tbuckley/cabot-search huggingface dataset:
Abstract 3643: Targeting the acetyl-lysine binding site of BRD4 with dual nanomolar BET-JAK2 inhibitors: A new anticancer therapeutic strategy
Authors: Steven Gunawan, Ayaz Muhammad, Stuart W. J. Ember, Jin-Yi Zhu, Rebecca A. Jacobsen, Norbert Berndt, Que T. Lambert, Gary W. Reuther, Harshani R. Lawrence, Ernst Schonbrunn, Nicholas J. Lawrence
Journal: Cancer Research (2015)

Abstract Bromodomain (BRD)-containing proteins are essential for the recognition of acetylated lysine residues of histones during transcriptional activation. The BRD-containing proteins have emerged as promising drug targets for a number of diseases, including many cancers, that are characterized by changes in the epigenetic cell signature. Recent reports have shown that targeting BRD4 with small molecules may represent a new way to treat prostate and breast cancer, acute myeloid leukemia and melanoma. We have identified many type 1 and type 2 kinase inhibitors which also inhibit BRD4 by robotic co-crystallization screening of kinase inhibitor libraries against BRD4. In each case the co-crystal structure unambiguously revealed the inhibitor bound to the acetyl lysine site of BRD4-1. The identified BRD4 ligands were subjected to differential scanning fluorimetry (DSF) and AlphaScreen assay to assess their binding and inhibitory potentials against BRD4. As shown previously for other BRD-inhibitor-protein complexes, the melting temperatures of BRD4-kinase inhibitor complexes were logarithmically proportional to their IC50 values. We now report the design, synthesis, structural analysis and biological evaluation of next-generation nanomolar BET-selective and nanomolar dual-activity BET-JAK2 inhibitors, based on the initial co-crystallization screening hits. Structure activity relationships were developed using both DSF and co-crystallization of the ligands with BRD4, to assess binding potential and binding modes, respectively. We report initial evaluation of the anticancer potential of compounds possessing dual potent BRD4 and JAK2 inhibitory properties. In addition to myeloma cell lines, this includes the evaluation of dual BRD4-JAK2 inhibitor compounds against JAK2-driven myeloproliferative neoplasm cell lines and primary cells from patients. Citation Format: Steven Gunawan, Ayaz Muhammad, Stuart W. J. Ember, Jin-Yi Zhu, Rebecca A. Jacobsen, Norbert Berndt, Que T. Lambert, Gary W. Reuther, Harshani R. Lawrence, Ernst Schonbrunn, Nicholas J. Lawrence. Targeting the acetyl-lysine binding site of BRD4 with dual nanomolar BET-JAK2 inhibitors: A new anticancer therapeutic strategy. [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 3643. doi:10.1158/1538-7445.AM2015-3643
Abstract 4974: IL-1 receptor-associated kinase-1 and -4 expression in Hodgkin lymphoma
Authors: Victoria S. Giffi, Kenisha M. Younger, Zeba Singh, Qing Chen, Eduardo Davila, Amy S. Kimball
Journal: Cancer Research (2015)

