tbuckley/cabot-search huggingface dataset:
Abstract 1952: Adverse effects of erythropoietin stimulates tumor growth via EphB4
Authors: Sunila Pradeep, Jie Huang, Edna Mora, Alpa Nick, Minsoon Cho, Sherry Wu, Rajesha Rupaimoole, Chiyi Xiong, Chun Li, Gabriel Lopez-Berestein, David Jackson, Anil Sood
Journal: Cancer Research (2015)

Abstract Abstract: While recombinant human erythropoietin (rhEpo) has been widely used to treat anemia in cancer patients, concerns about its adverse effects on patient survival have emerged. However the lack of correlation between expression of the canonical EpoR and rhEpo's effects on cancer cells prompted us to consider the existence of an alternative Epo receptor. Methods: We analyzed the membrane-bound portion of the proteome for candidate receptors possessing structural, regulatory, and functional features consistent with Epo binding and tumorigenic signaling. To examine the potential for EphB4 binding to Epo, we generated EpoR−/- MEFs from EpoR−/- mice. We injected A2780-shControl and-shEpoR cells, shEphB4 or -shEpoR/shEphB4 cells in nude mice to study rhEpo induced tumor progression. We also assessed potential effects of tumoral EpoR or EphB4 expression on the effects of ESA treatment in patients with ovarian (N = 175) or breast (N = 88) cancer. Results: Through systems-based approaches we identified EphB4 as an alternate Epo receptor. MST experiments with fluorophore labeled rhEpo demonstrated binding to EpoR with an apparent dissociation constant (KD,app) of 28.0 ± 14.0 nM and EphB4 with a KD,app value of 880.6 ± 128.6 nM. EphB4 and EphrinB2 bound with a KD,app value of 140.5 ± 28.3 nM. We showed that [I125]rhEpo can bind to these cells EpoR−/- MEFs cells. EphB4 triggered the downstream signaling via STAT3 and promoted rhEpo-induced tumor growth and progression. rhEpo stimulated in vivo growth of A2780-shControl (p&amp;lt;0.01) and-shEpoR cells (p&amp;lt;0.01), but not -shEphB4 or -shEpoR/shEphB4 cells. In human ovarian and breast cancer samples, expression of EphB4 rather than the canonical EpoR correlated with decreased disease-specific survival in rhEpo-treated patients. Conclusion: These results identify EphB4 as a critical mediator of erythropoietin-induced tumor progression in cancer patients and further provide a novel and clinically significant dimension to the biology of erythropoietin. Citation Format: Sunila Pradeep, Jie Huang, Edna Mora, Alpa Nick, Minsoon Cho, Sherry Wu, Rajesha Rupaimoole, Chiyi Xiong, Chun Li, Gabriel Lopez-Berestein, David Jackson, Anil Sood. Adverse effects of erythropoietin stimulates tumor growth via EphB4. [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 1952. doi:10.1158/1538-7445.AM2015-1952
The biology of early-onset colorectal cancer: An examination of tumor markers, pathology, and survival in a large cohort of patients.
