tbuckley/cabot-search huggingface dataset:
Emerging technologies towards enhancing privacy in genomic data sharing
Authors: Bonnie Berger, Hyunghoon Cho
Journal: Genome biology (2019)

As the scale of genomic and health-related data explodes and our understanding of these data matures, the privacy of the individuals behind the data is increasingly at stake. Traditional approaches to protect privacy have fundamental limitations. Here we discuss emerging privacy-enhancing technologies that can enable broader data sharing and collaboration in genomics research.
Abstract 3533: Low-frequency variant detection in cell-free DNA by integrating double-stranded unique molecular identifiers with ultrafast amplicon-based library preparations
Authors: Lucie S. Lee, Yang Lily Liu, Kathryn Pendleton, Jeffrey Liu, Lifeng Phil Lin, Guoying Liu, Zhitong Liu
Journal: Cancer Research (2019)

Abstract The use of liquid biopsy has seen tremendous growth in recent years as cell-free DNA (cfDNA) is a noninvasive and easily obtainable sample type with many diagnostics and prognostic values. While liquid biopsy can potentially enable new applications, such as early cancer detection, treatment monitoring, and drug resistance screening, it also presents challenges to accurate variant detection due to the low fraction of mutant DNA present in theses samples, which can be easily buried by the artifacts and background noise from systematic PCR and sequencing errors. While some success has been made using adapters with unique molecular identifiers (UMIs) in hybrid capture-based methods and performing deep sequencing, such approaches suffer from long, tricky, and tedious workflows and disappointingly low on-target rates. Additionally, the large amount of cfDNA required for hybrid capture workflows is not realistic to obtain from patients. We have developed the CleanPlex® UMI technology to provide a fast, simple, and reliable NGS solution for low-frequency variant detection. The technology features three simple steps to generate molecular-barcoded and target-enriched NGS libraries in under 4 hours. This amplicon-based method consists of a multiplex PCR reaction for molecular barcoding, followed by a biochemical reaction for removal of redundant PCR products, and finally a second round of PCR to add Illumina adapter sequences and sample indexes. To validate this new method, we designed an NGS panel targeting frequently mutated hotspots in 23 genes associated with lung cancer. NGS libraries were prepared with commercial reference cfDNA at 0.1% to 0.5% minor allele frequencies (mAF) and sequenced on an Illumina NextSeq®. Overall, we obtain high detection sensitivity for low-frequency alleles even at low DNA inputs. When including UMI in the analysis, we observe significant reductions in false positive calls. Nearly all known mutations covered by the CleanPlex UMI panel (12 out of 13) are detected at 0.1% mAF using 50ng of the reference cfDNA. At 0.25% mAF, all known mutants are detected with 100% PPV using 50ng of DNA. With only 20 ng of cfDNA, the method can achieve the same 100% detection at 0.5% mAF. The CleanPlex® UMI technology demonstrates high sensitivity with low false positive rate, for the detection of low-frequency alleles. Citation Format: Lucie S. Lee, Yang Lily Liu, Kathryn Pendleton, Jeffrey Liu, Lifeng Phil Lin, Guoying Liu, Zhitong Liu. Low-frequency variant detection in cell-free DNA by integrating double-stranded unique molecular identifiers with ultrafast amplicon-based library preparations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3533.
Abstract 702: Kinetic analysis identifies determinants of sensitivity to MEK inhibitor-induced cell death
Authors: Zintis Inde, Kyuho Han, Michael C. Bassik, Scott J. Dixon
Journal: Cancer Research (2019)