Abstract BACKGROUND: The Toll-like receptor (TLR) mediates nuclear factor kappa B (NFkB) activation in lymphocytes using a family of intermediary proteins called IL-1 receptor associated kinase (IRAK). Mutations within and upregulation of this pathway have been described in the carcinogenesis of non-Hodgkin lymphoma (NHL), but it is not known whether IRAK proteins are present in Hodgkin lymphoma (HL). Furthermore, Epstein-Barr virus (EBV) has been shown to activate NFkB in HL but its association with proteins upstream of NFkB is not described. METHODS: 1. We performed Western blots on two Hodgkin Reed-Sternberg (HRS) cell lines to detect total IRAK-1 and -4, and phospho-IRAK-1 and -4 (the activated forms). 2. Archived lymph node biopsy samples from Hodgkin lymphoma patients diagnosed at the University of Maryland were stained for IRAK-4. RESULTS: 1. IRAK-1, IRAK-4, p-IRAK-1 and p-IRAK-4 were present in the malignant HRS cells in two HRS cell lines (HDLM-2 and KM-H2). 2. Seventeen lymph node biopsy samples showed marked positivity for IRAK-4 (mean of 2.3 on a 0-4 scale), as well as lesser positivity in surrounding reactive lymphocytes and histiocytes (mean of 1.6). The only sample to achieve a staining level of 4 was of mixed cellularity subtype, and was EBER-positive and HIV-negative. CONCLUSIONS: The IRAK proteins are present in the malignant HRS cells of Hodgkin lymphoma. Further work will examine IRAK-1, and phospho-IRAK-1 and -4 in the lymph node samples. Future studies should also examine whether IRAK causes downstream NFkB activation in HL as it does in NHL, and whether HRS cells depend on IRAK's presence for survival. A possible association with EBV infection will also be investigated. IRAK is a targetable protein with inhibitors available, so this and future studies may reveal new therapeutic strategies in relapsed Hodgkin lymphoma. Citation Format: Victoria S. Giffi, Kenisha M. Younger, Zeba Singh, Qing Chen, Eduardo Davila, Amy S. Kimball. IL-1 receptor-associated kinase-1 and -4 expression in Hodgkin lymphoma. [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 4974. doi:10.1158/1538-7445.AM2015-4974
Dynamics of clonal evolution in myelodysplastic syndromes
Authors: Hideki Makishima, Tetsuichi Yoshizato, Kenichi Yoshida, Mikkael A Sekeres, Tomas Radivoyevitch, Hiromichi Suzuki, Bartlomiej Przychodzen, Yasunobu Nagata, Manja Meggendorfer, Masashi Sanada, Yusuke Okuno, Cassandra Hirsch, Teodora Kuzmanovic, Yusuke Sato, Aiko Sato-Otsubo, Thomas LaFramboise, Naoko Hosono, Yuichi Shiraishi, Kenichi Chiba, Claudia Haferlach, Wolfgang Kern, Hiroko Tanaka, Yusuke Shiozawa, Inés Gómez-Seguí, Holleh D Husseinzadeh, Swapna Thota, Kathryn M Guinta, Brittney Dienes, Tsuyoshi Nakamaki, Shuichi Miyawaki, Yogen Saunthararajah, Shigeru Chiba, Satoru Miyano, Lee-Yung Shih, Torsten Haferlach, Seishi Ogawa, Jaroslaw P Maciejewski
Journal: Nature Genetics (2016)
PP-002 Effect of administering Picolax prior to colonoscopy on renal function, electrolytes and magnesium in all patients in a gastroenterology day unit
Authors: Y T Al-Naeeb, Y Bowzyk, R Tighe
Journal: Gut (2010)

<h3>Introduction</h3> In general, oral bowel cleansing preparations are safe and well tolerated. The National Patient Safety Agency (NPSA) issued a Rapid Response Report in February 2009, alerting to the potential risk of harm associated with the use of oral bowel cleansing preparations. These risks included harm as a result of renal failure due to phosphate nephropathy; complications of hypovolaemia; and electrolyte disturbances. The risk of complications depends on the choice of bowel preparation and on risk factors present in the individual patient. <h3>Methods</h3> It is a prospective study on 159 individuals, who underwent colonoscopy as a day case at the Gastroenterology Day Unit, Norfolk and Norwich University Hospital in September 2009. They all had two sachets of Picolax bowel cleansing preparation. The data collected included sex; age; history of chronic kidney disease (CKD); whether patients were on ACEi, Diuretics, and NSAIDs. We also looked at their renal function and estimated Glomerular Filtration Rate (eGFR) before and on the day of their colonoscopy. Serum Magnesium level was checked on the day of the procedure. <h3>Results</h3> 140 out of 159 patients had no abnormality in their renal function. Six patients had a slight hyponatraemia with sodium of 131–133 mmol/l, while three other patients had significant hyponatraemia: 130 mmol/l, who was on bendrofluazide; 128 mmol/l, who was on spironolactone and furosemide; and126 mmol/l, who was not on diuretics. One had hypernatraemia (150 mmol/l). Significant hypokalaemia (3.0 mmol/l) was identified in one patient. 157/159 patients had elevation in serum Magnesium, highest level was 1.4 mmol/l. Two patients maintained normal Magnesium. Two patients with normal background renal function had only a mild rise in serum urea with normal creatinine and eGFR. Six patients were identified with CKD, three stage 3, and three stage 4/5. Only one patient of the six who was on Ramipril had mild rise in the creatinine level and eGFR dropped from 61 to 52. There was no alteration in the eGFR of other five patients. While 2/6 patients showed improvement in their renal function after taking bowel preparation. 28 patients were on one or a combination of ACEi, Diuretics and NSAIDs, only three of those patients had mildly abnormal biochemistry. <h3>Conclusion</h3> Only a small number of patients (9%) suffered minor deterioration of their renal function or electrolyte disturbances. All but two patients had minimally raised Magnesium level of no clinical significance. None of these patients required admission to hospital as a result of these abnormalities. Patients who had CKD had no deterioration in their biochemical profile. Over all there was no clinically significant biochemical abnormality following Picolax administration.
142. Functionalized Selenium Nanoparticles for mRNA Delivery
Authors: Fiona C. Maiyo, Moganavelli Singh
Journal: Molecular Therapy (2016)