Authors: S. A. Khan, M. Morris, K. Idrees, M. Gimbel, S. Rosenberg, Z. Zeng, J. Shia, M. P. La Quaglia, P. Paty
Journal: Journal of Clinical Oncology (2011)

3537 Background: Colorectal cancer (CRC) diagnosed before age 30 is a rare and often fatal disease whose biology remains poorly understood. To better understand its pathogenesis, we compared tumor markers, immunohistochemistry and clinical data in early-age onset and adult onset patients. Methods: In an international collaboration between academic centers in the United States and Australia, clinical data and archival tumor tissue were accrued for 94 patients treated surgically for early-age onset CRC (≤age 30). Cases were compared to 276 surgically treated adult onset CRC patients (≥age 50). Tumor tissue was assessed for morphology, microsatellite instability (MSI-H), microsatellite stability (MSS), Kras and Braf mutations, and expression of mismatch repair (MMR) proteins (MSH2, MLH1, MSH6, PMS2). Results: Early-age onset CRC was distinguished from adult onset CRC by poorer median disease-specific survival (44 vs. >120 mo, P<0.01), more advanced stage (III/IV) cancers (76% vs 50%, P<0.01), and higher prevalence of poorly differentiated (37% vs 8%, P<0.01) and signet ring histologies (13% vs <1%, P<0.01). Both groups had a similar prevalence of Kras (28% vs 36%, P=NS) and Braf (9% vs 8%, P=NS) mutations, however a MSI-H genotype was more common in early-age onset CRC (27% vs 13%, P<0.01). Though MSI-H was associated with improved survival and loss of MMR gene expression in both groups, in early-age CRC it was not tightly linked to the loss of MLH1/PMS2 genes and never associated with BrafV600E mutations (p<0.01). The MSS/BrafV600E genotype had a poor prognosis group for all ages, but was more prevalent in early-age onset CRC (Table). Conclusions: Early-onset CRC is driven by the same genes and genetic pathways as adult onset CRC, yet overall cancer biology is more aggressive. Enrichment of a clinically unfavorable MSS/BrafV600E genotype and absence of a favorable MSI-H/BrafV600E genotype partly account for the poor prognosis of early onset CRC. Genotype Early onset (n=94) Adult onset (n=276) P 0 (0%) 14 (5%) MSI-H/BrafV600E Stage III/IV: - Stage III/IV: 93% <0.01 5-yr DSS: - 5-yr DSS: 100% 8 (9%) 8 (3%) MSS/BrafV600E Stage III/IV: 100% Stage III/IV: 100% <0.01 5-yr DSS: 16% 5-yr DSS: 75%
162. Functional Correction of Mucopolysaccharidosis I in Adult Mice by a Systemic rAAV9-IDUA Gene Delivery
Authors: Aaron Meadows, Ricardo Pineda, Marybeth Camboni, Kathryn Waligura, Darren Murrey, Douglas M. McCarty, Haiyan Fu
Journal: Molecular Therapy (2016)

Mucopolysaccharidosis (MPS) I is a lysosomal storage disease caused by autosomal recessive defect in iduronidase (IDUA). The lack of IDUA activity results in the accumulation of GAGs in cells in virtually all organs, leading to profound somatic and neurological disorders. No treatment is currently available for the neurological disorders of MPS I. In this study, we have developed a self-complementary (sc) AAV9 vector expressing human IDUA, targeting the root cause. A single intravenous injection of scAAV9-hIDUA vector at 5×1012vg/kg led to the rapid and persistent restoration of IDUA activity and the clearance of lysosomal storage pathology throughout the CNS, peripheral nervous system (PNS) and broad peripheral tissues, as well as the correction of astrocytosis in the CNS and PNS. Furthermore, we demonstrate that a single systemic scAAV9-IDUA gene delivery provides long-term neurological benefits in MPS I mice, resulting in significant improvement in cognitive and motor function, and extension of survival (ongoing). More importantly, functional benefits were also achieved in MPS I mice that were treated at advanced disease stages. These data demonstrate the promising clinical potential of systemic scAAV9-hIDUA gene delivery for treating MPS I and other neurogenetic diseases.
Abstract 4103: Knockdown of Notch1 inhibits tumor cell proliferation, migration, and invasion and reverses epithelial-mesenchymal transition (EMT) in nasopharyngeal carcinoma
Authors: Huajiao Guo, Yi Lu, Chaonan Qian, Jian Zhang
Journal: Cancer Research (2015)

