tbuckley/cabot-search huggingface dataset:
Abstract 3597: EZH2 D1 domain mutants confer acquired resistance to EZH2-targeted inhibitors and reprogram B-cell transcription
Authors: Francois Gonzalvez, Theresa Baker, Justin Pritchard, Victor M. Rivera, Andrew Garner
Journal: Cancer Research (2015)

Abstract Aberrant epigenetic changes play an important role in the onset and progression of numerous tumor types, and targeting enzymes that regulate these processes holds significant promise for cancer treatment. The identification of Y641 and A677 oncogenic mutations in the histone methyl-transferase EZH2 in hematological cancers and melanoma, has led to a surge of interest in exploring the therapeutic potential of targeting EZH2. Several potent and selective small-molecule inhibitors targeting EZH2 (EZH2i) have recently been generated. The most advanced compounds, EPZ-6438 (E7438) and GSK126 (GSK2816126), are currently tested in lymphoma and advanced solid tumors, with EPZ-6438 exhibiting preliminary evidence of efficacy (ENA, 2014). As observed with other targeted cancer therapies, acquired resistance may pose a major clinical challenge to EZH2i. However, at this early stage in clinical development, mechanisms of acquired resistance to EZH2i remain unidentified. Nonetheless, it is critical to anticipate future clinical resistance mechanisms in order to develop effective patient treatment strategies. To explore EZH2i resistance, we used an innovative forward genetic approach that combined a mutagenesis screen with next-generation sequencing technologies. Using this strategy, we identified a hotspot of EZH2 missense mutations (Y111 and I109) that conferred cross-resistance to both EPZ-6438 and GSK126. Surprisingly, the mutation hotspot lies outside the EZH2 catalytic region in its D1 domain, signifying a unique allosteric mechanism of drug resistance. Importantly, to drive resistance, the EZH2 mutants still required an active histone methyl-transferase catalytic domain and the main components of the polycomb repressive complex 2. Furthermore, we also uncovered an unexpected neomorphic role for these mutations in controlling the expression of genes typically involved in B-cell differentiation. This work describes the first evidence of acquired resistance to EZH2i, and identifies potential clinically relevant resistance mutations. Moreover, our findings provide new mechanistic insights into the function of EZH2, and importantly, suggest that acquired-resistance to EZH2i may arise in the clinic in a manner that remains targetable by inhibitors, thus, providing a foundation for the discovery of second-generation EZH2i to treat relapsed patients. Citation Format: Francois Gonzalvez, Theresa Baker, Justin Pritchard, Victor M. Rivera, Andrew Garner. EZH2 D1 domain mutants confer acquired resistance to EZH2-targeted inhibitors and reprogram B-cell transcription. [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 3597. doi:10.1158/1538-7445.AM2015-3597
Abstract 4120: Tasquinimod inhibits local invasion and metastases in two preclinical models of renal cell carcinoma
Authors: Li Shen, Valerie Pierron, Anne-Laure Bauchet, Jessica Nakhle, Ashley Orillion, Remi Adelaiye, Eric Ciamporcero, Florence Meyer-Losic, Helena Eriksson, Nathalie Lassau, Ingrid Leguerney, Fabien Schmidlin, Anders Olsson, Roberto Pili
Journal: Cancer Research (2015)

Abstract Renal clear cell carcinoma (RCC) is the most common type of kidney cancer in adults and represents 80% of cases. At the time of diagnosis, approximately 30% of patients have distant metastases. In addition, one third of patients who have surgical resection of the primary tumor eventually relapse and develop metastases. Effective agents that help to prevent the development of metastatic RCC are not available. Tasquinimod is a novel agent in clinical development for metastatic castration-resistant prostate cancer that has been shown to have immunomodulatory, anti-angiogenic, and anti-metastatic properties. In the current study, we tested whether tasquinimod effectively inhibits local invasion and spontaneous lung metastases in RCC. Two preclinical mouse models of RCC were used for this purpose: a xenograft nude model A498 and a recently established patient-derived xenograft model, RP-R-02 LM. In both models, tasquinimod had a modest effect on the growth of the primary tumors implanted subcutaneously. Interestingly, in the A498 RCC model, gene expression analysis in tumors revealed that tasquinimod increased E-cadherin and decreased vimentin expression, suggesting an effect on reversal of epithelial-mesenchymal transition. In addition, tasquinimod