Abstract Successful identification of the genetic determinants of drug sensitivity has been a long-standing goal of cancer research and, more recently, of precision medicine. In cancer cells, drug treatment can induce both growth arrest and death. The distinction between these outcomes is important but can be overlooked in large-scale analyses that rely on traditional metabolism-based methods for quantifying cell viability. We recently demonstrated that Scalable Time-Lapse Analysis of Cell Death Kinetics (STACK) effectively quantifies cell death in response to diverse lethal stimuli. We investigated cases in which this approach captured drug-induced lethality more effectively than traditional assays. We found that inhibitors of mitogen activated protein kinase 1 and 2 (MEK1/2) arrested proliferation in diverse cancer cell lines, but induced cell death in only a subset of these lines. We sought to identify the factors that determine whether a cancer cell will undergo growth arrest or death in response to MEK inhibition. MAP kinase pathway activation has previously been reported as a determinant of MEK inhibitor sensitivity; we determined that the dynamics of Bcl-2 family proteins in response to MEK inhibitor treatment correlate with death sensitivity independent of pathway activation. In a genome-wide CRISPR screen, we identified a lipid metabolic enzyme that is a novel modulator of MEKi sensitivity. Our results suggest new approaches for predicting and enhancing sensitivity to cancer therapeutics in tumors and demonstrate that direct measurement of cell death provides clear advantages over proliferation-based metrics. Citation Format: Zintis Inde, Kyuho Han, Michael C. Bassik, Scott J. Dixon. Kinetic analysis identifies determinants of sensitivity to MEK inhibitor-induced cell death [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 702.
Abstract 15032: Oxygen Induces a p53-Dependent NOS3-Mediated Survival Pathway in the Infarct Myocardium by Regulating p53(Lys120) Acetylation and p53 DNA Interaction
Authors: Rajan Gogna, Esha Madan, Mahmood Khan, Periannan Kuppusamy
Journal: Circulation (2012)

We have recently showed that supplemental oxygen (Ox), administered as 100% O2, 60 min/day for 2 wk, was capable of promoting NOS3-dependent myocyte survival in the infarct (MI) heart. Interestingly, the proapoptotic p53, which is known to transcriptionally regulate members of the NOS family, was consistently overexpressed in the MI+Ox hearts (Fig A) with higher survival potential when compared to MI hearts. We hypothesized that p53 plays an oxygen-dependent dual role in generating apoptotic signals in the MI hearts and NOS3-mediated survival signals in the MI+Ox hearts. A 23-bp p53 response element (p53RE) was identified in NOS3 promoter and p53 was found to directly bind and transcriptionally regulate NOS3 promoter in the MI+Ox hearts. p53 from the MI heart did not bind to NOS3-p53RE and showed affinity towards apoptotic BAX-p53RE. p53 from MI+Ox heart showed affinity towards NOS3-p53RE. Analysis of p53 post-translational modifications showed differential acetylation of p53 core-domain at p53(Lys120) re...
Abstract 4622: The YUMMER.G mouse melanoma model recapitulates the heterogeneous response to immune checkpoint blockade based on patient sex
Authors: Julie Y. Ramseier, Alexandra Charos, Koonam Park, William Damsky, Marcus W. Bosenberg
Journal: Cancer Research (2019)

Abstract Existing murine melanoma models, such as syngeneic transplantation of the B16 melanoma cell line, are aggressive, but poorly immunogenic, and as a result, studying the response to immunotherapy in these models has been challenging. Furthermore, in humans, a heterogeneous response to immune checkpoint inhibitor therapy has been observed between male and female melanoma patients, yet no immunogenic murine cancer model exists to study this sex-related dimorphism. To address these challenges, we created the YUMMER.G model, a melanoma cell line driven by human-relevant Braf activation and loss of Pten and Cdkn2a. YUMMER.G is related to the previously described YUMMER1.7 model; however important differences include: diploid state, female genotype, and Mc1re/e (pheomelanin producing) background. YUMMER.G was created by treatment with UV-light, resulting in a neoantigen rich subclone. Subcutaneous injection of 2 million YUMMER.G cells into C57BL/6J mice resulted in melanoma formation in both male and female mice. Treatment of established tumors with anti-CTLA-4 resulted in a comparable response between male and female mice, with complete, durable tumor regression in 100% of female mice and 88% of male mice. However, when established YUMMER.G tumors were treated with anti-PD-1, 63% of female mice, but only 13% of male mice exhibited complete tumor regression (p = 0.0330). These findings demonstrate the important role of host sex in the response to immunotherapy, and they parallel the sex-related differences in checkpoint inhibitor efficacy that have been observed in human patients. In summary, the YUMMER.G model is a human-relevant, immunogenic mouse melanoma model that will serve as a valuable platform for further investigating the mechanisms that mediate the sex-related dimorphism in anti-tumor immunity and response to immunotherapy. Citation Format: Julie Y. Ramseier, Alexandra Charos, Koonam Park, William Damsky, Marcus W. Bosenberg. The YUMMER.G mouse melanoma model recapitulates the heterogeneous response to immune checkpoint blockade based on patient sex [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4622.
Incidence of Visually Impairing Cataracts Among Older Adults in Kenya
Authors: Andrew Bastawrous, Wanjiku Mathenge, John Nkurikiye, Kevin Wing, Hillary Rono, Michael Gichangi, Helen A. Weiss, David Macleod, Allen Foster, Matthew Burton, Hannah Kuper
Journal: JAMA Network Open (2019)

