tbuckley/cabot-search huggingface dataset:
Abstract 1163: Phosphoserine aminotransferase 1 (PSAT1) as a novel anti-tumor target in hepatocellular carcinoma
Authors: Zhaobing Ding, Kenneth Wee, Eung-Sam Kim, Animesh Samanta, Michael Steckel, Marian Raschke, Sendhil Velan, Young-Tae Chang, Andrea Haegebarth, Karl Ziegelbauer, Sylvia Gruenewald, Weiping Han
Journal: Cancer Research (2015)

Abstract With an estimated 700,000 new cases per year, hepatocellular carcinoma (HCC) represents the fifth commonest cancer and is the third leading cause of cancer death worldwide. Its 5-year survival rate after surgery is only 5-6%. Although HCC cases occur predominantly in the East and Southeast Asia and Sub-Saharan Africa, the incidence is rising in the West, largely due to an increasing incidence of Hepatitis C virus infection, alcoholic liver disease, and non-alcoholic steatohepatitis related to obesity and type II diabetes. Besides sorafenib, an oral multikinase inhibitor approved for the treatment of HCC, there is no other pharmacological agent in the treatment of HCC. Cancer cells undergo dramatic metabolic reprogramming to sustain uncontrolled proliferation. Accumulating evidence supports abnormal metabolic pathways as an emerging hallmark of cancer. To identify metabolic genes required for HCC tumorigenesis, we compared gene expression profiles of a rat orthotopic and a mouse DEN (Diethylnitrosamine)-induced HCC model to a liver regeneration model and to normal liver by PCR arrays, transcriptomic analysis, and metabolomic profiling. Serine and glycine levels were increased in tumors of the HCC models as determined by NMR spectroscopy. PSAT1 (phosphoserine aminotransferase 1), an enzyme in the serine biosynthesis pathway, was identified as one of the top up-regulated genes in the HCC models. An increase in PSAT1 protein levels in tumor samples versus normal liver tissue was confirmed by Western blot. Knockdown of PSAT1 in rat hepatoma cells (MH3924a) led to a dramatic reduction in cell proliferation in vitro and in vivo. Moreover, a doxycycline-inducible knockdown approach confirmed the anti-proliferation effect of PSAT1 depletion. Interestingly, depletion of PSAT1 showed a variable effect on other HCC cells (e.g. Hep3B and Huh-7), suggesting the involvement of other genetic and metabolic factors. Detailed analysis of PSAT1 as a potential drug target for HCC is currently being addressed in in vivo studies. Citation Format: Zhaobing Ding, Kenneth Wee, Eung-Sam Kim, Animesh Samanta, Michael Steckel, Marian Raschke, Sendhil Velan, Young-Tae Chang, Andrea Haegebarth, Karl Ziegelbauer, Sylvia Gruenewald, Weiping Han. Phosphoserine aminotransferase 1 (PSAT1) as a novel anti-tumor target in hepatocellular carcinoma. [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 1163. doi:10.1158/1538-7445.AM2015-1163
Abstract IA17: Adoptive T cell therapy with CAR modified T cells: We have a Model A Ford, can we build a Ferrari?
