tbuckley/cabot-search huggingface dataset:
Abstract 3416: Customizable gene panels overcome challenges associated with targeted resequencing
Authors: Andrew John Barry, Kruti M. Patel, Amy B. Emerman, Scott Adams, Sarah Bowman, Evan Mauceli, Fiona Stewart, Eileen Dimalanta, Salvatore Russello, Charles Elfe, Theodore Davis, Cynthia Hendrickson
Journal: Cancer Research (2018)

Abstract Efficient utilization of targeted gene panels for clinical research is challenged by the wide variation in gene constituents specific to a given study. While focused gene panels efficiently provide the necessary depth of coverage for low-frequency variant detection, the high costs and technical requirements associated with panel design present obstacles to delivering assays that are focused on the specific targets of interest. The NEBNext DirectTM technology utilizes a novel approach to selectively enrich nucleic acid targets ranging from a single gene to several hundred genes, without sacrificing specificity. The approach rapidly hybridizes both strands of genomic DNA with biotinylated probes prior to streptavidin bead capture, enzymatic removal of off-target sequences, and conversion of captured molecules into sequence-ready libraries. This results in an exceptionally uniform coverage profile for a given target. Unlike alternative hybridization methods, this 1-day workflow does not necessitate upfront library preparation, and instead converts the captured molecules into libraries compatible with Illumina sequencing. We have designed and optimized baits specific to the full exonic content of &amp;gt;800 genes associated with cancer as well as a variety of other disease areas. These are designed, balanced, and pooled on a per gene basis, and can be readily combined into customized panels, allowing rapid turnaround of specific custom gene subsets. Here, we present the ability to rapidly deploy custom gene panels across a variety of panel sizes and content, while maintaining high specificity, uniformity of coverage across target content, and sensitivity to detect nucleic acid variants from clinically relevant samples. Citation Format: Andrew John Barry, Kruti M. Patel, Amy B. Emerman, Scott Adams, Sarah Bowman, Evan Mauceli, Fiona Stewart, Eileen Dimalanta, Salvatore Russello, Charles Elfe, Theodore Davis, Cynthia Hendrickson. Customizable gene panels overcome challenges associated with targeted resequencing [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 3416.
Abstract 1707: Tumor treating fields exert cellular and immunologic effects
Authors: Eric T. Wong, Joshua Timmons, Kenneth D. Swanson
Journal: Cancer Research (2018)

Abstract While there is clear clinical evidence to support the therapeutic efficacy of low dose alternating electric fields (TTFields) in treating glioblastoma, their intracellular targets and mechanism of action remains poorly defined. Historically, TTFields have been thought to operate by inducing extensive plasma membrane blebbing during the entry into anaphase resulting in aberrant mitotic exit and cell death. However, we have found that cells exposed to TTFields exhibited increased granularity and evidence of endoplasmic reticulum stress and genotoxic stress suggesting other mechanisms to explain their clinical efficacy. Cells exposed to TTFields exhibited reductions in levels of culture media acidification and analysis of intracellular metabolism showed evidence for an increase in mitochondrial respiration and glutaminolysis pathway. Our previous analysis of data from the pivotal phase III EF-11 clinical trial showed that increased corticosteroid use was strongly correlated with poor outcomes in TTFields-treated patients, possibly by suppressing immune effector function required for to drive tumor regression. TTFields drives the cell surface expression of immune stimulatory stress marker proteins calreticulin, and the secretion of the Alarmin/DAMP protein, HMGB1 which are together suggest that TTFields can stimulate immunogenic cell death. Co-culture of bone marrow derived macrophages with TTFields-treated CT26 cells resulted in the up-regulation of cell surface activation markers in the macrophage population that was blocked by a monoclonal antibody directed against HMGB1. Further, supernatants from these co-cultures contained increased levels of pro-inflammatory cytokines and chemokines and a reduction of anti-inflammatory cytokines associated with the presence of the TTFields-treated cells relative to co-cultures containing naïve tumor cells. Further, in vivo, engrafted Lewis lung carcinoma tumors exhibited increased levels of granzyme positive cells following TTFields treatment. Together, these data suggest that TTFields affect cancer cells during interphase and this insult leads to alterations in cancer cell metabolism and increased tumor cell immunogenicity and thus act to drive increased immune recognition and tumor rejection. In patients, these effects are likely to be opposed by the immune suppressive functions within the tumor microenvironment and corticosteroid use. Therefore, this model of TTFields action may provide a therapeutically rational base to devise improved TTFields treatment strategies from. Citation Format: Eric T. Wong, Joshua Timmons, Kenneth D. Swanson. Tumor treating fields exert cellular and immunologic effects [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 1707.
GMC's guidelines should be followed before information is put on Internet
Authors: D. Nicholl, G. Winters, D. Davies
Journal: BMJ (1996)

