tbuckley/cabot-search huggingface dataset:
Abstract 1865: TRIM24 acts as a transcriptional co-activator of the androgen receptor during prostate cancer progression
Authors: Anna C. Groner, Jonas de Tribolet-Hardy, Jean-Philippe Theurillat, Peter J. Wild, Myles Brown
Journal: Cancer Research (2015)

Abstract The steroid hormone androgen mediates a wide range of developmental, physiological and malignant responses by acting as an agonist for the androgen receptor (AR). AR in turn functions as a nuclear receptor transcription factor and executes specific gene expression programs in an androgen-dependent manner. Since the growth of prostate cancer cells initially depends on androgen, cancer therapy uses hormone-deprivation approaches to reduce the levels of androgen. While prostate cancer (PC) initially responds to androgen-ablation, most tumors progress to a castration resistant (CR) state insensitive to treatment. Both the androgen-dependent and the CRPC state depend on AR, which is probably activated by alternative molecular pathways in CRPC in response to low androgen levels. Here, we assessed the role of the transcriptional co-activator TRIM24 in mediating AR-dependent gene expression and growth in our CRPC cell model LNCaP-abl. We observed that knock-down of TRIM24 impairs CRPC cell growth, while TRIM24 and AR physically interact in these cells in the absence of androgen. When we identified TRIM24-dependent gene expression programs by combining genome-wide binding analyses with microarray studies, we found that TRIM24 and AR co-regulated many genes in CRPC cells. TRIM24- and AR-co-activated genes often function in mitosis and their expression is higher in patients with an increased chance of prostate cancer recurrence. These findings are corroborated by IHC-analyses of prostate cancer patients, where higher TRIM24 protein levels correlated with a greater chance of biochemical recurrence, higher Gleason scores and larger tumor sizes. Importantly, TRIM24 staining was positively correlated with AR staining. This supports a model where TRIM24 acts as an important activator of AR in the castration-resistant setting and therefore may harbor therapeutic potential. Citation Format: Anna C. Groner, Jonas de Tribolet-Hardy, Jean-Philippe Theurillat, Peter J. Wild, Myles Brown. TRIM24 acts as a transcriptional co-activator of the androgen receptor during prostate cancer progression. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1865. doi:10.1158/1538-7445.AM2015-1865
Activity and Tolerability of Azacitidine in Patients Who Relapse after Allogeneic Stem Cell Transplantation (allo-SCT) for Acute Myeloid Leukemia (AML) and Myelodysplasia (MDS): a Survey from the European Society for Blood and Marrow Transplantation (EBMT
Authors: Charles Craddock, Myriam Labopin, Mohamed Houhou, Marie Robin, Juergen Finke, Patrice Chevallier, Ibrahim Yakoub-Agha, Jean-Henri Bourhis, Henrik Sengelov, Didier Blaise, Peter Dreger, Michael Hallek, Arnon Nagler, N Kroger, Mohamad Mohty
Journal: Blood (2014)
Abstract 1359: Co-expression of ULBP1 and NKG2D are related to better overall survival in patients with gastric cancer
Authors: Kiyoshi Yoshimura, Moeko Inoue, Ryoji Kamei, Shigehisa Kitano
Journal: Cancer Research (2015)

Abstract Objective The relationship between expressions of ULBP1/NKG2D and their clinicopathological outcome in patients with gastric cancer were investigated. Background ULBP1 which is one of NKG2D ligand and expressing on tumor cell surface binds to the NKG2D receptor presenting on NK, CD8+ T and gamma delta T cell. It was considered that innate immunity is mainly induced through the interaction between ULBP1 and NKG2D. The role of this immune response is not clear yet, and is controversial whether it is inhibited or activated signal. Methods We performed immunohistochemical staining of gastric cancer tissue with antibody against ULBP1 and NKG2D in 98 patients who received surgery in 2004 to 2008. We investigated expression of ULBP1 in tumor and NKG2D in mononuclear cells around tumor by multiple points observation. These results were compared to their association