tbuckley/cabot-search huggingface dataset:
Abstract 4540: Development of well characterized breast, lung, and brain cancer copy number variation reference materials
Authors: Dana Ruminski Lowe, Jessica Dickens, Catherine Huang, Yves Konigshofer, Bharathi Anekella
Journal: Cancer Research (2018)

Abstract Introduction: Copy number variation (CNV), including gene amplification and deletion, can be a key driver of oncogenesis. Pathogenic CNVs are often associated with unfavorable prognosis and drug resistance, therefore detection of these types of genetic changes will be important for personalized treatment. Many tumor profiling workflows can detect CNVs in addition to somatic mutations, but well-characterized reference materials for CNVs are not widely available, which makes it difficult to assess accuracy and sensitivity. CNV content of cell lines can be variable and may change with passages, the genomic background may not be diploid, and germline and somatic variants may not be well characterized. Remnant patient samples often lack characterization and the volumes needed for such characterization and larger validation studies. Therefore, we developed and evaluated Seraseq CNV reference materials to serve as accuracy, precision, and limit-of-detection (LOD) controls for tumor profiling assay development and validation. By providing a consistent source of purified DNA with stable CNV content, these reference materials allow for repeatable assessment of clinical diagnostic assays targeting CNVs. Methods: Seraseq CNV reference materials were prepared by mixing genomic DNA with additional copies of target genes from the well-characterized cell line GM24385. Copies of ERBB2, FGFR3, and MYC were combined with genomic DNA to simulate CNVs found in breast cancer, while sequences for EGFR, MET, and MYCN were used to mimic lung and brain cancer CNVs. Three levels of amplification were targeted: +3, +6, and +12 additional copies. The copy number of each gene was precisely quantified using digital PCR and confirmed on several NGS-based assays internally and externally. Results &amp; Conclusions: Testing revealed CNVs of each target gene were close to the expected copy number. Good correlation was observed between digital PCR data and NGS data generated internally with the Archer VariantPlex Solid Tumor assay. In addition, internal and external NGS data showed correlation and broad assay compatibility. While CNVs observed clinically can be upwards of 50 additional copies and more easily detectable, LOD controls such as those described here are imperative in evaluating assay performance. Collectively, the data demonstrate the utility of biosynthetic Seraseq CNV reference materials, which serve as superior alternatives to DNA from cell lines or patient-derived material. Citation Format: Dana Ruminski Lowe, Jessica Dickens, Catherine Huang, Yves Konigshofer, Bharathi Anekella. Development of well characterized breast, lung, and brain cancer copy number variation reference materials [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4540.
Abstract MP19: Glycemic Load is Associated with Increased Odds of Cognitive Impairment in the REasons for Geographic And Racial Differences in Stroke (REGARDS) Cohort
Authors: Keith Pearson, Virginia Wadley, Barbara Gower, James Shikany, Paula Chandler-Laney, George Howard, Leslie McClure, Fred Unverzagt, Suzanne Judd
Journal: Circulation (2016)

Introduction: Carbohydrate quality and quantity have been associated with several chronic diseases, but few studies have investigated associations with cognitive impairment. The objective of this study was to test the hypothesis that higher glycemic load (GL), glycemic index (GI), and available carbohydrate intakes are associated with higher odds of incident cognitive impairment in a large, prospective cohort. Methods: This analysis utilized the REGARDS study, a national cohort of 30,239 black and white participants (age &gt; 45 yr). Dietary intake was assessed by the Block98 food frequency questionnaire, from which values for GL, GI, and available carbohydrate (total carbohydrate minus dietary fiber) were estimated. Incident cognitive impairment was defined as shifting from an intact cognitive status (a score &gt;4) at the first cognitive assessment to an impaired cognitive status (a score ≤4) at the most recent cognitive assessment, measured by the Six-Item Screener. Logistic regression was used to evaluate the odds of incident cognitive impairment by quintile of GL, GI, and available carbohydrate. Results: This analysis included 16,755 participants free of stroke and cognitive impairment at baseline. A total of 1,513 cases of incident cognitive impairment were observed over a mean follow-up of 7.5 years. After adjustment for sociodemographic variables and cognitive risk factors, participants in the highest quintile of glycemic load had 42% higher odds of incident cognitive impairment compared to those in the lowest quintile (Q5 vs Q1: OR=1.42; 95% CI: 1.06, 1.89; p for trend: 0.02). Similarly, participants in the highest quintile of available carbohydrate had 42% higher odds of incident cognitive impairment (Q5 vs Q1: OR=1.42; 95% CI: 1.05, 1.91; p for trend: 0.04). No significant associations were observed with glycemic index (See Table 1). Conclusion: Consuming a dietary pattern lower in available carbohydrate and glycemic load may aid in the preservation of cognitive function in older ages.
Abstract 23: Chemotherapy and tau interplay facilitates breast-to-brain metastasis
Authors: Behnaz Saatian, Krutika Deshpande, Alex Julian, Brooke Naomi Nakamura, Ling Shao, Josh Neman
Journal: Cancer Research (2018)

