tbuckley/cabot-search huggingface dataset:
Abstract 295: The cytosine deaminase APOBEC3B affects responses to therapy in estrogen receptor positive breast cancer cells
Authors: Kelly S. LaPara, Emily Law, Reuben Harris, Douglas Yee
Journal: Cancer Research (2016)

Abstract Endocrine therapy, chemotherapy, or both represent the mainstay of therapy for estrogen receptor positive (ER+) breast cancer. However, acquired (secondary) drug resistance is a major clinical problem. We identified APOBEC3B (A3B), a DNA cytosine deaminase, as a source of DNA mutagenesis driving tumor evolution and contributing to poor clinical outcomes in several cancers by catalyzing genetic changes required for drug resistance and metastasis. A3B accounts for up to half of the mutational load in breast carcinomas expressing this enzyme. High levels of A3B correlate with poor clinical outcomes in tamoxifen treated patients. To evaluate the role for A3B in resistance to therapy, we used the ER+ MCF-7L breast cancer cell line. These cells have modestly elevated levels of endogenous A3B and we suppressed A3B levels by shRNA and enhanced levels by transduction. In vitro, alterations in A3B levels do not affect monolayer growth or cell doubling times. However, in vitro response to tamoxifen was prolonged in MCF-7L cells with suppressed A3B. In a xenograft model, MCF-7 cells with suppressed A3B remained responsive to tamoxifen for a longer period of time compared to wild type cells. Cells with overexpression of A3B had a very short period of tamoxifen suppression compared to wild-type cells. These data suggest high A3B levels are associated with a shorter period of response to tamoxifen. To evaluate the role for A3B in chemotherapy resistance, we treated cells with 5-fluorouracil. In contrast to tamoxifen therapy, cells with elevated A3B levels remained responsive to fluorouracil for longer periods of time compared to wild-type cells. Since A3B converts cytosine to uracil (C-to-U), we speculate that A3B enzymatic activity might enhance sensitivity to a fluoropyrimidine. Thus, the ability of A3B to affect therapeutic resistance in breast cancer may be dependent on the type and mechanism of drug treatment. Citation Format: Kelly S. LaPara, Emily Law, Reuben Harris, Douglas Yee. The cytosine deaminase APOBEC3B affects responses to therapy in estrogen receptor positive breast 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 295.
Abstract 50: 2-Deoxy-2-halo-D-glucose derivatives inhibition of glycolysis in pancreatic cancer
Authors: Rafal Zielinski, Izabela Fokt, Aleksandra Rusin, Stanislaw Skora, Waldemar Priebe
Journal: Cancer Research (2016)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is one of the most hypoxic and subsequently glycolytic tumors. Thus the inhibition of glycolysis appears to be an attractive therapeutic approach that should be explored. Methods: A series of 2-deoxy analogs of D-glucose, namely, 2-deoxy-D-glucose (2-DG), 2-fluoro-D-glucose (2-FG), 2-chloro-D-glucose (2-CG), 2-bromo-D-glucose (2-BG), and 2,2-difluoro-D-glucose (2,2-diFG) were synthesized in our laboratory. The ability of 2-deoxy-2-halo-D-glucose derivatives to inhibit glycolysis in pancreatic cancer cell lines was tested using Seahorse 96 analyzer and XF Glycolysis Stress Test kit. The cellular ATP level was measured using CellTiter-Glo assay. Viability of cells cultured in normoxic and hypoxic conditions were assessed using MTS assay. Results: 2,2-diFG and 2-FG were significantly more potent inhibitors than 2-DG of the Extracellular Acidification Rate (ECAR) of medium in oligomycin-stimulated PDAC cells (complete inhibition at &amp;lt;12.5 mM, whereas, the 100 mM is a commonly used concentration for 2-DG in Seahorse 96 experiments). Interestingly, 2-bromo (2-BG) and 2-chloro (2-CG) analogs have a limited or no effect on glycolysis at tested concentration. Consistently, both, 2,2-diFG and 2-FG, inhibited proliferation of pancreatic cancer cell lines more potently than 2-DG in either normoxic and hypoxic conditions, with the differential effects being significantly more pronounced under hypoxia. Conclusion: Both, 2,2-diFG and 2-FG have a superior to 2-DG ability to inhibit glycolysis in vitro and should be further evaluated in vivo in the PDAC models as a potential anticancer agents. Citation Format: Rafal Zielinski, Izabela Fokt, Aleksandra Rusin, Stanislaw Skora, Waldemar Priebe. 2-Deoxy-2-halo-D-glucose derivatives inhibition of glycolysis in pancreatic 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 50.
Stimulation of Natural Killer Cell–Mediated Tumor Immunity by an IL15/TGFβ–Neutralizing Fusion Protein
Authors: Spencer Ng, Jiusheng Deng, Raghavan Chinnadurai, Shala Yuan, Andrea Pennati, Jacques Galipeau
Journal: Cancer Research (2016)

