The defect on the right body of mandible was left alone while the similar mandibulectomy defect on the left body of mandible was reconstructed using a cortico-cancellous block of radiosterilised lyophillised bovine bone xenograft which was procured from a calve femur. The bone xenograft was fixed and immobilized using titanium mini plates and screws. All the sheep returned to the controlled grazing ground on the 7th. Postoperative day. One sheep was sacrificed every month and the mandible was retrieved for postmortem gross and microscopical histological examination. Clinical results showed no evidence of tissue rejection in the mandible of the sheep and all the wounds healed well. All sheep showed no problem with normal eating habits. Histological examination showed resorption of the xenograft very early at one month postoperative and xenograft resorption together with new host bone deposition started at 2 months postoperative and maximise at 6 months postoperative. There is also evidence showing that the cancellous portion resorp more than the cortical portion of the xenograft. In conclusion, cortico-cancellous blocks of bovine bone xenograft may be use in mandibular reconstructive surgery giving esthetically acceptable, functional, biocompatible and overall clinically predictable results

  16. [Expression of Jagged1 mRNA in human epithelial ovarian carcinoma tissues and effect of RNA interference of Jagged1 on growth of xenograft in nude mice].

    Science.gov (United States)

    Liu, G Y; Gao, Z H; Li, L; Song, T T; Sheng, X G

    2016-06-25

    To investigate the expression of Jagged1 in human epithelial ovarian carcinoma tissues and the effect of Jagged1 on growth of xenograft in nude mice. (1) Forty-eight cases of ovarian cancer and 30 cases of patients with benign epithelial ovarian tumor in the Henan Province Xinxiang Central Hospital during Feb. 2011 to Mar. 2014 were enrolled in this study. The mRNA expression of Jagged1, Notch1 and the downstream target genes Hes1, Hey1 were analyzed by using realtime PCR method. (2) The ovarian cancer xenograft models in nude mice were constructed by injecting SKOV3 cells in axillary subcutaneouswere. The nude mice were randomly divided into Jagged1 interference group, blank plasmid group and control group. Each group had 10 mice. They were transfected with pcDNA3.1(+)-siRNA-Jagged1, blank plasmid pDC3.1 and phosphate buffer, respectively. The tumor volumes and tumor masses were measured 14 days after transfection and the inhibition rate was calculated. The relative mRNA expression of Jagged1, Notch1, Hes1 and Hey1 in xenograft tissues after transfection in each group was detected by using realtime PCR technique and the relative protein expression of Jagged1, Notch1, Hes1 and Hey1 in xenograft tissues was detected by utilizing western blot method. (1) The relative mRNA expression of Jagged1, Notch1, Hes1 and Hey1 in ovarian cancer tissues were higher than benign ovarian tumor tissues, the differences were statistically significant (Ptissues of nude micein Jagged1 interference group were lower than that in the other two groups, the differences were statistically significant (Ptissues of nude mice among the three groups (P>0.05). Jagged1 is highly expressed in epithelial ovarian carcinoma. Jagged1 gene interference in xenograft tumor can inhibit ovarian cancer cell growth and improve tumor suppressor rate, which probably play roles by inhibiting Notch1 signaling pathway.

  17. Determinants of physical activity in primary school students using the health belief model.

    Science.gov (United States)

