tbuckley/cabot-search huggingface dataset:
Abstract 1027: Development of orthotopically grafted organoid models to study pancreatic cancer progression
Authors: Chang-Il Hwang, Eunjung Lee, Brandon Da Silva, Kevin Wright, Youngkyu Park, David A. Tuveson
Journal: Cancer Research (2017)

Abstract Pancreatic ductal adenocarcinoma (PDA) is one of the most difficult human malignancies to treat. The 5-year survival rate of PDA patients is 7% and PDA is predicted to become the second leading cancer-related cause of death in the USA. A subset of potential tumor suppressor genes was identified by genome-wide analysis of human PDA and insertional mutagenesis in genetically engineered mouse models (GEMMs). Since the functional validation of these genes in GEMMs is time-consuming and labor-intensive, we have developed a rapid and efficient ‘orthotopically grafted organoid’ (OGO) models in conjunction with RNAi and CRISPR/Cas9 technology to study PDA progression. Previously, we showed that OGO model represents the full spectrum of PDA progression in vivo upon orthotopic engraftment. Here, as a proof-of-concept experiment, we demonstrate that ablation of Trp53 by viral introduction of shRNA or gRNA in PanIN-derived organoids accelerates PDA progression upon transplantation. In addition, we engineered tetracyclin-inducible shRNA against Trp53 in ColA1 locus by Flpe recombinase-mediated cassette exchange in organoids derived from Kras +/G12D ; Rosa26-rtTA ; ColA1-homing cassette mouse. Orthotopic transplantation followed by doxycycline administration resulted in rapid PDA progression with metastases. Isolated tumor organoids were re-transplanted to evaluate the effect of p53 restoration in PDA progression. Restoration of p53 by doxycycline withdrawal led to reduced liver metastases, although there was no difference in survival and primary tumor growth. This will provide a new insight how p53 regulates PDA metastasis. Therefore, OGO models should provide an excellent platform to study the functional role of genes in PDA progression in vivo. Citation Format: Chang-Il Hwang, Eunjung Lee, Brandon Da Silva, Kevin Wright, Youngkyu Park, David A. Tuveson. Development of orthotopically grafted organoid models to study pancreatic cancer progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1027. doi:10.1158/1538-7445.AM2017-1027
Combined use of rapid D-dimer testing and estimation of clinical probability in the diagnosis of deep vein thrombosis: systematic review
Authors: Richard Smith, Shah Ebrahim, Stephen Clarke
Journal: BMJ (2004)

comparison of hospital at home and hospital care.The outcome is based on QALYs formed from a five dimension quality of life scale.The cost of treating the patient in the hospital at home was £1200 more than in hospital and made little difference to the mean number of QALYs gained (0.02), where QALYs combine information about mortality and quality of life.This results in an incremental cost per QALY gained for hospital at home of £60 000 ($107 000, €87 000).Using the cost effectiveness acceptability curve (figure), decision makers would estimate their maximum willingness to pay for a QALY.If, for example, this was £30 000, the probability that hospital at home is more cost effective is slightly less than 20%, but if their willingness to pay for an additional QALY was as high as £80 000, the probability that hospital at home is the more cost effective option would be more than 80%.The table shows a simplified version of the cost-consequences analysis.A full table might additionally include: anxiety and depression, pain control, carer quality of life, costs to social services, accessibility to the service.Decision makers would use the information provided in the table to make decisions or, if desired, they could also use monetary valuation or discrete choice experiments to obtain utility values for the different elements.The relative efficiency of different options would depend on the implicit or explicit values attached by decision makers to the different elements of cost and outcome.A cost-consequences approach would more closely meet the needs of decision makers than current practice and avoid extensive use of inadequate assumptions.Such an approach may not earn researchers the same kudos for methodological research or technical capability as current methods, but it is closer to both Paretian welfare economics and a true decision making approach.It has the additional benefit of being easily understood and thus more likely to influence decision making in practice.
