tbuckley/cabot-search huggingface dataset:
Abstract 1916: Targeting a MAPK-miR-124-Sox9 axis radiosensitizes human glioblastoma cells
Authors: Hanna Sabelstrom, Rahul Jandial, Ksenya Shchors, Selma Masic, Edith Yuan, Trenten Fenster, Supna Saxena, Allen Ho, Theodore P. Nicolaides, Robyn Wong, Stanislava Yakovenko, Mitchel H. Berger, Evan Y. Snyder, Johan Jakobsson, William A. Weiss, Anders I. Persson
Journal: Cancer Research (2016)

Abstract Glioblastoma (GBM) is the most common and aggressive malignant primary brain tumor. Although genetic alterations and overexpression of genes in the RTK/RAS/MEK/ERK pathway (MAPK) is known to drive GBM aggressiveness, less is known about down-stream effector genes. We confirmed that EGFR amplified human GBMs display high levels of the transcription factor SOX9, a known barrier to neurogenesis and target of microRNA-124 (miR-124). Surprisingly, a subpopulation of SOX9-negative tumor cells expressed markers of mature neurons. Here, we demonstrate that the MEK inhibitor PD325901 depletes SOX9, reduces proliferation, and induces neurogenesis in a mouse GBM model and human GBM cells. We find that MAPK signaling regulates a large cluster of miRNAs in mouse neurosphere cultures, including miR-124. In addition, PD325901 effectively induced miR-124 levels in SOX9-expressing human GBMs. Using a doxycycline-regulable approach, we demonstrate that miR-124 overexpression depletes SOX9 levels and induces neurogenesis in a concentration- and time-dependent manner in human GBM tumorsphere cultures. Doxycycline treatment of athymic nude mice intracranially xenografted with human GBM cells resulted in reduced tumor growth, robust neuronal differentiation, and increased overall survival. Finally, we demonstrate that a brief 3-day treatment with PD325901 or doxycycline effectively radiosensitizes human GBM cells and extends overall survival of xenografted mice. Our work shows that the miR-124-SOX9 axis is a down-stream effector pathway that drives GBM aggressiveness. Long-term exposure to PD325901 is associated with adverse side-effects in patients. We propose that a priming regimen of the clinically relevant MEK inhibitor PD325901 should radiosensitize SOX9-expressing tumors in patients and result in reduced side-effects compared to continuous treatment protocols. Citation Format: Hanna Sabelstrom, Rahul Jandial, Ksenya Shchors, Selma Masic, Edith Yuan, Trenten Fenster, Supna Saxena, Allen Ho, Theodore P. Nicolaides, Robyn Wong, Stanislava Yakovenko, Mitchel H. Berger, Evan Y. Snyder, Johan Jakobsson, William A. Weiss, Anders I. Persson. Targeting a MAPK-miR-124-Sox9 axis radiosensitizes human glioblastoma cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1916.
Antitumour Activity of Bortezomib-Pegylated Liposomal Doxorubicine Association: Results of an Ongoing Study in Multiple Myeloma Patients.
Authors: Giulia Braccalenti, Pasqualinda Ferrara, Marta Gubbiotti, Paola Cerroni, Rita Emili, Maria Grazia Morandi, Roberta Pace, Anna Marina Liberati
Journal: Blood (2006)
Hypoxia Reoxygenation Treatment Induces Platelet Hyperactivity and Relieves Calpain-1-Mediated Inhibition of Platelet Aggregation in a Mouse Model of Severe Sickle Cell Disease
Authors: Jennifer O. Nwankwo, Rod R. Warburton, Thomas Gremmel, Anja J. Gerrits, Lauren J. Richey, Nicholas S. Hill, Alicia Rivera, Joseph A. Jakubowski, Andrew L. Frelinger, Athar H. Chishti
Journal: Blood (2015)
Impact of <i>KRAS</i> mutations on adjuvant carboplatin/paclitaxel in surgically resected stage IB NSCLC: CALGB 9633.