Half of all the cases of blindness worldwide are associated with cataract. Cataract disproportionately affects people living in low- and middle-income countries and persons of African descent.To estimate the 6-year cumulative incidence of visually impairing cataract in adult participants in the Nakuru Eye Disease Cohort Study in Kenya.This secondary analysis of the Nakuru Eye Disease Cohort Study was conducted from February 2016 to April 2016. This cohort comprised citizens of Nakuru, Kenya, aged 50 years or older who consented to participate in the initial or baseline survey from January 2007 to November 2008, as well as the follow-up conducted from January 2013 to March 2014. All participants at baseline (n = 4364) and follow-up (n = 2159) underwent ophthalmic examination.Six-year cumulative incidence of visually impairing cataract, risk factors of incidence, population estimates, and required cataract surgical rates to manage incident visually impairing cataract.In total, 4364 individuals (with a mean [SD] age of 63.4 [10.5] years and with 2275 women [52.1%]) had complete eye examinations at baseline, and 2159 participants (with a mean [SD] age of 62.5 [9.3] years and with 1140 men [52.8%]) were followed up 6 years later. The 6-year cumulative incidence of visually significant cataract in either eye was 251.9 per 1000 (95% CI, 228.5-276.8), with an increase with age from 128.9 (95% CI, 107.9-153.2) per 1000 for the group aged 50 to 59 years to 624.5 (95% CI, 493.1-739.9) per 1000 for the group aged 80 years or older. This equated to an annual incidence of visually significant cataract of 45.0 per 1000 people aged 50 years or older. Multivariable analysis showed alcohol consumption (risk ratio [RR], 1.4; 95% CI, 1.1-1.8), diabetes (RR, 1.7; 95% CI, 1.3-2.3), educational level, and increasing age (RR, 3.8; 95% CI, 2.6-5.5 for those aged ≥80 years) were associated with incident visually impairing cataract. Extrapolations to all people aged 50 years or older in Kenya indicated that 148 280 (95% CI, 134 510-162 950) individuals might develop new visually impairing cataract in either eye (visual acuity <6/18 in the worse-seeing eye) and that 9540 (95% CI, 6610-13 750) might become cataract blind in both eyes (visual acuity <3/60 in better-seeing eye).Adults in Kenya appeared to have a high incidence of visually impairing cataract, making cataract a priority for blindness prevention programs in the region; surgical interventions and awareness of these services are also required.
Abstract 16641: High Dose Omega-3 Fatty Acid Supplements to Lower Triglyceride Levels in 10-19 Year-Olds
Authors: Sarah D de Ferranti, Erica R Denhoff, Sarah K Steltz, Carly E Milliren, Henry A Feldman, Stavroula K Osganian
Journal: Circulation (2012)

Objective: To evaluate the triglyceride (TG) lowering effect of high dose omega-3 fatty acids (FA) in hypertriglyceridemic adolescents. Patients and Methods: One month after screening, 25 patients ...
Abstract 5094: SCOPE: A normalization and copy number estimation method for single-cell DNA sequencing
Authors: Rujin Wang, Danyu Lin, Yuchao Jiang
Journal: Cancer Research (2019)

