tbuckley/cabot-search huggingface dataset:
Abstract 2592: Anti-tumor activity of icotinib (BPI-2009H) and BPI-403B in the BxPC-3 pancreatic cancer cell line
Authors: Victoria Lynn Wilde, Don Zhang, Jirong Peng, Michael A. Green, Michael N. Greco, Michael Costanzo
Journal: Cancer Research (2015)

Abstract Introduction: The purpose of this research was to investigate the anti-tumor effect of BPI-2009H and BPI-403B, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) in the human pancreatic cancer cell lines BxPC-3 and Panc-1, in vitro and in vivo and determine the maximum tolerated dose (MTD) of the compound in mouse. Experimental Design: In vitro, human pancreatic cancer cell lines, BxPC-3 and Panc-1 were exposed to varying concentrations of BPI-2009H and BPI-403B, the concentration of compound required to inhibit growth by fifty percent (IC50) was estimated. In vivo, tumor growth inhibition of low dose BPI-2009H was tested in xenografted nude mice with BxPC-3 pancreatic cancer tumors. The maximum tolerated dose (MTD) was established via oral administration of low, mid and high doses to Harlan mice of both BPI-2009H and BPI-403B. Upon determination of the MTD, the in vivo efficacy of high dose BPI-2009H was evaluated via tumor growth inhibition study on xenografted nude mice with BxPC-3 pancreatic cancer tumors. Results: BPI-2009H, as a single agent, inhibited the growth of BxPC-3 cells in a dose dependent manner, with a relative IC50 value of 25.8 μM. BPI-403B, as a single agent, inhibited growth of BxPC-3 cells in a dose dependent manner as well, with a relative IC50 value of 2.7 μM. BPI-2009H and BPI-403B were tested up to 50μM in Panc-1 cells with no apparent effect at the upper limit of the study for either of the compounds. In vivo, the mice treated with BPI-403B demonstrated a statistically significant tumor growth delay, 14.3 days. 20% of the mice experienced tumor regression. The compound was well tolerated with minimal body weight loss. At low doses, BPI-2009H did not show any statistically significant tumor growth delay, but upon increasing the dose to the MTD, significant signs of anticancer activity was demonstrated, with an increase in tumor growth delay. Conclusions: The in vitro and in vivo findings show that both BPI-2009H and BPI-403B have antiproliferative effects against BxPC-3 pancreatic cancer cells. These compounds are both well tolerated and may prove to be an alternative option of EGFR-TKI to erlotinib treatment in pancreatic cancer cases. Citation Format: Victoria Lynn Wilde, Don Zhang, Jirong Peng, Michael A. Green, Michael N. Greco, Michael Costanzo. Anti-tumor activity of icotinib (BPI-2009H) and BPI-403B in the BxPC-3 pancreatic cancer cell line. [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 2592. doi:10.1158/1538-7445.AM2015-2592
Abstract 5473: Human cancer cells acquire chemoresistance to gemcitabine mainly through loss-of-function mutations in the DCK gene
Authors: Akira Horii, Yuriko Saiki, Tomohiro Nakano, Chiharu Kudo, Makoto Sunamura
Journal: Cancer Research (2015)

Abstract Gemcitabine (GEM) has shown clinical activity in several solid tumors such as pancreatic and biliary tract cancers, urinary cancer, and non-small cell lung cancers, but a substantial number of patients acquire GEM chemoresistance. GEM functions after phosphorylation by deoxycytidine kinase (DCK) and its inactivation is one of the important mechanisms for acquisition of gemcitabine resistance. We established eight GEM resistant cell lines including four pancreatic, two biliary tract, and two gastrointestinal cancers and investigated mechanisms for acquisition of GEM resistances; six GEM resistant cell lines harbored complete inactivating mutations of DCK by protein-truncating mutation or complete or partial loss of the gene, and one gastric cancer cell line harbored a missense mutation that inactivate DCK activity. One