Authors: M. Capelletti, X. F. Wang, L. Gu, S. L. Graziano, R. A. Kratzke, G. M. Strauss, M. Maddaus, M. R. Green, E. E. Vokes, P. A. Janne
Journal: Journal of Clinical Oncology (2010)

7008 Background: CALGB 9633 randomized surgically resected stage IB NSCLC patients to carboplatin/paclitaxel (CP) or observation (OBS). A retrospective assessment suggested a survival benefit in patietns with tumors > 4.0 cm in size (G. Strauss JCO 2008). KRAS mutations were associated with lack of benefit from adjuvant chemotherapy in the JBR.10 trial. The impact of KRAS mutations on outcome in CALGB 9633 was evaluated. Methods: Pretreatment tumor specimens from CALGB 9633 were evaluated for presence of KRAS (codons 12, 13, 61) mutations using mass spectrometry. Outcomes based on presence/absence of KRAS mutations were evaluated. Results: Tumor specimens were available for KRAS genotyping from 267/344 (78%) patients (CP: 139; OBS: 128). KRAS mutations were detected in 71 (27%) of all KRAS evaluable patients: CP: 35 pts (25%); OBS 36 pts (28%). KRAS mutations were more common in adenocarcinomas vs. non-adeno (41% vs. 11%; p < 0.0001) and in ≥ 4.0 cm vs. < 4 cm (32% vs. 18%; p = 0.0144). 5 yr OS (90% CI) for all pts receiving CP: KRAS WT: 62% (53-69) Mut: 55% (35-63); HR 1.2 (p = 0.581). 5 yr OS for pts with ≥ 4.0 cm tumors receiving chemo. KRAS WT: 73% (62-82); Mut: 38% (23-54); HR = 2.3 (p = 0.011). 5 yr OS (90% CI) for all pts on OBS: KRAS WT: 59% (50-67) Mut: 67% (52-78); HR 1.1 (p = 0.747). 5 yr OS for pts with ≥ 4.0 cm tumors on OBS. KRAS WT: 66% (54-76); Mut: 61% (42-75); HR = 1.4 (p = 0.366). Interaction for KRAS mutations and tumor size (≥ 4.0 cm vs. < 4 cm) is significant (p=0.0036) in a multivariate analysis including all patients and adjusting for treatment, KRAS, tumor size and their interactions. Adjuvant CP in KRAS WT pts with > 4.0 cm tumors was suggestively associated with a benefit (HR = 0.69; p = 0.18) while in KRAS mut pts there was no benefit (HR = 1.2; p = 0.5457) However a three-way interaction between KRAS mutation, treatment and tumor size was not significant. Conclusions: KRAS mutations may identify a subset of stage IB NSCLC pts, especially those with ≥ 4.0 cm tumors, that have a worse prognosis and derive less benefit from adjuvant CP. No significant financial relationships to disclose.