and community controls we published both sets of results.The component of the study that looked at acute myocardial infarction was not powerful enough for analysis of subgroups (except perhaps the community controls).In the British dataset for the component that looked at venous thromboembolic disease there were no differences in the estimates of risk between the hospital and community controls.Table 1-Use of oral contraceptives by controls in component oftransnational study looking at venous thromboembolic disease No Third Second current generation generation use pills pills Hospital controls 470 103 180 Community controls
Abstract 17217: Serum Paraoxonase 1 (PON1) Activity is Associated With Indices of Hypertensive Heart Disease and Cardiac Remodeling in the Dallas Heart Study Population
Authors: John F Teiber, Gerald L Kramer, James A de Lemos, Mark H Drazner, Robert W Haley
Journal: Circulation (2015)

Introduction: A recent study in clinic patients found serum activity of the anti-oxidative, anti-inflammatory HDL-associated enzyme paraoxonase 1 (PON1) inversely associated with plasma brain natriuretic peptide (BNP), a marker of heart failure, and predictive of cardiovascular events. We tested whether PON1 protects from hypertensive heart disease in a population sample. Methods: The Dallas Heart Study measured blood biomarkers at baseline in a population sample of 3480 subjects. Left ventricular mass and ejection fraction were measured by cardiac MRI. Serum PON1 activity was measured by the standard arylesterase enzymatic assay. Incident deaths and causes of death were ascertained for 9 years from baseline through the National Death Index where ICD-9 codes I10 –I13.1 indicated hypertensive heart disease. Multivariable models controlled for age, sex, race, cystatin-C, LDL, HDL, high sensitivity C-reactive protein and uncontrolled hypertension. Preliminary mechanistic studies explored effect modification of 34 biomarkers by PON1. Results: In a general linear model PON1 activity was independently associated inversely with log Pro-BNP (standardized r = -0.11, s.e. 0.015, P&lt;0.001) and log BNP (std r = -0.07, s.e. 0.017, P&lt;0.001). It was also inversely associated with left ventricular mass (std r = -0.05, s.e. 0.012, P&lt;0.001) but not with ejection fraction (std r = -0.02, s.e. 0.018, P=0.19). In multivariable logistic regression low PON1 activity predicted the 28 incident deaths from hypertensive heart disease (odds ratio for PON1 activity below the median = 3.58, 95% CI 1.42 – 9.05, P=0.007). Significant interactions indicated that high PON1 activity mitigates the strong association of log Pro-BNP with periostin, a matricellular protein associated with cardiac fibrotic remodeling (P interaction &lt; 0.001, Fig.). Conclusions: The findings suggest that PON1, a component of HDL, may protect from hypertensive heart disease by mitigating cardiac remodeling.
Abstract 3808: Interrogation and modulation of the immunosuppressive activity of human TAM-like macrophages using in vitro cultures
Authors: Laura E. Gallagher, Andrew Hall, Lauren A. Patience, Lucia Janicova, Stephen Anderton
Journal: Cancer Research (2018)