pancreatic cancer cell line lost GEM sensitivity by unknown mechanism. Our present results strongly suggest that genetic alteration of DCK can be the major cause of acquisition of GEM resistance. Further studies analyzing primary tumors will give us (1) the fully understanding of acquisition of GEM resistance, and (2) desirable clues to overcome the acquisition of GEM resistance. Citation Format: Akira Horii, Yuriko Saiki, Tomohiro Nakano, Chiharu Kudo, Makoto Sunamura. Human cancer cells acquire chemoresistance to gemcitabine mainly through loss-of-function mutations in the DCK gene. [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 5473. doi:10.1158/1538-7445.AM2015-5473
Abstract 3154: Identification of CD4+ T cell epitopes specific for the breast cancer associated antigen NY-BR-1
Authors: Adriane Gardyan, Wolfram Osen, Maria Agawal, Inka Zörnig, Eliana Ruggiero, Manfred Schmidt, Andreas Schneeweiss, Dirk Jäger, Stefan B. Eichmüller
Journal: Cancer Research (2015)

Abstract Questions: Whether CD4+ T cell epitopes specific for the breast cancer associated antigen NY-BR-1 can be identified using HLA-transgenic (HLAtg) mice. Introduction: Adoptive transfer of TCR-transduced autologous tumor antigen-specific T cells provides an innovative strategy for cancer immunotherapy. The differentiation antigen NY-BR-1 is over-expressed in approx. 60% of all invasive mammary carcinomas, thus representing a potential target for cancer immunotherapy. We thus screened NY-BR-1 for the presence of CD4+ T cell epitopes. Methods: Splenocytes from DNA immunized HLA-DRB1*0301 and HLA-DRB1*0401 tg mice were screened ex vivo by IFNγ ELISpot assay against a NY-BR-1-derived peptide library. In silico predicted candidate epitopes present among recognized library peptides were used to establish CD4+ T cell lines as a read tool to prove HLA-DR-restriction and natural processing of these epitopes by human cells. NY-BR-1-specific CD4+ T cell reactivity among PBMC of breast cancer patients was tested after long term in vitro restimulation with synthetic 15mers by intracellular cytokine staining. Results: Three HLA-DRB1*0301-restricted and four HLA-DRB1*0401-restricted NY-BR-1-specific CD4+ T cell epitopes were identified in HLAtg mice. HLA-DR-restriction was confirmed upon specific recognition of peptide-loaded T2/DR3 and T2/DR4 target cells by epitope-specific CD4+ T cell lines established from HLAtg mice. These T cell lines specifically recognized human dendritic cells loaded with cell lysates from Ad5-NY-BR-1 infected melanoma cells, showing natural processing of the epitopes. Moreover, upon deep sequencing of TCRs from these murine CD4+ T cell lines two NY-BR-1-specific TCRs were identified which could be considered for the generation of autologous TCR-transduced T cells lines. Finally, CD4+ T cells reactive against the NY-BR-1 specific epitopes were also detected among PBMCs of HLA-DR matched breast cancer patients. Conclusion: NY-BR-1-specific, HLA-DRB1*0301 and HLA-DRB1*0401 restricted CD4+ T cell epitopes could be identified using HLAtg mice and CD4+ T cells reactive against these epitopes are present among PBMCs of breast cancer patients. Finally, murine HLA-restricted CD4+ T cell lines might serve as source of NY-BR-1-specific TCRs for adoptive immunotherapy approaches. Citation Format: Adriane Gardyan, Wolfram Osen, Maria Agawal, Inka Zörnig, Eliana Ruggiero, Manfred Schmidt, Andreas Schneeweiss, Dirk Jäger, Stefan B. Eichmüller. Identification of CD4+ T cell epitopes specific for the breast cancer associated antigen NY-BR-1. [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 3154. doi:10.1158/1538-7445.AM2015-3154
The Prolonged Time to Progression with Pegylated Liposomal Doxorubicin + Bortezomib Versus Bortezomib Alone in Relapsed or Refractory Multiple Myeloma Is Unaffected by Extent of Prior Therapy or Previous Anthracycline Exposure.