Abstract Despite a large bodies of evidences support an oncogenic role of Notch signaling in several human solid cancers, however, the pleiotropic effects and molecular mechanisms of blockage of Notch signaling on nasopharyngeal carcinoma (NPC) remain unclear. In this study, Real-time RT-PCR and western blotting were firstly used to examine the expression of Notch1 receptor in a panel of NPC cell lines. CNE1 and CNE2 cells expressed a higher level of Notch1 compared to HONE1, SUNE1 and HK cells. Then Notch1 expression was specifically knocked down in CNE1 and CNE2 cells by Notch1 short hairpin RNA (shRNA). This resulted in a significant inhibition of cell proliferation, migration, and invasion; and interestingly, epithelial-mesenchymal transition (EMT) was reversed in these Notch1-transfected cells along with demonstration of epithelialioid-like morphology change and increase of E-cadherin and decrease of Vimentin expressions. In addition, targeted knockdown of Notch1 dramatically inhibited expression of urokinase plasminogen activator (uPA) and its receptor uPAR, chemokine CCL2 and CXCL16 indicating that these factors are downstream targets of Notch1. Finally, knockdown of Notch1 significantly diminished CNE1 cell growth in a murine model concomitant with inhibition of cell proliferation and induction of apoptosis. Taken together, these results suggest Notch1 may become a therapeutic target in nasopharyngeal carcinoma. Note: This abstract was not presented at the meeting. Citation Format: Huajiao Guo, Yi Lu, Chaonan Qian, Jian Zhang. Knockdown of Notch1 inhibits tumor cell proliferation, migration, and invasion and reverses epithelial-mesenchymal transition (EMT) in nasopharyngeal 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 4103. doi:10.1158/1538-7445.AM2015-4103
Abstract 4502: Identification of an aspirin-derived small molecule as a potential therapeutic for colorectal cancer
Authors: Deepkamal Karelia, Manoj Pandey, Daniel Plano, Satya Narayan, Jitesh Jani, Jay Sharma, Shantu Amin, Arun K. Sharma
Journal: Cancer Research (2015)

Abstract In the US, colorectal cancer (CRC) remains the second leading cause of cancer-related death. The 5-year survival rate for patients with CRC is 64%, although for patients who present with distant metastases at diagnosis the 5 year survival is only 12%. Currently used standard care for CRC can only marginally extend the survival of patients and is associated with numerous adverse events. Hence, there remains an urgent need for more effective and less toxic treatments, which can increase CRC patient survival with better quality of life. Non-steroidal anti-inflammatory drugs (NSAIDs) (e.g. Aspirin, Ibuprofen, Naproxen), which are widely used for their anti-inflammatory and analgesic effects, have also been shown to be effective in reducing colon cancer incidences and are proposed to be effective chemopreventive agents. However, these NSAIDs are not potent enough to be used as cancer therapeutics and also carry a liability of gastrointestinal bleeding mainly associated with COX inhibition. Through extensive structure activity relationship (SAR) studies based on newly synthesized NSAID-analogs, we have identified a novel aspirin analog, ASD-49, as the most effective small molecule that showed efficacy in different cancer cell lines, including CRC cells with an EC50 ranging between 1 to 2.5 μM at 48 h treatment in culture. This unique compound selectively killed cancer cells and is &amp;gt;50-times more potent than the current therapy for CRC and &amp;gt;100-times more potent than the parent compound, aspirin. Our preliminary results show that ASD-49 induces G1 and G2 cell cycle arrest in HT29 cells. In addition, ASD-49 induced apoptosis as indicated by PARP cleavage in HCT116 and RKO cells. Furthermore, we observed down-regulation of anti-apoptotic protein Bcl-2 in a dose-dependent manner in both HCT116 and RKO cell lines. Unlike aspirin, the novel analog did not alter COX-2 protein expression, suggesting that ASD-49 may not possess adverse effects related to COX-2 inhibition. In addition, &amp;gt;100-times lower dose requirement as compared to aspirin is expected to further minimize side effects associated with aspirin structure. Taken together, our results suggest that ASD-49 may be a promising agent for CRC treatment. Detailed results regarding the efficacy and mechanism of action of ASD-49 will be presented. Citation Format: Deepkamal Karelia, Manoj Pandey, Daniel Plano, Satya Narayan, Jitesh Jani, Jay Sharma, Shantu Amin, Arun K. Sharma. Identification of an aspirin-derived small molecule as a potential therapeutic for colorectal 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 4502. doi:10.1158/1538-7445.AM2015-4502
Sorafenib In Combination with Standard Induction and Consolidation Therapy In Elderly AML Patients: Results From a Randomized, Placebo-Controlled Phase II Trial