Authors: Renier Brentjens
Journal: Clinical Cancer Research (2015)

Abstract Recently published reports support the novel approach of treating cancer with patient derived T cells genetically modified to express artificial T cell receptors, termed chimeric antigen receptors (CARs), targeted to tumor associated antigens. To this end, initial clinical trial outcomes of patients with relapsed B cell acute lymphoblastic leukemia (B-ALL) treated with T cells genetically modified to express a CAR specific to the CD19 antigen demonstrate that this approach is a very promising therapeutic intervention which potentially may dramatically alter the standard of care in this disease. In contrast far more modest clinical responses were seen in patients with relapsed low grade B cell malignancies including chronic lymphocytic leukemia (CLL) and B cell non-Hodgkins lymphomas (NHL). The etiologies of discordant clinical outcomes between B-ALL and CLL/NHL patients treated with CD19 targeted CAR T cells remains a subject of conjecture although the tumor microenvironment is a strong focus for further investigation. To this end, we will present novel data on a next generation of CAR T cells, termed “armored CAR” T cells genetically designed to enhance persistence, anti-tumor efficacy, and an ability to overcome an immune suppressive tumor microenvironment through further genetic modification. Promising preclinical studies utilizing various “armored CAR” T cell approaches and their role in future clinical trials will be discussed as well as the relevance of these findings to the extrapolation of this technology from hematologic tumors to far more prevalent solid tumor malignancies. Note: This abstract was presented as part of the Joint Session: Clinical Science Interactions between Melanoma and Hematologic Malignancies with the AACR Special Conference on Advances in Melanoma: From Biology to Therapy held September 20-23, 2014 in Philadelphia, PA. Citation Format: Renier Brentjens. Adoptive T cell therapy with CAR modified T cells: We have a Model A Ford, can we build a Ferrari? [abstract]. In: Proceedings of the AACR Special Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(17 Suppl):Abstract nr IA17.
Abstract 546: Soluble EphA2 is a potential serum biomarker for lung cancer
Authors: Tadanori Kondo, Hiroki Yumoto, Kento Usui, Kazunori Kato
Journal: Cancer Research (2015)

Abstract EphA2 is a cell surface glycoprotein expresses in various tumor tissues including lung, breast and pancreas carcinoma. As the patients with a highly positive surface expression of EphA2 carcinomas have the poor prognosis, therefore, preclinical and clinical studies using antibody targeting to EphA2 are underlying. Previous study has reported that EphA2 fragment is also released in a soluble form by the proteolytic cleavage from tumor cell surface. In this study, we tried to detect the soluble form of EphA2 (sEphA2) in the serum specimens of lung cancer patients. By using antibodies to EphA2, we developed a new sandwich ELISA system detecting human sEphA2 with high sensitivity and specificity. With this system, we measured the concentration of sEphA2 in the serum of normal healthy donors and lung cancer patients. The concentration of sEphA2 was significantly higher in sera of 15 lung cancer patients than 15 healthy donors (p&amp;lt;0.01). We also examined the other diagnostics biomarkers such as CYFRA and CEA. The levels of sEphA2 in serum of lung cancer patients are correlated with CYFRA and CEA. These data indicate that the diagnosis of the lung cancer enabled by measuring the concentration of sEphA2. However, detail clinicopathological characteristics are necessary for the feasible diagnosis for sEphA2 as a biomarker of lung cancer. Citation Format: Tadanori Kondo, Hiroki Yumoto, Kento Usui, Kazunori Kato. Soluble EphA2 is a potential serum biomarker for lung 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 546. doi:10.1158/1538-7445.AM2015-546
Prevalence and Clinical Significance of Diabetes in Asian Versus White Patients With Heart Failure
Authors: Ingrid E.M. Bank, Crystel M. Gijsberts, Tiew-Hwa K. Teng, Lina Benson, David Sim, Poh Shuan Daniel Yeo, Hean Yee Ong, Fazlur Jaufeerally, Gerard K.T. Leong, Lieng H. Ling, A. Mark Richards, Dominique P.V. de Kleijn, Ulf Dahlström, Lars H. Lund, Carolyn S.P. Lam
Journal: JACC Heart Failure (2016)