Authors: Joan Blade, Jesus San Miguel, Arnon Nagler, Pieter Sonneveld, Andrew Spencer, Tadeusz Robak, Kathleen Hennessey, Suneel D. Mundle, Sen H. Zhuang, Jean-Luc Harousseau, Robert Z. Orlowski
Journal: Blood (2007)
Lenalidomide Upregulates CXCR4 on CD34+ Hematopoietic Cells Resulting In Increased Binding to Bone Marrow Niche and Inhibiting Mobilization Into Peripheral Blood In Multiple Myeloma Patients
Authors: Shirong Li, Rentian Feng, Huihui Ma, G. David Roodman, Markus Y Mapara, Suzanne Lentzsch
Journal: Blood (2010)
Abstract 3028: Tolerance and intolerance of proximal thymine glycol in DNA double-strand break repair by nonhomologous end joining
Authors: Duaa Bafail, Sri Lakshmi Chalasani, Mohammed Al mohaini, Konstantin Akopiants, Lawrence F. Povirk
Journal: Cancer Research (2015)

Abstract Double-strand breaks (DSBs) induced by ionizing radiation are often accompanied by ancillary oxidative base damage that could prevent or delay their repair. In order to better define the features that make some DSBs repair-resistant, plasmid DSB substrates were constructed with two blunt ends, one having the oxidatively modified nonplanar base thymine glycol at the first, second or third positions from the 3′ terminus (Tg1, Tg2 and Tg3, respectively). End joining was examined in extracts of Bustel fibroblasts, wherein end joining is completely dependent on addition of exogenous recombinant XLF, and therefore reflects classical nonhomologous end joining. Tg at the third position had almost no effect on end-joining even when present on both ends of the break. However, the Tg1 and Tg2 substrates yielded tenfold to twentyfold less head-to-tail joins and no detectable head-to-head joins, suggesting that Tg as the terminal or penultimate base is a serious barrier to NHEJ and an absolute barrier when present at both ends. For all substrates, Tg-containing ligation products predominated at early times, and remarkably, a 3′ terminal Tg was in some cases directly ligated to an undamaged blunt end. Dideoxy trapping of base excision repair intermediates indicated that Tg was excised in the extracts, but largely if not exclusively after DSB ligation. For all substrates, accurate blunt end ligation without end trimming predominated. However addition of excess Artemis nuclease to the extracts resulted in a slightly shorter ligation product, and a slight increase in yield, for the Tg2 substrate only. For the Tg1 substrate, there was a distinct 2-hr delay between addition of substrate and the detection of ligated products, while the unmodified and Tg3 products showed a much shorter delay of ∼30 min. Overall, the results suggest that Tg can be a major impediment to DSB repair when present as the terminal or penultimate base, being relatively resistant to both trimming and ligation. Citation Format: Duaa Bafail, Sri Lakshmi Chalasani, Mohammed Al mohaini, Konstantin Akopiants, Lawrence F. Povirk. Tolerance and intolerance of proximal thymine glycol in DNA double-strand break repair by nonhomologous end joining. [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 3028. doi:10.1158/1538-7445.AM2015-3028
Genome-Wide Methylation Analysis of Primary Mantle Cell Lymphomas Identifies Novel Gene Targets for Epigenetic Drug Therapy.
Authors: Violetta Leshchenko, Pei-Yu Kuo, Rita Shaknovich, Tobias Gellen, Yvonne Remache, Marc Weniger, K. Stephen Suh, Andre Goy, Wyndham Wilson, Ira Braunschweig, Amit Verma, Adrian Wiestner, Ari Melnick, Samir Parekh
Journal: Blood (2009)
Response to Frontline Therapy with Second Generation Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia: Analysis of Outcome for b3a2 Vs. b2a2 Fusion Transcripts
Authors: Carlos G. Romo, Hagop M Kantarjian, Rajyalakshmi Luthra, Alfonso Quintás-Cardama, Elias J. Jabbour, Gautam Borthakur, Tapan M. Kadia, Farhad Ravandi, Naveen Pemmaraju, Sherry A. Pierce, Susan O'Brien, Jorge E. Cortes
Journal: Blood (2012)
545. Strong Cortico-Spinal Transduction After AAV5 Delivery into the Central Nervous System of Nonhuman Primates
Authors: Lluis Samaranch, Bas Blits, John Bringas, Michael Macayan, Foad Green, Waldy San Sebastian, John Forsayeth, Krystof Bankiewicz
Journal: Molecular Therapy (2015)

Widespread distribution of gene products at clinically relevant levels throughout the central nervous system (CNS) without involving peripheral organs is still a challenge. Previous work demonstrated that infusion of adeno-associated virus (AAV) serotypes 9 (AAV9) and 7 (AAV7) into the cerebrospinal fluid (CSF) via cisterna magna of nonhuman primates (NHP) resulted in widespread transduction throughout cortex and spinal cord. Adeno-associated virus serotype 5 (AAV5) is also a potential candidate for CNS gene therapy when delivered into brain parenchyma but its performance in CSF has not been described. In the present work, we compared transduction patterns after CSF and parenchymal delivery of AAV5-GFP. For CSF delivery, we injected various doses of AAV5 (1E+14, 1E+13 and 1E+12 vg/mL) into CSF via lumbar routes in naïve NHP and studied vector distribution and cellular transduction 4 weeks after CSF delivery. We found a dose-dependent increase in transduction with strong levels of cell transduction and distribution throughout cortex and along the spinal cord at the highest doses and no signal in the low-dose group. These results suggest a dose threshold when delivering into CSF, most likely due to a dilution of the viral particles. Both astrocytes and neurons were transduced by AAV5 when infused either in CSF or directly into brain parenchyma. Parenchymal delivery of AAV5-GFP was analyzed 8 weeks after surgery. Interestingly, when infused into the thalamus and the contralateral putamen, AAV5 resulted in higher levels of expression in cortical and subcortical structures than those observed in high-dose CSF animals. Surprisingly, thalamic injection directed spinal cord transduction throughout the cortico-bulbar axis. These results suggest not only that smaller volumes of AAV5 infused directly into the thalamus can result in robust and widespread cellular transduction in the brain but also to spinal cord. Our results confirm AAV5 as a powerful viral vector for gene transfer in the CNS and underscore its translational potential for treating neurological disorders of the brain and spinal cord.