Authors: Hubert Serve, Ruth Wagner, Cristina Sauerland, Uta Brunnberg, Utz Krug, Markus Schaich, Oliver G. Ottmann, Justus Duyster, Hannes Wandt, Wolfgang Herr, Aristoteles A.N. Giagounidis, Andreas Neubauer, Albrecht Reichle, Walter E. Aulitzky, Richard Noppeney, Igor Wolfgang Blau, Volker Kunzmann, Norbert Schmitz, Karl-Anton Kreuzer, Alwin Krämer, Christian Brandts, Björn Steffen, Achim Heinecke, Christian Thiede, Carsten Müller-Tidow, Gerhard Ehninger, Wolfgang E. Berdel
Journal: Blood (2010)
584. Improvement of Gene Delivery By Inhibition of Endonucleases
Authors: Dae Song Jang, Tariq Fahmi, Narsimha R. Penthala, Eugene O. Apostolov, Peter A. Crooks, Alexei G. Basnakian
Journal: Molecular Therapy (2015)

One of the fundamental problems for gene therapy is poor gene transfer/expression efficiency resulting from DNase/endonuclease activity that plays important role of the host cell defense by degrading foreign DNA. The bulk of endonuclease activity in cells and biological fluids is formed by apoptotic endonucleases which depolymerize DNA by hydrolyzing phosphodiester bonds within the polynucleotide chain. Among the identified nine apoptotic endonucleases, deoxyribonuclease 1 (DNase I) and endonuclease G (EndoG) are the most abundant and most active in mammals. However, there is small number of available inhibitors for DNase I and EndoG, and they are mostly non-specific and inapplicable in vivo. Our in vitro experiments comparing blood plasma of DNase I or EndoG knockout mice with wild-type mice showed that DNase I and EndoG are responsible for degradation of DNA in blood plasma. The genetic inactivation of endonucleases resulted in an improvement of CFP gene expression in HCC1954 cell line after exposure with pECFP plasmid DNA with blood plasma. However using chemical inhibitors would be more translation in this regard. To search for endonuclease inhibitors, we have developed a high-throughput DNase assay using fluorophore-labeled oligonucleotide to screen a home-made chemical library and identify two inhibitors: IG-17 (1, 3-phenylene-bis-aminoguanidine hydrochloride) for DNase I and PNR-3-82 (5-((1-(2-naphthoyl)-5-methoxy-1H-indol-3-yl)methylene)-2-thioxodihydropyrimidine-4,6(1H, 5H)-dione) for EndoG. The inhibitors are found to be specific in vitro and non-toxic in cellular assays. They significantly reduced the in vitro and in vivo (total body) endonuclease activity. In addition, we found that CFP gene delivery to various mouse organs measured by real-time RT-PCR was increased if the inhibitors were administered 2 days before intravenously injection of pECFP plasmid DNA compared to the vehicle-injected mice. This finding can be utilized for further improvement of gene delivery-based therapeutic strategies.
Abstract 1810: Three-dimensional microtissues as phenotypic screening model to identify radiation modifiers for breast cancer
Authors: Natasa Anastasov, Ines Höfig, Vanja Radulovic, Sabine Richter, Jan Lichtenberg, Jens M. Kelm, Christian Thirion, Michael J. Atkinson
Journal: Cancer Research (2015)

Abstract Among breast cancer patients, radiation therapy resistance is a common problem in treatment. Overcoming the mechanisms responsible for this phenotype is an ongoing challenge. Options include repurposing established chemotherapeutics and the discovery of new radiosensitizing compounds. Three-dimensional (3D) microtissue models offer a physiological environment for efficient preclinical drug testing. We have adopted the 3D microtissue technology (Insphero, AG) to generate highly reproducible mammary cancer microtissues in a 96 well format. Two breast cancer cell lines (T47D and MDA-MB-361) were shown to be able to form 3D spheroids and grow in a reproducible manner over time. Validation of the phenotypic screen using breast cancer 3D microtissues was performed by HER2_shRNA knockdown, exposure to ionizing radiation and a panel of selected chemotherapeutic compounds. HER2_shRNA knockdown and irradiation decelerated growth, as proven by measuring the area of the cell spheroids after treatment. Of ten analyzed chemotherapeutics, vinblastine was the most effective compound, with docetaxel and doxorubicine being less effective in combination with radiation. To investigate the response in a model closer to the in vivo situation we investigated the response of heterotypic 3D microtissues containing both fibroblasts and breast cancer cells. Drug treatment of these heterotypic 3D cultures confirmed treatment with radiation