bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4302: Targeting the sphingolipid pathway in NK large granular lymphocyte leukemia
Authors: Watters Rebecca J. , Liu Xin , Fox Todd E. , Kester Mark , Loughran Thomas P. 
Published: July 2012

Abstract
Large granular lymphocytes (LGL) are a lymphoid subset that consists of 10-15% of peripheral blood mononuclear cells. LGL can be divided into (2) major lineages of CD3- NK cells and CD3+ T Cells. Symptoms may include rheumatoid arthritis and neutropenia which leads to recurrent bacterial infections. The sphingolipid metabolism pathway has been found to be deregulated in NK-LGL leukemia. Glucosylceramide synthase (GCS), a key component of this pathway is an enzyme that catalyzes the conversion of proapoptotic ceramide to inactive glucosylceramide by transferring a glucose residue from UDP-glucose to ceramide. GCS has been found to be upregulated in cancer cells and its overexpression has been associated with multidrug resistance in leukemia cells. Both rat and human leukemic LGL cells have been treated with a combination treatment targeting two key components of the sphingolipid pathway. One of the agents in use is the C6-ceramide (C6) nanoliposome which has led to caspase-dependent apoptosis in a time- and dose-dependent manner. Systemic i.v. delivery of nanoliposomal ceramide led to complete remission in 5/14 syngeneic Fischer F344 rat model of NK-LGL leukemia. However a greater response will be achieved by combination treatment of C6 and through targeting a second key component of ceramide metabolism with DL-threo-1-Phenyl-2-palmitoylamino-3-morpholino-1-propanol (PPMP). PPMP is a GCS inhibitor that prevents the endogenous ceramide already present in the cell from being glycosylated into its inactive form where it can no longer induce cell death. Overall, this combination treatment shows a synergistic effect with increase of ceramide levels in order to induce apoptosis and therefore death of these persistent LGL cells. Cell flow cytometry examining 7AAD/Annexin V staining has shown ∼80% apoptosis when 6.25 uM C6 ceramide and 15 uM PPMP are used in combination on aggressive rat LGL cells. Whereas, only ∼19% is observed with C6 and ∼17% of PPMP are observed individually in treatment. Overall, apoptosis appeared increased in a dose response manner after treatment with PPMP and C6. This is a significant finding of P&lt;0.005, when compared to DMSO and ghost nanoliposome controls which only induce ∼15% apoptosis. In addition, this combination treatment has been utilized on normal human peripheral blood mononuclear cells where only 11.2% apoptosis was induced and 9% in the normal spleen mononuclear cells in rats. As a result, this combination treatment appears promising in specifically targeting LGL cells while sparing normal cells.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4302. doi:10.1158/1538-7445.AM2011-4302
Abstract 4303: The Jackson Laboratory Repository: resource for mouse strains modeling cancer
Authors: Boswell Deborah M. , Donahue Leah Rae , Lutz Cathleen M. , Rockwood Stephen F. , Sasner Michael 
Published: July 2012

Abstract
The Jackson Laboratory Repository is an established resource for the importation, cryopreservation, development, and distribution of mouse strains vital to biomedical research. More than 500 new strains are added annually to the approximately 5,000 strains and stocks of mice currently held in the Repository collection.
Newly acquired or developed strains include a model of malignant melanoma and metastasis; a xenotransplant model that provides continuous circulation of human growth factors; a targeted mutation strain for studying myeloproliferative diseases such as chronic myelomonocytic leukemia and Chronic Familial Myelocytic Leukemia-Like Syndrome; and a knock-in strain that mimics the t(9;11)(p22;q23) translocation identified in acute myeloid leukemia. Also under development are a transgenic/targeted mutation strain with increased mammary gland tumor incidence and three targeted mutation strains with increased sensitivity to carcinogens or radiation.
The Repository's inducible and conditional mutation mouse strains allow researchers to generate temporal and/or tissue-specific tools for modeling human cancer. New additions to the Repository collection include strains with Cre recombinase expression specific to the colon and rectum, as well as a transgenic strain that can be used as part of a bitransgenic system utilizing the tetracycline-inducible expression of a gene of interest in blood vessel endothelial cells. For non-invasive in-vivo imaging studies, the Repository distributes a xenograft/transplant host with widespread expression of firefly luciferase and enhanced green fluorescence protein.
The Repository maintains a searchable on-line resource (www.jax.org) for each strain. Researchers can submit their strains to be considered for inclusion in the Repository by using the on-line form available at The Jackson Laboratory website: http://www.jax.org/grc/index.html.
The Jackson Laboratory Repository is supported by the NCRR, The Howard Hughes Medical Institute, The Ellison Medical Foundation and donations from private charitable foundations.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4303. doi:10.1158/1538-7445.AM2011-4303
Abstract 4304: Developing T-LGL leukemia model for targeted therapy
Authors: Ren Tong , Liu Xin , Loughran Thomas P. , Cheng Hua 
Published: July 2012