Characteristics of patients who refuse medically appropriate do not resuscitate orders (DNR) upon admission to a palliative care (PC) unit in a comprehensive cancer center
Authors: H. A. Parsons, M. de La Cruz, M. O. Delgado-Guay, A. E. Akitoye, R. Chacko, V. Poulter, E. Bruera
Journal: Journal of Clinical Oncology (2009)

9589 Background: Cardiopulmonary resuscitation (CPR) has limited benefit in advanced cancer patients (pts). Refusal of medically appropriate DNR (maDNR) may cause harm and distress for pts, families, and the medical team. We conducted a retrospective study to determine the frequency of refusals of maDNR in a tertiary PC unit in a comprehensive cancer center, and characterize the differences between maDNR acceptors (A) and refusers (R). Methods: We reviewed 2538 consecutive admissions to the PC unit to find refusals of maDNR. Data were collected regarding demographical/clinical factors, 0–10 Edmonton Symptom Assessment System, DNR, CPR, and death for the first 100 R and 200 A pts. Results: DNR was considered medically appropriate for 2530/2538 (99%) admissions. 2374/2530 admissions were of unique pts, and 100/2374 (4%) refused maDNR. 3/3 (100%) R pts who coded underwent CPR versus 0/87 A pts who coded (0%, p&lt;0.0001). 2/3 CPR pts survived code and were discharged but died in less than 10 days. Median age (62), female gender (54%), and religious affiliation were not different between R and A. African-Americans and pts with head and neck malignancies were more frequently R than others (OR=1.99, CI=1.13–3.51, p=0.02 and OR=2.62, CI=1.05–6.56, p=0.04, respectively). A had more hematological malignancies and advance directives (OR=2.66, CI=1.07–6.63, p=0.02, and OR=2.80, CI=1.68–4.66, p&lt;0.0001, respectively). Multivariate regression analysis revealed that pts with hematologic malignancies (OR 2.69, CI=1.05–6.90 p= 0.04) and advance directives (OR 1.46, CI=1.46–4.27, p= 0.001) were associated with A. R pts presented with median (interquartile range, IR) pain of 7(4–9) vs 5(3–8, p=0.0005) nausea of 2(0–7) vs 1(0–4, p=0.05), and dyspnea of 1(0–5) vs 4(0–7, p=0.002). Median (IR) time between PC consult and death and discharge and death were 143 (49–329) days for R vs 25(10–77) for A (p&lt;0.0001) and 85 (25–206) for R and 18 (8–35) for A (p&lt;0.0001). Conclusions: DNR refusal in pts after PC consult is low, more frequent among African Americans, pts with head and neck cancers, pts with more pain or nausea, and is associated with longer survival. This study demonstrates possible predictors of complicated DNR discussions. No significant financial relationships to disclose.