Abstract Tumor Associated Macrophages (TAMs), characteristic of an M2-like immune-suppressive phenotype, can induce proliferation and survival of tumor cells, facilitate angiogenesis, and suppress anti-tumor immune responses via expression of co-inhibitory molecules (e.g. PD-L1) and cytokines (e.g. IL-10, TGF-β). TAMs are therefore a highly attractive target of innovative cancer immunotherapies. Understanding the ability of pre-clinical candidate compounds to reverse TAM (M2-like)-mediated immune suppression and the potential for reprogramming of M2-like macrophages to a M1-like phenotype is key in the development of effective TAM-targeted cancer immunotherapies. Here we outline development of an assay to assess the capabilities of pre-clinical compounds to reverse M2 macrophage-mediated immune suppression. Monocytes were isolated from whole blood obtained from healthy volunteers and cultured under M2-polarising conditions. The resulting macrophages were phenotypically characterized and then used in co-culture with autologous PBMC, stimulated through T cell receptor ligation. Resulting cytokine production was assessed, alongside CD4+ and CD8+ T cell viability and cell cycle status (flow cytometry). M2-like macrophages polarized with M-CSF displayed an immune suppressive phenotype as shown by their production of IL-10 and their inhibition of IFN-γ production by, and cell cycle status of, T cells in co-culture assays. This suppressive activity was only partially reversed by PD-1-blockade. Modifications to the macrophage polarization protocol were seen to alter the resulting macrophage cell surface phenotype (e.g. expression levels of PD-L1, TIM-3 and CD200R) and their suppressive activity in the co-culture assay. These cell surface phenotypes broadly reflected those seen amongst tumor-derived macrophages from renal and ovarian carcinoma patients (CD14+ CD163+ with expression of TIM-3 and LAG-3). Moreover, compound-mediated changes in functionality seen with macrophages polarized from healthy PBMC monocytes could also be seen using patient-derived material. The assay outlined here therefore provides a M-o-A human in vitro system to test novel compound activity (either singly or in combination) upon TAM-like macrophage generation, phenotype and suppressive function. This allows selection of the most efficacious compounds for further investigation using patient-derived immune cells. Citation Format: Laura E. Gallagher, Andrew Hall, Lauren A. Patience, Lucia Janicova, Stephen Anderton. Interrogation and modulation of the immunosuppressive activity of human TAM-like macrophages using in vitro cultures [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 3808.
Abstract 20864: The Inflammatory Biomarkers IL-6 and IP-10 Predict Amputation and Mortality in Patients With Severe Limb Ischemia
Authors: Hendrik Gremmels, Martin Teraa, Joost O Fledderus, Bas W van Balkom, Marianne C Verhaar
Journal: Circulation (2016)

Background: Patients with Severe Limb Ischemia (SLI) have a high risk of amputations and mortality. In this study we investigate whether levels of inflammatory plasma cytokines, angiogenic growth f...
Abstract 3542: Missense mutations in USE1 promote lung tumorigenesis
Authors: Peter C. W. Lee
Journal: Cancer Research (2018)

Abstract The UBA6-USE1 enzyme cascade is a poorly characterized arm of the ubiquitin-proteasome system. We found that UBA6 and USE1 proteins are frequently overexpressed in lung cancer patients (83.01% and 92.45%, respectively; n = 106). Stable overexpression of UBA6 or USE1 significantly increased cell proliferation, migration, and invasiveness in lung cancer cells and xenograft models, whereas their knockdown significantly reduced cell proliferation, migration, and invasion. USE1 has a conserved D-box domain and the level of the protein was regulated by the anaphase-promoting complex through its interaction with CDC20 and CDH1. Furthermore, several missense mutations in USE1 identified in patients prolong the half-life and stability of the protein. Our findings reveal novel roles for USE1 in lung cancer and the possible use of USE1 as a novel biomarker and therapeutic target for lung cancer treatment. Citation Format: Peter C. W. Lee. Missense mutations in USE1 promote lung tumorigenesis [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 3542.
Mitochondrial Electron Transport Complex I Is a Potential Source of Oxygen Free Radicals in the Failing Myocardium
Authors: TomomiIde, HiroyukiTsutsui, ShintaroKinugawa, HideoUtsumi, DongchonKang, NobutakaHattori, KojiUchida, Ken-ichiArimura, KensukeEgashira, AkiraTakeshita
Journal: Circulation Research (1999)