Abstract
T cell type of large granular lymphocyte (T-LGL) leukemia is a hematological malignancy and the disease course is frequently associated with autoimmune diseases. Many patients with T-LGL leukemia have no response to the currently available immunosuppressive therapies. T-LGL leukemia cells display the CD3+/CD8+/CD57+ surface markers, representing activated cytotoxic T lymphocytes with the TCR rearrangement pattern that implicates their clonal expansion nature. The primary leukemic cells exhibit constitutive activities of STAT3 and NF-κB, and both factors are critical mediators of oncogenic signaling and survival pathways. Activated STAT3 contributes to chemotherapy resistance as the repression of STAT3 in LGL leukemic cells down-regulates a survival protein Mcl-1, resulting in an increased sensitivity to apoptosis. Thus, STAT3 activation plays an essential role in promoting aberrant proliferation of the leukemic cells. In addition, NF-κB is activated in LGL leukemia, which also plays a crucial role in survival and proliferation of the leukemia cells. It is of paramount significance to further verify therapeutic agents that target STAT3 and NF-κB for treatment of T-LGL leukemia in a well-defined leukemia model. Extensive efforts, however, failed to establish in vitro culture of primary T-LGL leukemia cells for extended time, because T-LGL leukemia cells are terminally differentiated cytotoxic T lymphocytes and undergo rapid replicative senescence. Lack of T-LGL leukemia model apparently prevents further understanding of the disease pathogenesis and development of targeted therapy.
We have developed a strategy that can prolong in vitro culture of T-LGL leukemia cells. Primary CD8+ populations from T-LGL leukemia patients are stably transduced with the retroviral tax gene derived from human T cell leukemia virus type 2. Expression of Tax overrides replication senescence and promotes unlimited expansion of the CD8+ T cells. These cells exhibit features characteristic to T-LGL leukemia, such as resistance to FasL-mediated apoptosis, sensitivity to inhibitors for sphingolipid kinase, IκB kinases and Stat3 as well as expression of cytotoxic gene products including granzyme B, perforin and IFNγ. Collectively, these results indicate that the immortalized CD8+ species from T-LGL leukemia patients constitutes a significant portion of T-LGL leukemic cells, and this leukemia model can duplicate main phenotypes of clinical isolates of T-LGL leukemia. The establishment of the T-LGL leukemia model is tremendously useful for investigating molecular pathogenesis of the disease and for testing novel therapeutics.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4304. doi:10.1158/1538-7445.AM2011-4304
Abstract 4305: Invasion of primary glioma- and cell line-derived spheroids implanted into corticostriatal slice cultures
Authors: Aaberg-Jessen Charlotte , Norregaard Annette , Christensen Karina Garnier , Jensen Stine Skov , Andersen Claus , Kristensen Bjarne Winther 
Published: July 2012

