tbuckley/cabot-search huggingface dataset:
Opt-in method is vital for data sharing
Authors: Frank Sullivan, Brian McKinstry, Colin Palmer
Journal: BMJ (2016)

We agree with van Staa and colleagues on health data, that “The ultimate solution, however, must combine new technologies with clear accountability, transparent operations, and public trust.”1 One method to achieve the necessary confidence is to create an opt-in mechanism for the use of patient identifiable data.2

Building on the Scottish Health Informatics Programme (SHIP) governance mechanisms and …
Cash strapped CCG plans to halt non-urgent referrals
Authors: Anne Gulland
Journal: BMJ (2016)

Fears over potential risks to patients have been raised after a clinical commissioning group (CCG) in England proposed suspending all non-urgent referrals to secondary care, in a bid to save at least £2.5m (€3m; $3.3m) over the current financial year.

In its two year financial recovery plan, published at the beginning of August, St Helens CCG, in Merseyside, proposed a temporary halt on all non-urgent referrals to secondary care for four months during the coming winter. Clinically urgent referrals, suspected cancer, and referrals of sick children would not be affected. The CCG has to make £12.5m worth of savings this financial year and £17.5m in 2017-18 to balance its budget.

St Helens CCG told …
Abstract 4863: PF-06840003: a highly selective IDO-1 inhibitor that shows good in vivo efficacy in combination with immune checkpoint inhibitors
Authors: Joseph Tumang, Bruno Gomes, Martin Wythes, Stefano Crosignani, Patrick Bingham, Pauline Bottemanne, Hélène Cannelle, Sandra Cauwenberghs, Jenny Chaplin, Deepak Dalvie, Sofie Denies, Coraline De Maeseneire, Peter Folger, Kim Frederix, Jie Guo, James Hardwick, Ken Hook, Katti Jessen, Erick Kindt, Marie-Claire Letellier, Kai-Hsin Liao, Wenlin Li, Karen Maegley, Reece Marillier, Nichol Miller, Brion Murray, Romain Pirson, Julie Preillon, Virginie Rabolli, Chad Ray, Stephanie Scales, Jay Srirangam, Jim Solowiej, Nicole Streiner, Vince Torti, Konstantinos Tsaparikos, Paolo Vicini, Gregory Driessens, Manfred Kraus
Journal: Cancer Research (2016)

Abstract Tumors use tryptophan-catabolizing enzymes such as Indoleamine 2,3-dioxygenase-1 (IDO-1) to induce an immunosuppressive microenvironment. IDO-1 expression is upregulated in many cancers and described to be a resistance mechanism to immune checkpoint therapies. IDO-1 is induced in response to inflammatory stimuli such as IFN-ã and promotes immune tolerance through the catabolism of tryptophan and accumulation of tryptophan catabolites including kynurenine. IDO-1 activity leads to effector T-cell anergy and enhanced Treg function through upregulation of FoxP3. As such, IDO1 is a nexus for the induction of key immunosuppressive mechanisms and represents an important immunotherapeutic target in oncology. We have identified and characterized a new IDO-1 inhibitor. PF-06840003 is a highly selective orally bioavailable IDO-1 inhibitor. PF-06840003 reversed IDO-1-induced T-cell anergy in vitro. In vivo, PF-06840003 reduced intratumoral kynurenine levels in mice by &amp;gt;80% and inhibited tumor growth in multiple preclinical syngeneic models in mice, in combination with immune checkpoint inhibitors. PF-0684003 has favorable predicted human pharmacokinetic properties, including a predicted t1/2 of 16-19 hours. These studies highlight the strong potential of PF-06840003 as a clinical candidate in Immuno-Oncology. Citation Format: Joseph Tumang, Bruno Gomes, Martin Wythes, Stefano Crosignani, Patrick Bingham, Pauline Bottemanne, Hélène Cannelle, Sandra Cauwenberghs, Jenny Chaplin, Deepak Dalvie, Sofie Denies, Coraline De Maeseneire, Peter Folger, Kim Frederix, Jie Guo, James Hardwick, Ken Hook, Katti Jessen, Erick Kindt, Marie-Claire Letellier, Kai-Hsin Liao, Wenlin Li, Karen Maegley, Reece Marillier, Nichol Miller, Brion Murray, Romain Pirson, Julie Preillon, Virginie Rabolli, Chad Ray, Stephanie Scales, Jay Srirangam, Jim Solowiej, Nicole Streiner, Vince Torti, Konstantinos Tsaparikos, Paolo Vicini, Gregory Driessens, Manfred Kraus. PF-06840003: a highly selective IDO-1 inhibitor that shows good in vivo efficacy in combination with immune checkpoint inhibitors. [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 4863.
Comparison Of Unrelated Cord Blood (CB) and Peripheral Blood Stem Cell (PB) Transplantation In Adults With Myelodysplastic Syndrome (MDS) After Reduced Intensity Conditioning Regimen (RIC): A Collaborative Study From Eurocord and Chronic Malignancies Working Party (CMWP-EBMT)
Authors: Marie Robin, Annalisa Ruggeri, Myriam Labopin, Dietger Niederwieser, Reza Tabrizzi, Guillermo Sanz, Jean-Henri Bourhis, Anja van Biezen, Christian Koenecke, Didier Blaise, Johanna Tischer, Charles Craddock, Natacha Maillard, Mohamad Mohty, Nigel Russel, Johannes Schetelig, Jürgen Finke, Eliane Gluckman, Theo M. de Witte, Vanderson Rocha, Nicolaus Kroeger
Journal: Blood (2013)
Abstract 2882: HnRNP Q1, a novel translational regulator for Aurora-A protein synthesis in colorectal cancer
Authors: Chien-Hsien Lai, Liang-Yi Hung
Journal: Cancer Research (2016)

