tbuckley/cabot-search huggingface dataset:
Abstract 3632: Adaptive operations and technology platform for nation-scale precision oncology
Authors: Ogan Abaan, Amrita Basu, David Deal, Michael Hultner
Journal: Cancer Research (2016)

Abstract Precision oncology requires predictive models for therapy selection using variety of biomarkers and clinical features as input. Building and validating these models requires analysis of large numbers of diverse cases in order to relate markers and treatments to positive outcomes. The -omics technologies provide a rich source of genetic and epigenetic markers but demand large compute and storage systems to process the data. Thus, there is an urgent need for scalable and reliable information systems to support nation-scale research and delivery of precision oncology. At Lockheed Martin, we deliver operational solutions to complex problems. Here, we present our vision for a precision oncology platform. This solution integrates best-in-class capabilities from multiple sources/vendors to support innovation, research and clinical care for a whole nation. We not only thought about the basic -omics based data collection, but also an infrastructure to collect and store data within a compliant privacy and security framework that also facilitates collaborative analytics and data sharing for deeper insight. Taking a systems engineering approach, we have examined some of the challenges to implement such a platform. For instance, running the basic genomic data processing pipelines to yield variant calls, which in turn will feed the variant store, should be a single scalable workflow. Accounting for multiple data sources, various use cases and selections of tools are at the core of an adaptable workflow. A variant store design that can scale and support a national cohort with an overlaying cohort selection tool are all part of this intricate design. It is our vision that a systems engineering and integration approach can deliver a unified solution for the national precision oncology roadmap. It is paramount that all the individual pieces should be well tuned to deliver scalability and reliability and simultaneously work in complete harmony. Only then we can process data at-scale needed for finding actionable mutations, designing effective treatments and implementing prevention strategies, affordably and reliably. Citation Format: Ogan Abaan, Amrita Basu, David Deal, Michael Hultner. Adaptive operations and technology platform for nation-scale precision oncology. [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 3632.
Prospective Study to Evaluate the Efficacy and Safety of Gemcitabine Combined with GMCSF and Rituximab in Heavily Pre-Treated Relapsed / Refractory B-Lymphoproliferative Disorders
Authors: Shinoj Pattali, Stephanie A. Gregory, Melissa Leigh Larson, Jamile M. Shammo, Elena Bogdanova, Teresa Obrien, Parameswaran Venugopal
Journal: Blood (2011)
Abstract 1904: MiR641 regulates EMT, ovarian cancer stem cell and angiogenesis by targeting p63/miR200 axis
Authors: Yajuan Li, Edward Richards, Mark Coppola, Cheng-Xiong Xu, Jin Q. Cheng
Journal: Cancer Research (2016)

Abstract MiR641 is an uncharacterized miRNA which locates intron 1 of AKT2, a gene residing in the chromosome 19q13.2 amplicon and frequently amplified/overexpressed in refractory ovarian cancer. Here, we demonstrated that frequent upregulation of miR641 was observed in human ovarian cancer tissues and in ovarian cancer cell lines. Knockdown of miR641 inhibited cell proliferation, migration, invasion, epithelial-mesenchymal transition (EMT) as well as angiogenesis and ovarian cancer stem cell growth. Enforced expression of miR641 had opposite effect. In addition, ectopic expression of miR641 promoted VEGF protein expression and secretion but had no effect on VEGF mRNA level. Mechanistically, we found that miR641 directly targeted the 3’UTR of p63 and reduced p63 expression, which leads to a decrease of miR200a/b. As a result, ZEB1 and VEGF, two validated targets of miR200, were upregulated by miR641 overexpression. Furthermore, expression of miR641 induced anchorage-independent growth. Taken together, these findings suggest that miR641 is an onco-miRNA and plays a pivotal role in ovarian oncogenesis. Citation Format: Yajuan Li, Edward Richards, Mark Coppola, Cheng-Xiong Xu, Jin Q. Cheng. MiR641 regulates EMT, ovarian cancer stem cell and angiogenesis by targeting p63/miR200 axis. [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 1904.
The anticancer effects of supinoxin (RX-5902) in pancreatic carcinoma.
Authors: Young Lee, Reza Mazhari, Deog Joong Kim
Journal: Journal of Clinical Oncology (2016)