Abstract—Oxidative stress in the myocardium may play an important role in the pathogenesis of congestive heart failure (HF). However, the cellular sources and mechanisms for the enhanced generation of reactive oxygen species (ROS) in the failing myocardium remain unknown. The amount of thiobarbituric acid reactive substances increased in the canine HF hearts subjected to rapid ventricular pacing for 4 weeks, and immunohistochemical staining of 4-hydroxy-2-nonenal ROS-induced lipid peroxides was detected in cardiac myocytes but not in interstitial cells of HF animals. The generation of superoxide anion was directly assessed in the submitochondrial fractions by use of electron spin resonance spectroscopy with spin trapping agent, 5,5′-dimethyl-1-pyrroline-N-oxide, in the presence of NADH and succinate as a substrate for NADH–ubiquinone oxidoreductase (complex I) and succinate–ubiquinone oxidoreductase (complex II), respectively. Superoxide production was increased 2.8-fold (P<0.01) in HF, which was due to t...
Abstract 359: Higher ROS Generation and Lower Threshold of mPTP Opening May Underlie Increased Vulnerability of Late Pregnant Heart to Ischemia-Reperfusion Injury
Authors: JingyuanLi, AndreaIorga, Ji-YounYoun, HuaCai, VeraRegitz-Zagrosek, MansourehEghbali
Journal: Circulation Research (2012)

Although the murine late pregnant (LP) heart is speculated to be a better functioning heart during physiological conditions, the susceptibility of LP hearts to I/R injury is still unknown. The aims of this study were to investigate the cardiac vulnerability of LP rodents to ischemia/reperfusion (I/R) injury and to explore its underlying mechanisms. In-vivo female rat hearts (non-pregnant (NP) or LP) or Langendorff-perfused mouse hearts were subjected to ischemia followed by reperfusion. The infarct size was ∼4 fold larger in LP compared to NP both in the in-vivo rat model and ex-vivo mouse model. The hemodynamic parameters were similar between NP and LP before ischemia. However, the postischemic functional recovery was extremely poor in LP mice comparing to NP mice. RPP was reduced from 12818±1213mmHg*beats/min in NP to 1617± 287mmHg*beats/min in LP mice at the end of reperfusion. Interestingly, all of the hemodynamic parameters almost fully recovered in hearts seven days post-partum (PP7)( RPP= 9604±1215...
Abstract 4744: Disruption of Clever-1 in macrophages activates the innate immune response and mediates tumor rejection
Authors: Miro Viitala, Reetta Virtakoivu, Sina Tadayon, Sirpa Jalkanen, Maija Hollmén
Journal: Cancer Research (2018)

Abstract Macrophages are considered the main obstacles for successful cancer treatment since they can dampen anti-tumor immune responses and promote tumor progression and resistance formation. Macrophages are highly eligible candidates for targeted therapies since these cells are abundantly present in various tumors, they are very plastic and can be converted into pro-inflammatory macrophages supporting T cell activation and tumor rejection. Clever-1 (also known as Stabilin-1) is a multifunctional molecule conferring scavenging ability on a subset of alternatively activated macrophages. The aim of this study is to uncover previously unknown functions of Clever-1 in the regulation of macrophage-mediated anti-tumor immune responses and develop anti-Clever-1 therapy into clinical use for those suffering from refractory, untreatable solid tumors. By using in vivo tumor models and sophisticated immunological assays, our data show that mice carrying a macrophage-specific genetic deletion of Clever-1 (Lyz2-Cre/Stab1fl/fl) reject implanted Lewis lung carcinoma and EL4 lymphoma tumors. Macrophage Clever-1 deficiency induced proliferation of Ly6Chi monocytes in the tumor microenvironment but impaired their maturation and polarization into tumorigenic Ly6Clo macrophages. Tumors in Lyz2-Cre/Stab1fl/fl mice consisted almost completely of proliferating CD8 T cells with an exhausted PD-1+Lag3+ phenotype two weeks after implantation. Functionally, Clever-1 depleted macrophages showed enhanced pro-inflammatory responses following TLR activation with a shift in IL-12/IL-10 secretion levels. This was due to enhanced activation of mTORC1 and NFκB signaling, which resulted in increased secretion of TNFα in steady state and after LPS induction. In conclusion, our data show an important function of Clever-1 in controlling macrophage mediated local immune responses. Moreover, our data supports Clever-1 targeting as a novel approach to increase host defenses against immune compromised tumors and promotes anti-Clever-1 immunotherapy into clinical trials where it may have benefits in comparison with currently available immune activating drugs. Citation Format: Miro Viitala, Reetta Virtakoivu, Sina Tadayon, Sirpa Jalkanen, Maija Hollmén. Disruption of Clever-1 in macrophages activates the innate immune response and mediates tumor rejection [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 4744.
Ultrahigh Dose-rate Radiotherapy: Next Steps for FLASH-RT
Authors: Kevin J. Harrington
Journal: Clinical Cancer Research (2018)