Abstract HnRNP Q1 is a multifunctional RNA-binding protein and has an abundant expression level compared with hnRNP Q member. In colorectal cancer, hnRNP Q has been reported to associate with cell proliferation, but the underlying mechanism is still unclear. By RNA-immunoprecipitation assay following next-generation sequencing (NGS), a group of cell cycle-related genes was identified to be targeted by hnRNP Q1, including Aurora-A kinase. Aurora-A is a cell cycle dependent kinase involved in regulating centrosome duplication, maturation and spindle assembly during mitosis. Abnormally elevated Aurora-A will cause mitotic defects and aneuploidy, which might lead to genomic instability and tumorigenesis. Our previous work has demonstrated that Aurora-A can be translational up-regulated in colorectal cancer. In order to investigate the role of hnRNP Q1 in Aurora-A expression, GFP-hnNRP Q1 was overexpressed in colorectal cancer cells. We found that Aurora-A protein, but not the mRNA level, was up-regulated in those GFP-hnRNP Q1-overexpressing cells. By biotin pull down and Biacore analysis, we revealed that hnRNP Q1 binds to the 5’-UTRs of Aurora-A mRNA directly, and their interacting domain was mapped. Importantly, we found that hnRNP Q1 can enhance Aurora-A protein synthesis through IRES-mediated translational regulation in a cell cycle-regulated manner by ribosomal protein S6 immunoprecipitation, polysome fractionation and bicistronic reporter assay. CCK-8 assay, colony formation and in vivo xenograft assay all suggested that overexpression of hnRNP Q1 can promote cell proliferation and tumorigenesis of colorectal cancer cells. In addition, the expression level of hnRNP Q1 is positively correlated with Aurora-A in clinical colorectal cancer tissues. Taken together, our data indicate that hnRNP Q1 is a novel trans-acting factor that binds to Aurora-A 5’-UTRs and regulates its translation, which may increase cell proliferation and contribute to the tumorigenesis of colorectal cancer. Citation Format: Chien-Hsien Lai, Liang-Yi Hung. HnRNP Q1, a novel translational regulator for Aurora-A protein synthesis in colorectal cancer. [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 2882.
Abstract LB-206: A bromodomain-swap allele demonstrates that on-target chemical inhibition of BRD9 limits the proliferation of acute myeloid leukemia cells
Authors: Anja F. Hohmann, Laetitia J. Martin, Jessica Minder, Jae-Seok Roe, Junwei Shi, Steffen Steurer, Gerd Bader, Darryl McConnell, Mark Pearson, Thomas Gerstberger, Teresa Gottschamel, Diane Thompson, Yutaka Suzuki, Manfred Koegl, Christopher Vakoc
Journal: Cancer Research (2016)