with histological and clinical outcome. Results The positive group of NKG2D expression on mononuclear cells around gastric cancer tissue had significantly longer overall survival (OS) than the negative group (p = 0.0217). Although it was not recognized significant difference of ULBP1 expression on gastric cancer cells, in a combination of ULBP1 and NKG2D expression, both positive group had best OS, and both negative group had poorest OS in this study. Conclusion The interaction between ULBP1 and NKG2D in gastric cancer may have positive signal which relates to good OS. Although the mechanism of immune system through ULBP1/NKG2D is controversial, we obtained an interesting result according to this mechanism. Citation Format: Kiyoshi Yoshimura, Moeko Inoue, Ryoji Kamei, Shigehisa Kitano. Co-expression of ULBP1 and NKG2D are related to better overall survival in patients with gastric cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1359. doi:10.1158/1538-7445.AM2015-1359
Causes of Death in Sickle Cell Disease Adult Patients: Old and New Trends
Authors: Stéphanie Ngo, Pablo Bartolucci, David Lobo, Armand Mekontso-Dessap, Justine Gellen-Dautremer, France Noizat-Pirenne, Vincent Audard, Bertrand Godeau, Frédéric Galacteros, Anoosha Habibi
Journal: Blood (2014)
High Response Rate with Favorable Survival Projections in High-Risk Patients with Diffuse Large B-Cell Lymphoma (DLBCL) Receiving R-CHOP-14 or Early Intensified Chemotherapy with Rituximab and Autograft (R-HDS): Results of the Interim Analysis of A GITIL Prospective Multicenter Phase III Study.
Authors: Sergio Cortelazzo, Corrado Tarella, Alessandro M. Gianni, Marco Ladetto, Manuela Zanni, Paolo Corradini, Massimo Di Nicola, Caterina Patti, Antonino Mulè, Ignazio Majolino, Atto Billio, Angela Gueli, Francesco Di Raimondo, Annalisa Chiarenza, Andrea Gallamini, Andres Ferreri, Giovanni Pizzolo, Fabio Benedetti, Giorgio La Nasa, Pietro Leoni, Guido Gini, Livio Trentin, Francesco Rodeghiero, Roberto Marchioli, Tiziano Barbui, Anna Barbui, Alessandro Rambaldi
Journal: Blood (2009)
Abstract 5173: Androgen receptor status is highly conserved during tumor progression of breast cancer
Authors: André Grogg, Katrin Pfaltz, Claudia Lädrach, Nikola Cihoric, Martin Zweifel, Coya F. M. Tapia
Journal: Cancer Research (2015)

Abstract Introduction: Many clinical trails are ongoing targeting androgen receptor (AR) in breast cancer (BC). Anti-androgen therapy is increasingly accepted in BC patients since the new compounds have less androgenic side effects. The assessment of AR status is generally performed on the primary tumor even when treating metastatic disease. To the best of our knowledge, nothing is known regarding discrepancies of AR status between the primary tumor and the metastatic site. Therefore, we investigated AR status on a large cohort of primary BCs and matched metastases. Method: A next-generation Tissue Microarray (ngTMA) was constructed harboring 356 primary BCs, 133 matched metastases and 11 recurrences. A commercially available monoclonal AR antibody (DAKO) was used to evaluate AR-Status by immunohistochemistry. AR positivity was defined as ≥1% of nuclear staining in tumor cells. The results of the primary tumor and metastases/recurrences were compared. Additionally, the results of AR status were correlated with other pathological tumor features. Result: AR could be evaluated in 353/356 (99.2%) of primary BCs and a positivity was detected in 307 (87%). A discordant result was seen in 4.3% metastasized BC's with informative results (5/117). Three negative BCs were positive in the metastases representing 16.7% of all negative BCs with informative results (3/18). Two BCs were positive in the primary and negative in the metastases representing 2.0% of all positive BCs with metastases and informative results (2/99). No discrepancies were seen between primary and loco-regional recurrences. Further, AR expression was significantly correlated with a positive estrogen (p&amp;lt;0.001) and progesterone receptor (p&amp;lt;0.001) status and a low proliferation (≤15%) (p&amp;lt;0.001). Negative AR status was