238 Background: DEAD box RNA helicase DDX5/p68, and its phosphorylated form in particular, may play several important roles in cancer by means of cell transformation, epithelial mesenchymal transition (EMT), and cell migration, deeming it a promising target for novel anti-cancer therapeutics. We have previously shown that Supinoxin (RX-5902) interacts with phosphorylated p68 on Tyr593, interfering with the phosphorylated p68-β-catenin signaling pathway. Supinoxin also inhibits motility of MDA-MB231 breast cancer cell lines and could potentially prevent metastasis in cancer. Methods: In this study, we first demonstrated anti-proliferative effects in several cell lines originated from pancreas (5 cell lines) with a high level of sensitivity to Supinoxin (IC50 of 18 nM). We also sought to examine the tumor growth inhibition (TGI) and/or tumor growth delay (TGD), and survival benefits of Supinoxin in the human pancreatic carcinoma (MiaPaCa-2) xenograft mouse model. Results: In the MiaPaCa-2 model, at 50 and 70 mg/kg daily (oral, 5 days on/2 days off) for 3 weeks, both doses delayed tumor growth significantly (83% and 339%; P &lt; 0.001). All animals in the high dose showed complete regression (CR) and completing the study as tumor free survival (TFS; Day 65); one animal showed CR and TFS in the lower dose. Gemcitabine (120 mg/kg ip; Q3D for 4 weeks) resulted in TGD of 71% (P &lt; 0.001), with no CRs. Supinoxin did not result in a reduction in body weight gain, treatment related deaths, or clinical observations in this tumor model. Conclusions: These data support the potential therapeutic activity of Supinoxin in pancreatic cancer. A Phase 1 study of Supinoxin on relapse/refractory solid tumors is ongoing (NCT02003092).
Abstract 2418: Microenvironment-on-chip: Development of a microfluidics-based tumor ecosystem
Authors: Gonzalo Torga, Ke-Chih Lin, Robert H. Austin, Kenneth J. Pienta
Journal: Cancer Research (2016)

Abstract Despite its limited clinical predictive capacity, conventional cell culture remains the most frequently used preclinical model in biomedical research. For many years, microfluidics-based organ-on-chips have been proposed to overcome conventional cell culture limitations but given their inability to provide reliable and reproducible data, their usage remains anecdotal. Immune, stromal and cancer cells constitute a complex adaptive system in each tumor microenvironment. To study the causes and consequences of tumor heterogeneity in these complex adaptive systems, we have developed a platform to model and investigate tumor microenvironments at primary and metastatic sites in which multiple nuclear-labelled cell types can be grown in a multi-welled, communicating habitat with controlled gradients for temperature, pH, nutrients, and oxygen tension. In conjunction with labelled-nuclei, genetically-engineered cell lines with fluorescence-based biosensors can be generated to detect specific genetic expression changes in response to cell to cell interactions as well as varying environmental conditions over time. One of the major caveats for microfluidics prototypes is reproducibility. The proposed design is easily adaptable to most of the commercially available incubation microscopy systems, allowing the experiments to be replicated by independent groups in an effort to provide reliable and reproducible data. The ability to establish dynamic gradients within individual habitats longitudinally over time and space provides the capacity to study the effect of chemokines and drugs on the tumor ecosystem in order to discover key interactions between host cells and cancer cells and to develop improved therapeutic strategies. In contrast to previous organ-on-chip models, our technology is not limited to a mere observational platform for automated cell counting and tracking but also provides flexibility for downstream capacities such as immunofluorescence, in situ hybridization or single-cell sequencing, as well as retrieval of single cells or specific subpopulations based on the fluorescent reporters and labelled nuclei. The presented engineered microenvironment allows continued in vitro quantitative studies of the interactions of multiple cell types as well as varying environmental conditions. Here we propose a cancer-on-chip platform that is able to recapitulate key components and interactions to mimic different tumor microenvironments in a comprehensive manner, yet simple enough to provide reliable and reproducible data. Citation Format: Gonzalo Torga, Ke-Chih Lin, Robert H. Austin, Kenneth J. Pienta. Microenvironment-on-chip: Development of a microfluidics-based tumor ecosystem. [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 2418.
Abstract A1-52: Identification of drug-sensitive Notch receptor alterations in human breast cancer
Authors: Kai Wang, Qin Zhang, Danan Li, Keith Ching, Cathy Zhang, Xianxian Zheng, Mark Ozeck, Stephanie Shi, Xiaorong Li, Hui Wang, Paul Rejto, James Christensen, Peter Olson
Journal: Cancer Research (2015)