Treatment Choice of Decitabine Versus Conventional Chemotherapy for the Treatment of Elderly Patients with Newly Diagnosed Acute Myeloid Leukemia
Authors: Hyunsung Park, Hyunsoo Cho, Jungyeon Lee, Jieun Jang, Yundeok Kim, Soo Jeong Kim, Yu Ri Kim, Jin Seok Kim, Yoo Hong Min, June-Won Cheong
Journal: Blood (2015)
Abstract 3531: Companion diagnostics-based telomerase-specific oncolytic virotherapy: preclinical evaluation in human colorectal cancer cell lines differentially affected in the RAS/RAF/MEK signaling pathway
Authors: Shuta Tamura, Hiroshi Tazawa, Naoto Hori, Takeshi Koujima, Satoru Kikuchi, Shinji Kuroda, Hiroyuki Kishimoto, Takeshi Nagasaka, Masahiko Nishizaki, Yasuo Urata, Shunsuke Kagawa, Toshiyoshi Fujiwara
Journal: Cancer Research (2015)

Abstract Colorectal cancers harboring KRAS or BRAF mutations often show resistance to anti-cancer drugs, and are poor prognostic disease that causes metastasis and recurrence compared to those with wild type KRAS and BRAF. KRAS/BRAF-wild type colorectal cancers are sensitive to both cetuximab and panitumumab that are epidermal growth factor receptor (EGFR)-targeting agents. However, KRAS/BRAF-mutant colorectal cancers are resistant to EGFR-targeting agents because of constitutive activation of the EGFR-downstream RAS/RAF/MEK signaling pathway. Therefore, the development of novel therapeutic strategy is required to improve the clinical outcome in patients with KRAS/BRAF-mutant colorectal cancers. We developed two types of telomerase-specific replication-competent oncolytic adenoviruses, OBP-301 and OBP-702 armed with the wild-type p53 tumor suppressor gene. In this study, we established the companion diagnostics-based selection algorithm for our oncolytic viruses. We compared the antitumor effects of OBP-301 and OBP-702 in human colorectal cancer cells with wild type KRAS/BRAF (SW48, Colo320DM), mutated KRAS (DLD-1, SW620) and mutated BRAF (RKO, HT29). We evaluated the antitumor effect of OBP-301 and OBP-702 in human colorectal cancer cells using XTT assay. Oncolytic adenovirus-mediated induction of apoptosis- and autophagy-related cell death was analyzed by Western blot analysis. KRAS-mutant colorectal cancer cells were sensitive to both OBP-301 and OBP-702 as well as KRAS/BRAF-wild type cells. In contrast, BRAF-mutant colorectal cancer cells were sensitive to OBP-702 rather than OBP-301. Western blot analysis showed that OBP-301 induced autophagy, whereas OBP-702 induced both autophagy and apoptosis. Taken together, our data suggest that oncolytic viruses should be used according to the genetic background of the RAS/RAF/MEK signaling pathway, especially in patients with colorectal cancer. Citation Format: Shuta Tamura, Hiroshi Tazawa, Naoto Hori, Takeshi Koujima, Satoru Kikuchi, Shinji Kuroda, Hiroyuki Kishimoto, Takeshi Nagasaka, Masahiko Nishizaki, Yasuo Urata, Shunsuke Kagawa, Toshiyoshi Fujiwara. Companion diagnostics-based telomerase-specific oncolytic virotherapy: preclinical evaluation in human colorectal cancer cell lines differentially affected in the RAS/RAF/MEK signaling pathway. [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 3531. doi:10.1158/1538-7445.AM2015-3531
557. Impact of the Integrity of the ITRs on the Production of rAAV Vectors
Authors: Lionel Galibert, Lucile Nauwynck, Adrien Savy, Fulvio Malvilio, Otto-Wilhelm Merten
Journal: Molecular Therapy (2015)

The Adeno-Associated Virus's (AAV) Inverted Terminal Repeats (ITRs) are key features of the AAV. ITRs are implied in the replication, encapsidation of the AAV genome, along with its integration in the host genome and its excision. These sequences are the only AAV DNA sequences conserved in the recombinant AAV as they allow its replication, encapsidation and long-term maintenance in the host non-dividing target cells. The ITRs are highly GC rich and structured due to the presence of repetitive palindromic sequences. During its replication, the AAV is able to reconstitute incomplete or imperfect ITR sequences. Thus it is often found that rAAV genomes cloned into the backbones of the DNA plasmids used for production, have imperfect ITRs sequences which are shortened or contain mutations. In this work, we study the impact of those imperfect ITRs and their impact on the levels of encapsidated rAAV genomes and cellular/baculovirus contaminating DNA sequences, in the baculovirus/Sf9 cells production system.