A Randomized Phase III Trial of ABVD Vs. Stanford V +/− Radiation Therapy In Locally Extensive and Advanced Stage Hodgkin's Lymphoma: An Intergroup Study Coordinated by the Eastern Cooperatve Oncology Group (E2496)
Authors: Leo I Gordon, Fanxing Hong, Richard I Fisher, Nancy L. Bartlett, Joseph M. Connors, Randy D. Gascoyne, Henry Wagner, Patrick J Stiff, Bruce D. Cheson, Mary Gospodarowicz, Ranjana Advani, Brad Kahl, Jonathan W. Friedberg, Kristie A. Blum, Thomas M. Habermann, Joseph Tuscano, Richard Hoppe, Sandra J. Horning
Journal: Blood (2010)
Abstract 2123: Protein synthesis and its control in cancer development, progression and treatment
Authors: Armen Parsyan
Journal: Cancer Research (2015)

Abstract A central dogma of molecular biology posits that the protein biosynthetic pathway generally follows the three major events: replication, transcription and translation. The abnormal functioning of any of these processes can nurture malignant cellular transformation. While other components of the central dogma were front-page in cancer research, translation, somewhat, remained in the shades. This presentation is based on the recently published book “Translation and Its Regulation in Cancer Biology and Medicine”* that for the first time comprehensively summarizes and analyzes decades of information into the role of the aberrations in protein synthesis, translation, as well as its regulation in the biology of cancer. The mechanisms of action of various translation factors, such as oncoprotein eIF4E, and tumor suppressors, such as PDCD4, are intensively discussed. Other, less-studied protein factors participating in the complex process of translation are presented in light of their known or emerging roles in cancer development and progression. In addition, the presentation focuses on the oncogenic role of the regulation of the translation machinery by fundamental cellular signal transduction pathways, such as mTOR, MAPK and others. Finally, clinical applications of the current knowledge regarding the translation machinery, its function and regulation in cancer are highlighted, including the use of the translation factors as diagnostic and prognostic markers, as well as factors for novel approaches to targeted pharmacologic treatment. * Translation and Its Regulation in Cancer Biology and Medicine Parsyan, Armen (Ed.) 2014, XXXIV, 697 p. 52 illus., 44 illus. in color., Hardcover ISBN 978-94-017-9078-9 Springer Publishing Website: http://www.springer.com/biomed/cancer/book/978-94-017-9077-2 Citation Format: Armen Parsyan. Protein synthesis and its control in cancer development, progression and treatment. [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 2123. doi:10.1158/1538-7445.AM2015-2123
Sequentially-crosslinked bioactive hydrogels as nano-patterned substrates with customizable stiffness and degradation for corneal tissue engineering applications
Authors: Muhammad Rizwan, Gary S.L. Peh, Heng-Pei Ang, Nyein Chan Lwin, Khadijah Adnan, Jodhbir S. Mehta, Wui Siew Tan, Evelyn K.F. Yim
Journal: Biomaterials (2016)
Abstract 499: Characterization of the cell death mechanism after silencing of PAX3-FOXO1 in alveolar rhabdomyosarcoma using a CRISPR-Cas mediated knockout approach
Authors: Marco Wachtel, Felix Niggli, Beat Schäfer
Journal: Cancer Research (2015)

Abstract Chromosomal translocations leading to the generation of PAX-FOXO1 fusion oncogenes are found in about 80 percent of all alveolar Rhabdomyosarcoma (aRMS). Recent whole genome sequencing studies revealed that apart from these translocations mutation frequency is generally very low in aRMS, with no other genetic changes detected in some cases. aRMS tumor cells depend on the fusion protein and exhibit cell cycle arrest or undergo cell death upon blocking of its activity. Taken together this strongly suggests that the PAX-FOXO1 fusion represents the tumor initiating event and that it remains the most important tumorigenic factor for aRMS maintenance at later tumor stages. However, the molecular mechanisms involved in tumorigenesis downstream of PAX3-FOXO1 are only partially understood yet, including the ones involved in oncogene addiction. We therefore aimed to further characterize the molecular events leading to cell death after silencing of PAX3-FOXO1. Towards this aim, we used an inducible shRNA system to silence PAX3-FOXO1 in different aRMS cell lines. Reduction of PAX3-FOXO1 below a threshold of about 20 percent of its basal level efficiently induced Caspase-dependent cell death. CRISPR-Cas