significantly decreased CXCR4 expression, suggesting a reduction in invasiveness and metastatic phenotype. To further test this hypothesis, we used the RP-R-02 LM model that is able to develop lung metastases. Tasquinimod induced a 66% reduction of lung metastases in comparison with the control group (p&amp;lt;0.01). Following tasquinimod treatment CD206+/Arginase 1+/high suppressive M2-polarized infiltrating macrophages were decreased in primary tumors, but even more so in the lung parenchyma and tumor nodules. In summary, our results demonstrate that tasquinimod has immunomodulatory and anti-metastatic properties in RCC models, providing a biological rationale for the clinical assessment of tasquinimod in RCC patients. Citation Format: Li Shen, Valerie Pierron, Anne-Laure Bauchet, Jessica Nakhle, Ashley Orillion, Remi Adelaiye, Eric Ciamporcero, Florence Meyer-Losic, Helena Eriksson, Nathalie Lassau, Ingrid Leguerney, Fabien Schmidlin, Anders Olsson, Roberto Pili. Tasquinimod inhibits local invasion and metastases in two preclinical models of renal cell 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 4120. doi:10.1158/1538-7445.AM2015-4120
PTH-032 Scintigraphic gastric emptying: clinical impression vs outcome
Authors: L I Sonoda, M Y Halim, C Solanki, N J Bird, S Middleton, K K Balan
Journal: Gut (2010)

<h3>Introduction</h3> In patients presenting with upper gastrointestinal (GI) symptoms, clinical impression of rapid or delayed gastric emptying (GE) may be misleading. This study was undertaken to determine the frequency of rapid/delayed GE compared to clinical presentation in patients referred for GE scintigraphy. <h3>Methods</h3> A retrospective review of 642 (234 males, 408 females, mean age 45 years old) consecutive GE studies was performed. Each patient received a standard solid meal containing two large eggs labelled with 12 MBq of 99mTc-tin colloid and a glass of water. Static imaging in upright position (anterior and posterior 60 s) every 15 min was performed for 150 min using a large field of view gamma camera fitted with a low energy collimator and a computer system. GE was classified as normal, rapid and delayed based on half-emptying time and percentage retained at 150 min. <h3>Results</h3> Seventy (11%) patients with suspected rapid and 572 (89%) with suspected delayed GE were studied. Normal, rapid and delayed GE, respectively, were observed in 11 (16%), 54 (77%) and 5 (7%) patients with the clinical suspicion of rapid GE and 178 (31%), 215 (37%) and 178 (31%) patients with suspected delay in GE. One patient with suspected delay had a biphasic GE pattern. Positive Predictive Value (PPV) of clinical suspicion for rapid GE was 77% while PPV of clinical suspicion for delayed GE was 31%. <h3>Conclusion</h3> Our experience demonstrates that clinical impression is often an unreliable predictor of the outcome of GE scintigraphy, especially in patients suspected of having a delayed GE. GE scintigraphy using solid egg meal is a very useful investigation in the management of patients presenting with complex upper GI symptoms.
684. Enhanced FVIII AAV Vector Cassette Produces Improved Virus Yields and Supraphysiological FVIII Levels In Vivo
Authors: Brigit Riley, Jeff Boonsripisal, Alicia Goodwin, Eudean Garces, Stephen Ballaron, Hung Tran, Andrea Kang, Lei Zhang, Judy Greengard, Richard Surosky, Kathleen Meyer, Dale Ando, Geoff Nichol, Michael C. Holmes
Journal: Molecular Therapy (2016)

Hemophilia A is the most common inherited bleeding disorder in humans and is caused by a deficiency of blood coagulation factor VIII (FVIII). This disease is an ideal candidate for liver-directed gene therapy, as even modest increases in FVIII activity (>1% of normal) can ameliorate the severe bleeding phenotype. Adeno-associated viral (AAV) vectors have shown great promise in both preclinical and clinical trials to efficiently deliver therapeutic transgenes to the liver. Suboptimal virus yields of AAV comprising human FVIII (hFVIII) for use in human therapy have hampered clinical scale manufacturing, both from mammalian (HEK293) and insect cells (Baculovirus system). We optimized an hFVIII AAV vector cassette to improve both virus yields and liver-specific hFVIII expression. Compared to historical hFVIII AAV vector cassettes that routinely produce 20% of standard, non-hFVIII containing AAV2/6 virus preparations, the improved hFVIII AAV vector cassette produced yields 100% of standard AAV2/6, both from HEK293 cells at the cell factory (CF) scale, but also in the Baculovirus system at large scale. Improved yields were also observed using other AAV serotypes including