tbuckley/cabot-search huggingface dataset:
Abstract 2109: Short isoform ARID5B protein is expressed in endometrial cancer cell lines by usage of the second translation initiation codon
Authors: Norihiko Kawamata, Keiichi Itakuara
Journal: Cancer Research (2015)

Abstract ARID5B, also known as MRF2, is a transcription factor with the ARID-type DNA binding domain. The ARID5B gene generates two types of mRNA isoforms (short and long isoforms) using alternative first exons; the long and short mRNA isoforms encode 130kDa long and 100kDa short isoform ARID5B proteins, respectively. The ARID5B gene is highly mutated in endometrial cancer. Nonsense and frame-shift mutations, generating premature termination codons, are common. This transcription factor may play a role as a tumor suppressor in development of endometrial cancer and the inactivation of the gene by the mutations may contribute to carcinogenesis of this cancer. To characterize functional significance of the gene products in this cancer, we analyzed the ARID5B gene in three endometrial cancer cell lines (Ishikawa, HEC59, and KLE). Two cell lines, Ishikawa and HEC59, predominantly expressed the long isoform mRNA while KLE expressed both the long and short isoform mRNAs. However, surprisingly, all the cell lines predominantly expressed the 100 kDa protein, which was detected by an antibody recognizing the ARID-domain. To characterize the 100kDa protein, we generated rabbit anti-serum recognizing amino-terminus of the long isoform protein, which failed to detect the 100kDa protein. The data suggested that the 100kDa protein lacked the N-terminus of the long isoform ARID5B protein. Internal ribosome entry site (IRES) activity was found in the sequence between the first and second ATGs of the long isoform ARID5B mRNA by the bicistronic reporter gene assay. Our data suggested that the second translation initiation codon was used to generate the short isoform ARID5B protein in the cell lines. To elucidate functional property of this short isoform ARID5B protein expressed in the cell lines, we suppressed the expression of the ARID5B protein by shRNA. The expression was decreased by 50% using the shRNA constructs. Colony formation assay of Ishikawa cells transfected with the shRNA constructs showed that repression of ARID5B short isoform protein decreased the number of the colonies. In summary, the short isoform ARID5B protein generated by usage of the second translation initiation site was indispensable in these endometrial cancer cells. Citation Format: Norihiko Kawamata, Keiichi Itakuara. Short isoform ARID5B protein is expressed in endometrial cancer cell lines by usage of the second translation initiation codon. [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 2109. doi:10.1158/1538-7445.AM2015-2109
Abstract 2083: TFAP4 inhibits differentiation of MYCN-amplified neuroblastoma
Authors: Shuobo Zhang, Gonzalo Lopez, Jiyang Yu, Jose Silva, Angela Kadenhe-Chiweshe, Andrea Califano, Darrell Yamashiro
Journal: Cancer Research (2015)

Abstract Background. Despite the identification of MYCN-amplification as an adverse prognostic marker in neuroblastoma, no drugs that target MYCN have yet been developed. An alternative approach is to identify genes synthetically lethal to MYCN-amplified neuroblastoma. Through a whole genome shRNA screen, we have previously identified transcription factor AP4 (TFAP4) as a synthetic lethal gene of MYCN-amplified neuroblastoma. Silencing of TFAP4, both in vitro and in vivo inhibited the growth of MYCN-amplified neuroblastoma. TFAP4 has previously reported to repress neuronal specific genes in non-neuronal cells (Kim et al, 2006). Here, we investigate the function of TFAP4 in inhibiting