plus vinblastine to be additive in causing breast cancer growth inhibition. Additionally a histological method to embed 3D microtissues in paraffin was established. The expression of the proliferation marker Ki67 and the apoptosis marker active Caspase 3 was evaluated in MDA-MB-361 cells after irradiation and concurrent vinblastine treatment. Such combined treatment caused prominent 3D microtissue damage - defined as extensive staining of active Caspase 3 and less Ki67. This suggests that combining vinblastine and radiation may be an effective radiation sensitizing strategy. Citation Format: Natasa Anastasov, Ines Höfig, Vanja Radulovic, Sabine Richter, Jan Lichtenberg, Jens M. Kelm, Christian Thirion, Michael J. Atkinson. Three-dimensional microtissues as phenotypic screening model to identify radiation modifiers for 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 1810. doi:10.1158/1538-7445.AM2015-1810
Abstract 2087: Regulation of p53 function by KLF5
Authors: Yizeng Yang, Taicheng Zhou, Zhen Zong, Gwen Lomberk, Raul Urrutia, Jonathan Katz
Journal: Cancer Research (2015)

Abstract Background: The transcription factor Krüppel-like factor 5 (KLF5) is essential for normal homeostasis, stemness, and tumorigenesis. Typically, KLF5 functions as a transcriptional activator, including in esophageal epithelia where KLF5 promotes keratinocyte proliferation and migration by activating EGFR and ILK, respectively, and prevents transformation by activating Notch1. Yet, the function of KLF5 is context dependent, and mutation of the tumor suppressor p53 switches KLF5 from a transcriptional activator to a repressor of p21Waf1/Cip1 and from pro-proliferative to anti-proliferative. Interestingly, KLF5 also inhibits p53 itself, though the mechanism of this inhibition is unknown. We hypothesized that the functional switch of KLF5 from transcriptional activator to repressor involves the recruitment of a co-repressor. Methods: Primary human esophageal keratinocytes immortalized with hTERT were stably infected with inducible lentivirus containing shRNA against KLF5 or Sin3A. p53 mRNA and protein levels were assessed by real-time quantitative PCR and Western blotting, respectively, and p53 protein stability was evaluated by pulse-chase experiments. We employed ChIP across a 4 kb region on the p53 gene, from 2 kb upstream to 2 kb downstream of the transcription start site, to identify the region of KLF5 binding on p53. Promoter activity was assessed with a series of luciferase reporters containing varying lengths of p53 and its upstream regulatory region. Protein-protein interaction was examined by co-IP. Results: KLF5 knockdown significantly increased p53 both at the mRNA and protein levels. In unstressed cells p53 protein undergoes rapid degradation such that p53 levels are typically low. Yet, with KLF5 knockdown, despite increased p53 protein levels, we saw no changes in p53 protein stability. By ChIP, we identified a region of KLF5 binding to p53 between -600 to -356 bp upstream of the transcription start site. Several other KLF family members can interact with the co-repressor Sin3A, and we found that Sin3A also complexed with KLF5 in human primary esophageal keratinocytes. Knockdown of Sin3A abolished the inhibitory effect of KLF5 on p53, resulting in elevated p53 expression, growth inhibition, and increased apoptosis. Conclusion: KLF5 transcriptionally represses p53 via the co-repressor Sin3A. Thus, KLF5 promotes cell proliferation in normal keratinocytes by both activating pro-growth signals and inhibiting the brake machinery of the cell cycle. Citation Format: Yizeng Yang, Taicheng Zhou, Zhen Zong, Gwen Lomberk, Raul Urrutia, Jonathan Katz. Regulation of p53 function by KLF5. [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 2087. doi:10.1158/1538-7445.AM2015-2087
Gene Expression Profiling Analysis in Splenic Marginal Zone Lymphoma Allows To Predict Survival and Histological Transformation.
Authors: C. Thieblemont, B. Ballester, V. Nasser, S. Gazzo, G. Doucet, P. Felman, E. Callet-Bauchu, F. Berger, L. Loi, G. Salles, D. Birnbaum, B. Coiffier, R. Houlgatte
Journal: Blood (2004)
18F-Fluorodeoxyglucose (FDG) Positron Emission Tomography (PET): An Important Tool in the Management of Infection in Patients with Hematological Cancer.
Authors: Elias J. Anaissie, Marisa H. Miceli, Steve D. Strout, Laurie Jones-Jackson, Ronald C. Walker, Gary Purnell, Jose A. Diaz, Fariba Saghafifar, Klaus A. Hollmig, Anasthasios Fassas, Guido Tricot, Bart Barlogie
Journal: Blood (2004)