    Ar-Yuwat, Sireewat; Clark, Mary Jo; Hunter, Anita; James, Kathy S

    2013-01-01

    Thailand is a middle-income country in which two-thirds of children demonstrate an insufficient level of physical activity. Physical inactivity is a major risk factor for obesity and many other health-related consequences in children. Thus, it is important to understand how primary school children perceive things in their daily life as determinants of physical activity. The purpose of this study was to investigate the impact of cues, perceived benefits, and perceived barriers on the level of physical activity among primary school students. A cross-sectional study was conducted in Phitsanulok Province, Thailand, in 2011. Multistage sampling selected a total of 123 primary school students. The Physical Activity Questionnaire for Older Children and the Cues, Perceived Benefits, and Barriers to Physical Activity Questionnaire were used to assess the student levels of physical activity, as well as the perceived benefits, barriers, and cues to action. The association between these factors and the level of physical activity was determined by correlation statistics and confirmed by robust regression. Multivariate analysis of variance compared health belief model determinants: perceived benefits, perceived barriers, and cues to action on physical activity between male and female students. Self-administered questionnaires were validated and tested in a pilot study. The level of activity among primary school children was significantly influenced by perceived barriers, such as fear of strangers when playing outdoors, bad weather, and too much homework. However, activity was not influenced by cues to action or perceived benefits. Perceived benefits, barriers, and cues to physical activity did not differ by gender. A safe environment and fewer barriers, such as amount of homework, could enhance physical activity in primary school children.

  18. Sri Lanka's Health Unit Program: A Model of "Selective" Primary Health Care

    Directory of Open Access Journals (Sweden)

    Soma Hewa

    2011-12-01

    Full Text Available This paper argues that the health unit program developed in Sri Lanka in the early twentieth century was an earlier model of selective primary health care promoted by the Rockefeller Foundation in the 1980s in opposition to comprehensive primary health care advocated by the Alma-Ata Declaration of the World Health Organization. A key strategy of the health unit program was to identify the most common and serious infectious diseases in each health unit area and control them through improved sanitation, health education, immunization and treatment with the help of local communities. The health unit program was later introduced to other countries in South and Southeast Asia as part of the Rockefeller Foundation's global campaign to promote public health.

  19. Modelling the behaviour of corrosion products in the primary heat transfer circuits of pressurised water reactors

    International Nuclear Information System (INIS)

    Rodliffe, R.S.; Polley, M.V.; Thornton, E.W.

    1985-05-01

    The redistribution of corrosion products from the primary circuit surfaces of a water reactor can result in increased flow resistance, poorer heat transfer performance, fuel failure and radioactive contamination of circuit surfaces. The environment is generally sufficiently well controlled to ensure that the first three effects are not limiting. The last effect is of particular importance since radioactive corrosion products are major contributors to shutdown fields and since it is necessary to ensure that the radiation exposure of personnel is as low as reasonably achievable. This review focusses attention on the principles which must form the basis for any mechanistic model describing the formation, transport and deposition of radioactive corrosion products. It is relevant to all water reactors in which the primary heat transfer medium is predominantly single-phase water and in which steam is generated in a secondary circuit, i.e. including CANDU pressurised heavy water reactors, Sovient VVERs, etc. (author)

  20. Standardized 3D Bioprinting of Soft Tissue Models with Human Primary Cells.

    Science.gov (United States)

    Rimann, Markus; Bono, Epifania; Annaheim, Helene; Bleisch, Matthias; Graf-Hausner, Ursula

    2016-08-01

    Cells grown in 3D are more physiologically relevant than cells cultured in 2D. To use 3D models in substance testing and regenerative medicine, reproducibility and standardization are important. Bioprinting offers not only automated standardizable processes but also the production of complex tissue-like structures in an additive manner. We developed an all-in-one bioprinting solution to produce soft tissue models. The holistic approach included (1) a bioprinter in a sterile environment, (2) a light-induced bioink polymerization unit, (3) a user-friendly software, (4) the capability to print in standard labware for high-throughput screening, (5) cell-compatible inkjet-based printheads, (6) a cell-compatible ready-to-use BioInk, and (7) standard operating procedures. In a proof-of-concept study, skin as a reference soft tissue model was printed. To produce dermal equivalents, primary human dermal fibroblasts were printed in alternating layers with BioInk and cultured for up to 7 weeks. During long-term cultures, the models were remodeled and fully populated with viable and spreaded fibroblasts. Primary human dermal keratinocytes were seeded on top of dermal equivalents, and epidermis-like structures were formed as verified wit