Abstract Recent studies have revealed vital roles of SWI/SNF complexes in leukemia and a variety of other cancers, making this chromatin remodeler a candidate drug target in human malignancy. Chemical modulation of SWI/SNF activity, however, remains to be achieved. Given the success of pharmacological bromodomain inhibition, we evaluated the role of bromodomain-carrying SWI/SNF subunits and identified Bromodomain-containing protein 9 (BRD9) as critical for the growth of Acute Myeloid Leukemia (AML). In AML cells, BRD9 binds the enhancer of the MYC proto-oncogene and sustains MYC transcription, rapid cell proliferation, as well as a block in differentiation. Based on these observations, we derived a small-molecule inhibitor of the BRD9 bromodomain, which partially displaces BRD9 from MYC enhancer elements and selectively suppresses the proliferation of mouse and human AML cell lines. Given the known role of other bromodomains, namely those of BRD4, in leukemia growth, ruling out potential off-target activity of our BRD9 inhibitor was critical. Traditionally, bromodomain inhibitor selectivity is tested using in vitro binding assays that examine a subset of other bromodomains. To sample the entire space of potential off-target proteins, we sought an in-cell selectivity assay. To this end, we engineered a bromodomain-swap allele of BRD9, which retains functionality despite a radically altered bromodomain pocket. Expression of this allele in AML cells confers resistance to the anti-proliferative effects of our BRD9 inhibitor, thus establishing BRD9 as the relevant cellular target. Furthermore, we used an analogous domain-swap strategy to generate an inhibitor-resistant allele of EZH2. Our study provides the first evidence for a role of BRD9 in cancer and further highlights a simple genetic strategy for constructing resistance alleles to demonstrate on-target activity of chemical probes in cells. Citation Format: Anja F. Hohmann, Laetitia J. Martin, Jessica Minder, Jae-Seok Roe, Junwei Shi, Steffen Steurer, Gerd Bader, Darryl McConnell, Mark Pearson, Thomas Gerstberger, Teresa Gottschamel, Diane Thompson, Yutaka Suzuki, Manfred Koegl, Christopher Vakoc. A bromodomain-swap allele demonstrates that on-target chemical inhibition of BRD9 limits the proliferation of acute myeloid leukemia 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 LB-206.
Abstract 4550: High-level nuclear GSK3β promotes glioma tumorigenesis by phosphorylating KDM1A and inducing its deubiquitination by USP22
Authors: Aidong Zhou, Kangyu Lin, Sicong Zhang, Suyun Huang
Journal: Cancer Research (2016)

Abstract Glioblastoma multiforme (GBM) is the most lethal brain tumors and is resistant to most therapeutic endeavors. Glioma stem cells (GSCs) in GBM are responsible for glioma propagation and resistance to conventional therapies. GSK3β is a multifunctional serine/threonine kinase. Growing evidences have supported the oncogenic roles of GSK3β in diverse cancers, including in GBM; however, the functional mechanism of GSK3β in tumor initiation and propagation remains elusive. Our study showed that nuclear GSK3β is responsible for overexpression of the histone demethylase KDM1A and critically regulates histone H3K4 methylation during glioma tumorigenesis. GSK3β phosphorylates KDM1A, which induces its binding and deubiquitination by USP22, leading to KDM1A stabilization. GSK3β and USP22-dependent KDM1A stabilization is required for the demethylation of histone H3K4, thereby repression of BMP2, CDKN1A, and GATA6 transcription, and result in GSCs self-renewal and brain tumorigenesis. Moreover, introduction of a GSK3β-phosphorylation-mimic mutant KDM1A rescues the effect of GSK3β depletion on the inhibition of glioma tumorigenesis. In human glioblastoma specimens, KDM1A levels are correlated with nuclear GSK3β and USP22 levels. Furthermore, a GSK3 inhibitor tideglusib in a GBM mouse model inhibits the tumor initiating ability of GSCs, sensitizes tumors to temozolomide, and prolongs mice survivals via KDM1A down-regulation. Our findings demonstrate that nuclear GSK3β and USP22-mediated KDM1A stabilization is essential for glioma tumorigenesis and highlights that targeting GSK3β as a therapeutic target for GBM. Citation Format: Aidong Zhou, Kangyu Lin, Sicong Zhang, Suyun Huang. High-level nuclear GSK3β promotes glioma tumorigenesis by phosphorylating KDM1A and inducing its deubiquitination by USP22. [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 4550.
Building a new process: Nursing verification of pediatric oral chemotherapy.
Authors: Jessica A. Zerillo, Erin Santacroce, Mary Ann Zimmerman, Melissa Freeman, Teresa Lau Greenberg, Phuong Nguyen, Susan N. Chi, Pratiti Bandopadhayay, Sharon Lane, Audrea Szabatura, Kathleen Houlahan, Amy Billett
Journal: Journal of Clinical Oncology (2016)

