tbuckley/cabot-search huggingface dataset:
Abstract 4671: Identification of novel drugs for glioblastoma using chemical biology fingerprinting
Authors: Darren Finlay, Harshil Dhruv, Lisa Evers, Sen Peng, Jeff Kiefer, Seungchan Kim, Jeffrey Raizer, Michael Berens, Kristiina Vuori
Journal: Cancer Research (2015)

Abstract Glioblastoma Multiforme (GBM) is an aggressive brain tumor with very poor prognosis and extremely limited therapeutic options. GBM is the most common malignant brain tumor and the search for novel targets and/ or the repurposing of already extant drugs to treat the disease is therefore of utmost importance. We describe here a comprehensive multidisciplinary approach to identifying said targets and ergo potential therapies. We have applied a novel analytical strategy to The Cancer Genome Atlas (TCGA) GBM expression data to stratify GBM into novel subtypes we call molecular contexts, or mCs. Subsequently, a panel of patient-derived GBM xenografts was ascribed to our novel mCs. Utilizing a technique we term Chemical Biology Fingerprinting, or CBF, short-term cultures derived from these clinically-relevant preclinical models were screened for chemosensitivity with a deeply annotated, yet clinically relevant, chemical library. Agents that were statistically more toxic to one context than another were then re-tested in true drug dose response experiments to confirm sensitivity. Preliminary data demonstrated that mC14, characterized by mutant p53 and transcriptionally similar to the GBM proneural subtype, showed distinct vulnerability to Arsenic Trioxide (ATO) as compared to mC4, enriched for NF1 mutations and with transcriptional patterns similar to the GBM mesenchymal subtype. To validate the ATO vulnerability signature in GBM, we acquired 20 treatment naïve archival patient samples, that were part of a Phase I/II clinical trial to study the efficacy of ATO and Temozolomide in combination with ionizing radiation (NCT00275067). Participants in the trial exhibited varied survival with ATO treatment (91 days to &amp;gt;1000 days) and the clinical samples were subtyped into our molecular contexts using RNAseq data. In summary, we demonstrate a subclassification of GBM into novel molecular contexts (mCs) and show that these contexts are differentially sensitive to clinically relevant drugs. Citation Format: Darren Finlay, Harshil Dhruv, Lisa Evers, Sen Peng, Jeff Kiefer, Seungchan Kim, Jeffrey Raizer, Michael Berens, Kristiina Vuori. Identification of novel drugs for glioblastoma using chemical biology fingerprinting. [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 4671. doi:10.1158/1538-7445.AM2015-4671
Cost of 90Y-Ibritumomab Tiuxetan Radioimmunotherapy Versus Cost of Standard Regimens for the Treatment of Relapsed or Refractory Indolent Non-Hodgkin’s Lymphoma in Switzerland.
Authors: Andreas Frei, Geoffrey Delmore, Felicitas Hitz, Matthias Schwenkglenks, Thomas Szucs
Journal: Blood (2007)
High‐Titer Rheumatoid Arthritis Antibodies Preferentially Bind Fibrinogen Citrullinated by Peptidylarginine Deiminase 4
Authors: Nathalie E. Blachère, Salina Parveen, Mayu O. Frank, Brian D. Dill, Henrik Molina, Dana E. Orange
Journal: Arthritis & Rheumatology (2016)

Objective Most patients with rheumatoid arthritis (RA) harbor antibodies to citrullinated autoantigens such as citrullinated fibrinogen. Two isoforms of peptidylarginine deiminase (PAD), PAD type 2 (PAD2) and PAD4, which catalyze citrullination with different substrate specificities, can be detected in the synovium of RA patients. This study was undertaken to determine whether RA antibodies preferentially bind PAD2‐ or PAD4‐citrullinated fibrinogen. Methods RA patient and normal donor plasma specimens were tested for binding to PAD2‐ or PAD4‐citrullinated fibrinogen, native fibrinogen, or citrullinated fibrinogen peptides in various dilutions by enzyme‐linked immunosorbent assay (ELISA) and Western blotting. Bands corresponding to masses demonstrating RA antibody reactivity by Western blotting were excised and analyzed by mass spectrometry. Results At low antibody titers (1:40 and 1:100), there was no significant difference between RA antibody reactivity to PAD2‐ and PAD4‐citrullinated fibrinogen. When plasma was further diluted to 1:250 and 1:1,000, RA patient plasma bound PAD4‐citrullinated fibrinogen significantly more than PAD2‐citrullinated fibrinogen, as measured by ELISA and Western blotting. An increased antibody titer was associated with increased avidity for both PAD2‐ and PAD4‐citrullinated fibrinogen. Both enzymes hypercitrullinated fibrinogen, but PAD4 citrullinated arginines more intermittently, generating a mix of citrullinated and noncitrullinated arginines. Peptide ELISA and preadsorption assays confirmed that the region of intermittent citrullination accounts for the majority of RA antibody binding to the β‐chain of citrullinated fibrinogen. Conclusion At high titers, RA antibodies preferentially bind fibrinogen modified by PAD4, because intermittent citrullination offers a more diverse assortment of citrullinated epitopes.
Abstract 3744: Single-cell analysis of adaptive resistance and fractional responses of melanoma cells to RAF/MEK inhibition
Authors: Mohammad Fallahi-Sichani, Nathan J. Moerke, Mario Niepel, Tnghu Zhang, Nathanael S. Gray, Peter K. Sorger
Journal: Cancer Research (2015)