significantly (p&amp;lt;0.001) associated with a higher tumor grade. Triple negative BCs were in 11.4% AR positive (4/35). Conclusion: AR positivity is frequent in primary BCs (87%) and AR status is highly conserved during tumor progression. In a small fraction AR status changes (4.3%) either from positive to negative status or vise versa. However, even AR status is highly preserved we would recommend reevaluation of the metastatic site in negative BC's since a positive AR status can be seen in 16.7% of this subgroup. Citation Format: André Grogg, Katrin Pfaltz, Claudia Lädrach, Nikola Cihoric, Martin Zweifel, Coya F. M. Tapia. Androgen receptor status is highly conserved during tumor progression of breast cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5173. doi:10.1158/1538-7445.AM2015-5173
Minimally Invasive Pancreaticoduodenectomy for the Treatment of Pancreatic-Head and Periampullary Tumors
Authors: Marco Del Chiaro, Roberto Valente, Urban Arnelo
Journal: JAMA Surgery (2016)

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Abstract 1967: Elucidation of signaling pathways that mediate gastrin-induced JNK activation and pGSK3β/Snail induction in gastric cancer cells
Authors: Aninda Basu, Goutam Sondarva, Sreevidya Santha, Ajay Rana, Basabi Rana
Journal: Cancer Research (2015)

Abstract The gastrointestinal peptide hormone gastrin is known to regulate various cellular processes including proliferation, migration and metastasis in gastrointestinal cells. Our previous studies indicated that amidated gastrin (G-17) induced gastric cancer cell migration through two separate signaling axes. These revealed that inhibition of Glycogen Synthase Kinase-3β (GSK3β) was necessary to activate G17-induced migratory pathways in gastric cancer cells. Incubation of AGSE gastric cancer cells overexpressing CCK2 receptor (CCK2R) with G17 resulted in a dose and time dependent increase of GSK3βSer9 phosphorylation, indicative of an inhibition of the kinase. Treatment with G-17 was also associated with increased Snail expression, a downstream target of GSK3β and p21-activated protein kinases (PAKs). In a second pathway, G-17 also induced JNK phosphorylation through activation of Mixed Lineage Kinase 3 (MLK3). This axis also promotes gastric cancer cell migration via CCK2R. In the present study our goal was to determine whether PAKs, which are effectors for the Rho GTPases Cdc42 and Rac and are central players in cell proliferation, survival and motility, are involved in the G-17 effects on gastric cancer cells. Our studies showed that in AGSE cells when pretreated with a commercially available PAK4 inhibitor PF 3758309, G-17 was unable to phosphorylate GSK3β and G-17-induced Snail expression was markedly inhibited. G17-induced p-JNK expression was also significantly attenuated with PAK4 inhibitor pretreatment. The inhibitory effect was stronger when PAK4 inhibitor was used in combination with a pan-MLK inhibitor CEP11004. The involvement of PAK4 in G17-induced events were also confirmed by using the PAK4 siRNA. Knockdown of PAK4 inhibited G17-induced p-JNK expression which was more pronounced when both PAK4 and MLK3 were knocked down in AGSE gastric cancer cells. However, knocking down PAK4 alone does-not seem to inhibit G-17-induced p-GSK3β expression completely, which suggest the potential involvement of other PAK family members. Studies are currently underway to determine which PAK(s) is involved in mediating G17-pGSK3β-Snail axis and also to elucidate any crosstalk of PAK4 and MLK3 in this pathway. Elucidation of the signaling pathways that mediate G17-induced cellular events will be very important in designing therapeutic approaches in the future to restrict gastric cancer cell migration and metastasis. Citation Format: Aninda Basu, Goutam Sondarva, Sreevidya Santha, Ajay Rana, Basabi Rana. Elucidation of signaling pathways that mediate gastrin-induced JNK activation and pGSK3β/Snail induction in gastric cancer cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1967. doi:10.1158/1538-7445.AM2015-1967
Rituximab Retreatment in B-Cell Non-Hodgkins Lymphoma Patients.