Abstract Whole genome single-cell DNA sequencing (scDNA-seq) enables characterization of copy number profiles at the cellular level. This circumvents the averaging effects associated with bulk-tissue sequencing and has increased resolution yet decreased ambiguity in deconvolving cancer subclones and elucidating cancer evolutionary history. ScDNA-seq data is, however, sparse, noisy, and highly variable even within a homogeneous cell population, due to the biases and artifacts that are introduced during the library preparation and sequencing procedure. Here, we propose SCOPE, a normalization and copy number estimation method for scDNA-seq data. The distinguishing features of SCOPE include: (i) utilization of cell-specific Gini coefficients for quality controls and for identification of normal/diploid cells, which are further used as negative control samples in a Poisson latent factor model for normalization; (ii) modeling of GC content bias using an expectation-maximization algorithm embedded in the Poisson generalized linear models, which accounts for the different copy number states along the genome; (iii) a cross-sample iterative segmentation procedure to identify breakpoints that are shared across cells from the same genetic background. We evaluate performance of SCOPE on real scDNA-seq data sets from cancer genomic studies. Compared to existing methods, SCOPE more accurately estimates subclonal copy number aberrations and is shown to have higher correlation with array-based copy number profiles of purified bulk samples from the same patient. We further demonstrate SCOPE on three recently released data sets using the 10X Genomics single-cell CNV pipeline and show that it can reliably recover 1% of the cancer cells from a background of normal and recover the cancer subclonal compositions of 10,000 breast cancer cells. Citation Format: Rujin Wang, Danyu Lin, Yuchao Jiang. SCOPE: A normalization and copy number estimation method for single-cell DNA sequencing [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5094.
Abstract 18347: Patterns of Physical Activity and Survival Following CRT-D Implantation: The ALTITUDE Activity Study
Authors: Daniel Kramer, Paul W Jones, Tyson Rogers, Susan L Mitchell, Matthew R Reynolds
Journal: Circulation (2015)

Background: Device-detected physical activity predicts survival following ICD implantation. CRT is implanted in part to improve the functional status of patients with CHF. Patterns of activity changes following CRT implantation, and their relationship to survival, have not been described. Methods: CRT-D patients in the Boston Scientific ALTITUDE registry from 2008-2012 with activity measurements through 210 days were eligible. Remote monitoring data were used to calculate physical activity differences (mean minutes/day) between baseline post-implant (first 3-10d); short-term (30-60 days) and 6 months (180-210 days). The relationship between activity changes between baseline and 6 months by quintile and survival were modeled using Cox regression. Results: Among 36,699 patients (mean age 70.8 + 10.9, 29.5% women), mean activity was 68.9 + 48.9 min/day at baseline, 97.9+ 60.7 min/day at 30-60 days, and 100.0+ 64.9 min/day at 6 months. Mean paired differences between baseline and 6 month activity was 31.1 min/day (95% CI, 30.6-31.6, P&lt;0.0001). However, mean paired differences between 30-60 days and 6 months was only 2.2 min/day (95% CI 1.8-2.5, P&lt;0.0001). Unadjusted survival from 6-months post-CRT-D implant in the highest vs lowest quintile of activity change (baseline - 6 months) was 96.8% vs 83.9% at 1 year, and 87.6% vs 62.1% at 3 years (log-rank P &lt;0.0001 for both comparisons). After adjustment for age, gender, and baseline activity, change in activity at 6 months strongly predicted survival (HR 1.51 per 30 min change, 95% CI 1.48-1.55, two-sided Wald test P &lt;0.0001). Conclusion: This large, nationwide sample of CRT-D recipients suggests that physical activity following implantation increases an average of over 30 min/day, with most of the change manifest in the 2nd month of therapy. Adjusted survival is markedly improved in patients who demonstrate improved activity levels.
Abstract 18873: Protection of CD39 Transgenic Mice From Cerebral Ischemic Injury
Authors: Amy Baek, Danica Petrovic-Djergovic, Hui Liao, Jessica Ray, Nadia Sutton, Yogendra Kanthi, David Pinsky
Journal: Circulation (2013)