differentiation of MYCN-amplified neuroblastoma. Methods: Master regulators specifically associated to MYCN amplified patients were identified by MARINA (Master Regulator Inference algorithm). TFAP4 expression was measured by real-time PCR, Western blot and immunohistochemistry. GAP43 expression was detected by Western blot. Gene expression changes after silencing of TFAP4 or retinoic acid treatment was determined by RNAseq. Results: TFAP4 was identified as a master regulator specifically in MYCN amplified neuroblastoma patients in both NCI-TARGET dataset and a published GEO dataset (Kocak et al, 2013). We determined that TFAP4 is a direct target of MYCN and TFAP4 expression was highly correlated with Stage 4, MYCN-amplified neuroblastoma in both patient datasets. Neuronal markers TUBB3 and GAP43 expression were inversely correlated with TFAP4 expression in TARGET (P = 9.77e-03 and P = 7.78e-08). Silencing TFAP4 in MYCN amplified cells induced a differentiated phenotype, as shown by markedly increased the number of neurites, and an increase in the neuronal differentiation marker GAP43. Forty hours after silencing TFAP4, we observed 415 genes that were significantly up-regulated and 457 genes down-regulated (P&amp;lt;0.01). Genes with increased expression were enriched for gene ontology terms associated with neuronal activity. Gene signature of TFAP4 also showed a strong correlation with the treatment signature of the differentiation agent retinoic acid in SKNDZ. Conclusions. We demonstrated that TFAP4 is an important downstream effector of MYCN, that inhibits the neuronal differentiatin of MYCN-amplified neuroblastoma. This may provide novel targets for the treatment of neuroblastoma. Citation Format: Shuobo Zhang, Gonzalo Lopez, Jiyang Yu, Jose Silva, Angela Kadenhe-Chiweshe, Andrea Califano, Darrell Yamashiro. TFAP4 inhibits differentiation of MYCN-amplified neuroblastoma. [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 2083. doi:10.1158/1538-7445.AM2015-2083
Abstract 3645: A non-ATP competitive IKKβ inhibitor for cancer therapy
Authors: Sandeep Rana, Elizabeth Blowers, Amarnath Natarajan
Journal: Cancer Research (2015)

Abstract Kinases are promising targets in cancer drug discovery. IKKβ is an important kinase in the canonical NF-κB pathway, which promotes survival of cancer cells and is constitutively active in number of cancers including pancreatic cancer. Inflammatory stimulus such as tumor necrosis factor-α (TNFα) is known to activate the canonical IKKβ-NF-κB pathway. Upon TNFα stimulation, serine residues 177 and 181 in the activation loop of IKKβ undergo phosphorylation resulting in activated IKKβ. Immunohistochemistry (IHC) studies showed the presence of the proinflammatory cytokine TNFα in ∼50% of surgically resected tumor specimens but in only ∼10% of corresponding normal tissues. Consistently, IHC studies by us with patient samples obtained from the UNMC rapid autopsy pancreatic cancer program showed elevated levels of phosphorylated S181 IKKβ in the tumor and liver metastases samples when compared to the stroma and ductal cells for normal pancreas. Several small molecule IKKβ inhibitors were developed by pharmaceutical industry to treat chronic inflammatory diseases. Despite complete preclinical characterization of many candidates, to date none of them has been approved by the FDA for clinical use. Nearly all the small molecule IKKβ inhibitors reported are ATP competitive. These inhibitors completely block IKKβ mediated NF-κB activity as a result chronic administration in mice leads to granulocytosis and increased susceptibility to infection-mediated death. Here we report the discovery a non-ATP competitive IKKβ inhibitor that allows