The use of inorganic nanoparticles as gene and drug delivery agents has raised expectations in cancer treatment and diagnostics, and is considered as a promising research orientation for oncotherapy. Selenium, an essential trace element plays a fundamental role in cell metabolism, being responsible for the functioning of many enzymes and other proteins, and is also known for its chemopreventative and chemotherapeutic activities. However, its use as a gene delivery vehicle remains largely unexplored. In this study, chitosan, a positively charged natural polysaccharide was grafted onto selenium nanoparticles. Functionalized and non-functionalized SeNPs were synthesized and characterized using Transmission and Scanning Electron Microscopy, UV spectroscopy, IR spectroscopy and Nanoparticle Tracking Analysis. This study demonstrates that the coating of SeNPs with chitosan influences nanoparticle size, distribution and charge. Gel retardation and enzyme protection studies confirmed that these chitosan functionalized SeNPs were capable of binding, condensing and protecting the mRNA luc from degradation. Evaluation of the effects of functionalized and non-functionalized SeNPs on the cell viability of the human colon adenocarcinoma (HT-29) cancer cell line and Human Embryonic Kidney (HEK293) non-cancer cell line was studied using the MTT cell viability assay. SeNPs at concentrations of up to 200 µg mL−1, demonstrated low toxicity to both cell lines with percentage cell survival over 70 %. Complexes of NP: mRNA at different weight ratios (w/w) similarly exhibited low toxicity levels to both cell lines. Transfection studies were accomplished using the luciferase reporter gene assay. Results showed that the functionalized SeNPs (FSeNPs) produced greater transgene activity than the cationic polymer/mRNA complexes on their own. The results of this study suggest that FSeNP's low cytotoxicity coupled with their small particle size and surface properties, make them suitable non-viral gene delivery vectors. However further engineering and modifications of the FSeNPs may be required to enable in vivo gene delivery. The use of SeNPs has opened a new direction for synergistic treatment of cancer with higher efficiency and reduced side effects.
Allogeneic Hematopoietic Stem Cell Transplantation in Paroxysmal Nocturnal Hemoglobinuria: A Transplant Versus No Transplant Matched Comparison Study On Behalf of the Severe Aplastic Anemia Working Party (SAA WP) of the European Group for Blood and Marrow Transplantation (EBMT) Group and the French Society of Hematology (SFH)
Authors: Régis Peffault de Latour, Hubert Schrezenmeier, Andrea Bacigalupo, Didier Blaise, Carmino Antonio De Souza, Stephane Vigouroux, Roelof Willemze, Louis Terriou, André Tichelli, Mohamad Mohty, Sophie De Guibert, Judith C. W. Marsh, Jakob Passweg, Jean-Yves Mary, Gerard Socie
Journal: Blood (2011)
Abstract 5525: Antibody/drug-conjugated micelle as a versatile platform technology for targeted tumor delivery
Authors: Mitsunori Harada
Journal: Cancer Research (2015)

Abstract Background: Antibody-drug conjugates (ADCs) have been recognized as a promising anticancer agent, despite their stringent requirements of antibody affinity, internalization, payload potency, and linker stability. To drive the next generation of ADCs and improve versatility of the component combination, we have designed, prepared and recently developed Antibody/Drug-Conjugated Micelle (ADCM) system. ADCM is composed of polyethylene glycol-poly (amino acid derivative) polymers, which can form a micellar nanoparticle spontaneously in aqueous media with a diameter of 20-100 nm. Antibodies are attached to the surface of the nanoparticle, while payloads are incorporated in the inner core at a payload-to-antibody molecular ratio of 100-200. In this study, monoclonal antibody, trastuzumab or cetuximab, and anticancer drug, anthracycline antibiotic epirubicin or novel hemiasterlin analogue E7974, were used as a targeting sensor and a payload of the ADCM, respectively. Here we report the results of in vitro and in vivo studies. Methods: The ADCMs were prepared as described previously (Japan Patent No.4538666) with slight modification. To examine the cell binding behavior, flow cytometry analysis was performed using an Accuri C6 system. The antigen affinity was evaluated using a Biacore system. The cellular uptake was examined fluorescently using ADCMs employing Alexa 488-labeled antibodies. To compare the in vivo antitumor effects, ADCM, untargeted micelle and the payload were administered intravenously 3 times weekly at the same payload-equivalent dose to nude mice bearing human tumor xenografts with HER2 (NCI-N87 gastric or trastuzumab-resistant JIMT-1 breast tumor) or EGFR (BxPC-3 pancreatic or LS174T colon tumor) expression. Tumor volumes and animal body weights were monitored 2 or 3 times a week. Results: The ADCMs showed similar cell-binding behavior and antigen affinity to the original antibodies. They were found to be internalized more efficiently than the original antibodies. In vivo efficacy studies demonstrated that the ADCMs inhibited tumor growth most effectively compared to control formulations. The therapeutic indexes were significantly improved in terms of the maximum tolerated dose/ED50 (50% effective dose) compared to untargeted micelles and native payloads. These results suggest the potential clinical application of the ADCMs. Conclusion: These data showed improved versatility of the component combination and increased therapeutic indexes of ADCM system, indicating a promising next generation of ADCs. Citation Format: Mitsunori Harada. Antibody/drug-conjugated micelle as a versatile platform technology for targeted tumor delivery. [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 5525. doi:10.1158/1538-7445.AM2015-5525
Identification of BRCA1/BRCA2 carriers by screening in the healthy population and its implications.
Authors: E. Levy-Lahad, E. Gabai-Kapara, B. Kaufman, R. Catane, S. Segev, P. Renbaum, U. Beller, M. King, A. Lahad
Journal: Journal of Clinical Oncology (2011)