Cerebral tissue damage after an ischemic event can be exacerbated by inflammation and thrombosis. Elevated levels of extracellular ATP and ADP are associated with cellular injury and promote inflammation and thrombosis. Ectonucleoside triphosphate diphosphohydrolase 1 (CD39), an enzyme expressed on the plasmalemma of leukocytes and endothelial cells, suppresses platelet activation and leukocyte infiltration by phosphohydrolyzing ATP and ADP. To investigate the effects of increased CD39 in an in vivo model of cerebral ischemia, we developed a transgenic mouse expressing human CD39 (hCD39). A floxed stop sequence was inserted prior to the transcriptional start site of hCD39, generating a mouse in which the expression of hCD39 can be controlled in a tissue-specific manner with specific Cre recombinase mice. Here, we generated mice that express hCD39 globally, using an EIIA-Cre mouse. Bone marrow analysis showed similar endogenous CD39 mRNA between transgenic (TG) and wild type (WT) mice while expression of the human transgene was &gt;3,600-fold greater than the mouse gene (p&lt;0.0001, n=3). Cerebral ischemia was induced using a photothrombotic model of middle cerebral artery (MCA) occlusion, which is clinically relevant to ischemic stroke. After 48 hours, mice underwent brain MRI and infarct volumes were quantified. TG hCD39 mice had 37.8% smaller infarct volumes (p&lt;0.05, n=5). A second cohort of mice was assessed for neurological deficits - TG mice showed lower deficits compared to WT (1.0 vs 1.5 based on an established 5-point scale p&lt;0.02, n=8). Western blot analysis of non-ischemic hemispheres showed that TG mice had significantly more CD39 expression than WT mice (5.4-fold, n=3, p&lt;0.0001) Leukocytes from ischemic and contralateral hemispheres were purified for flow cytometric analysis. While contralateral hemispheres had the same numbers of macrophages and neutrophils (CD45+/ F4/80+ and CD45+/Ly6g+ respectively), ischemic hemispheres from TG mice had 64% fewer infiltrating macrophages and 68% fewer neutrophils (p&lt;0.001, n=8). This is the first report of transgenic overexpression of CD39 in mice imparting a protective phenotype following stroke, with reduced leukocyte infiltration, smaller infarct volumes and decreased neurological deficit.
Inhibitory effects of beta-boswellic acids on 12-O-tetradecanoylphorbol-13-acetate-induced inflammation, expression of pro-inflammatory cytokines, arachidonic acid metabolism, and tumor promotion in mouse skin
Authors: Mou-Tuan Huang, Yue Liu, Vladimir Badmaev, Chi-Tang Ho
Journal: Cancer Research (2005)

749  Boswellia serrata extracts have been used for centuries as an herbal medicine for the treatment of inflammation and related diseases in India and China. A preparation of Boswellia extract (BE) contains about 35-40% total beta-boswellic acids and further separated and purified by a Phenomenex Synergi MAX-RP 80A column into 6 peaks. Four peaks were identified as beta-boswellic acid, 3-O-acetyl-beta-boswelic acid, 11-keto-beta-boswellic acid and 3-O-acety-11-keto-beta-boswellic acid, respectively. The other 2 peaks were alpha-boswellic acid and 3-O-acetyl-alpha-boswellic acid. Beta-boswellic acid and its 3 derivatives had strong anti-inflammatory activity in mouse ear edema test. Topical application of TPA (0.8 nmol) onto ears of CD-1 mice once a day for 4-5 days induced persistent inflammation that was corrected with elevated protein levels of pro-inflammatory cytokines as well as formation of PGE2 and LTB4 levels in the mouse ears. Topical application of BE and pure beta-boswellic acid at 30 min before each TPA application once a day for 4 days inhibited TPA-induced persistent inflammation and expression IL-1beta and IL-6 protein levels as well as inhibited formation of LTB4 levels, but not PGE2 levels in mouse ears. Oral administration of 3.5 and 14 mg of 3-O-acetyl-11-keto-beta-boswellic acid in corn oil to the female CD-1 mouse at 30 min before TPA treatment inhibited TPA-induced ear edema by 53% and 64%, respectively. Beta-boswellic acid appears to have advantage with high systemic bioavailability in comparison to other anti-inflammatory and anti-tumor agent such as curcumin. Topical application of 1.2 and 3.6 mg of BE before TPA (5 nmol) to skin of DMBA-initiated mice twice a week for 16 weeks inhibited the average number of skin tumors per mouse by 87 and 99%, respectively, and the percent of the mice with skin tumors was decreased by 59 or 92%, respectively. The results indicating that BE and beta-boswellic acids had strong anti-inflammatory and cancer preventive activities.