hFVIII AAV2/8 and AAV2/9. Using virus produced from the improved hFVIII AAV cassette we transduced mice at 6E+10 vg/mouse (~2E+12 vg/kg). Peak levels of hFVIII protein were achieved in mouse plasma at day 14 and represented supraphysiological levels of normal hFVIII in humans with serotypes AAV2/8 and AAV2/9; up to 337% and 516% of normal hFVIII plasma levels respectively (1U = 200 ng/mL = 100%). Transducing mice with serotype AAV2/6, known to be inefficient at transducing mouse liver, at 6E+10 vg/mouse (~2E+12 vg/kg) we achieved a mean peak value of 91.9 % +/- 15.5 SEM (n=6) of normal hFVIII plasma levels in humans. At a higher dose representing ~6E+12 vg/kg we achieved a mean peak value of hFVIII plasma over six independent in vivo mouse studies of 169.2 % +/- 10.1 SEM (n = 36). Supraphysiological hFVIII plasma levels were also achieved in non-human primates at a dose of 2E+12 vg/kg using serotype AAV2/6, representing up to 840% of normal hFVIII levels (8.4U). The robust production of hFVIII from the enhanced hFVIII AAV vector could significantly reduce the dose required to achieve therapeutic levels in human subjects. Additionally the improved hFVIII AAV vector cassette will enable clinical scale manufacturing.
A Phase 2 Study of Bendamustine Plus Melphalan Conditioning for Second Autologous Stem Cell Transplantation in "De-Novo" Multiple Myeloma Patients in a Tandem Transplant Strategy
Authors: Massimo Martino, Messina Giuseppe, Roberta Fedele, Giuseppe Irrera, Console Giuseppe, Giuseppe Alberto Gallo, Iolanda Donatella Vincelli, Francesca Ronco, Massimo Gentile, Fortunato Morabito
Journal: Blood (2015)
Randomized, Double-Blind, Placebo-Controlled Trial of Epoetin Alfa (Procrit) in Patients with Rectal and Gastric Cancer Undergoing Chemo-Radiotherapy (CT/RT) Followed by Surgery: Early Termination of the Trial Due to Increased Incidence of Thrombo-Embolic Events (TEE).
Authors: Saroj Vadhan-Raj, John M. Skibber, Christopher Crane, Carlos E. Bueso-Ramos, Miguel A. Rodriguez-Bigas, Barry W. Feig, Edward H. Lin, Jaffer A. Ajani, Mindy Collard, Marcella M. Johnson, Stanley R. Hamilton, Nora JanJan
Journal: Blood (2004)
Abstract 4955: Somatic alteration and depleted nuclear expression of BAP1 in human esophageal squamous cell carcinomas
Authors: Takahiro Mori, Makiko Sumii, Fumiyoshi Fujishima, Kazuko Ueno, Masao Nagasaki, Chikashi Ishioka, Natsuko Chiba
Journal: Cancer Research (2015)

Abstract We have found a case of somatic non-synonymous mutation of BAP1, substituting phenylalanine to isoleucine at codon 170 (F170I) out of 49 patients with esophageal squamous cell carcinomas (ESCs) examined by Sanger's direct sequencing. By in vivo Ubiquitination assay, deubiquitininase activity was suppressed in F170I, comparing with wild BAP1. BAP1 localization assay revealed that F170I mutant preferred to localize within cytoplasm although wild BAP1 mostly localizes within nucleus. Microarray analysis revealed that F170I has drastically altered gene expression profile. The following gene-ontology analyses indicated that expression of genes involved in oncogenic pathways has drastically altered by F170I. We have also found that BAP1 expression was depressed around 10% of ESCs examined by immunohistochemistry. It is interesting that nuclear BAP1-depleted cases have strong cytosolic expression of BAP1, instead. As nuclear localization of BAP1 is important in tumor suppressor function, BAP1 may be functionally inactivated around 10% of ESCs. Citation Format: Takahiro Mori, Makiko Sumii, Fumiyoshi Fujishima, Kazuko Ueno, Masao Nagasaki, Chikashi Ishioka, Natsuko Chiba. Somatic alteration and depleted nuclear expression of BAP1 in human esophageal squamous cell carcinomas. [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 4955. doi:10.1158/1538-7445.AM2015-4955
The association of anticoagulation, ischemic stroke, and hemorrhage in elderly adults with chronic kidney disease and atrial fibrillation
Authors: Vaibhav Keskar, Eric McArthur, Ron Wald, Ziv Harel, Deborah Zimmerman, Amber O. Molnar, Amit X. Garg, Ngan N. Lam, Megan K. McCallum, Sarah E. Bota, Jeffrey Perl, Manish M. Sood
Journal: Kidney International (2016)
Inhibitors of PI3K/Akt and/or mTOR Inhibit the Growth of Cells of Myeloproliferative Neoplasms and Synergize with JAK2 Inhibitor and Interferon,
Authors: Alessandro M. Vannucchi, Costanza Bogani, Niccolò Bartalucci, Lorenzo Tozzi, Serena Martinelli, Paola Guglielmelli, Chiara Paoli, Lisa Pieri, Alberto Bosi
Journal: Blood (2011)
Vaccination of cancer patients with whole-virion, adjuvant-free pandemic influenza H1N1 vaccine: Patient acceptance and vaccine immunogenicity.