The clinical efficacy of immune cytokines used for cancer therapy is hampered by elements of the immunosuppressive tumor microenvironment such as TGFβ. Here we demonstrate that FIST15, a recombinant chimeric protein composed of the T-cell-stimulatory cytokine IL15, the sushi domain of IL15Rα and a TGFβ ligand trap, can overcome immunosuppressive TGFβ to effectively stimulate the proliferation and activation of natural killer (NK) and CD8+ T cells with potent antitumor properties. FIST15-treated NK and CD8+ T cells produced more IFNγ and TNFα compared with treatment with IL15 and a commercially available TGFβ receptor-Fc fusion protein (sTβRII) in the presence of TGFβ. Murine B16 melanoma cells, which overproduce TGFβ, were lysed by FIST15-treated NK cells in vitro at doses approximately 10-fold lower than NK cells treated with IL15 and sTβRII. Melanoma cells transduced to express FIST15 failed to establish tumors in vivo in immunocompetent murine hosts and could only form tumors in beige mice lacking NK cells. Mice injected with the same cells were also protected from subsequent challenge by unmodified B16 melanoma cells. Finally, mice with pre-established B16 melanoma tumors responded to FIST15 treatment more strongly compared with tumors treated with control cytokines. Taken together, our results offer a preclinical proof of concept for the use of FIST15 as a new class of biological therapeutics that can coordinately neutralize the effects of immunosuppressive TGFβ in the tumor microenvironment while empowering tumor immunity. Cancer Res; 76(19); 5683-95. ©2016 AACR.
Abstract 3641: ReCapSeg: Validation of somatic copy number alterations for CLIA whole exome sequencing
Authors: Lee Lichtenstein, Betty Woolf, Alyssa MacBeth, Ozge Birsoy, Niall Lennon
Journal: Cancer Research (2016)

Abstract The presence of specific somatic copy number alterations (SCNAs) in tumor genomes can be used to predict sensitivity to specific treatments and to predict outcomes. CapSeg Revised (ReCapSeg) detects SCNAs from tumor sequencing data. The Broad Institute is integrating ReCapSeg into the Clinical Research Sequencing Platform (CRSP), a CLIA-certified platform, to enable physicians to use detected SCNAs in treatment decisions. By using sequencing data CRSP can produce SCNA reports using the same data being generated for other reports (e.g. somatic single nucleotide variants). ReCapSeg produces copy ratio estimates for regions of the genome and includes a caller that labels regions as amplified, deleted, or neutral. ReCapSeg leverages a panel of normals (PoN), which obviates the need for the matched normal for a given tumor sample. Validation for ReCapSeg, in CRSP, is repeatable and standardized with a process for creating a PoN and gathering performance metrics from case samples. Additional QC metrics and criteria on input sequencing data were identified and included, so that reports can indicate when reduced performance can be expected. Citation Format: Lee Lichtenstein, Betty Woolf, Alyssa MacBeth, Ozge Birsoy, Niall Lennon. ReCapSeg: Validation of somatic copy number alterations for CLIA whole exome sequencing. [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 3641.
P0435 : Identification of miR-192 as a novel key regulator of quiescence maintenance in human hepatic stellate cells
Authors: M. Coll, A. El Taghdouini, L. Perea, I. Mannaerts, M. Vila-Cadasesus, J.J. Lozano, D. Blaya, D. Rodrigo-Torres, P. Ginés, L.A. van Grunsven, P. Sancho-Bru
Journal: Journal of Hepatology (2015)
Innate Immunity and Asthma Risk in Amish and Hutterite Farm Children
Authors: Michelle M. Stein, Cara L. Hrusch, Justyna Gozdz, Catherine Igartua, Vadim Pivniouk, Sean E. Murray, Julie G. Ledford, Mauricius Marques dos Santos, Rebecca L. Anderson, Nervana Metwali, Julia W. Neilson, Raina M. Maier, Jack A. Gilbert, Mark Holbreich, Peter S. Thorne, Fernando D. Martinez, Erika von Mutius, Donata Vercelli, Carole Ober, Anne I. Sperling
Journal: New England Journal of Medicine (2016)