Abstract
Gliomas are known for being highly invasive and therefore incurable by surgery explaining a recurrence rate close to 100%. The aim of the present study was to develop and evaluate an in vivo-like in vitro model preserving the invasive features of glioma cells in order to facilitate research using more true models. This study was performed by implantation of glioma spheroids into organotypic corticostriatal slice cultures. The spheroids chosen for implantation were primary glioma spheroids as well as spheroids derived from the U87 glioblastoma cell line. Primary glioma spheroids are cultured small glioma fragments obtained from freshly removed tumor tissue. In contrast to cell line-derived spheroids, primary glioma spheroids preserve the tumor tissue components and structures such as cell-to-cell interactions, blood vessels and macrophages. In the present study, primary glioma spheroids from one anaplastic astrocytoma (WHO grade III) and two glioblastomas (WHO grade IV) were included in addition to U87 spheroids. The spheroids were labelled with the fluorescent dye DiI and implanted into 400 µm thick corticostriatal slice cultures prepared from newborn rat pups. The tumor cell invasion was followed by confocal microscopy. Hereafter the co-cultures were prepared for anti-human vimentin immunohistochemical staining identifying invasive tumor cells. The results showed that the primary glioma spheroid area was constant after implantation, but there was a clear increase in number of invading cells with time. In contrast, the U87 spheroid area increased after implantation, but there was only relatively few invading cells entering the brain tissue. Anti-human vimentin stained paraffin sections of co-cultures confirmed the tumor cell invasion recorded by confocal microscopy. The present study suggests implantation of primary glioma spheroids into corticostriatal slice cultures as an excellent in-vivo like in-vitro model suitable for studies of invasion. Similar to earlier results obtained in vivo, the U87 cell line, when used in vitro as well, appears to have lost the invasive feature of gliomas, preventing the use of this cell line in studies of invasion.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4305. doi:10.1158/1538-7445.AM2011-4305
Abstract 4306: KLF8 promotes human ovarian tumorigenesis in athymic mouse models
Authors: Lu Heng , Wang Xianhui , Urvalek Alison M. , Li Tianshu , Yu Lin , Zhao Jihe 
Published: July 2012

Abstract
KLF8 is a dual transcription factor that plays a role in oncogenic transformation in mouse fibroblast cells and is highly over-expressed in human ovarian cancer. To test if KLF8 alone or together with each of the ovarian oncoprotein c-Myc, Stat3c or Akt plays a role in ovarian cell transformation, we used the immortalized normal human ovarian epithelial cell line T80 to generate stable cell lines that overexpress KLF8 alone or its combination with one of the other three oncoproteins. The Soft agar assay showed that T80/KLF8 formed significantly more colonies compared with the mock control cells, suggesting that KLF8 may play a role to transform T80 cells. Interestingly the cells expressing both KLF8 and c-Myc formed the largest amounts of colonies that were even greater than the sum of colonies formed by the cells expressing either KLF8 or c-Myc alone, suggesting a potential synergistic role of KLF8 with c-Myc. Surprisingly, however, overexpression of KLF8 alone was sufficient to induce tumorigenesis in athymic mice when the T80/KLF8 cells were injected subcutaneously (s.c.), intraperitoneally (i.p.) or orthotopically into the ovarian bursa. HE and IHC staining identified the tumors’ epithelial origin characteristic of human ovarian cancer. The s.c. growth rate of the T80/KLF8 tumors was greater than the T80/Stat3c tumors and similar to T80/Akt tumors although slower than the tumors formed by SKOV3ip1 and T80/c-Myc cells. The average survival time for the mice with the i.p. implantations was about six months for T80/KLF8 as compared to approximately two months for SKOV3ip1. These novel findings suggest that KLF8 plays a critical oncogenic role in synergy with c-Myc in the ovarian cancer progression. The mouse tumor models generated in this work provide important tools for the studies of mechanisms underlying human ovarian cancer progression.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4306. doi:10.1158/1538-7445.AM2011-4306
Abstract 4309: Establishment of the chick chorioallantoic membrane (CAM) as an ex vivo model system to study mechanisms underlying epithelial ovarian tumour growth and metastasis
Authors: Reed Jason , Correa Rohann , Ramos-Valdes Yudith , Dinulescu Daniela M. , Vanderhyden Barbara C. , Lewis John D. , DiMattia Gabriel E. , Shepherd Trevor G. 
Published: July 2012