Erlotinib Increases Efficacy of 5-Azacitidine (AZA) by Inhibiting Drug Efflux Via ABC-Transporters
Authors: Elodie Lainey, Marie Sebert, Sylvain Thepot, Maximilien Tailler, Lionel Ades, Claude Gardin, Guido Kroemer, Pierre Fenaux, Simone Boehrer
Journal: Blood (2010)
Ultrasound (US) and US-guided fine needle aspiration cytology (FNAC) prior to sentinel lymph node biopsy (SLNB) in melanoma patients: Accuracy of US-FNAC and lack of further improvement by RT-PCR of the aspirate
Authors: C. A. Voit, G. Schaefer, A. Schoengen, A. C. Akkooi, A. M. Eggermont, J. Rademaker, A. Lukowsky, M. Schwuerzer, W. Sterry, M. Kron
Journal: Journal of Clinical Oncology (2006)

8059 Background: We have previously shown that US guided FNAC identifies positive SNs prior to SLND in 19% of cases (Voit et al., Ann Surg Oncol: 2006, in press). Originally, in this prospective study, we had tested the feasibility of in vivo US as screening tool and FNAC for verification of sentinel nodes (SN) prior to SLNB. Here we report the results of tyrosinase RT-PCR examinations of SNs aspirated pre-SLNB and of post-SLNB FNAC of the excised SN. Additionally, pts were followed up by blood sample tyrosinase RT-PCR at regular intervals. Methods: Between 7/2001 and 7/2003, 127 AJCC staged melanoma pts with a median tumor thickness of 2.1mm [0.4–18] underwent a FNAC to verify SN detected by US. Follow-up data are updated until 1/1/2006 (mean/median FU 29/31 (0 - 51) months). In 127 pts 141 SNs have been excised. SN involvement was predicted with a combined sensitivity for US with FNAC of 82% [65–93%] and a specificity of 72% [62–81%]. 19 patients already identified as SN+ by US guided FNAC reduced the need for the SLNB procedure in 16% (19/121). SN Size pre- and post-SLNB was measured by US. Results: US identified the SN in 121/141 (86%). None of the 20 SNs not identified by US were malignant. Median pre-SLNB SN size was 842 mm 3 [35–107,272], median post-SLNB SN size was 714 mm³ [32–13,409]. Pre- and post-SLNB SN sizes were virtually identical. 34/121 SNs were histologically malignant. In 7/34 no measurements were made for various reasons. In 27 SNs histological patterns of involvement were examined. 10/27 showed solitary nests in subcapsular/parenchymal or combined localization. 17/27 SN were involved by multiple nests. RT-PCR of the aspirate of SNs was confirmative pos. in 11/27 and false neg. in 16/27. Size analyses of the lesions showed an av. 2.8 mm 2 (median 0.5 [0.005–32.0]) in the false neg. pop. and 28.5 mm 2 (median 20 [0.003–80.0]) in the confirmative pos. pop. Blood RT-PCR as well as DFS and OS will be updated and provided at the meeting. Conclusions: US guided FNAC is highly accurate. Additional RT-PCR of the aspirate does not further enhance SN pos. identification rate. US-FNAC can reduce the need of SLNB in 16% of patients. No significant financial relationships to disclose.
Humoral tumor-associated immune responses induced by catumaxomab in patients with malignant ascites.