Authors: Osnat Bairey, Eldad J. Dann, Yair Herishanu, Rosa Ruchlemer4, Tamar Tadmor5, Israel Gavish6, Yulia Volchek7, Mona Yuklea8, Shlomo Bulvik9, Menachem Ben-Shahar10, Itai Levy11, Hanna Rosenbaum, Miriam Quitt12, Liora Solomon13, Ofer Shpilberg
Journal: Blood (2005)
439. Prolonged Expression of Secreted Enzymes in Dogs After Liver Delivery of Sleeping Beauty Transposons: Implications for Non-Viral Gene Therapy of Mucopolysaccharidoses Types I and VII
Authors: Elena L. Aronovich, Kendra A. Hyland, Bryan C. Hall, Jason B. Bell, Erik R. Olson, Myra Rusten, David W. Hunter, Chester B. Whitley, N. Matthew Ellinwood, R. Scott McIvor, Perry B. Hackett
Journal: Molecular Therapy (2016)

The non-viral integrating vector the Sleeping Beauty (SB) transposon system is efficient in treating systemic monogenic diseases in mice including mucopolysaccharidosis (MPS) types I and VII caused by α-iduronidase (IDUA) and β-glucuronidase (GUSB) deficiency, respectively. More recently we have used modified approaches of the hydrodynamic procedure to deliver therapeutic transposons to dog liver. Reproducible delivery and transposition in dogs are about 1% the levels in mice. Using a transgenic canine reporter secreted alkaline phosphatase (cSEAP), in the absence of immune suppression we can detect transgenic protein for up to six weeks post infusion using catheter-mediated hydrodynamic delivery. A proof-of-principle immunomodulation using GdCl3 to block macrophages in liver and spleen prolonged the presence of the cSEAP protein in circulation from 6 weeks to up to at least 5 months after a single vector infusion. We achieved stabilized activity in one dog at about 2-fold of baseline values. Durability of cSEAP in serum was inversely correlated with transient increase of liver enzymes ALT and AST in response to the vector delivery procedure, pointing to the deleterious effect of hepatocellular toxicity on transgene maintenance. However, GdCl3 immunomodulation was ineffective for repeat vector infusions, suggesting a possibility of an alternative, more potent immunosuppression regimen. Evidence of transposition was obtained with the most efficient transposase SB100X but not with SB11. For transgenic IDUA and GUSB, therapeutic activity in serum peaked at 50-350% of wild-type at 2-4 days post-treatment, but lasted only a few days. The differences in levels and duration of detection of cSEAP in the blood compared to those of IDUA and GUSB may be in part due to the facilitated uptake of lysosomal enzymes into cells compared to cSEAP. Longer endurance of transgenic proteins at therapeutic levels may be possible in SB-treated dogs using alternative immunosuppressive regimens.
Abstract 4172: Differential angiogenesis-related cytokines release in tumor interstitial fluid and plasma in ER-positive and triple-negative breast cancers overexpressing VEGF
Authors: Louis Dore-Savard, Esak Lee, Aleksander S. Popel, Zaver M. Bhujwalla
Journal: Cancer Research (2015)

Abstract Interstitial fluid (IF) is a key component of the tumor microenvironment (TME) that has been largely overshadowed by proteomic and genomic analysis of the cancer cell and stromal compartments of the TME. Early studies of tumor IF by Gullino and colleagues showed elevated protein and lactic acid levels and the absence of glucose. Modern analytical methods allow for comprehensive characterization of IF proteins to better understand the TME. We modified Gullino's model and created a collection chamber adapted to collect IF from mouse tumors. We used ER-positive MCF-7 and triple negative MDA-MB-231 breast cancer cells in SCID mice. Additionally, we created VEGF-overexpressing cells from each cell line to evaluate the effect of VEGF overexpression on angiogenic cytokines in tumor IF. The chamber was implanted with small tumor pieces in the subcutaneous space until the tumor encompassed the chamber (4 to 12 weeks depending on cell types). The tumor was then removed and the tumor IF (approximate volume 40μl) and blood plasma were collected. IF and plasma samples were analyzed using a multiple cytokine immunoassay (Proteome Profiler Human Angiogenesis Kit, R &amp; D Systems Inc., Minneapolis MN). Among the 55 human angiogenesis-related cytokines tested, only 4 were detected in MCF-7 tumors IF, and 24 were detected in MDA-MB-231 