Abstract Breast cancer represents the second most common cause of brain metastasis with the rate of 10-16% after lung cancer. The overall survival in brain metastatic patients is very short ranging from 2 to 25 months. Considering the high incidence of brain metastasis and the limitation of available therapies, developing preventive strategies and early detection methods are required to improve the survival rate in the patients. Many primary and brain metastatic breast cancer patients represent cognitive deficits. Besides, chemo-treated breast cancer patients show memory problems before brain metastases diagnosis. Although the cause of cognitive impairments after chemotherapy have not been explored, a recent study revealed that chemotherapy promotes breast cancer metastasis. Correspondingly, our mRNA expression analysis showed downregulation of the tight junction markers in chemo-treated choroid plexus cells (CPs), suggesting that chemotherapy is likely to cause an increase in the blood-cerebral spinal fluid barrier (BCSFB) permeability. Chemotherapy also induces upregulation of tau expression in CP cells. Tau is known as a pathological hallmark of Alzheimer's disease (AD) and neurodegenerative disorders. The abnormally phosphorylated and aggregated form of tau play critical role in neurodegenerative diseases as of AD. Tau expression, both at the mRNA and protein level, is significantly elevated in breast to brain metastases (BBMs). Therefore, we hypothesized that chemotherapy upregulates tau expression in breast cancer cells leading to the BCSFB and blood-brain barrier (BBB) permeability, and consequently, breast to brain metastasis and neurodegeneration. To test our hypothesis, the effect of chemotherapy on the BCSFB and BBB permeability were investigated using the trans endothelial electrical resistance (TEER) and migration assays in the in vitro models. Our results show an increase in abnormal tau expression in chemo-treated primary breast cancer cells. BBM-derived tau is abnormal and forms paired helical filaments (PHFs), similar to Alzheimer's. We conclude that breast to brain metastasis is facilitated through an interplay between chemotherapy, and tau expression and release from breast cancer cells. Additionally, we suggest that tau plays a key role in neurodegeneration defects in brain metastatic patients. This study opens a new path towards prevention and early detection of breast cancer metastasis to the brain, cognitive decline and neurodegeneration in metastatic patients. Citation Format: Behnaz Saatian, Krutika Deshpande, Alex Julian, Brooke Naomi Nakamura, Ling Shao, Josh Neman. Chemotherapy and tau interplay facilitates breast-to-brain metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 23.
Abstract 432: Establishment of reference samples for the detection of somatic variants in cancer
Authors: Li Tai Fang, Wenming Xiao
Journal: Cancer Research (2018)