The Amish and Hutterites are U.S. agricultural populations whose lifestyles are remarkably similar in many respects but whose farming practices, in particular, are distinct; the former follow traditional farming practices whereas the latter use industrialized farming practices. The populations also show striking disparities in the prevalence of asthma, and little is known about the immune responses underlying these disparities.We studied environmental exposures, genetic ancestry, and immune profiles among 60 Amish and Hutterite children, measuring levels of allergens and endotoxins and assessing the microbiome composition of indoor dust samples. Whole blood was collected to measure serum IgE levels, cytokine responses, and gene expression, and peripheral-blood leukocytes were phenotyped with flow cytometry. The effects of dust extracts obtained from Amish and Hutterite homes on immune and airway responses were assessed in a murine model of experimental allergic asthma.Despite the similar genetic ancestries and lifestyles of Amish and Hutterite children, the prevalence of asthma and allergic sensitization was 4 and 6 times as low in the Amish, whereas median endotoxin levels in Amish house dust was 6.8 times as high. Differences in microbial composition were also observed in dust samples from Amish and Hutterite homes. Profound differences in the proportions, phenotypes, and functions of innate immune cells were also found between the two groups of children. In a mouse model of experimental allergic asthma, the intranasal instillation of dust extracts from Amish but not Hutterite homes significantly inhibited airway hyperreactivity and eosinophilia. These protective effects were abrogated in mice that were deficient in MyD88 and Trif, molecules that are critical in innate immune signaling.The results of our studies in humans and mice indicate that the Amish environment provides protection against asthma by engaging and shaping the innate immune response. (Funded by the National Institutes of Health and others.).
Abstract 2500: Grape compounds suppress colon cancer stem cells in vitro and in a rodent model of colon carcinogenesis
Authors: Lavanya Reddivari, Venkata Charepalli, Ramakrishna Vadde, Sridhar Radhakrishnan, Joshua D. Lambert, Ryan J. Elias, Jairam KP Vanamala.
Journal: Cancer Research (2016)

Abstract We have previously shown that the grape bioactive compound resveratrol (RSV) potentiates grape seed extract (GSE)-induced colon cancer cell apoptosis at physiologically relevant concentrations. However, RSV-GSE combination efficacy against colon cancer stem cells (CSCs), which play a key role in chemotherapy and radiation resistance, is not known. Hence, we tested the anti-cancer efficacy of the RSV-GSE in an azoxymethane-induced mouse model of colon carcinogenesis. RSV-GSE suppressed tumor incidence similar to sulindac, without any gastrointestinal toxicity. Additionally, RSV-GSE treatment reduced the number of crypts containing cells with nuclear β-catenin (an indicator of colon CSCs) via induction of apoptosis. In in vitro mechanistic studies, RSV-GSE suppressed proliferation and sphere formation properties of colon CSCs (positive for CD44, CD133 and ALDH1b1), suppressed pGSK3β and nuclear translocation of β-catenin, a critical regulator of CSC proliferation, similar to sulindac. RSV-GSE, but not sulindac, suppressed nuclear levels of downstream proteins of Wnt/β-catenin pathway, c-Myc and cyclin D1. RSV-GSE also induced mitochondrial-mediated apoptosis in colon CSCs characterized by elevated p53, Bax/Bcl-2 ratio and cleaved PARP. Furthermore, shRNA-mediated knockdown of p53, a tumor suppressor gene that is mutated in advanced stages of colon cancer, in the colon CSCs did not alter efficacy of RSV-GSE. The suppression of Wnt/β-catenin signaling and elevated mitochondrial-mediated apoptosis in colon CSCs support potential clinical testing/application of grape bioactives for colon cancer prevention and/or therapy. Citation Format: Lavanya Reddivari, Venkata Charepalli, Ramakrishna Vadde, Sridhar Radhakrishnan, Joshua D. Lambert, Ryan J. Elias, Jairam KP Vanamala. Grape compounds suppress colon cancer stem cells in vitro and in a rodent model of colon carcinogenesis. [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 2500.
Risk-Reduction Program for Cardiovascular and Limb Events in Patients With Peripheral Arterial Disease—Reply
Authors: Mohamad A. Hussain, Mohammed Al-Omran, Thomas F. Lindsay
Journal: JAMA Surgery (2016)