Abstract While the Notch pathway is reportedly activated in breast cancer, the molecular mechanisms leading to its aberrant activation remain elusive, hampering the optimal development of Notch inhibitors in the clinics. In an effort to identify predictive biomarkers of response to Notch targeted therapies in breast cancer, we used several computational approaches, including novel algorithms for detecting complex structural rearrangements, to analyze next generation sequencing and related omic datasets from The Cancer Genome Atlas (TCGA) breast cancer cohort. We identified simple mutations and complex rearrangements in NOTCH1, NOTCH2 and NOTCH3 that compromised the function of the PEST domain, a negative regulatory domain controlling the duration of active Notch signaling. Focal amplifications of NOTCH2 and NOTCH3 were also observed, as were heterodimerization or extracellular domain alterations, at lower incidence. Mutations and amplifications often activated the Notch pathway as evidenced by increased expression of canonical Notch target genes, and functional mutations were significantly enriched in the triple negative breast cancer (TNBC) subtype. We also sequenced a panel of breast cancer xenograft models and identified models that harbor functionally equivalent PEST domain alterations. These models were significantly more sensitive to a gamma secretase inhibitor (GSI) compared to models without Notch alterations. Gene expression and functional analyses were performed to study the mechanism of activation through mutation and inhibition by GSI. In summary, we demonstrated that Notch pathway is activated via multiple mutational mechanisms primarily involving the PEST domains of NOTCH1, NOTCH2 and NOTCH3. Collectively, approximately 13% of TNBC exhibits a genetic alteration coupled with pathway up-regulation and these alterations may serve as biomarkers to identify patients most likely to respond to Notch inhibitors. Citation Format: Kai Wang, Qin Zhang, Danan Li, Keith Ching, Cathy Zhang, Xianxian Zheng, Mark Ozeck, Stephanie Shi, Xiaorong Li, Hui Wang, Paul Rejto, James Christensen, Peter Olson. Identification of drug-sensitive Notch receptor alterations in human breast cancer. [abstract]. In: Proceedings of the AACR Special Conference on Translation of the Cancer Genome; Feb 7-9, 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 1):Abstract nr A1-52.
Antihypoxic Potentiation of Standard Therapy for Experimental Colorectal Liver Metastasis through Myo-Inositol Trispyrophosphate
Authors: Perparim Limani, Michael Linecker, Ekaterina Kachaylo, Christoph Tschuor, Philipp Kron, Andrea Schlegel, Udo Ungethuem, Jae Hwi Jang, Stavroula Georgiopoulou, Claude Nicolau, Jean-Marie Lehn, Rolf Graf, Bostjan Humar, Pierre-Alain Clavien
Journal: Clinical Cancer Research (2016)

Abstract Purpose: Tumor hypoxia activates hypoxia-inducible factors (Hifs), which induce a range of malignant changes including vascular abnormalities. Here, we determine whether inhibition of the hypoxic tumor response through myo-inositol trispyrophosphate (ITPP), a compound with antihypoxic properties, is able to cause prolonged vascular normalization that can be exploited to improve standard-of-care treatment. Experimental Design: We tested ITPP on two syngeneic orthotopic mouse models of lethal colorectal cancer liver metastasis. Tumors were monitored by MRI and analyzed for the hypoxic response and their malignant potential. A Hif activator and in vitro assays were used to define the working mode of ITPP. Hypoxic response and vasculature were re-evaluated 4 weeks after treatment. Finally, we determined survival following ITPP monotherapy, FOLFOX monotherapy, FOLFOX plus Vegf antibody, and FOLFOX plus ITPP, both overlapping and sequential. Results: ITPP reduced tumor load, efficiently inhibited the hypoxic response, and improved survival. These effects were lost when mice were pretreated with a Hif activator. Its immediate effects on the hypoxic response, including an apparent normalization of tumor vasculature, persisted for at least 4 weeks after treatment cessation. Compared with FOLFOX alone, Vegf antibody combined with FOLFOX prolonged survival by &amp;lt;30%, whereas ITPP combined with FOLFOX extended survival by &amp;gt;140%, regardless of whether FOLFOX was given in overlap or after ITPP exposure. Conclusions: Our findings reveal a truly antihypoxic mechanism for ITPP and demonstrate the capacity of this nontoxic compound to potentiate the efficacy of existing anticancer treatment in a way amenable to clinical translation. Clin Cancer Res; 22(23); 5887–97. ©2016 AACR.
Abstract LB-365: Novel susceptibility loci for colorectal cancer: Findings from the colorectal transdisciplinary (CORECT) study OncoArray analysis
Authors: Stephanie L. Schmit, Fredrick R. Schumacher, Christopher K. Edlund, Jian Gong, Gad Rennert, Wei Zheng, Loic Le Marchand, Ulrike Peters, Graham Casey, Li Hsu, Stephen B. Gruber, David V. Conti
Journal: Cancer Research (2016)