mediated knock-out of individual members of the apoptotic cascade was then used to further characterize the involved apoptotic mechanism. BH3-only proteins including Bim were found as relevant sensors detecting cellular stress after silencing of PAX3-FOXO1. This data suggests that combined interference with PAX-FOXO1 activity and anti-apoptotic Bcl-2 family members might accelerate tumor cell death. Citation Format: Marco Wachtel, Felix Niggli, Beat Schäfer. Characterization of the cell death mechanism after silencing of PAX3-FOXO1 in alveolar rhabdomyosarcoma using a CRISPR-Cas mediated knockout approach. [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 499. doi:10.1158/1538-7445.AM2015-499
New Allosteric Inhibitors of Mutant IDH1 in Acute Myeloid Leukemia
Authors: Ujunwa Cynthia Okoye-Okafor, Boris Bartholdy, Jessy Cartier, Enoch Gao, Beth Pietrak, Alan R. Rendina, Cynthia Rominger, Chad Quinn, Angela Smallwood, Ken Wiggall, Alexander Reif, Stan Schmidt, Hongwei Qi, Huizhen Zhao, Gerard Joberty, Maria Faelth-Savitski, Marcus Bantscheff, Gerard Drewes, Chaya Duraiswami, Pat Brady, Swathi-rao Narayanagari, Ileana Antony-Debre, Kelly Mitchell, Luis Carvajal, Heng Rui Wang, Laura Barreyro, Yun-Ruei Kao, Maximilian Christopeit, Elisabeth Paietta, Hideki Makishima, Britta Will, Nestor Concha, Nicholas Adams, Benjamin Schwartz, Michael T. McCabe, Jaroslaw P. Maciejewski, Amit Verma, Ulrich Steidl
Journal: Blood (2015)
Abstract 2853: Investigating DNAPK as a biomarker and a novel therapeutic target in aggressive prostate cancer
Authors: Vishal Kothari, Jonathan F. Goodwin, Shuang Zhao, Elai Davicioni, Jeffrey R. Karnes, Robert B. Den, Rohit Mehra, Karen E. Knudsen, Felix Y. Feng
Journal: Cancer Research (2015)

Abstract Background/purpose: Despite recent advances in the development of androgen deprivation therapies (ADT), prostate cancer (PCa) remains the second leading cause of cancer death in American men. Thus, there is a critical need to improve treatment outcomes for men with aggressive PCa. The purpose of this study was to identify and functionally characterize kinases that can serve as both prognostic biomarkers and therapeutic targets in PCa. Methods: To identify kinases associated with metastatic progression of PCa, we utilized high-density oligonucleotide arrays to interrogate the expression of all kinases in 545 prostatectomy samples, obtained from high-risk patients with long-term clinical follow-up (&amp;gt;10 years). We ranked all kinases by their fold change in expression between PCas that subsequently metastasized versus those that did not. We then characterized the top ranked kinase in preclinical PCa models with in vitro mechanistic experiments and in vivo therapeutic studies. Results: We nominated DNA-dependent protein kinase (DNAPK) as the top kinase associated with metastatic PCa progression. Interrogation of pathways associated with DNAPK knockdown in PC3, DU145, VCaP and C4-2B, identified canonical Wnt signaling as the top DNAPK-activated pathway. In PCa cells (PC3, LNCaP C.S. {LNCaP grown under charcoal-stripped serum condition}, C4-2B and LNCaP-AR) DNAPK inhibition significantly abrogates Wnt signaling and abolishes cell proliferation, migration and invasion. Interestingly, we found that DNAPK directly modulates the Wnt signaling independent of the androgen receptor (AR), highlighting the therapeutic potential of DNAPK inhibition in cancers resistant to ADT. Indeed, in VCaP xenograft models, pharmacologic inhibition of DNAPK with NU7441 demonstrated 3.4 fold (p&amp;lt;0.01) reduction of tumor growth at non-toxic doses. Using an independent prostate cancer tissue cohort, we validate DNAPK expression as a biomarker for metastatic disease progression (p = 6.4 e−06, hazard ratio = 2). Conclusion: In summary, we nominate DNAPK as a potential biomarker of disease progression and as a novel therapeutic target in aggressive prostate cancer. Our data suggests that DNAPK mediates PCa progression by upregulating Wnt signaling, and demonstrates that DNAPK inhibition results in significant tumor responses in PCa xenografts. Citation Format: Vishal Kothari, Jonathan F. Goodwin, Shuang Zhao, Elai Davicioni, Jeffrey R. Karnes, Robert B. Den, Rohit Mehra, Karen E. Knudsen, Felix Y. Feng. Investigating DNAPK as a biomarker and a novel therapeutic target in aggressive prostate 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 2853. doi:10.1158/1538-7445.AM2015-2853
Phase I trial erlotinib, gemcitabine, and the hedgehog inhibitor, GDC-0449.