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VENTANA anti-PD-L1 (SP263) rabbit monoclonal antibody: A high specificity and sensitivity anti-human PD-L1 antibody.
Authors: Chenglu Quon, Xiaoling Xia, Margaret Smith, Colene Drace, Amita Mistry, Alma Nielsen, Costi Sabalos, Penny Towne
Journal: Journal of Clinical Oncology (2016)

e14509 Background: Immune checkpoint inhibition targeting the programmed death receptor (PD-1) and its ligand PD-L1 has emerged as a very promising therapeutic avenue in the treatment of cancer patients. A high quality PD-L1 companion diagnostic test may help predict which patients are more likely to respond to PD-1/PD-L1 antibody-based therapy. An IHC assay was optimized using VENTANA anti-PD-L1 (SP263) Rabbit Monoclonal Antibody (SP263 anti-PD-L1) on the automated BenchMark ULTRA platform. Here we report a series of studies addressing specificity and sensitivity of this antibody. Methods: Peptide inhibition was used to confirm binding of SP263 anti-PD-L1to PD-L1. A panel of cell lines expressing various levels of PD-L1 was employed in Western Blot studies to characterize the immunoreactivity of SP263 anti-PD-L1. Analytical specificity and sensitivity were determined by staining multiple cases of normal and neoplastic human tissue with SP263 anti-PD-L1. Results: Inhibition of PD-L1 IHC staining from the immunizing peptide confirmed that SP263 anti-PD-L1 binds to an epitope corresponding to amino acids 284-290 of PD-L1 protein. Western Blot studies using four cell lines expressing high, medium, low and non PD-L1 protein levels demonstrated that SP263 anti-PD-L1 specifically binds to purified recombinant PD-L1 and not to its negative control. SP263 anti-PD-L1 also binds to endogenous PD-L1 in the cell lines H820, MDA-MB-231 and H1975 and not in the negative cell line Calu-3. The relative levels of PD-L1 protein observed in these four cell lines by Western Blot correlate with PD-L1 protein levels determined by IHC staining as well as with mRNA data. Immunoreactivity of SP263 anti-PD-L1 was run on Tour Of Body (TOB) and Tour of Tumor (TOT) arrays. Specific staining was observed only in normal lymph node tissues, spleen, tonsil, and thymus gland tissues on TOB. On TOT array, 6 out of 71 cases of neoplastic tissues stained positively with SP263 anti-PD-L1. Conclusions: These studies highlighted biochemical and immunological characterization of the SP263 anti-PD-L1 and demonstrated its high specificity and sensitivity in support of the Ventana IHC assay.
Relationship of patient-reported outcomes with MRI measures in rheumatoid arthritis
Authors: Joshua F Baker, Philip G Conaghan, Paul Emery, Daniel G Baker, Mikkel Ostergaard
Journal: Annals of the Rheumatic Diseases (2016)

We assessed whether MRI measures of synovitis, osteitis and bone erosion were associated with patient-reported outcomes (PROs) in a longitudinal clinical trial setting among patients with rheumatoid arthritis (RA).This longitudinal cohort of 291 patients with RA was derived from the MRI substudy of the GO-BEFORE randomised controlled trial of golimumab among methotrexate-naïve patients. Correlations between RAMRIS scores (synovitis, osteitis, bone erosion) and physical function (Health Assessment Questionnaire (HAQ)), pain and global patient scores were determined at 0, 12, 24 and 52 weeks. Correlations between interval changes were also assessed. Multivariable regression models using robust generalised estimating equations evaluated associations over all time-points and their relationship to other clinical disease activity measures.Greater synovitis, osteitis and bone erosion scores were positively associated with HAQ at all time-points (all p<0.05) and with pain and patient global scores at 24 and 52 weeks. Over all visits, synovitis was associated with HAQ, pain and patient global scores (p≤0.03) independent of clinical disease activity measures. Improvements in synovitis and bone erosion were also associated with improvements in PROs. Less improvement in synovitis and progression in MRI erosion at 52 weeks were both independently associated with worsening in all PROs at 52 weeks while progression on X-ray was not associated. Similar associations were observed across treatment groups.MRI measures of inflammation and structural damage correlate independently with physical function, pain and patient global assessments. These observations support the validity of MRI biomarkers.NCT00264537; Post-results.
Abstract SY43-01: Precision cancer medicine using BH3 profiling
Authors: Anthony G. Letai
Journal: Cancer Research (2016)