Authors: H. Lagler, S. Tobudic, J. Leitner, K. Elandt, G. G. Steger, J. W. Drach, C. Marosi, M. Redelberger-Fritz, T. Popow-Kraupp, C. Zielinski, H. Burgmann
Journal: Journal of Clinical Oncology (2011)

e16574 Background: During the H1N1 pandemic 2009, a whole virion, verocell derived, inactivated, unadjuvanted influenza vaccine (A/California/07/2009 (H1N1)v) was used in Austria. This was the only adjuvant-free pandemic H1N1 vaccine licensed in Europe at this time. The objective of this study was to evaluate cancer patients’ acceptance of the vaccine and its immunogenicity. Methods: Adult patients with malignant diseases and concurrent chemotherapy were recruited during the pandemic, which was widely publicised in the media from Nov. 2009 to March 2010. Patients were offered free vaccination on the day of their chemotherapy. The vaccination schedule consisted of two intramuscular injections in an at least 3 week-interval. Efficacy of the vaccination was assessed by using a haemagglutination inhibition (HI) assay before and after each vaccination. The primary immunological end point was seroconversion rate which was deﬁned as the proportion of subjects with a 4-fold increase in HI titer. H1N1 specific IgG was determined by ELISA. Results: 260 (91%) out of a total of 286 cancer patients refused to be vaccinated, whereas the remaining 26 patients (9%; n=15 females, n=11 males) agreed. The patients’ median age was 62 years. The studied patients had cancers of the breast (n=14), bladder (n=3), prostate (n=3), colon (n=2), pancreas (n=2), breast/colon (n=1) and prostate/liver (n=1). In 20 patients, the fully scheduled course of 2 vaccinations took place. Before the first vaccination, 54% (n=13) of the patients had HI titer >1:40 and only one was positive for virus-specific IgG. After 1st vaccination, 13% (n=3) had experienced seroconversion in the HI, whereas 38% were seropositive for IgG. After 2nd vaccination, 33% (n=4) had seroconversion in the HI, whereas 50% were seropositive for IgG. Seroconversion occurred in 60% of patients <60 years and in 12% of patients > 60 years. In contrast, the development of virus-specific IgG was seen in 80% and 38% of patients. Conclusions: Our results have demonstrated a very low acceptance of the pandemic H1N1-Influenza vaccine in cancer patients. The licensed adjuvant-free vaccine resulted in only limited protective immune responses.