Abstract The FDA is well aware of the crucial role that next generation sequencing (NGS) plays in precision medicine, and this technology is already leveraged in regulatory decision-making. However, lack of well-characterized and community-validated reference samples and data benchmarks creates a potential challenge for development and review of NGS applications. To address this challenge, 60+ institutions and 160+ scientists have come together to form a somatic mutation working group within the FDA-led Sequencing Quality Control Phase II (SEQC2) consortium. We present genomic samples with high-confidence germline and somatic mutation data in order to establish a community standard against which new tools and platforms can be evaluated and benchmarked. Our initial reference samples are a triple-negative breast cancer cell line: HCC1395, and its B lymphocyte derived normal cell line: HCC1395BL. To minimize bias, we sequenced these two cell lines at up to 10 sequencing centers using multiple sequencing platforms. In totality, we have performed whole genome sequencing of the two cell lines to coverage depths of 2400X on Illumina HiSeq, 450X on NovaSeq, 600X on 10X Genomics and 50X on PacBio. Additionally, we performed whole exome sequencing at 1200X on HiSeq and 100X on Ion Torrent. Lastly, we sequenced (RNAseq) &amp;gt;5000 single cells for cellular heterogeneity studies. We applied machine learning algorithms to define high confidence mutation calls with datasets from 8 NGS platforms combined with 9 bioinformatics analysis pipelines. Each mutation in the “gold standard” dataset was annotated with confidence scores and supporting evidence. To independently evaluate accuracy of our call set, we selected a subset of mutation calls for additional validation using orthogonal methods, including ddPCR. To summarize, we present the first release of high-confidence germline variants and somatic mutations on a pair of well characterized cell lines. We plan to continuously advance accuracy and completeness of our reference sample data, in order to serve as a standard for the community for years to come. Citation Format: Li Tai Fang, Wenming Xiao, Somatic Mutation Working Group, SEQC2 Consortium. Establishment of reference samples for the detection of somatic variants in cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 432.
Abstract 1157: The B-NDG mouse is a perfect tool for immune system humanization and patient derived xenograft transplantation
Authors: Meiling Zhang, Chaoshe Guo, Yuelei Shen, Yanan Guo
Journal: Cancer Research (2018)

Abstract The B-NDG mice (NOD-Prkdcscid Il2rgtm1/Bcgen), independently developed by Biocytogen, display a severe immunodeficiency phenotype, with no mature T, B or functional NK cells, and deficient in cytokine signaling. The B-NDG mouse is one of the best models for reconstitution of human immune system using peripheral blood mononuclear cells (PBMC) or hematopoietic stem cells (CD34+). Human PBMC reconstituted well in B-NDG mice, with the percentage of hCD45+ cells was over 50% in five weeks. To further analyze the subsets of immune cell composition, we found the majority of human cells were CD8+ T lymphocytes. Other than PBMC, human CD34+ hematopoietic stem cells also demonstrated a high-engraftment efficacy in B-NDG mice. Successful engraftment of CD34+ cells develops all major cell types via myeloid and lymphoid lineage to reconstitute functional human immune system. At 10 weeks post CD34+ cell implantation, the percentage of hCD45+ cells is over 30% with detectable human T, B and NK cells. Therefore, the immuno-humanized B-NDG mice are useful tools for studying hematopoiesis, immunology, infectious disease, and ES/iPS cell research. With barely any rejection to human derived cells, the B-NDG mouse is an ideal host for transplantation of PDX (Patient-Derived Xenograft), and retains the high heterogeneity characteristics of tumor tissues. Each PDX model can be considered as a single tumor patient and fully embodies the patient group characteristics. We have a collection of various PDX models including leukemia, breast cancer, gastric, lung, pancreatic, and colon et al. The humanized PDX model by implantation of PDX on the immuno-humanized B-NDG mice will be a promising tool to evaluate the in vivo efficacy of immune checkpoint antibodies in monotherapy or in combination. Therefore, therapeutic efficacy studies using B-NDG based PDX models are more meaningful and predictive in preclinical drug development and discovery. Citation Format: Meiling Zhang, Chaoshe Guo, Yuelei Shen, Yanan Guo. The B-NDG mouse is a perfect tool for immune system humanization and patient derived xenograft transplantation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1157.
Polymorphism of the NADH/NADPH Oxidase p22 phox Gene in Patients With Coronary Artery Disease
Authors: NobutakaInoue, SeinosukeKawashima, KenjiKanazawa, ShinichiroYamada, HozukaAkita, MitsuhiroYokoyama
Journal: Circulation (1998)

Background—Oxidative stress in the vasculature has been implicated in the pathogenesis of coronary artery disease (CAD). NADH/NADPH oxidase is a key enzyme of superoxide production in the vasculature. p22 phox, an essential component of NADH/NADPH oxidase, has four types of polymorphism. The C242T polymorphism changes histidine-72 to tyrosine, located in the potential heme-binding sites, whereas A640G polymorphism is located in the 3′ untranslated region. Methods and Results—We investigated whether these polymorphisms were associated with risk of CAD by use of restriction fragment length polymorphism (RFLP). The prevalence of the TC+TT genotype of the C242T polymorphism was significantly more frequent in control subjects (n=201) than in the patients with CAD (n=201). The odds ratio of the TC+TT versus CC genotype of the C242T polymorphism between control subjects and case patients was 0.49 (95% CI, 0.28 to 0.87) (P=.015). The prevalence of the genotypes of the A640G polymorphism was not different between ...
Regulation of Cardiomyocyte Polyploidy and Multinucleation by CyclinG1
Authors: ZhipeiLiu, ShijingYue, XiaoboChen, ThomasKubin, ThomasBraun
Journal: Circulation Research (2010)