transient activation but blocks the sustained activation of IKKβ mediated NF-κB activity. We present a model that has a novel-binding site, which is accessible upon activation of IKKβ and explains the observed experimental results. Our IKKβ inhibitor does not share the toxicity profile of the ATP competitive IKKβ inhibitors. In an orthotopic pancreatic tumor model mice treated with our inhibitor showed reduced tumor growth and metastasis compared to vehicle controls. We also showed that in a mantle cell lymphoma model the median survival of mice treated with our inhibitor nearly doubled when compared vehicle treated mice. Our results suggest that non-ATP competitive IKKβ inhibitors are viable lead candidates for cancer therapy. Citation Format: Sandeep Rana, Elizabeth Blowers, Amarnath Natarajan. A non-ATP competitive IKKβ inhibitor for cancer therapy. [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 3645. doi:10.1158/1538-7445.AM2015-3645
Erythropoietin alpha (EPO) and darbepoetin (D) use in chemo induced anemia (CIA) in U.S. community oncology practices
Authors: P. G. Kwan, J. Koeller, R. Smith, J. Simon
Journal: Journal of Clinical Oncology (2004)

8275 Background: Though D has been available for a year, no comparative trials between EPO and D have been presented. Also, there are few effectiveness evaluations aimed at highlighting differences between the two. Therefore, evidence supporting product selection rational is scant. NSCLC is a tumor type in which EPO treatment (tx) is common. We report an effectiveness evaluation of D and EPO in advanced NSCLC patients in the community practice setting. Methods: From 1/03 to 10/03 a 4-member research team performed direct medical record abstraction as part of a NSCLC disease map research trial at 10 community practices, involving 49 physicians overall. St IIIb / IV NSCLC pts who received EPO or D for CIA were reviewed. Data included demographics, tx info (date, dose, route), hgb, Fe stores, and blood transfused. Transfused pts were excluded. Inclusion / Response criteria \(\underline{\mathrm{for\ 4\ wk\ endpt}}\): 2 or more wkly doses / ≥1 hgb rise by day 30; \(\underline{\mathrm{for\ 8\ wk\ endpt}}\): 4 or more wkly doses / ≥2 hgb rise by day 58. The data was also analyzed for appropriate dose adjustment in pts not responding at 4 wks (95%CIs). Results: Visits to med onc practices in CT, FL, ME, LA, KY, IN, and NV resulted in a total database of 730 NSCLC pts. 276 (38%) received EPO, and 61 (9%) received D. See Data Table. Appropriate dose adjustment was required in 35/178 (20%) of \(\underline{\mathrm{responding}}\) patients. However, there was no adjustment by week 8 in \(\underline{\mathrm{non\ responding}}\) patients at a rate of 40/61 (66%, CI 54–78%). Conclusions: Though EPO had a higher response at 4wk and 8wk, the low n of D made statistical comparison difficult. More data is needed to explore if time to response is indeed faster with EPO. Regarding dose adjustment of EPO or D in non responding patients, there exists a significant gap between the recommended guidelines and what the community practices. Table 1. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Amgen
Emergence of Long-Lived Autoreactive Plasma Cells in the Spleen of ITP Patients Treated with Rituximab
Authors: Matthieu Mahévas, Marc Michel, Pauline Patin, Francois Huetz, Marc Descatoire, Nicolas Cagnard, Christine Bole-Feysot, Medhi Khellaf, Lionel Galicier, David Boutboul, Mikael Ebbo, Simon le Gallou, Olivier Fain, Olivier Lambotte, Corinne Haouin, Philippe Bierling, Bertrand Godeau, Jean-claude Weill, Claude-Agnès Reynaud
Journal: Blood (2012)
LACE: A conditioning regimen for patients with lymphoma undergoing autologous transplant.