Abstract Genome-wide association studies (GWAS) have identified 58 susceptibility alleles across 37 regions associated with the incidence of colorectal cancer (CRC) with P&amp;lt;5E-08, yet much of the disease's familial risk remains to be explained. In its first phase, the Colorectal Transdisciplinary (CORECT) study, in collaboration with the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), the Colon Cancer Family Registry (CCFR), the Asian Colorectal Cancer Consortium (ACCC) and the Multiethnic Cohort (MEC), identified 6 of these loci based on 18,299 cases and 19,656 controls. The CORECT consortium recently completed genotyping on approximately 26,000 cases and 18,000 controls using the Illumina Infinium® OncoArray platform with the goals of 1) identifying novel overall and ethnic-specific susceptibility alleles and 2) fine-mapping known CRC risk loci. Newly genotyped samples represent multiple ethnic groups and include individuals primarily of European (75%), Asian (19%) and Hispanic (2.5%) origins. Combining both phases of CORECT, this study constitutes the largest GWAS meta-analysis of CRC to date. Here, we present European-specific results derived from genetically-defined Europeans genotyped on the OncoArray (16,456 cases and 10,442 controls), CORECT Phase I (5,584 cases and 5,329 controls), and CCFR/GECCO (12,715 cases and 14,327 controls), for a total of 34,755 cases and 30,098 controls. OncoArray genotype data were imputed to the 1000 Genomes Phase III reference panel, and summary results from logistic regression adjusting for age, sex, global ancestry, and study-specific covariates were combined in a fixed-effects inverse variance-weighted meta-analysis. Preliminary results indicate at least 10 new low-penetrance risk variants that reach genome-wide significance (P&amp;lt;5E-08) and that are independent of known risk loci. Further, fine-mapping of well-established CRC susceptibility regions is underway. This investigation provides additional insight into the etiology of CRC and informs future risk modeling efforts. Citation Format: Stephanie L. Schmit, Fredrick R. Schumacher, Christopher K. Edlund, Jian Gong, Gad Rennert, Wei Zheng, Loic Le Marchand, Ulrike Peters, Graham Casey, Li Hsu, Stephen B. Gruber, David V. Conti, CORECT, GECCO, CCFR, ACCC, and MEC. Novel susceptibility loci for colorectal cancer: Findings from the colorectal transdisciplinary (CORECT) study OncoArray analysis. [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-365.
Anti Tumor Activity Of Selinexor (KPT-330), A First-In-Class Oral Selective Inhibitor Of Nuclear Export (SINE) XPO1/CRM1 Antagonist In Patients (pts) With Relapsed / Refractory Multiple Myeloma (MM) Or Waldenstrom’s Macroglobulinemia (WM)
Authors: Martin Gutierrez, Peter de Nully Brown, Nashat Gabrail, Rachid Baz, Donna E. Reece, Michael Savona, Suzanne Trudel, David S. Siegel, Morten Mau-Sorensen, John Kuruvilla, John C. Byrd, Sharon Shacham, Tami Rashal, Cindy Yf Yau, Ccrp, Dilara McCauley, Jean-Richard Saint-Martin, John McCartney, Yosef Landesman, Boris Klebanov, Greg Pond, Amit M. Oza, Michael Kauffman, Mansoor R Mirza
Journal: Blood (2013)
Sarcoidosis incidence and prevalence: a nationwide register-based assessment in Sweden
Authors: Elizabeth V. Arkema, Johan Grunewald, Susanna Kullberg, Anders Eklund, Johan Askling
Journal: European Respiratory Journal (2016)