Abstract
Epithelial ovarian cancer (EOC) accounts for approximately 90% of all human ovarian malignancies. Unfortunately, 75% of EOC cases are not diagnosed until advanced stages when the tumour has metastasized, after which standard therapy is less effective. Therefore, it remains vital to directly study the molecular and cellular mechanisms contributing to EOC metastasis in an experimentally-tractable system. The chick chorioallantoic membrane (CAM) is a highly-vascularized tissue responsible for gas and nutrient exchange in the avian embryo, and has been used extensively to study angiogenesis and tumour formation by highly-aggressive cancer cell lines. Herein, we report that ascites-derived primary human EOC cells and established EOC cell lines readily form well-vascularized tumours on the chick CAM. To investigate this property further, we have generated GFP-expressing clones from the mouse ovarian tumour cell lines MOSE-RM (oncogenic Ras & Myc overexpression, SV40 TAg), MASC-2 (SV40 TAg), and 4306 (oncogenic Kras & Pten-null) which will facilitate visualization of tumour growth on the CAM as well as complementary studies in syngeneic mouse models for future studies. Xenografts of MOSE-RM and 4306 cell lines onto the surface of the chick CAM establish tumours that are significantly larger in mass and size compared with MASC-2 cells. Importantly, EOC tumours grown on the chick CAM are histologically identical to those arising within the peritoneal cavity. MOSE-RM and 4306 cell lines promote angiogenesis using HUVEC cells and the chick CAM, whereas MASC-2 cells lack this ability. Overall, these results demonstrate that EOC tumour growth on the chick CAM can be exploited as a highly amenable model system for studying late-stage EOC metastasis. Our findings also indicate that neo-vascularization is an obligatory process for establishment of secondary tumours; thus, we are currently investigating signaling pathways that impact primary human EOC tumour growth and angiogenesis using the chick CAM.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4309. doi:10.1158/1538-7445.AM2011-4309
Abstract 431: Laminin-511 regulates melanoma cell function and tumor growth
Authors: Tang Ling , Cui Tengjiao , Li Jie 
Published: July 2012

Abstract
Laminin family proteins are major non-collagenous components of basement membranes and have been found to be involved in modulating cell behavior. Laminin-511, composed of α5, β1, γ1 chains, is a major component of basement membrane of epithelia and blood vessels. Our lab has recently found increased expression of laminin-511 in malignant tumors. It has been found that tumor cells can synthesize and secrete laminin matrix to modify cellular environment and promote cell invasion. To explore the potential role of laminin-511 in melanoma, we blocked the expression of laminin-511 in human melanoma cell line SK-Mel-28 using RNA silencing strategy by transducing cells with lentiviral vector carrying laminin α5 chain specific shRNA (Lenti-Lα5 shRNA). Our data demonstrated that blocking the expression of laminin-511 significantly inhibited melanoma cell proliferation, attachment, migration and invasion in vitro, as well as tumor growth in vivo. In melanoma cells transduced with Lenti-Lα5 shRNA, compared with control melanoma cells, in cell proliferation analysis the total viable cells were 34.49% and 26.28% reduced on day 3 and day 5, respectively; in cell attachment assay the cell binding ability was decreased by 36.4%, 37.65% and 36.2% at 15, 30 and 60 minutes, respectively; in a chamber migration assay the cell migratory rate was dramatically down 90% at 24 hours; and in a Metrigel invasion assay the cell invasive capacity was markedly reduced by 89% at 24 hours. Furthermore, blocking laminin-511 expression significantly reduced tumor growth in vivo in nude mice. 18 tumors grew out of 20 injections with average volume 206 mm3 8 weeks post injection in cells tranduced with Lenti-Lα5 shRNA compared with 20 tumors out of 20 injections with average volume 590 mm3 in control cells. These findings revealed that laminin-511 plays important roles in melanoma cell function and tumor growth. In addition, our results strongly indicate laminin-511 a potential target for melanoma therapy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 431. doi:10.1158/1538-7445.AM2011-431
Abstract 4311: Utilising the preclinical Vk*MYC model of multiple myeloma to rapidly and effectively screen novel therapies and their combinations
Authors: Matthews Geoffrey M. , Chesi Marta , Lefebure Marcus , Shortt Jake , Banks Kellie , Stanley Kym , Faulkner David , Atadja Peter , Bergsagel Leif , Johnstone Ricky W. 
Published: July 2012