1513 Background:Inherited BRCA1/BRCA2 mutations are associated with increased breast /ovarian cancer risks, and acceptable prevention measures (e.g. risk reducing salpingo-oophorectomy) reduce morbidity and mortality. In Ashkenazi Jews (AJ), three variants account for ~95% of deleterious mutations (BRCA1-185delAG, 5382insC; BRCA2-6174delT), with a combined BRCA1/BRCA2 carrier rate of 2.5%. General BRCA1/BRCA2 testing in AJ could therefore fulfill WHO screening criteria if carriers ascertained on the population level were shown to be at high cancer risk. Current risk estimates are based on female carriers ascertained through personal or family history of cancer and thus may suffer from biases. Aim: To determine cancer risk in carriers in the general AJ population, by identifying BRCA1/BRCA2 families through healthy males. Methods: 175 BRCA1/BRCA2 carriers, including 3 double BRCA1/BRCA2 heterozygotes, were identified by testing 8,196 AJ males with no cancer history (2.2% carrier rate). Relatives of carriers were tested and cancer risk was assessed based on testing and family history within these families. Results: Breast and ovarian cancer risks in female carriers ascertained through healthy males were comparable to current risk estimates (> 80% by age 70 for breast and ovarian cancer combined). Although family history was more suggestive of inherited predisposition in carriers vs. non carriers (p<0.001), family history was either not suggestive or minimal in 45% and 18% of BRCA1/BRCA2 families respectively. Thus, 63% of families would not be identified using current referral criteria. Lack of family history was related to low incidence as a result of paternal inheritance, small family size, male preponderance and few females inheriting the familial mutation. Cancer history was more suggestive of inherited predisposition in BRCA1 compared to BRCA2 families (p=0.015) Conclusions: Cancer risk in female BRCA1/BRCA2 carriers is high in the general population, suggesting general screening is justified. This is currently feasible, and likely cost-effective, in any population with common mutations, but could be universally applicable with advances in molecular testing.
Shortened Erythrocyte Life Span and Increased Oxidative Stress In Erythroid Precursors Are Consistent with Normocytic Anemia In Mice with Chronic Inflammation
Authors: Andrew J. Layman, Jacqueline M. Langdon, Qilu Yu, Olivier D. Prince, Jeremy D. Walston, Curt I. Civin, Cindy N. Roy
Journal: Blood (2010)
Consequent Iron Chelation Therapy in Patients with Low Risk Myelodysplastic Syndrome Leads to up-Regulation of .CXCL12, JAK2 and HSF2: Possible Link Between Iron Chelation and Improvement of Erythropoiesis.
Authors: Florian Nolte, Martin Neumann, Ouidad Benlasfer, Sandra Heesch, Eckhard Thiel, Uwe Platzbecker, Wolf-Karsten Hofmann
Journal: Blood (2009)
PIM Kinases Inhibition, a Rational Strategy in Peripheral T-Cell Lymphomas,
Authors: Esperanza Martin-Sanchez, Socorro M. Rodriguez-Pinilla, Margarita Sanchez-Beato, Beatriz Dominguez-Gonzalez, Magdalena B. Wozniak, Manuela Mollejo, Javier Alves, Jose Luis Rodriguez-Peralto, Javier Menarguez, Juan C. Cigudosa, Pablo L. Ortiz-Romero, Juan F. Garcia, James R. Bischoff, Miguel A. Piris
Journal: Blood (2011)
Mti-101 Induces Necrotic Cell Death in AML Cells Through Its Binding to Cell Surface Complexes Containing CD44 and ITGA4
Authors: Rajesh R Nair, Joel H Tolentino, Milijana Ugrenovic, Priyesh R Jain, Mark L McLaughlin, Jeffrey E Lancet, Lori A Hazlehurst
Journal: Blood (2012)
Therapeutic hypothermia during CPR did not improve survival to discharge in out-of-hospital cardiac arrest
Authors: Benton R. Hunter
Journal: Annals of Internal Medicine (2016)