199 Background: While team-based safety checks ensure safe prescribing of parenteral chemotherapy, oral chemotherapy is usually prescribed by a single clinician. With the growing use of oral chemotherapy, processes are needed to protect these vulnerable patients from prescription errors. Methods: A team of nurses, clinicians, pharmacists and administrators developed a new process and checklist for nursing verification of oral chemotherapy prescriptions at Dana-Farber’s pediatric neuro-oncology program. Prescriptions are verified against the treatment plan by two pediatric oncology nurses. The verification checklist includes drug, dose with any modifications, height and weight, laboratory values and patient instructions. When available, the prescription bottle is also verified. Data was collected over a three-month pilot period. Results: From 6/18/15-9/16/15, 56 prescription verifications occurred. Verification rate of on-site retail pharmacy filled prescriptions was 47% (32/68 prescriptions). Median time for verification was 20 minutes (IQR 15, 40) per nurse. Nurses identified problems outside of prescription verification, including missing prior authorizations and unclear treatment plans. Medication bottles were not routinely available for verification. One identified near miss would have resulted in an 80% under-dose of everolimus. Conclusions: Prescription verification by nursing in a pediatric oncology clinic was feasible. While it was successful in identification of one medication error before it reached the patient, only 47% of prescriptions were verified. Since prescription bottles are usually obtained after a visit, verification of the actual bottles will require new workflows, such as additional clinic visits or uploading a picture via the patient portal. Involving the nurse in the review of oral chemotherapy not only identified a prescription error, but also highlighted issues within other aspects of patients’ care, including inconsistent documentation of the treatment plan. The inclusion of nursing in the review and management of oral chemotherapy has the potential to improve safety and outcomes for these patients.
Abstract 3774: KD06 is a novel anti-cancer drug that causes cell death in triple-negative breast cancer cell lines and tumor xenografts
Authors: Nancy D. Ebelt, Clint D J Taveres, Xuemei Xie, Youssef W. Naguib, Jiney Jose, Tinashe B. Ruwona, Ashwini K. Devkota, Jihyun Park, Tamer S. Kaoud, Eric V. Anslyn, Jeffrey T. Chang, Zhengrong Cui, Chandra Bartholomeusz, Kevin N. Dalby
Journal: Cancer Research (2016)

Abstract Development and screening of small molecule compounds for anti-cancer activity has been of prime interest to the scientific community following the success of targeted, large anti-cancer molecules such as therapeutic antibodies. Small molecules pass more easily through cell membranes and may cross the blood-brain barrier. KD06 is a small molecule triptan-like compound whose parent molecule binds and inhibits serotonin receptors. This compound increases apoptosis of the triple-negative breast cancer cell lines MDA-MB-231 and MDA-MB-157 via caspase activation. Treatment with KD06 also causes increased autophagy as well as activation of ER stress responses. The growth of tumor xenografts of MDA-MB-231 cells in nude mice are significantly inhibited by twice weekly treatment with 30mg/kg KD06. Analysis of signaling changes by KD06 using reverse phase protein array (RPPA) revealed significant decreases in Akt/mTOR signaling leading to decreased activation of the translation initiation factor 4E-BP1. Other notable changes included decreased expression of proteins important for mitosis such as Cyclin B1, Aurora B and PLK1, and increased phosphorylation of EGFR and increased expression of PDGFR. Analysis of PIP3 and ATP levels showed no change after treatment with KD06, indicating that decreased signaling through Akt/mTOR is not likely due to PI3K inhibition or AMPK activation. Immunofluorescence with KD06 treated cells revealed a change in cell shape after 4 hours of treatment that was reminiscent of cells treated with microtubule binding drugs. Akt localization was affected. These results imply that KD06 may have anti-cancer activity through its effect on microtubule dynamics, inhibiting proper localization and signaling of molecules important for survival and protein translation such as Akt and mTOR. Citation Format: Nancy D. Ebelt, Clint D J Taveres, Xuemei Xie, Youssef W. Naguib, Jiney Jose, Tinashe B. Ruwona, Ashwini K. Devkota, Jihyun Park, Tamer S. Kaoud, Eric V. Anslyn, Jeffrey T. Chang, Zhengrong Cui, Chandra Bartholomeusz, Kevin N. Dalby. KD06 is a novel anti-cancer drug that causes cell death in triple-negative breast cancer cell lines and tumor xenografts. [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 3774.
Real world hospital costs associated with <i>nab</i>-paclitaxel plus gemcitabine (<i>nab</i>-P+G) and FOLFIRINOX (FFX) as first line (1L) treatment (tx) for metastatic pancreatic adenocarcinoma (MPAC).
Authors: George P. Kim, Monika Parisi, Manish Patel, Kathy Belk
Journal: Journal of Clinical Oncology (2016)