Renal Dysfunction in Pediatric Thalassemia Major Patients and Evaluation of Urine NGAL Levels in Thalassemia
Authors: Gulcihan Ozek, Özgür Carti, Erkin Serdaroglu, Serap Cuhadar, Yöntem Yaman, Yesim Oymak, Burcak Gunes, Salih Gözmen, Canan Vergin
Journal: Blood (2014)
Abstract 2742: USP37 promote oncogenesis by stabilizing protein involved in DNA damage repair pathway and provides a novel way to modulate Chk1 activity
Authors: mayank singh, Amy C. Burrows, Andrew Dickson, Matthew Summers
Journal: Cancer Research (2016)

Abstract Dysregulation of the Ubiquitin proteasome system (UPS), which comprises nearly 1000 different components is associated with many aspects of oncogenesis and has emerged as a novel therapeutic target. We have previously shown that USP37 (Ubiquitin specific peptidase 37) antagonizes the tumor suppressor APCCDH1and it promotes S phase entry while data from other groups have shown that it stabilizes oncoproteins, such as c-Myc. We have found USP37 protein levels to be high in many cancerous cell lines as compared to untransformed cells and it appears to help tumor survive the high level of replication stress associated with oncogene expression. It was found that USP37 over expression confers survival advantage to cancer cells while its depletion enhances chemo sensitization in response to variety of replication stresses. USP37 over expressing cells were able to resolve γ-H2AX foci much more effectively then the wild type or cells in which USP37 was depleted. Our data indicate that USP37 binds and stabilizes the active form of CHK1 as evident by its protein levels when USP37 over expressing or depleted cells were exposed to replication stress. Mechanistically, our analyses indicate that USP37 stabilizes CHK1 by its deubiquitination, preventing its degradation. As CHK1 has been pursued as a therapeutic target with limited success our work defines a novel way to modulate activity of CHK1 while simultaneously targeting multiple oncogenes and thereby providing a rationale to evaluate USP37 inhibitor over CHK1 inhibitor as a potential therapeutic target in different cancers. Citation Format: mayank singh, Amy C. Burrows, Andrew Dickson, Matthew Summers. USP37 promote oncogenesis by stabilizing protein involved in DNA damage repair pathway and provides a novel way to modulate Chk1 activity. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2742.
Abstract 2823: Identification of highly selective inhibitors of cyclin-dependent kinase 12
Authors: Axel Choidas, Carsten Schultz-Fademrecht, Carsten Degeenhardt, Peter Habenberger, Uwe Koch, Jan E. Eickhoff, Ann Kathrin Greifenberg, Peter Nussbaumer, Matthias Geyer, Bert M. Klebl
Journal: Cancer Research (2016)

Abstract CDK12 and CDK13 belong to the cyclin-dependent kinase (CDK) family, which includes at least 20 different human CDKs and CDK-like enzymes. One subclass of CDKs (e.g. CDK7, CDK8, CDK9, CDK12 and CDK13) preferentially regulates transcription by phosphorylation of the C-terminal domain of RNA polymerase II (RNAPII), whereas another subgroup of CDKs plays a pivotal role in controlling cell cycle progression (e.g. CDK1, CDK2, CDK4, CDK6 and CDK7). Both groups - cell cycle as well as transcriptional CDKs - have been reported to be involved in cancer development and progression. Recent reports indicated CDK12 to be involved in DNA damage repair mechanisms and linked its mutation to high-grade serous ovarian carcinoma rendering CDK12 a promising target for drug development. However, the pivotal role of individual CDKs and their complex regulation requests for highly selective inhibitors to avoid unwanted adverse effects. Non-specific first-generation CDK-inhibitors cause toxicity in vivo issues. They showed little to no therapeutic window in clinical trials and thus shifted the focus to the optimization of selective small molecule CDK inhibitors. To identify selective small molecular weight inhibitors of CDK12 and CDK13 we employed a rationale drug discovery approach based on a focused kinase library screen. Screening of slightly over 16.000 compounds identified several hit compound classes. Medicinal chemistry based optimization yielded nanomolar CDK12 inhibitors. The selectivity of these improved CDK12 inhibitors is excellent, when tested against 12 CDK family members. Such selective CDK12 inhibitors have also shown promising physicochemical properties, indicating lead- and drug-likeness. Although, potency on the target still needs to be improved, the frontrunners from our selective CDK12 inhibitor family have shown cellular inhibition of CDK12 substrate phosphorylation such as those of RNA polymerase II. Currently, potency of these CDK12 inhibitors is being improved by using structure-guided medicinal chemistry-based optimization. The resulting lead candidates will then be tested in in vivo cancer models. Citation Format: Axel Choidas, Carsten Schultz-Fademrecht, Carsten Degeenhardt, Peter Habenberger, Uwe Koch, Jan E. Eickhoff, Ann Kathrin Greifenberg, Peter Nussbaumer, Matthias Geyer, Bert M. Klebl. Identification of highly selective inhibitors of cyclin-dependent kinase 12. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2823.