A new way of delivering radiotherapy at very high dose rates is described and compared with conventional radiotherapy. The ultrahigh dose-rate therapy reduces damage to normal pig skin and exerts potent activity against spontaneous nasal tumors in cat patients. The implications for clinical development of this approach are discussed.
Abstract 5295: Toward high throughput immune infiltrate analysis from H&E stained images
Authors: Rishi R. Rawat, Daniel Ruderman, David B. Agus
Journal: Cancer Research (2018)

Abstract Our appreciation of the immune system in breast cancer is rapidly evolving. New methods to quantify the composition and spatial distribution of the immune infiltrate from pathology images are urgently needed to develop better strategies to activate the anti-tumor immune response. Existing methods to quantify the immune infiltrate are tedious (manual counting) or rely on immunohistochemistry (IHC) staining to identify immune cells. While significant efforts are underway to develop machine learning tools to categorize cells based on morphologic features in hematoxylin and eosin (H&amp;E) stained histopathology images, all approaches are limited by the scarcity of large, annotated ground truth training sets. In this work, we propose a new approach, leveraging “style-transfer” algorithms from the computer vision community to generate large quantities of training data from IHC stains. Using style transfer, we generate synthetic H&amp;E images from IHC stains for immune markers, such as CD45, CD8 and CD4. The generated images have pixel-perfect ground truth provided by IHC, and do not need manual labeling. We investigate the impact of training on increasing numbers of synthesized images and validate our algorithms on an independent test set annotated by a pathologist (n=100 patients, 3064 identified lymphocytes). Our baseline classifier achieves a 83% accuracy, compared to the pathologist ground truth. This work provides a novel, tractable, and efficient way to train data-hungry algorithms to identify multiple cell types from H&amp;E stained images. This work is supported by a grant from the Breast Cancer Research Foundation (BCRF-17-002) Citation Format: Rishi R. Rawat, Daniel Ruderman, David B. Agus. Toward high throughput immune infiltrate analysis from H&amp;E stained images [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 5295.
Abstract 20838: Aggressive Management of Bradycardia is Associated With Improved Clinical Outcomes and Shorter Length of Stay: A Comparison of Two Academic Centers
Authors: Victor Abrich, Rachel Le, Paul Friedman, Yong-Mei Cha, David Nestler, Eric H Yang, Gregory Barsness
Journal: Circulation (2016)

Introduction: Bradycardia symptoms range from fatigue to cardiac arrest. However, it is unclear to what extent management affects clinical outcomes. The purpose of the current study was to perform a retrospective analysis of the management of bradycardic patients at two tertiary care centers and to determine if the management styles resulted in any differences in clinical outcomes. Hypothesis: Aggressive management of bradycardia is associated with improved clinical outcomes. Methods: We retrospectively reviewed the charts of 555 patients from Mayo Clinic Rochester (n=358) and Mayo Clinic Scottsdale (n=197) who presented to the ED with bradycardia (heart rate ≤50 bpm) secondary to a mechanism other than sinus with 1:1 AV conduction from 2010 through 2015. Patients were categorized by treatment strategy: monitoring, medical therapy alone, medical therapy plus transcutaneous pacing (TCP), and medical therapy plus temporary transvenous pacemaker (TPM). Significant bradycardic events were defined as pauses >5...