Abstract 659: Sustained inhibition of HER3 and EGFR is necessary to induce regression of HER2-amplified gastrointestinal carcinomas
Authors: Simonetta Maria Leto, Francesco Sassi, Irene Catalano, Giorgia Migliardi, Eugenia Rosalinda Zanella, Andrea Bertotti, Livio Trusolino
Journal: Cancer Research (2015)

Abstract Purpose: Preclinical studies in HER2-amplified gastrointestinal cancer models have shown that co-targeting HER2 with a monoclonal antibody and a small molecule is superior to monotherapy with either inhibitor, but the underlying cooperative mechanisms remain unexplored. We investigated the molecular underpinnings of this synergy to identify key vulnerabilities susceptible to alternative therapeutic opportunities. Experimental Design: The signaling consequences of HER2, HER3 and EGFR (HERs) blockade were evaluated in HER2-overexpressing colorectal and gastric cancer cell lines by Western blotting. HERs’ canonical downstream transducers were quantitatively gauged by multiplex phospho-proteomics. The in vivo outcome of antibody-mediated HER2 blockade by trastuzumab, reversible HER2 inhibition by lapatinib, and irreversible HER2 inhibition by afatinib was assessed in patient-derived tumorgrafts and cell-line xenografts by monitoring tumor growth curves and by using antibody-based proximity assays for phosphoprotein analysis. Results: Trastuzumab monotherapy reduced HER3 phosphorylation, with minor consequences on downstream transducers. Lapatinib alone acutely inhibited all HER receptors and effectors but led to delayed rephosphorylation of HER3 and EGFR and partial restoration of ERK and AKT activity. When combined with lapatinib, trastuzumab prevented HER3/EGFR reactivation and caused prolonged inhibition of ERK/AKT. Afatinib alone was as effective as trastuzumab plus lapatinib in counteracting the reinstatement of HER3, EGFR, and downstream signaling activation. In vivo, the combination of trastuzumab and lapatinib - or monotherapy with afatinib - resulted in overt tumor shrinkage. Conclusions: Only prolonged inhibition of HER3 and EGFR, achievable by dual blockade with trastuzumab and lapatinib or irreversible HER2 inhibition by single-agent afatinib, led to regression of HER2-amplified gastrointestinal carcinomas. Citation Format: Simonetta Maria Leto, Francesco Sassi, Irene Catalano, Giorgia Migliardi, Eugenia Rosalinda Zanella, Andrea Bertotti, Livio Trusolino. Sustained inhibition of HER3 and EGFR is necessary to induce regression of HER2-amplified gastrointestinal carcinomas. [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 659. doi:10.1158/1538-7445.AM2015-659
Polymorphisms (Snps) in Multiple Genes of the Tgf-ß/Bmp Pathway Are Associated with a Global Measure of Sickle Cell Disease Severity.
Authors: Paola Sebastiani, Clinton T. Baldwin, Vikki Nolan, Diego F. Wyszynski, Qian-Li Ma, John Farrell, Alice Bisbee, Kristin Waraska, Lindsay A. Farrer, Martin H. Steinberg
Journal: Blood (2005)
Adverse Events in Treatment of Inherited Factor VII Deficiency: Final Analysis of the STER.
Authors: Guglielmo Mariani, Mariasanta Napolitano, Alberto Dolce, Marie Bertrand, Pimlak Charoenkwan, Dragan Micic, Maria Fernanda López Fernández, Arlette Ruiz de Saez, Sergio Siragusa, Jorgen Ingerslev
Journal: Blood (2012)
Platelet Recovery Prior to Stem Cell Transplantation Predicts for Post- Transplant Outcomes in Patients with AML
Authors: Gheath Alatrash, Matteo Pelosini, Rima M Saliba, Gabriela Rondon, Weiqing Zhang, Sergio Giralt, Partow Kebriaei, Amin Alousi, Issa F Khouri, Richard E Champlin, Marcos De Lima
Journal: Blood (2008)
A Bridging Protocol in High-Thrombotic Risk Mechanical Valve Bearers Undergoing Surgery or Invasive Procedures
Authors: Gentian Denas, Sophie Testa, Roberto Quintavalla, Giuliana Guazzaloca, Seena Padayattil Jose, Giacomo Zoppellaro, Alessia Bracco, Vittorio Pengo
Journal: Journal of the American College of Cardiology (2016)
Improving Survival in Multiple Myeloma: Impact of Novel Therapies.
Authors: Shaji Kumar, S. Vincent Rajkumar, Angela Dispenzieri, Martha Q. Lacy, Suzanne R. Hayman, Francis K. Buadi, Steven R. Zeldenrust, David Dingli, Stephen Russell, John A. Lust, Philip R. Greipp, Robert A. Kyle, Morie A. Gertz
Journal: Blood (2007)
Consolidation with Bortezomib, Thalidomide and Dexamethasone After High Dose Therapy Is Feasible, Safe and Effective In De Novo Multiple Myeloma Patients Who Already Received New Drugs Containing-Induction Regimen
Authors: Murielle Roussel, Gaëlle Dörr, Willy Vaillant, Anne Huynh, Michel Attal
Journal: Blood (2010)
The Folklore of Herpes Zoster
Authors: Valencia Long
Journal: JAMA Dermatology (2016)

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