Abstract 4711: Broad anti-tumor activity of a novel BET bromodomain inhibitor
Authors: Yan Ma, Ben Powell, Jiazhong Zhang, Ying Zhang, Heidi Carias, Ullrich Schwertschlag, Gaston Habets, Prabha Ibrahim, Wayne Spevak, Chao Zhang, Gideon Bollag
Journal: Cancer Research (2016)

Abstract Inhibitors against the bromodomain and extra terminal domain (BET) family of proteins have been pursued as promising oncology agents based on growing understanding of epigenetic control of disease processes. Through scaffold-based and crystallography-guided drug design, we discovered PLX51107, a potent and selective small molecule inhibitor of the BET family bromodomains. PLX51107 is structurally unrelated to the benzodiazepines such as JQ1, I-BET762, and OTX015 and other published BET inhibitors. PLX51107 exhibits low nanomolar potency in blocking interactions mediated by the four BET family proteins BRD2, BRD3, BRD4, and BRDT. Pharmacologic inhibition of BET proteins by PLX51107 suppresses the transcription of genes essential for tumor growth and survival and leads to selective killing of cancer cell lines across a broad range of hematologic malignancies (e.g. leukemia, lymphoma and multiple myeloma). A subset of solid tumors (e.g. melanoma and SCLC) is also sensitive to growth inhibition by the BET inhibitor PLX51107. Novel biomarkers in these diseases have been identified. PLX51107 is well tolerated and has sufficient potency and oral bioavailability to demonstrate in vivo efficacy in animal models of a variety of tumor types, representing both hematologic and solid tumors of diverse genetic backgrounds. In combination studies, PLX51107 showed potential to improve the efficacy (response rates and duration of response) of other anticancer treatments without increased toxicity. These results support further development of PLX51107 as an epigenetic-based therapy for a variety of cancer indications. Citation Format: Yan Ma, Ben Powell, Jiazhong Zhang, Ying Zhang, Heidi Carias, Ullrich Schwertschlag, Gaston Habets, Prabha Ibrahim, Wayne Spevak, Chao Zhang, Gideon Bollag. Broad anti-tumor activity of a novel BET bromodomain inhibitor. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4711.
THU0083 Simplified Patient-Derived Disease Activity Score (SPDAS2): A Simplified Version without Early Morning Stiffness
Authors: E. Choy, A.M.H. Leung
Journal: Annals of the Rheumatic Diseases (2016)

<h3>Background</h3> Treat-to-target is the standard of care in rheumatoid arthritis (RA). Integral to this is the regular assessment of disease activity. Several tools have been developed and validated to allow patients with RA to self-assess disease activity. One of these tools is the Patient-derived Disease Activity Score (PDAS). Two versions pf PDAS are available: PDAS1 and PDAS2. PDAS-2 is a composite score that includes patient global assessment of disease activity (PGA), modified health assessment questionnaire (MHAQ), patient self-assessed 28 swollen joint count (ptSJC28) and early morning stiffness score (EMS). PDAS2 correlated with DAS28ESR and Clinical Disease Activity Index (CDAI). <h3>Objectives</h3> In order to reduce patient burden, we developed a simplified PDAS2 (sPDAS2) by removing the need to assess EMS. <h3>Methods</h3> Data from 311 patients with established RA were analysed. The original model for calculating PDAS2 was: PDAS2 = 2.667 + [(0.021 x PGA) + (0.483 x MHAQ) + (0.033 x patient 28 SJC) + (0.002 x EMS)]. Linear regression was used to develop a sPAS2 using DAS28ESR as a dependent variable and including PGA, MHAQ and ptSJC28. R-squares were used to examine the statistical model fit of sPDAS2 compared with PDAS2. sPDAS2 was further validated using data from a different cohort of 204 patients with established RA. Correlation of sPDAS-2 with DAS28 and CDAI was examined to assess criterion and construct validity. <h3>Results</h3> Based on data from 311 patients with RA. The following model for sPDAS2 was developed: sPDAS2 =2.447 + 0.028 x PGA + 0.422 x HAQ + 0.053 x patients 28SJC. The R-square for PDAS2 (including EMS) was 0.601. R-square for sPDAS (without the EMS) was 0.594. A difference of 0.007 indicating minimal loss of statistical fit. Using data from a different cohort of RA patients. sPDAS2 correlated well with DAS28ESR (r=0.72, p&lt;0.001) and CDAI (r=0.74, p&lt;0.001) demonstrating criterion and construct validity. <h3>Conclusions</h3> A sPDAS2 has been developed and validated for patients with RA to self-assess disease activity. The components of sPDAS2 included PGA, mHAQ and ptSJC28 and do not require assessment of early morning stiffness. <h3>Acknowledgement</h3> The original developed of PDAS was supported by a grant from Arthritis Research UK. The CREATE Centre is funded by Arthritis Research UK and Health and Care Research Wales. <h3>Disclosure of Interest</h3> None declared