Abstract The job of precision medicine is to match the right patient to the right drug(s). While the term “precision medicine” is often considered synonymous with “cancer genomics,” -omics approaches have thus far enjoyed only inconsistent success in assigning therapy to patients, despite the abundance of data such approaches generate. We favor functional approaches that allow for perturbation of the cancer cells of interest. BH3 profiling can measure the state of the apoptotic pathway of a cancer cell before and after brief exposures to drugs. By identifying drugs that enhance apoptotic signaling in brief ex vivo exposures, we can identify agents that are active in vivo. An advantage to dynamic BH3 profiling is that its measurements can be made in less than 24 hours, removing the requirement for longer term ex vivo culture that has typically proved a major stumbling block for ex vivo approaches. Citation Format: Anthony G. Letai. Precision cancer medicine using BH3 profiling. [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 SY43-01.
Genomic Amplifications Cause False Positives in CRISPR Screens
Authors: Ankur Sheel, Wen Xue
Journal: Cancer Discovery (2016)

In CRISPR-based screens for essential genes, Munoz and colleagues and Aguirre and colleagues show that gene-independent targeting of genomic amplifications in human cancer cell lines reduces proliferation or survival. The correlation between CRISPR target site copy number and lethality demonstrates the need for scrutiny and complementary approaches to rule out off-target effects and false positives in CRISPR screens. Cancer Discov; 6(8); 824-6. ©2016 AACR.See related article by Munoz et al., p. 900See related article by Aguirre et al., p. 914.
Abstract 1178: Runx1 is obligatory for mammary epithelial cell morphology and phenotype
Authors: Deli Hong, Terri Messier, Andrew Fritz, Gillian Browne, Janet Stein, Jane Lian, Gary Stein
Journal: Cancer Research (2016)

Abstract Introduction: Runx1 belongs to the Runx family of transcription factors. Translocation of Runx1 is well established as a causative factor of leukemia. However the recognition of Runx1 expression in epithelial lining cells of glands suggests that Runx1 functions in maintaining the integrity of that cell layer. Recent studies have identified Runx1 as one of the top genes mutated in breast cancers. Further Runx1 levels are decreased in high-grade primary breast tumors compared to low/mid-grade tumors. Based on these findings, we raise the hypothesis that Runx1 is a tumor suppressor that functions to maintain the normal epithelial phenotype and that loss of Runx1 could promote epithelial to mesenchymal (EMT). Methods and results: We used two human breast cancer cell models systems, the MCF10A to MCF7/T47D and to MDA-MB-231 and the MCF10A progression model from normal-like mammary epithelial cells (MCF10A) to tumorigenic (MCF10AT1) and to metastatic (MCF10CA1a) cells. We observed that the level of Runx1 is decreased in tumorigenic cells. To understand Runx1 function, Runx1 was depleted by shRNA in mammary epithelial cells that resulting in disrupted/altered cellular morphology and suppressed expression of the epithelial gene E-cadherin. To reinforce this observation, EMT was induced by addition of TGFB1 or by growth factor depletion in MCF10A cells. A striking Runx1 decrease resulted suggesting that Runx1 has a crucial role in preventing EMT. Furthermore our analysis of breast tumors and survival data supports the above finding that loss of Runx1 promotes tumor progression. Conclusion and Impact: Our results highlight an essential role for Runx1 in maintaining normal epithelial phenotype and preventing epithelial to mesenchymal transition as well as tumor progression in breast cancer. Identifying this Runx1 mechanism provides the basis for a novel strategy to treat early stage breast cancer. Citation Format: Deli Hong, Terri Messier, Andrew Fritz, Gillian Browne, Janet Stein, Jane Lian, Gary Stein. Runx1 is obligatory for mammary epithelial cell morphology and phenotype. [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 1178.