Authors: P. Ruf, M. Jäger, B. Foerster, H. Martinius, D. Seimetz, H. Lindhofer
Journal: Journal of Clinical Oncology (2011)

2575 Background: Catumaxomab is the first EU approved bispecific (anti-EpCAM x anti-CD3) trifunctional antibody for the intraperitoneal (ip) treatment of malignant ascites (MA) in patients (pts) with EpCAM-positive tumors. Methods: In the ongoing phase IIIb study CASIMAS catumaxomab is investigated with/without prednisolone premedication in pts with MA due to epithelial cancer. Pts received four 3-hour infusions of 10, 20, 50 and 150 µg catumaxomab over 11 days. Plasma samples of 15 pts were quantified for autologous anti-EpCAM and anti-HER2 immunoglobulin (Ig) responses by ELISA. Additionally, MA samples were screened for EpCAM-positive tumor cells by immunocytochemistry and anti-drug antibody (ADA) responses were monitored. Results: At screening EpCAM-positive tumor cells were detected in the ascites fluid of all 15 pts. Thereof, 8 individuals (53%) showed a median 3-4 times increase of the initial anti-EpCAM Ig titer after treatment, whereas in 7/15 pts (47%) the titer did not increase. Although anti-EpCAM Ig screening values varied largely (2 -855 ng/ml) no significant distinction between the anti-EpCAM responder group (R) and non-responders (NR) was measured (p = 0.96; Mann Whitney test). However, there was a significant difference in the mean ADA concentrations of available samples determined 7 or 8 d after the last catumaxomab infusion (27,103 [R, n=5] vs. 910 ng/ml [NR, n=5]). Moreover, in 5/11evaluable pts (45%) HER2 -specific Ig could be quantified. In contrast to the augmented anti-EpCAM antibody levels which rapidly appeared (d 10) anti-HER2 responses developed de novo, started delayed (d 18) and peaked at the last sample collection (d 38, median=17 ng/ml). Interestingly, available samples of 2 pts who received a second treatment cycle after recurring MA displayed an anti-HER2 Ig booster reaction with peak levels of 48 and 209 ng/ml. Conclusions: The results indicate an active immunization induced by catumaxomab. Most importantly, the humoral immune response was not restricted to the EpCAM targeted but antigen spreading to the non-targeted HER2 tumor-associated antigen occurred. The impact of this immunization effect for the therapeutic benefit will be further investigated.
16. Exosome-Associated AAV as a Novel Platform for Gene Therapy of Hearing Loss
Authors: Bence Gyorgy, Cyrille Sage, Deborah Scheffer, Artur A. Indzhykulian, Dakai Mu, Xandra O. Breakefield, Casey A. Maguire, David P. Corey
Journal: Molecular Therapy (2015)

Introduction: In recent gene therapy trials, adeno-associated virus (AAV) vectors for diseases such as blindness and hemophilia were found to be safe and effective. Gene therapy for hearing and balance disorders is not as advanced, because gene delivery into the cochlea (particularly to sensory hair cells) is generally inefficient. Here we show that exosome-associated AAV vectors (vexosomes) are highly effective carriers of transgenes to hair cells. Methods: Vexosomes from media of AAV-producing cells (293T) were harvested by ultracentrifugation. For in vitro cochlear transductions, we explanted organs of Corti from P1 CD1 mice. Conventional AAV1 vectors or AAV1 vexosomes, encoding for GFP, were added to the culture medium to determine the extent of transgene delivery and expression. For in vivo studies, we injected vectors at P1 into the scala media through cochleostomy or into the scala tympani through the round window membrane (RWM). To study whether vexosomes can rescue a disease phenotype in vitro, we explanted Corti organs from Tmhs (Lhfpl5) knock-out mice, which lack mechanotransduction (and hearing and balance) beyond P5. Cultures were transduced with vexosomes encoding TMHS (tetraspan membrane protein of hair cell stereocilia) and restoration of function was assessed by FM1-43 dye uptake, which is trapped inside functional hair cells. Results: In vitro, AAV1-vexosomes led to almost 100% transduction of inner (IHCs) and outer hair cells (OHCs), while regular AAV1 was able to transduce only up to 30% of IHCs and OHCs at equivalent genome copies per cell (Figure 1). In vivo, vexosomes also outperformed regular AAV. Delivered by cochleostomy, AAV1-vexosomes transduced 63.7±6.5% and 30.0±9.8% of IHCs and OHCs, respectively, whereas AAV1 transduced only 35.8±0.7% and 16.7±1.9% (mean fraction of transduced cells from two experiments with 10 animals in each group). Delivered by RWM, AAV1-vexosomes transduced 88.0±2.2% and 25.2±10% of IHCs and OHCs, whereas AAV1 transduced 75.0±4.4% and 15.6±0.4% (two experiments)(Figure 2). Importantly, AAV1-vexosomes encoding TMHS were able to restore FM1-43 accumulation in TMHS KO hair cells in vitro, apparently rescuing mechanotransduction. Conclusion: Exosome-associated AAV is a powerful gene delivery system to the mammalian cochlea in vitro and in vivo, Therefore they may be utilized to study hair cell physiology in vitro, and—in the future—for in vivo gene therapy.