Authors: R. Thippeswamy, L. Mathew, B. Bhosale, N. Kumar, S. Kannan, A. Joshi, V. Rangarajan, N. Khattry
Journal: Journal of Clinical Oncology (2011)

6591 Background: Carmustine, etoposide, ARA-C, melphalan (BEAM) and carmustine, cyclophosphamide, etoposide (CBV) are commonly used high-dose chemotherapy regimens prior to autologous transplantation in patients of non-Hodgkin’s (NHL) and Hodgkin’s lymphoma (HL) but are associated with significant toxicity. We report the results of lomustine, ARA-C, cyclophosphamide, etoposide (LACE) regimen from our center and role of prognostic factors. Methods: Forty-two patients of relapsed and refractory NHL (14) and HD (28) who received LACE-regimen between November 2007- December 2010 were included in this retrospective study. LACE-regimen included lomustine-200 mg/m2 d-7, etoposide 1000mg/m2 d-7, ARA-C 2000 mg/m2 d-6, d-5 and cyclophosphamide 1,800mg/m2 d-4 to d-2. PET-CT was done pretransplant, on day 100 and at 1 year post transplant. Prognostic factors evaluated for overall survival (OS) and progression-free survival (PFS) included time between diagnosis - transplant, time between diagnosis - first relapse, PET uptake pretransplant, disease status at transplant and stage at diagnosis. Results: The median age at transplant was 23 years. The median time from diagnosis to first relapse and transplant were 1.57 and 1.95 years respectively. At the time of transplant, 62% were in complete remission (CR), 33% in partial remission (PR) and 5% had refractory state. The incidence of grade 3 or 4 oral mucositis was 15%. The incidence of grade 2-4 diarrhea was 30%. One patient died due to neutropenic sepsis. No patient developed veno-occlusive disease of liver while 1 patient developed pulmonary toxicity. Median days to neutrophil engraftment and platelet engraftment were 9 and 12.5 respectively. At day 100, 84% were in CR and 10% progressed. The median follow-up was 11.5 months. The probability of OS and PFS at 2.25 years was 66% and 46%. Univariate analysis identified time between diagnosis and first relapse greater than 1.57 years, time between diagnosis and transplant greater than 1.95 years and negative PET-CT at the time of transplant as factors associated with significant improvement in OS. Conclusions: LACE is an effective regimen with low incidence of acute toxicity. This regimen needs further evaluation.
Abstract 4816: Design, validation, and interpretation of an NGS assay for actionable variants in solid tumors
Authors: Susan M. Mockus, Guruprasad Ananda, Micaela Lundquist, Vanessa Spotlow, Al Simons, Talia Mitchell, Grace A. Stafford, Christopher S. Potter, Vivek Philip, Timothy Stearns, Anuj Srivastava, Mary Barter, Lucy Rowe, Joan Malcolm, Carol Bult, Radha Krishna Murthy Katuturi, Karen Rasmussen, Douglas Hinerfeld
Journal: Cancer Research (2015)

Abstract The Jackson Laboratory Cancer Treatment Profile™ (JAX-CTP™) is a next generation sequencing (NGS)-based molecular diagnostic assay that detects actionable gene variants in solid tumors to inform the selection of targeted therapeutics for cancer treatment. We will describe the design of the 358- gene panel, analytical validation, and the curation and clinical reporting of actionable variants. Selection of the gene panel was based on known drug targets, casual implications in cancer, and a thorough pathway analysis. DNA is extracted from FFPE tumor samples and using hybrid capture, the genes of interest are enriched and sequenced on Illumina HiSeq 2500 or MiSeq sequencers. FASTQ files generated from Illumina's CASAVA software are submitted to the JAX Clinical Genome Analytics (CGA) data analysis pipeline to perform automated read quality assessment, alignment, and variant calling. Identified variants are then submitted for clinical curation using a combination of the in-house JAX Clinical Knowledgebase (CKB) and the external Genetic Variant Annotation (GVA) from CollabRx. Once clinically annotated, the variants are graded relative to their clinical utility for the specific tumor type and compiled into a clinical report to inform patient treatment. Extensive analytical validation, following CAP guidelines, was conducted to assess limit of detection, accuracy, precision, sensitivity, and specificity of the assay. The summarized optimized sensitivity of the assay is a minimum coverage of samples at 300X, a limit of detection of 10% for SNP’s/indels and ≥6 copies for CNV’s, and an average of 3-4 actionable variants per sample. The challenges of interpreting gene variants for clinical actionability and for establishing an analytically valid bioinformatic pipeline will be discussed in-depth. Citation Format: Susan M. Mockus, Guruprasad Ananda, Micaela Lundquist, Vanessa Spotlow, Al Simons, Talia Mitchell, Grace A. Stafford, Christopher S. Potter, Vivek Philip, Timothy Stearns, Anuj Srivastava, Mary Barter, Lucy Rowe, Joan Malcolm, Carol Bult, Radha Krishna Murthy Katuturi, Karen Rasmussen, Douglas Hinerfeld. Design, validation, and interpretation of an NGS assay for actionable variants in solid tumors. [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 4816. doi:10.1158/1538-7445.AM2015-4816