Abstract
Introduction: Multiple myeloma (MM) is an incurable hematological neoplasm with an unmet need for novel therapeutic options. Here we employed the genetically tractable Vk*MYC murine model of MM to screen current and novel therapeutics in transgenic Vk*MYC mice and in transplant models of Vk*MYC MM. In addition to assessing single agent activity we also determined the effects of the histone-deacetylase inhibitor (HDACi) panobinostat (LBH-589) with the proteosome inhibitor bortezomib (Velcade) used in combination. Methods: Current and novel anti-MM agents (32) were screened in transgenic Vk*MYC mice (≥60wk) using clinically based regimens. Of these, panobinostat and bortezomib were shown to be the most efficacious and were selected to treat immunocompetent C57BL/6 mice bearing transplanted Vk*MYC MM (2 months post-transplant). Combination therapy was investigated in transplanted Vk*MYC MM consisting of low dose panobinostat (10mg/kg) with bortezomib (0.5mg/kg). Serum paraprotein levels were measured in all mice. Tumour load, drug targets and apoptosis were assessed by FACS or IHC staining of bone marrow sections. Results: Initial drug screening in Vk*MYC transgenic mice demonstrated anti-MM activity of panobinostat and bortezomib reflected by 50 and &gt;25% reductions from baseline paraprotein levels, respectively. Similarly, serum paraprotein in C57BL/6 mice bearing Vk*MYC MM was significantly reduced with panobinostat (25mg/kg, 4d; 15mg/kg 5d/wk, 3wk) and bortezomib (0.5mg/kg, every 4d) alone compared with vehicle-treated mice. Moreover, panobinostat induced a significant survival advantage compared with vehicle (36.5d vs. 16d, p&lt;0.01). Combination therapy using panobinostat and bortezomib at low doses reduced paraprotein significantly more than either agent alone. This was associated with histone-H3 acetylation, apoptosis induction and a reduction in viable plasma cells within bone marrow. Conclusions: These results suggest that panobinostat and bortezomib have single agent activity against MM and are the first to demonstrate therapeutic benefit in the pre-clinical Vk*MYC MM model. Moreover, combination therapies of panobinostat with proteosome inhibitors may be a rational approach for the treatment of MM. Future studies will investigate the molecular events underlying the single agent and combination effects of panobinostat and bortezomib using the Vk*MYC MM model.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4311. doi:10.1158/1538-7445.AM2011-4311
Abstract 4312: Loss of Ink4a and Arf each contributes to increased susceptibility to asbestos-induced malignant mesothelioma development
Authors: Altomare Deborah A. , Menges Craig W. , Xu Jinfei , Pei Jianming , Zhang Lili , Tadevosyan Ara , Neumann-Domer Erin , Liu Zemin , Carbone Michele , Chudoba Ilse , Klein-Szanto Andres J. , Testa Joseph R. 
Published: July 2012

Abstract
The CDKN2A/ARF locus encompasses overlapping tumor suppressor genes p16(INK4A) and p14(ARF), which are frequently co-deleted in human malignant mesothelioma (MM). The importance of p16(INK4A) loss in human cancer is well established, but the relative significance of p14(ARF) loss has been debated. The tumor predisposition of mice singly deficient for either Ink4a or Arf, due to targeting of exons 1α or 1β, respectively, supports the idea that both play significant and nonredundant roles in suppressing spontaneous tumors. To further test this notion, we exposed Ink4a(+/-) and Arf(+/-) mice to asbestos, the major cause of MM. Asbestos-treated Ink4a(+/-) and Arf(+/-) mice showed increased incidence and shorter latency of MM relative to wild-type littermates. MMs from Ink4a(+/-) mice exhibited biallelic inactivation of Ink4a, loss of Arf or p53 expression and frequent loss of p15(Ink4b). In contrast, MMs from Arf (+/-) mice exhibited loss of Arf expression, but did not require loss of Ink4a or Ink4b. Mice doubly deficient for Ink4a and Arf, due to deletion of Cdkn2a/Arf exon 2, showed accelerated asbestos-induced MM formation relative to mice deficient for Ink4a or Arf alone, and MMs exhibited biallelic loss of both tumor suppressor genes. The tumor suppressor function of Arf in MM was p53-independent, since MMs with loss of Arf retained functional p53. Collectively, these investigations provide in vivo evidence indicating that both CDKN2A/ARF gene products suppress asbestos carcinogenicity. Furthermore, while inactivation of ARF appears to be crucial for MM pathogenesis, the inactivation of both p16(INK4A) and p19(ARF) cooperate to accelerate asbestos-induced tumorigenesis.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4312. doi:10.1158/1538-7445.AM2011-4312