Abstract Treatment of BRAFV600E melanomas with drugs, such as vemurafenib, that inhibit RAF/MEK signaling is effective in the short term, but remission is not durable. Acquired drug resistance is thought to involve short-term adaptive responses that compensate for RAF/MEK inhibition via up-regulation of other pro-growth mechanisms. Thus, understanding and ultimately preventing adaptive responses is a key to durable therapy. Systematic data comparing BRAFV600E tumor cells is generally lacking and it is not known whether adaptation is fundamentally similar across cell types or among individual cells within a cell population. We apply a systematic approach to studying the responses of human melanoma cell lines to five drugs, RAF and MEK inhibitors, with the overall goal of (i) characterizing variability in adaptation with time, dose, cell type and across individual cells, (ii) discovering new or poorly characterized adaptive mechanisms, and (iii) demonstrating the effectiveness of a high-throughput approach involving multiplex measurement, single-cell analysis and computational modeling. The data involves time-course measurement of total level and activity of signaling proteins and cell state markers using array-based methods and single-cell immunofluorescence assays as well as measurement of apoptosis and cell viability under the same conditions. Statistical modeling using partial least squares regression (PLSR) revealed which of the changes in the ∼200,000 point dataset were phenotypically consequential. We found that responses to RAF inhibitors are remarkably diverse and involve multiple pathways that can be up or down-regulated over time, with significant variability across cell types and individual cells. We identified a role for JNK/c-Jun signaling in altering the cell-cycle distribution of melanoma cells, causing apoptosis-resistant cells to accumulate and drug maximal effect (Emax) to fall; co-drugging with RAF and JNK inhibitors or JUN knockdown reverse this effect. The primary effect of JNK inhibitors is to minimize the cell-to-cell variability in pS6 suppression, promoting the induction of apoptosis. Our study shows that a systems-level approach (combining high density time-dependent measurements, quantitative modeling and single-cell analysis) may provide a general framework for evaluating new drugs with adaptive and paradoxical response, and identifying potentially useful combination therapies. Citation Format: Mohammad Fallahi-Sichani, Nathan J. Moerke, Mario Niepel, Tnghu Zhang, Nathanael S. Gray, Peter K. Sorger. Single-cell analysis of adaptive resistance and fractional responses of melanoma cells to RAF/MEK inhibition. [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 3744. doi:10.1158/1538-7445.AM2015-3744
Abstract 3912: GDF2 promotes anoikis susceptibility in ovarian and breast epithelia
Authors: Archana Varadaraj, Pratik Patel, Anne Serrao, Tirthankar Bandyopadhyay, Nam Y. Lee, Amir Jazaeri, Susan Murphy, Karthikeyan Mythreye
Journal: Cancer Research (2015)