Source Citation Bernard SA, Smith K, Finn J, et al. Induction of therapeutic hypothermia during out-of-hospital cardiac arrest using a rapid infusion of cold saline: the RINSE trial (Rapid Infusion of Cold Normal Saline). Circulation. 2016;134:797-805. 27562972
Regulatory-Approval Driven Safety and Efficacy of MGMTP140K Lentivirus Transduction of Human CD34+ Cells for a Phase I Clinical Trial for Upfront Treatment of Glioma,
Authors: Yulan Qing, Jane Reese, Min Liu, Amar Desai, Heather Embree, Boro Dropulic, Stanton L. Gerson
Journal: Blood (2011)
SAKK 65/08: A Phase I Trial of the HIV Protease Inhibitor Nelfinavir in Combination with Bortezomib Identifies Nelfinavir As FDA Approved, Oral Drug that Inhibits the Proteasome and Induces Proteotoxic Stress in Vivo and has Potential Antimyeloma Activity.
Authors: Christoph Driessen, Dagmar Hess, Thomas Pabst, Sarah R Haile, Markus Joerger, Roger von Moos, Catherine Berset, Susanne Crowe, Hilde Rosing, Hermen S Overkleeft, Christiana Sessa, Marianne Kraus
Journal: Blood (2012)
Wearable Technologies in Collegiate Sports: The Ethics of Collecting Biometric Data From Student-Athletes
Authors: Jason F. Arnold, Robert M. Sade
Journal: The American Journal of Bioethics (2016)

The wearable technology market is booming and more than 400 million wearable smart devices, worth about $34 billion, will be sold in 2020 (Lamkin 2016). Fitness, activity, and sports trackers repre...
Abstract LB-279: Quantitative flux measurements of serum protein catabolism in PDAC and other KRAS-mutant cancers
Authors: Michel Nofal, Kevin Zhang, Josh Rabinowitz
Journal: Cancer Research (2015)

Abstract Activating KRAS mutations are prevalent in human cancer and are associated with poor prognosis. Among these malignancies is pancreatic ductal adenocarcinoma (PDAC), which is universally KRAS-driven and almost universally lethal. PDAC tumors are extremely fibrotic and hypovascularized, limiting perfusion of nutrients into the tumor, and tumor cells exhibit an altered metabolic program to support survival and proliferation in this environment. One metabolic activity upregulated in these tumor cells is the uptake and catabolism of serum protein. This process yields a substantial alternative source of amino acids and can support the proliferation of cultured cells lacking free essential amino acids. However, existing methods for assaying the uptake and degradation of intact protein provide qualitative outputs, and as such, do not yield accurate estimates of flux from serum protein to amino acid monomers. Here, we present a method for quantitative measurement of the catabolic production of amino acids from serum protein in cultured cells. By culturing cells in medium containing fully 13C-labeled glucose and amino acids supplemented with unlabeled albumin, we distinguish amino acids taken up as monomers from the medium from serum protein-derived amino acids. Using a variant of classical metabolic flux analysis, we derive flux estimates for serum protein catabolism from measurements of amino acid abundance and isotopic labeling over time. Our method is highly sensitive (i.e. can estimate “baseline” serum protein catabolism in KRAS wild-type cell lines) and yields precise estimates of amino acid influx from serum protein for all proteinogenic amino acids. We have measured serum protein catabolism in a variety of cultured cell lines and find that protein catabolism yields amino acids in comparable amounts to conventional uptake in various pancreatic and non-pancreatic lines. This approach enables estimation of protein catabolic flux in any cell line and can be used to assay the effects of various genetic and pharmacological perturbations on serum protein catabolism with high sensitivity and while accounting for growth rate differences. Citation Format: Michel Nofal, Kevin Zhang, Josh Rabinowitz. Quantitative flux measurements of serum protein catabolism in PDAC and other KRAS-mutant cancers. [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 LB-279. doi:10.1158/1538-7445.AM2015-LB-279