Authors: S. R. Palmer, C. Erlichman, M. Fernandez-Zapico, Y. Qi, L. Almada, A. McCleary-Wheeler, M. J. Borad, J. R. Molina, A. Grothey, H. C. Pitot, A. Jatoi, D. W. Northfelt, R. R. McWilliams, S. H. Okuno, P. Haluska, G. P. Kim, G. Colon-Otero
Journal: Journal of Clinical Oncology (2011)

3092 Background: Preclinical data have demonstrated interactions between the hedgehog (HH) and EGFR signaling pathways that contribute to pancreatic tumorigenesis. We have found that simultaneous targeting of both pathways resulted in synergistic antitumor activity in pancreatic tumor models. Additionally, HH inhibition has been shown to enhance uptake of gemcitabine in a murine model of pancreatic cancer. Based on these findings, a phase I trial was initiated to determine the maximally tolerated dose (MTD), toxicities and responses of the combination of GDC-0449, an orally administered HH pathway inhibitor and erlotinib (E), an EGFR tyrosine kinase inhibitor (cohort I), as well as the MTD of GDC-0449, E, and gemcitabine (GEM) (cohort II) in patients with unresectable solid tumors. Methods: The 3 + 3 phase I design was used for dose escalation in each group. Patients in cohort I received GDC-0449 at a fixed dose of 150 mg po and E 50, 75, 100, or 150 mg po daily at dose levels 1, 2, 3, and 4, respectively on each day of every 28-day cycle. Patients in cohort II received GDC-0449/E (150/75 mg po daily) combined with GEM 1,000 mg/m2 dose level 1 or 750 mg/m2 dose level -1 weekly x 7 with 1 week rest for cycle 1. All subsequent cycles, GEM was administered weekly for 3 of 4 weeks. Results: Fifteen patients were enrolled to cohort I and there was 1 DLT grade 4 rash observed at dose level 4. No other potential DLT was observed in five additional patients at this dose level. Accordingly, the MTD for cohort 1 was dose level 4 (GDC-0449 150 mg, E 150 mg). Fourteen patients were enrolled to cohort II and 3 DLTs (nausea, infection, visual disturbance) were observed in 2 of 3 evaluable patients at dose level 1. At dose level -1, two of five evaluable patients experienced DLT thrombocytopenia. The dosing schedule for this cohort is currently being revised. In cohort I, one patient being treated at dose level 1 had stable disease as best response for five cycles and another patient at dose level 2 had stable disease for 2 cycles. Conclusions: GDC-0449 and E, each at a dose of 150 mg po daily, is well tolerated and suitable for phase II evaluation. The definition of the MTD for the GDC-0449, E, and GEM combination is currently in progress. Supported by U01CA69912 and P50CA102701.
A Synthetic-Biology-Inspired Therapeutic Strategy for Targeting and Treating Hepatogenous Diabetes
Authors: Shuai Xue, Jianli Yin, Jiawei Shao, Yuanhuan Yu, Linfeng Yang, Yidan Wang, Mingqi Xie, Martin Fussenegger, Haifeng Ye
Journal: Molecular Therapy (2017)

Hepatogenous diabetes is a complex disease that is typified by the simultaneous presence of type 2 diabetes and many forms of liver disease. The chief pathogenic determinant in this pathophysiological network is insulin resistance (IR), an asymptomatic disease state in which impaired insulin signaling in target tissues initiates a variety of organ dysfunctions. However, pharmacotherapies targeting IR remain limited and are generally inapplicable for liver disease patients. Oleanolic acid (OA) is a plant-derived triterpenoid that is frequently used in Chinese medicine as a safe but slow-acting treatment in many liver disorders. Here, we utilized the congruent pharmacological activities of OA and glucagon-like-peptide 1 (GLP-1) in relieving IR and improving liver and pancreas functions and used a synthetic-biology-inspired design principle to engineer a therapeutic gene circuit that enables a concerted action of both drugs. In particular, OA-triggered short human GLP-1 (shGLP-1) expression in hepatogenous diabetic mice rapidly and simultaneously attenuated many disease-specific metabolic failures, whereas OA or shGLP-1 monotherapy failed to achieve corresponding therapeutic effects. Collectively, this work shows that rationally engineered synthetic gene circuits are capable of treating multifactorial diseases in a synergistic manner by multiplexing the targeting efficacies of single therapeutics. Hepatogenous diabetes is a complex disease that is typified by the simultaneous presence of type 2 diabetes and many forms of liver disease. The chief pathogenic determinant in this pathophysiological network is insulin resistance (IR), an asymptomatic disease state in which impaired insulin signaling in target tissues initiates a variety of organ dysfunctions. However, pharmacotherapies targeting IR remain limited and are generally inapplicable for liver disease patients. Oleanolic acid (OA) is a plant-derived triterpenoid that is frequently used in Chinese medicine as a safe but slow-acting treatment in many liver disorders. Here, we utilized the congruent pharmacological activities of OA and glucagon-like-peptide 1 (GLP-1) in relieving IR and improving liver and pancreas functions and used a synthetic-biology-inspired design principle to engineer a therapeutic gene circuit that enables a concerted action of both drugs. In particular, OA-triggered short human GLP-1 (shGLP-1) expression in hepatogenous diabetic mice rapidly and simultaneously attenuated many disease-specific metabolic failures, whereas OA or shGLP-1 monotherapy failed to achieve corresponding therapeutic effects. Collectively, this work shows that rationally engineered synthetic gene circuits are capable of treating multifactorial diseases in a synergistic manner by multiplexing the targeting efficacies of single therapeutics.