Abstract Resistance to anchorage independent cell death (anoikis) is one of the features of metastasis and can be regulated by a diverse array of growth factors. The protein encoded by GDF2 is BMP9 and is a member of the Bone Morphogenetic protein family and the TGFβ superfamily with defined roles in angiogenesis and emerging yet controversial roles in carcinogenesis. We used normal and oncogenic epithelial systems to examine the role of GDF2 in ovarian and breast epithelia. We find that both normal and transformed epithelial cells are competent to activate the Smad1/5 signaling cascade in response to GDF2. This activation occurs via specific complex formation between the Type I receptor Serine threonine kinases Alk3 and Alk6 and the Type II receptor serine threonine kinase BMPRII. We find that in breast and ovarian epithelial cells GDF2 specifically regulates anchorage independent growth by increasing anoikis sensitivity that is dependent on GDF2's ability to sustain SMAD1/5 activation via Alk3 and Alk6. Analysis of cell lines and patient data indicates epigenetic regulation of GDF2 expression in ovarian and breast cancers. These findings reveal an antimetastatic role for GDF2 in ovarian and breast cancer models of disease with significant implications for the use of epigenetic drugs currently in clinical trials. Citation Format: Archana Varadaraj, Pratik Patel, Anne Serrao, Tirthankar Bandyopadhyay, Nam Y. Lee, Amir Jazaeri, Susan Murphy, Karthikeyan Mythreye. GDF2 promotes anoikis susceptibility in ovarian and breast epithelia. [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 3912. doi:10.1158/1538-7445.AM2015-3912
Supra-additive effect of IMO-4200, a novel TLR7 and TLR8 dual agonist, with rituximab and cytotoxics in preclinical models of hematologic malignancies.
Authors: D. Wang, M. Precopio, M. Reardon, T. Lan, J. X. Tang, E. R. Kandimalla, A. S. Bexon, N. La Monica, S. Agrawal
Journal: Journal of Clinical Oncology (2011)

e13076 Background: IMO-4200, a dual agonist of toll-like receptors (TLR) 7 and 8, induces potent Th-1 immune responses and exerts significant antitumor effects in a number of tumor models. In this study, we evaluated IMO-4200 in combination with rituximab and bendamustine or rituximab and fludarabine in human lymphoma xenograft models. Methods: Mice implanted IV with Ramos cells were treated with IMO-4200 50 mg/kg SC every other day x 5, rituximab 10 mg/kg IP every other day x 5, both agents or saline control starting at day 8. The addition of bendamustine 15 mg/kg IP daily x 3 was then tested. In a second experiment in human B-cell lymphoma Raji xenografts, we used fludarabine 250 mg/kg IP instead of bendamustine plus 4 additional IMO-4200 injections. In a third set of experiments conducted in vitro, we monitored the impact of IMO-4200 on rituximab-mediated antibody-dependent cytotoxicity (ADCC) and direct apoptosis of the tumor cells. Results: The table shows that IMO-4200 significantly increased survival when added to rituximab alone and when combined with both rituximab and either cytotoxic. In addition, IMO-4200 enhanced the ADCC of rituximab on Raji and Granta human lymphoma cell lines. It also sensitized human B-cell lymphoma Ramos cells to rituximab-induced apoptosis. Conclusions: IMO-4200 enhances the antitumor activity of rituximab and standard cytotoxic agents used in non-Hodgkin's lymphoma or other hematologic malignancies. IMO-4200 has been selected as the lead candidate for clinical development. Bendamustine Fludarabine Median survival (days) P value vs. control Median survival (days) P value vs. control Control 23 18 – IMO-4200 25 0.233 ND – Rituximab 36 <0.01 24 <0.01 IMO-4200 + rituximab 45 0.012* 29 <0.01* Cytotoxic agent + rituximab 49 <0.01* 32 <0.01* IMO-4200 + rituximab + cytotoxic agent 59 0.026† 37 0.012† * vs rituximab; † vs rituximab + cytotoxic agent; ND, not done.
LH-receptor polymorphisms and response to androgen deprivation therapy in prostate cancer.
Authors: S. V. Liu, T. B. Dorff, Q. Wang, S. Xiong, E. Thara, M. Keng, S. A. Ingles, J. K. Pinski
Journal: Journal of Clinical Oncology (2011)