Abstract 2063: A novel ELAVL1-TYK2 fusion protein drives STAT3/5 activation and PIM-1 expression, survival and growth in the MOLM-16 acute myeloid leukemia cell line
Authors: Kristen McEachern, Erika Keeton, Keith Dillman, Minwei Ye, Chloe Stengel, Huawei Chen, Suping Wang, Shaun Grosskurth, Rosemary E. Gale, David C. Linch, Asim Khwaja, Zhongwu Lai, Dennis Huszar
Journal: Cancer Research (2015)

Abstract Pim kinases are upregulated in leukemias and lymphomas and mediate cell growth and survival. Acute myeloid leukemia cell lines sensitive to the pan-Pim kinase inhibitor AZD1208 showed elevated pSTAT5 and Pim-1 expression that correlated with known tyrosine kinase mutations. However, one of the most sensitive lines, MOLM-16, lacked a reported driver mutation. RNA transcriptome sequencing identified a novel fusion gene comprised of the TYK2 kinase domain fused to the N-terminus of the RNA binding protein ELAVL1/HuR. The genes are co-localized within ∼2 MB on the short arm of chromosome 19, at position 13.2. The fusion results in loss of the Tyk2 pseudokinase domain, which negatively regulates kinase activity, suggesting a gain of function genetic alteration. Tyk2 was highly expressed and found to be amplified in MOLM-16 cells, with a higher degree of amplification of the exons encoding the kinase domain. Knockdown experiments demonstrated that down-regulation of the fusion gene, but not of the wild type ELAVL1 or TYK2 transcripts, resulted in suppression of STAT3/5 phosphorylation, Pim1 levels, and proliferation. Conversely, expression of the ELAVL1-TYK2 fusion protein in FDCP1 cells was shown to confer IL-3 independent growth. The fusion was not identified in screening of ∼200 AML patient samples or through analysis of TCGA data suggesting that it occurs at a low frequency, but interestingly NPM1-Tyk2 fusions have recently been described in cutaneous CD30-positive lymphoproliferative disorders (Velusamy et al. Blood 2014). Citation Format: Kristen McEachern, Erika Keeton, Keith Dillman, Minwei Ye, Chloe Stengel, Huawei Chen, Suping Wang, Shaun Grosskurth, Rosemary E. Gale, David C. Linch, Asim Khwaja, Zhongwu Lai, Dennis Huszar. A novel ELAVL1-TYK2 fusion protein drives STAT3/5 activation and PIM-1 expression, survival and growth in the MOLM-16 acute myeloid leukemia 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 2063. doi:10.1158/1538-7445.AM2015-2063
BCIs and disability: enhancement, environmental modification, and embodiment
Authors: David Wasserman, Sean Aas
Journal: Brain-Computer Interfaces (2016)

:This paper explores the ways that BCIs can modify the environment as well as the individual, blur the boundaries between them, and thereby affect the physical functioning and social inclusion of people with disabilities. We begin by outlining the traditional distinction between two kinds of technology that serve people with disabilities: assistive devices and universal design. We then examine a spectrum of BCI applications, from prosthetic attachments to public infrastructure, with the potential to vastly improve the functioning of both disabled and nondisabled people, and to diminish the importance and salience of physical impairments. We suggest that these applications will erode the distinction between assistive devices and universal design as they blur the lines between individual and environmental modifications. Our optimism is tempered by concern for the impact that BCI technology may have on our embodied connection to the physical world and on people with intellectual disabilities. We find the latter concern more disturbing than the former, but speculate that both may be mitigated by the same technology that raises them. We conclude by suggesting that the complexities in appraising the impact of BCI technology on people with disabilities reflect their “dual valence”: the fact that the same uses of that technology have good and bad aspects.