Rationale: Polyploidy and multinucleation are characteristic features of mammalian cardiomyocytes, which develop shortly after birth when most differentiated cardiomyocytes become acytokinetic. Cardiac overload and hypertrophy further increase the degree of polyploidy of cardiomyocytes, suggesting a role in cell type–specific responses to physiological and pathological stimuli. Objective: We sought to study the function of cyclinG1 in the regulation of polyploidy and multinucleation in cardiomyocytes. Methods and Results: We found that expression of cyclinG1, a transcriptional target of p53, coincides with arrest of cardiomyocyte proliferation and onset of polyploidization. Overexpression of cyclinG1 promoted DNA synthesis but inhibited cytokinesis in neonatal cardiomyocytes leading to an enlarged population of binuclear cardiomyocytes. Reciprocally, inactivation of the cyclinG1 gene in mice lowered the degree of polyploidy and multinucleation in cardiomyocytes. Moreover, lack of cyclinG1 prevented the in...
Abstract LB-264: Alcohol-aversion drug disulfiram targets cancer via p97 segregase adaptor NPL4
Authors: Martin Mistrik, Zdenek Skrott, Marian Hajduch, Søren Friis, Petr Dzubak, Jan Gursky, Dusana Majera, Tomas Ozdian, Jana Vaclavkova, Martina Michalova, Pavla Pouckova, Boris Cvek, Klaus Kaae Andersen, Jiři Bartek
Journal: Cancer Research (2018)

Abstract Cancer incidence is rising and this global challenge is further exacerbated by resistance of advanced tumors to standard-of-care and emerging precision medicines. A promising approach to such unmet need for innovative and cost-effective cancer treatments is drug repurposing, exploitation of drugs already approved for other indications that show anticancer activity. Here we highlight the potential for repurposing disulfiram (Antabuse), an old alcohol-aversion drug that kills a broad range of cancer types in preclinical studies. Our nationwide population study reveals that patients who continued using disulfiram have a lower risk of death from cancer compared to those who stopped using the drug at their diagnosis. More importantly, we identify ditiocarb-copper complex as the metabolite of disulfiram responsible for anticancer effects, present methods to detect its preferential accumulation in tumors and candidate biomarkers of impact in cells and tissues. Finally, our functional and biophysical analyses reveal the long-thought molecular target: NPL4 adapter of the p97/VCP segregase essential for protein recycling involved in multiple stress-response cellular pathways. Citation Format: Martin Mistrik, Zdenek Skrott, Marian Hajduch, Søren Friis, Petr Dzubak, Jan Gursky, Dusana Majera, Tomas Ozdian, Jana Vaclavkova, Martina Michalova, Pavla Pouckova, Boris Cvek, Klaus Kaae Andersen, Jiři Bartek. Alcohol-aversion drug disulfiram targets cancer via p97 segregase adaptor NPL4 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-264.
Mitochondrial Dysfunction and Apoptosis Underlie the Pathogenic Process in α-B-Crystallin Desmin-Related Cardiomyopathy
Authors: AlinaMaloyan, AtsushiSanbe, HannaOsinska, MargaretWestfall, DustinRobinson, Ken-ichiImahashi, ElizabethMurphy, JeffreyRobbins
Journal: Circulation (2005)

Background— Mitochondria and sarcomeres have a well-defined architectural relation that partially depends on the integrity of the cytoskeletal network. An R120G missense mutation in the small heat shock protein α-B-crystallin (CryAB) causes desmin-related cardiomyopathy. Desmin-related cardiomyopathy is characterized by the formation of intracellular aggregates containing CryAB and desmin that are amyloid positive, and disease can be recapitulated in transgenic mice by cardiac-specific expression of the mutant protein. Methods and Results— To understand the resultant pathology, we explored the acute effects of R120G expression both in vitro and in vivo. In vitro, transfection of adult cardiomyocytes with R120G-expressing adenovirus resulted in altered contractile mechanics. In vivo, as the cytoskeletal network is disturbed but before deficits in organ function can be detected, alterations in mitochondrial organization and architecture occur, leading to a reduction in the maximal rate of oxygen consumption...
Protein Kinase C Activates ATP-Sensitive K+ Current in Human and Rabbit Ventricular Myocytes
Authors: KeliHu, DayueDuan, Gui-RongLi, StanleyNattel
Journal: Circulation Research (1996)