Abstract 4929: An ARMS PCR assay for detection of PI3KCA mutations in FFPE tumor samples
Authors: Dehua Derek Yu
Journal: Cancer Research (2015)

Abstract The activating mutations of phosphatidylinositol-3-kinase subunit pl10a (PIK3CA) occur in a variety of cancer types and serve as the predictive markers for response to inhibitors targeting a number of receptor tyrosine kinases (RTKs) and PI3K/AKT pathway. Therefore detection of PI3KCA mutations will guide patient selection for effective personalized cancer therapy. Here we reported a new method for the rapid and reliable detection of PI3KCA mutations by using modified mutation-specific ARMS primers. In this real-time PCR system, the mutant gene is selectively amplified by the modified ARMS primers and the amplicon extending signals are collected by the taqman-probe at the same time. The ARMS assay could detect 5 mutations on PI3KCA gene with a sensitivity of 0.5% under the background of a total of 10ng wild-type genomic DNA. By using this assay, we analyzed the PI3KCA mutations in 113 Chinese breast cancer FFPE samples in comparison with Sanger sequencing. Our results indicated that the positive rates were 27.4 %, while 24.8% when measured by Sanger sequencing. The coincidence rates of the two methods were 89.3 % for the positive samples and 96.5% for the negative samples. The total coincidence rate was 97.3%. In conclusion, our study provides a basis for the detection of somatic mutations in PI3KCA in a routine clinical setting. The ARMS PCR assay allows the detection of the PI3KCA mutations in FFPE samples with better sensitivity and feasibility than the current assays used in clinic. Note: This abstract was not presented at the meeting. Citation Format: Dehua Derek Yu. An ARMS PCR assay for detection of PI3KCA mutations in FFPE tumor samples. [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 4929. doi:10.1158/1538-7445.AM2015-4929
A Second Course of High-Dose Cytarabine before Autologous Stem Cell Transplantation Does Not Improve Outcome of Young Acute Myeloid Leukemia Patients in First Complete Remission: Results of the BGMT 95 Study.
Authors: Eric Jourdan, Françoise Rigal-Huguet, Gérald Marit, Norbert Vey, Nicole Dastugue, Nathalie Fegueux, Lysiane Molina, Jean-Albert Gastaut, Laurence Legros, Hacene Zerazhi, Sylvie Cailleres, Frédéric Bauduer, Dominique Bordessoule, Michel Attal, Didier Blaise, Arnaud Pigneux
Journal: Blood (2004)
IL-1 and IL-36 are dominant cytokines in generalized pustular psoriasis
Authors: Andrew Johnston, Xianying Xing, Liza Wolterink, Drew H. Barnes, ZhiQiang Yin, Laura Reingold, J. Michelle Kahlenberg, Paul W. Harms, Johann E. Gudjonsson
Journal: Journal of Allergy and Clinical Immunology (2017)
Combined Cyclophosphamide, Fludarabine, Alemtuzumab, and Rituximab (CFAR), an Active Regimen for Heavily Treated Patients with CLL.
Authors: William G. Wierda, Susan O’Brien, Stefan Faderl, Alessandra Ferrajoli, Farhad Ravandi-Kashani, Jorge Cortes, Francis Giles, Michael Andreeff, Charles Asa Koller, Susan Lerner, Hagop M. Kantarjian, Michael J. Keating
Journal: Blood (2006)
Phase II Testing of Lenalidomide Plus Melphalan for Previously Untreated Older Patients with Multiple Myeloma: The NCIC CTG MY.11 Trial
Authors: Darrell J White, Nizar J Bahlis, Deborah C Marcellus, Andrew Belch, A. Keith Stewart, Christine Chen, Michael J Kovacs, David A Macdonald, Donna E Reece, Erica Harnett, Judy-Anne W Chapman, Ralph M Meyer
Journal: Blood (2008)