Abstract 1213: Thymidine kinase 1 is on the cell surface of prostate cancer cells
Authors: Evita G. Weagel, Roger P. Chu, Wei Meng, Rachel A. Brog, Michelle H. Townsend, Richard A. Robison, Kim L. O’Neill.
Journal: Cancer Research (2016)

Abstract Thymidine Kinase 1 (TK1) is a salvage pathway enzyme that assists in DNA repair and is characteristically expressed in the cytosol, but it also presents at an abnormally high level in the serum of cancer patients. We developed a unique mouse-anti-human TK1 antibody (A72), and used it in conjunction with Flow Cytometry, Scanning Electron Microscopy (SEM), and Confocal Microscopy, to explore the presence of TK1 on the cell surface of two prostate cancer cell lines, namely PC3 and DU145. Flow Cytometry was performed using a standard protocol. Briefly, cells were stained with A72 conjugated to FITC. Anti-NF-κB-FITC and a non-specific IgG-FITC were used as negative controls. Anti-Na+/K+-ATPase-FITC was used as positive control. Cells were then analyzed using a Flow Cytometer. SEM was carried out by first incubating cells with anti-Na+/K+-ATPase and anti-TK1 conjugated to biotin. After probing with streptavidin-gold solution, cells were imaged to examine the presence of gold particles on cell surface. Our data demonstrated TK1-positive populations after flow cytometry analysis, and the presence of gold particles on the membrane of prostate cancer cells. The presence of TK1 on plasma membrane of PC3 and DU145 was further confirmed by Confocal Microscopy. Cells were first stained with A72-FITC and a red plasma membrane stain, then consecutively imaged with a Confocal Microscope. Results showed that A72-FITC associate with the cells in the same region that the membrane had been stained red, concluding that the A72 binds to the cell membrane. These data strongly suggest that TK1 is located on the surface of prostate cancer cells, and indicate that TK1 may be used as a new immunotherapy target for prostate cancer treatment. Citation Format: Evita G. Weagel, Roger P. Chu, Wei Meng, Rachel A. Brog, Michelle H. Townsend, Richard A. Robison, Kim L. O’Neill. Thymidine kinase 1 is on the cell surface of prostate cancer cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1213.
Supported Telemonitoring and Glycemic Control in People with Type 2 Diabetes: The Telescot Diabetes Pragmatic Multicenter Randomized Controlled Trial
Authors: Sarah H. Wild, Janet Hanley, Stephanie C. Lewis, John A. McKnight, Lucy B. McCloughan, Paul L. Padfield, Richard A. Parker, Mary Paterson, Hilary Pinnock, Aziz Sheikh, Brian McKinstry
Journal: PLoS Medicine (2016)

[This corrects the article DOI: 10.1371/journal.pmed.1002098.].