4597 Background: Androgen deprivation therapy (ADT) is the cornerstone of treatment for advanced prostate cancer. Our recent data demonstrates an integral role of luteinizing hormone (LH) signaling in androgen synthesis in prostate cancer cells. We therefore hypothesized that genetic variation in the LH receptor may impact the efficiency of signal transduction and influence the degree of castration, the duration of response to ADT and overall course. We now report the association between LH receptor genotype and response to ADT. Methods: Fifty eligible patients had a histopathological diagnosis of prostate cancer and had received ADT for advanced prostate cancer. The blood was collected from each patient after obtaining informed consent. DNA was extracted from blood and genotypes for LHR were assayed using the TaqMan method. The time to castration resistance and level of testosterone suppression were obtained by linking to clinical records. Genotype groups were compared using ANOVA or Kruskal-Wallis tests. Results: The median age at diagnosis was 59 (range 48-69). Of the 50 patients enrolled, 29 were treated for primary metastatic disease, 18 at biochemical recurrence (BCR) and 12 with BCR accompanied by radiographic metastases. The median PSA at initiation of ADT was 109.4 ng/ml for primary metastatic disease and 9.8 ng/ml for recurrent disease. The median time to castration resistance was 12 months in the primary metastatic group and 32.4 months in the recurrent group. In the recurrent group, the presence of minor alleles in the LH receptor genotype was associated with a shorter time to castration resistance with a median of 39 months in men with no minor alleles, 23 months in men with 1 minor allele and 16 months in men with 2 minor alleles (p<.05). Median testosterone levels (T) during ADT were higher for men carrying any minor alleles. Median nadir T was 7 ng/dL for men with no minor alleles compared to 22.5 ng/dL for those with 1-2 minor alleles (p=0.07) with median peak T of 19 ng/dL vs. 43 ng/dL, respectively (p=0.01). Conclusions: Genetic variation in the LH receptor was clearly linked with time to castration resistance and depth of castration and warrants further analysis to define its role as a prognostic and predictive marker.
Abstract 4765: A drill-down approach to identifying an ER negative-specific gene signature
Authors: Maria J. Worsham, Dhananjay Chitale, Kang Mei Chen, Indrani Datta, Josena K. Stephen, George Divine
Journal: Cancer Research (2015)

Abstract There has been relatively little advancement in changing the management of women with ER negative (ER-) breast cancer (BC). Our objective is to examine the contribution of aberrantly methylated genes to the pathogenesis of ER- BC, determine their utility in refining classification of ER- subtypes [basal-like (BL) and Her2-enriched], in differentiating ER- BC in African American (AA) and Caucasian American (CA) women, and as new prognostic and therapeutic targets for better management of ER- BC. The methylation status of 40 ER- and 40 ER positive (ER+) breast cancer samples was assessed using the Illumina 450K. A 3-tiered approach was used to call out genes most differentially methylated between ER- and ER+. The top 70 genes were further downsized using the TaqMan low-density array expression assays, Ingenuity Pathway Analysis (IPA) to assess their biologic significance, followed by targeted sequencing (Illumina Miseq). Further assessment of the genes in the 450K TCGA data sets (UCSC Brower 2015) was used for final downsizing. Of the 70 highly ranked differentially methylated genes, 56 were hypermethylated and 14 hypomethylated, with positive correlation with gene expression for the majority of genes. Expression verification and significant rankings in canonical pathways and bionetworks resulted in further downsizing to 41 genes upon confirmation by targeted sequencing. Further filtering of the 41 genes with 450K TCGA data sets provided additional refinement to a 10 gene candidate panel currently being vetted in a retrospective cohort of over 1000 ER negative BC (with 40% AA). Our iterative approach to identify an ER negative-specific gene signature has the potential to offer predictive and prognostic markers of improved classification for ER- BC in AA and CA women. Confirmation and validation of these methylation profiles in independent cohorts of BL BC defined by cDNA microarrays should further stratify poor prognosis breast cancers subgroups and serve as targets for epigenetic-modifying agents individualized to AA and CA women with ER- BC. Human therapeutic intervention trials to reverse deleterious epigenetic changes have shown promise in halting tumor growth by reactivation of the tumor suppressor genes or by reversing DNA hypomethylation. Support: Komen Foundation: KG110218 Citation Format: Maria J. Worsham, Dhananjay Chitale, Kang Mei Chen, Indrani Datta, Josena K. Stephen, George Divine. A drill-down approach to identifying an ER negative-specific gene signature. [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 4765. doi:10.1158/1538-7445.AM2015-4765
416. Immunotherapy of Hepatocellular Carcinoma With T Cells Engineered To Express Glypican-3-Specific Chimeric Antigen Receptors
Authors: Wenpeng Li, Guo Linjie, Marinova Ekaterina, Dotti Gianpietro, Gottschalk Stephen, Metelitsa Leonid, Heczey Andras
Journal: Molecular Therapy (2015)