e15741 Background: In independent phase III trials, both nab-P+G and FFX demonstrated superiority over G as 1L MPAC tx. Limited data exist on real world effectiveness and costs of nab-P+G v FFX. This study compared median time to tx discontinuation (TTD) and costs between the two cohorts. Methods: A retrospective study was conducted with MedAssets’ de-identified US hospital data. Patients (pts) ≥ 18 yo diagnosed with MPAC between 04/13 and 02/15, completing ≥ 1 cycle of nab-P+G or FFX as 1L, and with ≥ 6 months of data were included. Primary endpoints were median TTD and total costs. Supportive care use and costs were also examined. Between group comparisons used Kaplan-Meier (TTD) and ANOVA (costs). Multivariable general linear regression with gamma distributions were used for costs. Results: A total of 89 pts received nab-P+G, while 61 received FFX. nab-P+G pts were older (age ≥ 70: 31.5% v 11.5%; p < 0.05) compared to FFX, though Charlson Comorbidity Indices were similar (nab-P+G = 8.8, FFX = 9.0). More nab-P+G pts were treated in teaching (56% v 49%) and < 200 bed facilities (27% v 21%), but these differences were not significant. Median TTD did not differ significantly between nab-P+G (120 days) and FFX (98 days; p = 0.77). Median costs per month of tx were lower in nab-P+G pts ($12,192 v $18,743, p < 0.01). More FFX pts used GCSF (66.7% v 22.5%, p < 0.01), while more nab-P+G pts used blood products (BP) (30.0 v 10.4%, p < 0.05). Monthly GCSF and antiemetic costs were lower in nab-P+G pts ($1,584 v $4,793, p < 0.05; $595 v $1,351, p < 0.05). Multivariable analysis confirmed higher total costs (IRR = 1.4, p < 0.01), GCSF costs (IRR = 2.5, p < 0.05) and antiemetic costs (IRR = 6.4, p < 0.01) in FFX pts. No significant differences were seen in BP costs between cohorts. Monthly inpatient costs were lower for nab-P+G ($510 v $3,503, p < 0.01) but not significant (p = 0.18) when controlling for baseline variables. Conclusions: While median TTD was similar between nab-P+G and FFX cohorts, pts treated with FFX had higher total costs driven in part by use of GCSF, antiemetics, and inpatient visits.
Chimeric Immunoreceptor (T-Body) Targeting of Acute B-Cell Lymphoblastic Leukemia (B-ALL) through Lentivirus Engineering of Primary Human T Cells.
Authors: Michael C. Milone, Jonathan Fish, Carmine Carpenito, Mehdi Lakal, Ella Ofori, Gwenn Danet-Desnoyers, James L. Riley, Stephan A. Grupp, Carl H. June
Journal: Blood (2006)
Abstract 5291: OncoMD: A powerful genomics data analysis and interpretation platform for cancer discovery research
Authors: Ravi Gupta, Kiran V. Paul, Kartik Kumaramangalam, Sam Santhosh, Amitabha Chaudhuri
Journal: Cancer Research (2016)

Abstract Cancer cells gain fitness advantage over normal cells by accumulating mutations over time. Next Generation DNA sequencing technologies have made the detection of genetic alterations in tumor genomes affordable. Powerful data analysis and interpretation tools enable extraction of disease-relevant information from diverse genomics data to guide diagnosis and treatment decisions. We have built a robust cancer analytics platform OncoMD that combines tumor mutation profiles, expression signatures, copy number variations, epigenetic alterations and drug sensitivity to create a holistic view of human cancer enabling discovery of new targets for therapy and prognosis. We have analyzed the rich mutational data captured in OncoMD to identify potential T-cell neo-epitopes in different cancers and examined their prevalence in the context of the tumor microenvironment. The presence of T-cell neo-epitopes alone is not sufficient to sensitize tumors to immunotherapy drugs and requires cooperation from the tumor microenvironment. Although mutational burden was a strong predictor of T-cell neo-epitopes in our analysis, other genetic alterations such as overexpression, splicing, gene-fusions and insertions/deletions can produce altered peptides exhibiting high affinity binding to HLA class I and II molecules in cancers with low burden of missense mutations. We determined the number of potential T-cell neo-epitopes after classifying tumors based on their epithelial, stromal and immune cell content using gene expression signatures. We observed that the normalized T-cell neo-epitope burden was strongly anti-correlated with the T-cell content of the tumors, compared to their epithelial or stromal content. Together, our findings suggest that tumors enriched in T-cells may be subjected to immunoediting processes and carry relatively fewer T-cell neo-epitopes to avoid elimination. These tumors are likely to respond to immunotherapy treatments. Citation Format: Ravi Gupta, Kiran V. Paul, Kartik Kumaramangalam, Sam Santhosh, Amitabha Chaudhuri. OncoMD: A powerful genomics data analysis and interpretation platform for cancer discovery research. [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 5291.