Abstract 619: Identification of clinically actionable genomic alterations in the tumor and circulation of pancreatic cancer patients
Authors: Mark Sausen, Jillian Phallen, Vilmos Adleff, Siân Jones, Rebecca J. Leary, Karli Lytle, Sonya Parpart-Li, Derek Murphy, Michael T. Barrett, David C. Linehan, Anirban Maitra, Ralph Hruban, Daniel D. Von Hoff, Julia S. Johansen, Luis A. Diaz, Jeffrey A. Drebin, Victor E. Velculescu
Journal: Cancer Research (2015)

Abstract Pancreatic adenocarcinoma has the worst overall mortality of any solid tumor, with only 6% of patients surviving after 5 years. To evaluate the clinical implications of genomic alterations in this low cellularity tumor type, we deeply sequenced the genomes of 134 enriched pancreatic adenocarcinomas from patients who underwent potentially curative resections. Given the low neoplastic cellularity of pancreatic cancers, we enriched for neoplastic cells either by macrodissection of primary tumors or by flow-sorting of tumor nuclei, and performed deep sequencing (high coverage) of these enriched samples using next-generation sequencing approaches. We obtained a total of &amp;gt;1Tb of sequence data, resulting in an average coverage within the target regions of &amp;gt;200-fold for each tumor analyzed by whole-exome sequencing and &amp;gt;750-fold for each tumor analyzed by targeted cancer gene sequencing. These approaches allowed us to identify sequence changes, including single base and small insertion or deletion mutations, as well as copy number alterations in &amp;gt;20,000 genes in the whole-exome analyses and in 116 specific genes in the targeted analyses. These analyses revealed that somatic mutation of chromatin remodeling genes were associated with improved progression-free and overall survival. Alterations in genes with potential clinical utility were observed in a majority of cases and included alterations of AKT1, AKT2, BRCA2, ERBB2, KIT, and PIK3CA. Non-invasive liquid biopsy analyses were performed before and after surgery to evaluate the presence of circulating tumor DNA in the plasma of 83 patients. Through these approaches, we were able to diagnose early stage pancreatic tumors in the majority of patients and to detect the presence of circulating tumor DNA prior to clinical relapse. These observations provide genetic markers of clinical outcome in pancreatic cancer and suggest new avenues for personalized therapy. Citation Format: Mark Sausen, Jillian Phallen, Vilmos Adleff, Siân Jones, Rebecca J. Leary, Karli Lytle, Sonya Parpart-Li, Derek Murphy, Michael T. Barrett, David C. Linehan, Anirban Maitra, Ralph Hruban, Daniel D. Von Hoff, Julia S. Johansen, Luis A. Diaz, Jeffrey A. Drebin, Victor E. Velculescu. Identification of clinically actionable genomic alterations in the tumor and circulation of pancreatic cancer patients. [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 619. doi:10.1158/1538-7445.AM2015-619
PWE-011 Consistency between bowel cancer screening colonoscopists of varying backgrounds: the St Mark's experience: Abstract PWE-011
Authors: S Gupta, N Suzuki, C Fraser, M E Vance, B P Saunders, S Thomas-Gibson
Journal: Gut (2010)

<h3>Introduction</h3> St Mark9s Bowel Cancer Screening Centre (BCSC) became “live” from October 2006. It has five accredited screening colonoscopists of varying backgrounds-3 UK trained consultant gastroenterologists, one UK trained consultant nurse endoscopist and a very experienced Japanese trained honorary consultant endoscopist. <h3>Methods</h3> To compare endoscopic performance between the five screening colonoscopists at St Mark9s BCSC. Performance indicator data were prospectively collected for each endoscopist and analysed (October 2006–September 2009). <h3>Result</h3> Over 1200 colonoscopies were performed. Screeners 1, 2, 4 were accredited at the start. Screener 3 was accredited in 2007 and screener 5 has been performing screening lists for 13 months with no regular list to date (Abstract 011). <h3>Conclusion</h3> Polyp/adenoma detection rates were higher than expected. There was a significantly lower ADR for Colonoscopist 4 (38.57), however this was above the national target. There were no other significant differences in performance. A longer procedure time may be associated with higher completion and adenoma detection rates. Cancer rates were lower than national figures possibly due to a previous flexible sigmoidoscopy trial in the centre in 1999.