The E3 Ubiquitin Ligase Cbl-b Limits Nascent Th9 Differentiation
Authors: Isabelle Cornez, Sowmya Parampalli Yajnanarayana, Natascha Hermann-Kleiter, Stefan Ulrich Schmidt, Peter Brossart, Natalio Garbi, Gottfried Baier, Dominik Wolf
Journal: Blood (2015)
Abstract 1665: Design, synthesis, biological evaluation of cyclopenta[d]pyrimidines as antitubulin agents and discovery of N-(4-methylthiophenyl) and N-(4-dimethylaminophenyl) substituted N,2-dimethyl-cyclopenta[d]pyrimidines as long acting and poten
Authors: Aleem Gangjee, Weiguo Xiang, Susan L. Mooberry, Ernest Hamel
Journal: Cancer Research (2015)

Abstract Compounds that bind to the colchicine site of microtubules have promising antitumor potential. Some of these agents also possess the ability to overcome multiple drug resistance mechanisms, including those mediated by the expression of P-glycoprotein (Pgp) or expression of the tubulin β-III isotype. We have reported that compounds 1 and 2 were potent antiproliferative agents that bind to the colchicine site of tubulin. The previous structure-activity relationship studies of cyclopenta[d]pyrimidine based antitubulin agents demonstrated the importance of the para-methoxyphenyl moiety for antiproliferative activity. However, the literature suggests that the major metabolism of the methoxyphenyl moiety was likely O-demethylation. In order to increase the potency and in vivo stability of 1, we focused our attention on the variation of the para-methoxy aniline moiety. Compound 3 with a 4′-methylthiophenyl substitution was designed to decrease potential metabolic demethylation. This S-methyl analog was a potent inhibitor of proliferation with an IC50 of 4.6 ± 0.5 nM in MDA-MB-435 cells. The possible sulfoxide metabolite, 4 was synthesized and had an IC50 = 7.9 ± 0.5 nM. Each of these depolymerized microtubules. In addition, the 4′-dimethylamino moiety compound 5 also demonstrated potent antitubulin and antiproliferative activity (MDA-MB-435: IC50 = 8.2 ± 0.6 nM). The possible N-demethylated metabolite of 5, para-methylamino 6 was also a highly potent antiproliferative agent (MDA-MB-435: IC50 = 20 ± 1.9 nM). The parent compounds 3 and 5, as well as their probable metabolites 4 and 6, inhibited the binding of [3H]colchicine to tubulin, which showed that these compounds bind to the colchicine site. The potent antiproliferative activities of the parent compounds and the potential metabolites of compounds 3 and 5 suggest the utility of 3 and 5 as long acting, potent antimitotic agents. Finally, the in vivo efficacy of the S-methyl analog 2 was demonstrated against MDA-MB-435 triple negative breast cancer murine xenograft model, indicating the potential utility of these analogs as antitumor agents. Citation Format: Aleem Gangjee, Weiguo Xiang, Susan L. Mooberry, Ernest Hamel. Design, synthesis, biological evaluation of cyclopenta[d]pyrimidines as antitubulin agents and discovery of N-(4-methylthiophenyl) and N-(4-dimethylaminophenyl) substituted N,2-dimethyl-cyclopenta[d]pyrimidines as long acting and poten [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 1665. doi:10.1158/1538-7445.AM2015-1665
ADVATE [Antihemophilic Factor (Recombinant), Plasma/Albumin- Free Method] Post-Authorization Safety Surveillance (PASS): Safety and Efficacy Following Product Switch in Routine Clinical Practice.
Authors: Huong Luu, Gerald Spotts, Hartwig Gajek, Alex Kriukov, Roger Berg, Darby Stephens, Kerry Barker, Bruce M. Ewenstein
Journal: Blood (2008)