Our objective was to estimate the contemporary incidence and prevalence of sarcoidosis using Swedish population-based register data. Adults with any sarcoidosis-coded visit were identified from the National Patient Register (hospitalisations 1964–2013 and outpatient care 2001–2013). Demographic and medication dispensing data were retrieved from national registers. We estimated the prevalence of sarcoidosis in 2013 overall and by county of residence. The incidence of sarcoidosis during 2003–2012 was estimated by sex, age, education level and year of diagnosis. Case definitions were varied to test their robustness. More than 16 000 individuals had a history of sarcoidosis in 2013. When defined as two or more sarcoidosis-coded visits, the prevalence was 160 per 100 000. Using different definitions, the prevalence ranged from 152 (requiring a specialist visit) to 215 per 100 000 (only one visit required). The highest prevalence was observed in northern less densely populated counties. The incidence was 11.5 per 100 000 per year and varied by −10% to +30% depending on case definition. The incidence peaked in males aged 30–50 years and in females aged 50–60 years, but did not differ by education level and was stable over time. This study represents the largest epidemiological investigation of sarcoidosis using population-based individual-level data. Age at diagnosis in men was 10 years younger than in women and geographical variation was observed.
MicroRNA-17 Modulates Regulatory T Cell Function by Targeting Co-regulators of the Foxp3 Transcription Factor
Authors: Huang-Yu Yang, Joseph Barbi, Chao-Yi Wu, Ying Zheng, Paolo D.A. Vignali, Xingmei Wu, Jin-Hui Tao, Benjamin V. Park, Shashika Bandara, Lewis Novack, Xuhao Ni, Xiaoping Yang, Kwang-Yu Chang, Ren-Chin Wu, Junran Zhang, Chih-Wei Yang, Drew M. Pardoll, Huabin Li, Fan Pan
Journal: Immunity (2016)
The Regulatory B Cell Compartment Expands Transiently During Childhood and Is Contracted in Children With Autoimmunity
Authors: Ioannis Kalampokis, Guglielmo M. Venturi, Jonathan C. Poe, Jeffrey A. Dvergsten, John W. Sleasman, Thomas F. Tedder
Journal: Arthritis & Rheumatology (2016)

Objective Regulatory B cells that inhibit immune responses through interleukin‐10 (IL‐10) secretion (B10 cells) have been characterized in adult subjects with autoimmune disease. The aim of this study was to characterize B10 cells in individuals across the entire age range of normal human development and changes in their frequency and numbers in children with autoimmunity. Methods The phenotype and numbers of B10 cells in blood were examined in healthy individuals and children with autoimmunity, using flow cytometry. B10 cell function was assessed by measuring the effect of B cell–derived IL‐10 on interferon‐γ (IFNγ) expression by CD4+ T cells. Serum cytokine levels were measured by enzyme‐linked immunosorbent assay. Results The frequency of B10 cells transiently increased during childhood, when up to 30% of B cells were competent to produce IL‐10, compared with the low frequencies in healthy newborns (3–4%) and adults (7–9%). The surface phenotype of B10 cells in children revealed age‐dependent variability. B10 cells from children were distinct from proinflammatory cytokine–producing B cells and down‐regulated IFNγ production by CD4+ T cells in vitro. Compared with age‐matched healthy controls, children with autoimmunity had lower numbers and frequencies of B10 cells (decreased by 39% and 48%, respectively), higher IFNγ levels, and lower IL‐21 levels in serum. IFNγ inhibited, whereas IL‐21 promoted, B cell IL‐10 competence in vitro. Conclusion B10 cells, a functionally defined cell subset with a variable surface phenotype reflective of overall B cell development, transiently expand during childhood. B10 cell frequencies and numbers were decreased in children with autoimmunity, which may be explained in part by alterations in serum IFNγ and IL‐21 that differentially regulate B10 cell development.
Peri-Engraftment Syndrome in Pediatric Allogenetic Hematopoietic Stem Cell Transplantationand the Effect of Methylprednisolone on Improving the Process of Peri-ES
Authors: De-fei Zheng, Lin Wan, Jun LU, Peifang Xiao, Xin-ni Bian, Zong Zhai, Shaoyan Hu
Journal: Blood (2014)