Abstract 3964: How to fish a good micro-marker out from a worthless lake: The case of cell-free miR-181a-5p and breast cancer
Authors: Manuela Ferracin, Laura Lupini, Irene Salamon, Elena Saccenti, Barabara Zagatti, Alessandra Mangolini, Maria Vittoria Zanzi, Paolo Carcoforo, Andrea Rocchi, Giorgio Cavallesco, Antonio Frassoldati, Alan B. Hollingsworth, Massimo Negrini
Journal: Cancer Research (2015)

Abstract The hypothesis to use microRNAs (miRNAs) circulating in blood as cancer biomarkers was formulated some years ago based on promising initial results. After some exiting discoveries, however, it became evident that the accurate quantification of cell-free miRNAs (i.e. that retrieved in serum or plasma) was more challenging than expected. Difficulties were linked to the strong impact that many, if not all, pre- and post- analytical variables (i.e. tissue preparation, storage condition, extraction method, quantification technique, normalization approach) have on the final result. In this study, we used currently available high-throughput technologies to identify miRNAs present in plasma and serum of patients with breast, colorectal, lung and melanoma tumors, and healthy controls. Then, we used droplet digital PCR (ddPCR) technology to get an accurate absolute quantification of specific cell-free miRNAs. We assessed the level of 8 different miRNAs (miR-320a, miR-21-5p, miR-378a-3p, miR-181a-5p, miR-3156-5p, miR-2110, miR-125a-5p, miR-425-5p, miR-766-3p) in 180 samples from healthy controls and cancer patients. We identified miRNAs specifically modulated in one or more cancer types. Plasma and serum from the same patient provided different results in terms of absolute miRNA amount and modulation. The significant reduction of miR-181a-5p levels in serum of breast cancer patients was further validated using two independent cohorts, one from Italy (n = 70) and one from US (n = 90). This study finally powers the use miR-181a-5p as a breast cancer biomarker. Citation Format: Manuela Ferracin, Laura Lupini, Irene Salamon, Elena Saccenti, Barabara Zagatti, Alessandra Mangolini, Maria Vittoria Zanzi, Paolo Carcoforo, Andrea Rocchi, Giorgio Cavallesco, Antonio Frassoldati, Alan B. Hollingsworth, Massimo Negrini. How to fish a good micro-marker out from a worthless lake: The case of cell-free miR-181a-5p and 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 3964. doi:10.1158/1538-7445.AM2015-3964
Targeting β‐catenin in hepatocellular cancers induced by coexpression of mutant β‐catenin and K‐Ras in mice
Authors: Junyan Tao, Rong Zhang, Sucha Singh, Minakshi Poddar, Emily Xu, Michael Oertel, Xin Chen, Shanthi Ganesh, Marc Abrams, Satdarshan P. Monga
Journal: Hepatology (2016)

Recently, we have shown that coexpression of hMet and mutant-β-catenin using sleeping beauty transposon/transposase leads to hepatocellular carcinoma (HCC) in mice that corresponds to around 10% of human HCC. In the current study, we investigate whether Ras activation, which can occur downstream of Met signaling, is sufficient to cause HCC in association with mutant-β-catenin. We also tested therapeutic efficacy of targeting β-catenin in an HCC model. We show that mutant-K-Ras (G12D), which leads to Ras activation, cooperates with β-catenin mutants (S33Y, S45Y) to yield HCC in mice. Affymetrix microarray showed > 90% similarity in gene expression in mutant-K-Ras-β-catenin and Met-β-catenin HCC. K-Ras-β-catenin tumors showed up-regulation of β-catenin targets like glutamine synthetase (GS), leukocyte cell-derived chemotaxin 2, Regucalcin, and Cyclin-D1 and of K-Ras effectors, including phosphorylated extracellular signal-regulated kinase, phosphorylated protein kinase B, phosphorylated mammalian target of rapamycin, phosphorylated eukaryotic translation initiation factor 4E, phosphorylated 4E-binding protein 1, and p-S6 ribosomal protein. Inclusion of dominant-negative transcription factor 4 at the time of K-Ras-β-catenin injection prevented HCC and downstream β-catenin and Ras signaling. To address whether targeting β-catenin has any benefit postestablishment of HCC, we administered K-Ras-β-catenin mice with EnCore lipid nanoparticles (LNP) loaded with a Dicer substrate small interfering RNA targeting catenin beta 1 (CTNNB1; CTNNB1-LNP), scrambled sequence (Scr-LNP), or phosphate-buffered saline for multiple cycles. A significant decrease in tumor burden was evident in the CTNNB1-LNP group versus all controls, which was associated with dramatic decreases in β-catenin targets and some K-Ras effectors, leading to reduced tumor cell proliferation and viability. Intriguingly, in relatively few mice, non-GS-positive tumors, which were evident as a small subset of overall tumor burden, were not affected by β-catenin suppression.Ras activation downstream of c-Met is sufficient to induce clinically relevant HCC in cooperation with mutant β-catenin. β-catenin suppression by a clinically relevant modality is effective in treatment of β-catenin-positive, GS-positive HCCs. (Hepatology 2017;65:1581-1599).