Hepatocellular carcinoma (HCC) is the fifth most common cancer and the third most common cause of cancer-related death worldwide, with no curative therapies for unresectable HCC. Glypican-3 (GPC3), a membrane bound heparan sulfate proteoglycan is selectively expressed on HCC and has recently emerged as an attractive target for immunotherapy. GPC3-specific monoclonal antibody, GC33 has been shown to be safe in recent a Phase 1 clinical study. However, objective clinical responses to GC33 treatment were modest and transient. We hypothesized that the therapeutic efficacy of GPC3-targeting immunotherapy can be enhanced by combining the specificity of GC33 mAb with the advantages of adoptive cell therapy. To that end, we generated T cells genetically engineered to express GPC3 specific chimeric antigen receptors (GPC3 CARs). The signaling parts of GPC3 CAR constructs contained CD3ζ chain only (1st generation), with CD28 or 4-1BB (2nd generation), or both (3d generation) costimulatory endodomains. We found that GPC3 CAR T cells efficiently and specifically killed GPC3-positive HCC cell lines in vitro (figure 1); released IL-2 and IFN-γ, and proliferated in response to stimulation by HCC cell lines. The 2nd and 3rd generation GPC3 CARs induced superior killing, cytokine release and T cell expansion compared to 1st generation GPC3 CAR. Importantly, 2nd and 3rd generation GPC3 CAR T cells demonstrated curative antitumor activity by eliminating established orthotopic GPC3-positive Huh-7 xenografts in NOD/SCID/IL2gnull (NSG) mice. The results provide justification for testing safety and efficacy of GPC3 CAR T cells in a Phase 1/2a clinical trial in HCC patients.
Oligoclonal Bands In Patients with Multiple Myeloma In Complete Remission After Induction Chemotherapy: Strong Association with the Use of Novel Agents
Authors: Carlos Fernández de Larrea, Natalia Tovar, María Teresa Cibeira, Juan I. Aróstegui, Laura Rosiñol, Montserrat Elena, Xavier Filella, Jordi Yagüe, Joan Blade
Journal: Blood (2010)
Islet inflammation in type 2 diabetes and physiology
Authors: Kosei Eguchi, Ryozo Nagai
Journal: Journal of Clinical Investigation (2017)

The finding of islet inflammation in type 2 diabetes (T2D) and its involvement in β cell dysfunction has further highlighted the significance of inflammation in metabolic diseases. The number of intra-islet macrophages is increased in T2D, and these cells are the main source of proinflammatory cytokines within islets. Multiple human studies of T2D have shown that targeting islet inflammation has the potential to be an effective therapeutic strategy. In this Review we provide an overview of the cellular and molecular mechanisms by which islet inflammation develops and causes β cell dysfunction. We also emphasize the regulation and roles of macrophage polarity shift within islets in the context of T2D pathology and β cell health, which may have broad translational implications for therapeutics aimed at improving islet function.
Abstract 3255: The role of Hdj2 protein in metastatic progression of experimental intracranial glioma
Authors: Darya A. Meshalkina, Maxim A. Shevtsov, Boris A. Margulis, Irina V. Guzhova
Journal: Cancer Research (2015)

Abstract Glioblastoma is one of the most malignant cancer types with median survival of 15 months regardless of the application of combined radio- and chemotherapy. Expression of Hdj2 negatively correlates with the increase of tumor aggressiveness. For assessment of Hdj2 role in tumor progression, invasiveness and metastasis formation in gliomas we developed three C6-based cell lines with Hdj2 and related proteins knock-down: C6 shHsp70, C6 shHdj1 and C6 shHdj2 itself. Following intracranial injection of the modified tumor cells the animals’ survival was estimated. As compared to control C6 (25.4±3.9 days) and C6 shHdj1 (25.5±3.8) we observed a nearly 1.5-fold decrease in survival in C6 shHdj2 (16.8±3.5 days) (P&amp;lt;0.05). On the contrary, in C6 shHsp70 group the survival increased up to 42.5±12.0 days (the increase is completely explainable by the slower growth rate of the culture). Subsequent MR imaging and histological analysis of the tumors demonstrated elevated invasiveness and metastatic activity in C6 shHdj2 group in comparison to C6 shHsp70, C6 shHdj1 and control C6. High migration activity and the ability of detached C6 shHdj2 cells to settle on the substrate was proved in wound-healing assay, colony forming assay and calcium-dependent cell aggregation assay. Immunofluorescence analyses showed loss of membrane-expressed N-cadherin and loss of intercellular contacts mediated by N-cadherin in C6 shHdj2 cells in comparison to other considered cell lines. Actin staining with rhodamine-falloidin revealed highly abundant leading edges in C6 shHdj2 culture. Decrease of Hdj2 expression in gliomas has proved to be of high importance in tumor progression and formation of metastasis. Citation Format: Darya A. Meshalkina, Maxim A. Shevtsov, Boris A. Margulis, Irina V. Guzhova. The role of Hdj2 protein in metastatic progression of experimental intracranial glioma. [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 3255. doi:10.1158/1538-7445.AM2015-3255