Abstract Mediators involved in ischemic preconditioning, such as adenosine and norepinephrine, can activate protein kinase C (PKC), and a variety of observations suggest that both PKC and ATP-sensitive K+ current (IKATP) play essential roles in ischemic preconditioning. PKC is therefore a candidate to link receptor binding to IKATP activation, but it has not been shown whether and how PKC can activate IKATP in the heart. The present study was designed to determine whether PKC can activate IKATP in rabbit and human ventricular myocytes. Under conditions designed to minimize Na+ and Ca2+ currents, dialysis of rabbit ventricular myocytes with pipette solutions containing reduced [ATP] elicited IKATP, with a 50% effective concentration (EC50) of 260 μmol/L. In cells that failed to show IKATP under control conditions, superfusion with 1 μmol/L phorbol 12,13-didecanoate (PDD) elicited IKATP in a fashion that depended on pipette [ATP], with an [ATP] EC50 of 601 μmol/L. PDD-induced IKATP activation was concentrat...
The Impact of Depressive Disorder Symptoms and Subtypes on 6-Year Incidence of Somatic Diseases
Authors: Roxanne Gaspersz, Femke Lamers, Aartjan T.F. Beekman, Albert M. van Hemert, Robert A. Schoevers, Brenda W.J.H. Penninx
Journal: Psychotherapy and Psychosomatics (2018)
Abstract 20467: Sleep Debt: Weekday and Weekend Sleep Differences in Ideal Cardiovascular Health in Women
Authors: Tomas Cabeza De Baca, Fumika Matsushita, Susan Redline, Alan Zaslavsky, Julie E Buring, Michelle A Albert
Journal: Circulation (2017)

Background: Short sleep duration is associated with increased cardiovascular disease risk. However, whether sleep debt, a measure of sleep deficiency during the week compared to the weekend, confer...
Abstract 1288: A comprehensive investigation of factors impacting the accuracy of mutation detection using next generation sequencing technology
Authors: Wenming Xiao, Yongmei Zhao
Journal: Cancer Research (2018)

Abstract Next generation sequencing (NGS) allows researchers to survey DNA mutations in tumor cells at very large scales with affordable cost. However, distinguishing tumor cell sub-population mutations from errors due to NGS platform biases, sample preservation effects, assay protocols and suboptimal or incongruous bioinformatics analysis methods is currently complex and difficult. For NGS to be successfully leveraged in a clinical translational manner, increased ability to discriminate between true mutations and artifacts is paramount. To address this urgent unmet clinical need, we systematically investigated somatic mutation events in paired cell lines (breast cancer and normal) with multiple NGS platforms and protocols to fully characterize factors that affect accuracy, specificity and sensitivity of mutation detection. We applied machine learning algorithms to define high confidence mutation calls with data sets from 8 NGS platforms combined with 9 bioinformatic analysis pipelines. With “ground truth” established using multiple orthogonal sequencing platforms, we evaluated the performance of mutation detection under various circumstances, including: fresh cell vs FFPE, amount of DNA, library preparation, sequencing platform, tumor purity, and analysis algorithm. Moreover, we performed whole exome sequencing (WES) and whole genome sequencing (WGS) at 6 sequencing sites in parallel, which allowed us to assess the reproducibility of NGS runs on the same biological samples. By analyzing DNA variant detection recall and precision from data sets derived from various conditions, we identified statistical variance components in overall DNA variant detection framework as well as specific practices that will likely lead to the false identification of variants. By concomitantly examining the effects between sample processing and bioinformatics pipelines, here we recommend best practices for mutation detection using NGS technology and establish quality metrics for cancer studies involving NGS technology. Citation Format: Wenming Xiao, Yongmei Zhao, Somatic Mutation Working Group, SEQC2 Consortium. A comprehensive investigation of factors impacting the accuracy of mutation detection using next generation sequencing technology [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1288.