IF sample. As anticipated, high VEGF levels were detected in MCF-7 overexpressing cells. Additionally, we observed a tendency to an elevated level of TIMP metallopeptidase inhibitor 1 (TIMP-1). All 4 cytokines detected in MCF-7 IF were also detected in MDA-MB-231 IF. VEGF overexpression had minimal effect on the tested cytokines. However, decreased levels of angiogenin and endostatin were observed. In plasma of tumor-bearing mice, 5 cytokines were detected. For instance, Serpin E1 (PAI-1) and TIMP-1 were detected in the plasma of both MCF-7 and MDA-MB-231, at lower levels than in IF. However, urokinase plasminogen activator was present only in mice with triple negative MDA-MB-231 tumors. We anticipate that a better understanding of the TME, via the characterization of the IF, will help identify new targets for diagnosis and therapy of cancer. We intend to examine correlations between the present data and human databanks to confirm the relevance of our model systems. Citation Format: Louis Dore-Savard, Esak Lee, Aleksander S. Popel, Zaver M. Bhujwalla. Differential angiogenesis-related cytokines release in tumor interstitial fluid and plasma in ER-positive and triple-negative breast cancers overexpressing VEGF. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4172. doi:10.1158/1538-7445.AM2015-4172
694. Anti-Transgene Cellular Immune Repsonses Can Be Induced by Subretinal Gene Transfer with rAAV in a Dose-Dependent Manner
Authors: Julie M. Vendomele, Quentin Khebizi, Mirella Mormin, Sabrina Donnou, Catherine Poinsignon, Anne Galy, Sylvain Fisson
Journal: Molecular Therapy (2016)

From animal experiments to the first human clinical trials in 2007, recombinant adeno-associated virus (rAAV)-mediated ocular gene therapy has shown successful results which have been attributed in part to the immune-privileged situation of the eye. Recently, some ocular gene therapy clinical trials have reported that visual acuity returned to baseline 6 to 12 months after therapy. The involvement of anti-transgene immune responses may lead to loss of therapeutic efficacy. This prompted us to evaluate in a murine model if rAAV gene transfer leads to the expected immune ignorance of the transgene or perhaps to an immuno-modulatory mechanism already described with subretinal peptide injection (eg. Anterior Chamber Associated Immune Deviation / ACAID), or to anti-transgene immunization. In this study, we characterized the CD4 and CD8 T cell responses specifically directed toward the transgene product in a murine model following rAAV2/8-mediated subretinal gene transfer. An rAAV2/8 encoding for the GFP-HY fusion protein under the phosphoglycerate kinase (PGK) promoter was used. The transgene expresses the HY male antigen which contains MHC class I and MHC class II-restricted T cell epitopes (UTY and DBY, respectively) that are immunodominant in female mice. For the study, 2µL of endotoxin-free, PBS-formulated rAAV2/8 PGK GFP-HY were injected subretinally in C57Bl/6 female mice. At day 7, mice were challenged subcutaneously with the UTY and DBY peptides adjuvanted in CFA, and the immune response was analyzed at day 14 by IFNγ ELISpot, cytokine titration and proliferation assays. Our results revealed that: (i) The subretinal injection of 10E8 to 2.10E9 vg/mouse of rAAV2/8 PGK GFP-HY did not induce a significant HY-specific peripheral immune modulation in contrast to the ACAID obtained after subretinal injection of UTY and DBY peptides (50µg each); (ii) Higher doses of rAAV2/8 PGK GFP-HY (5.10E10 vg/mouse) triggered increased Th1 and Tc1 cellular immune responses against the transgene product in peripheral lymphoid organs. Lower doses of vector did not increase peripheral immune responses toward the transgene product following the challenge. We have thus far failed to demonstrate the induction of ACAID by rAAV2/8 subretinal gene transfer. We show that rAAV2/8 vector-mediated subretinal gene transfer is not necessarily ignored at the immunological level. High doses of vector can effectively trigger anti-transgene T-cell responses with the potential for elimination of transgene-expressing cells. Clearly, anti-transgene-specific immune monitoring should be refined at least in preclinical models, to improve the biosafety and the long-term efficacy of rAAV-mediated ocular gene transfer.