Prognostic Significance of FLT3 Mutations in Paired Initial and Relapse Marrow Samples of Acute Myeloid Leukemia Excluding Acute Promyelocytic Leukemia.
Authors: Young-Uk Cho, Hyun-Sook Chi, Seongsoo Jang, Chan-Jeoung Park, Je-Hwan Lee, Kyoo Hyung Lee, Jung-Hee Lee, Ho-Jun Lim, Jong-Jin Seo
Journal: Blood (2006)
Predictive Factors of Early Mortality in Patients with Multiple Myeloma (MM). Multicentric Study in Chile (1998–2002).
Authors: Guillermo F. Conte, Gaston L. Figueroa, Vivianne I. Lois, Maria E. Cabrera, Alvaro R. Leon, Hernan L. Garcia, Hernan H. Rojas
Journal: Blood (2006)
191. Development of an Effective Cancer Vaccine Platform Using Attenuated Salmonella to Deliver Recombinant Tumor-Associated Antigens
Authors: Xin Xu, Michael S. Wood, Suhrab Kurbanov, Linjie Guo, Xiuhua Gao, James E. Galen, Leonid S. Metelitsa
Journal: Molecular Therapy (2016)

Inadequate antigen delivery is one of the major limitations of modern cancer vaccine vectors. To overcome this challenge, we exploited Salmonella Pathogenicity Island 2 (SPI2) and its type III secretion system (T3SS) to deliver a tumor-associated antigen (TAA) of choice into the cytosol of antigen-presenting cells (APC) in situ. The goal of this study was to explore and exploit the potential of SPI2-encoded T3SS of clinically validated S. typhi strain CVD908 for construction of an effective cancer vaccine. We engineered the clinically validated S. typhi strain CVD908 to express SPI2-regulated dominant-negative oncoproteins survivin and MYCN. To adapt CVD908 to stably express recombinant antigens without antibiotic-dependent selection, we used a recently reported plasmid stabilization system that encodes the single-stranded binding protein (SSB), an essential protein in DNA metabolism, which was deleted from the bacterial chromosome. The SPI2-regulated expression cassette was then cloned into the SSB plasmid, so that the resultant construct maintained bacterial vector stability. We found that CVD908Δssb vector could effectively infects dendritic cells and induce antigen-specific CD8 T cell responses in vitro and in vivo. Furthermore, therapeutic vaccination with CVD908Δssb vector expressing survivin or MYCN produced potent antitumor activity in murine models of neuroblastoma and lymphoma. Thus, oral antigen delivery via SPI2-encoded T3SS of Salmonella typhi may provide the foundation of an effective cancer vaccine platform. Supported by grants from CPRIT (RP121035) and The Leukemia and Lymphoma Society.
Generation of Melanoma Antigen Specific T Cells From Human Ips Cells Using a Feeder Free System.
Authors: Raul Vizcardo, Kyoko Masuda, Daisuke Yamada, Tomokatsu Ikawa, Kanako Shimizu, Shin-ichiro Fujii, Haruhiko Koseki, Hiroshi Kawamoto
Journal: Blood (2012)