tbuckley/cabot-search huggingface dataset:
Biobanks Linked to Electronic Health Records Accelerate Genomic Discovery
Authors: Dana C. Crawford, John R. Sedor
Journal: Journal of the American Society of Nephrology (2021)

Genome-wide association studies (GWAS), now celebrating a decade and a half of successful genomic discovery, are the main study design applied at the population scale to identify individual genetic variants, genes and genic regions, and pathways associated with complex human diseases and traits. In
Abstract 15110: Cardiogenic Shock Management: International Survey of Contemporary Practices
Authors: Angie S Lobo, Yader Sandoval, Jose P Henriques, Stavros G Drakos, Iosif Taleb, Jayant Bagai, Mauricio G Cohen, Yiannis S Chatzizisis, Benjamin Sun, Katarzyna Hryniewicz, Peter M Eckman, Holger Thiele, Emmanouil S Brilakis
Journal: Circulation (2019)

Introduction: Cardiogenic shock (CS) is a low cardiac output state resulting in critical organ hypoperfusion. Despite advances in care, CS continues to have high mortality. Hypothesis: Examine CS c...
Pristine submucosal visibility using Texture and Color Enhancement Imaging during saline-immersion rectal endoscopic submucosal dissection
Authors: Arnaud Lemmers, Ana-Maria Bucalau, Laurine Verset, Jacques Devière
Journal: Endoscopy (2021)

Endoscopic submucosal dissection (ESD) is spreading worldwide to remove large protruded adenoma in the colorectum with the aim to obtain adequate pathological examination and virtual recurrence rate [1]. Up to now, no virtual enhancement tool has been described to facilitate submucosal visibility during submucosal space endoscopy.
Phase-Specific and Lifetime Costs of Multiple Myeloma Among Older Adults in the US
Authors: Kaustuv Bhattacharya, John P. Bentley, Sujith Ramachandran, Yunhee Chang, Benjamin F. Banahan, Ruchit Shah, Nickhill Bhakta, Yi Yang
Journal: JAMA Network Open (2021)

<h3>Importance</h3> Health care costs associated with diagnosis and care among older adults with multiple myeloma (MM) are substantial, with cost of care and the factors involved differing across various phases of the disease care continuum, yet little is known about cost of care attributable to MM from a Medicare perspective. <h3>Objective</h3> To estimate incremental phase-specific and lifetime costs and cost drivers among older adults with MM enrolled in fee-for-service Medicare. <h3>Design, Setting, and Participants</h3> A retrospective cohort study was conducted using population-based registry data from the 2007-2015 Surveillance, Epidemiology, and End Results database linked with 2006-2016 Medicare administrative claims data. Data analysis included 4533 patients with newly diagnosed MM and 4533 matched noncancer Medicare beneficiaries from a 5% sample of Medicare to assess incremental MM lifetime and phase-specific costs (prediagnosis, initial care, continuing care, and terminal care) and factors associated with phase-specific incremental MM costs. The study was conducted from June 1, 2019, to April 30, 2021. <h3>Main Outcomes and Measures</h3> Incremental MM costs were calculated for the disease lifetime and the following 4 phases of care: prediagnosis, initial, continuing care, and terminal. <h3>Results</h3> Of the 4533 patients with MM included in the study, 2374 were women (52.4%), 3418 (75.4%) were White, and mean (SD) age was 75.8 (6.8) years (2313 [51.0%] aged ≥75 years). The characteristics of the control group were similar; however, mean (SD) age was 74.2 (8.8) years (2839 [62.6%] aged ≤74 years). Mean adjusted incremental MM lifetime costs were $184 495 (95% CI, $183 099-$185 968). Mean per member per month phase-specific incremental MM costs were estimated to be $1244 (95% CI, $1216-$1272) for the prediagnosis phase, $11 181 (95% CI, $11 052-$11 309) for the initial phase, $5634 (95% CI, $5577-$5694) for the continuing care phase, and $6280 (95% CI, $6248-$6314) for the terminal phase. Although inpatient and outpatient costs were estimated as the major cost drivers for the prediagnosis (inpatient, 55.8%; outpatient, 40.2%), initial care (inpatient, 38.1%; outpatient, 35.5%), and terminal (inpatient, 33.0%; outpatient, 34.6%) care phases, prescription drugs (44.9%) were the largest cost drivers in the continuing care phase. <h3>Conclusions and Relevance</h3> The findings of this study suggest that there is substantial burden to Medicare associated with diagnosis and care among older adults with MM, and the cost of care and cost drivers vary across different phases of the cancer care continuum. The study findings might aid policy discussions regarding MM care and coverage and help further the development of alternative payment models for MM, accounting for differential costs across various phases of the disease continuum and their drivers.
ROLE OF PKC ISOFORMS AND PKD1 IN THE INHIBITION OF NF-kappa B ACTIVATION BY A VITAMIN K2 IN HUMAN HEPATOCELLULAR CARCINOMA CELLS
Authors: Mizuta T, Eguchi Y, Takahashi H, Iwane S, Hamajima H, Matsuhashi S, Ozaki I, Xia Hj
Journal: Hepatology (2011)
Animal Models of Drug Relapse and Craving after Voluntary Abstinence: A Review
Authors: Ida Fredriksson, Marco Venniro, David J. Reiner, Jonathan J. Chow, Jennifer M. Bossert, Yavin Shaham
Journal: Pharmacological Reviews (2021)

Relapse to drug use during abstinence is a defining feature of addiction. During the last several decades, this clinical scenario has been studied at the preclinical level using classic relapse/reinstatement models in which drug seeking is assessed after experimenter-imposed home-cage forced abstinence or extinction of the drug-reinforced responding in the self-administration chambers. To date, however, results from studies using rat relapse/reinstatement models have yet to result in Food and Drug Administration<b>–</b>approved medications for relapse prevention. The reasons for this state of affairs are complex and multifaceted, but one potential reason is that, in humans, abstinence is often self-imposed or voluntary and occurs either because the negative consequences of drug use outweigh the drug's rewarding effects or because of the availability of nondrug alternative rewards that are chosen over the drug. Based on these considerations, we and others have recently developed rat models of relapse after voluntary abstinence, achieved either by introducing adverse consequences to drug taking (punishment) or seeking (electric barrier) or by providing mutually exclusive choices between the self-administered drug and nondrug rewards (palatable food or social interaction). In this review, we provide an overview of these translationally relevant relapse models and discuss recent neuropharmacological findings from studies using these models. We also discuss sex as a biological variable, future directions, and clinical implications of results from relapse studies using voluntary abstinence models. Our main conclusion is that the neuropharmacological mechanisms controlling relapse to drug seeking after voluntary abstinence are often different from the mechanisms controlling relapse after home-cage forced abstinence or reinstatement after extinction. <h3>Significance Statement</h3> This review describes recently developed rat models of relapse after voluntary abstinence, achieved either by introducing adverse consequences to drug taking or seeking or by providing mutually exclusive choices between the self-administered drug and nondrug rewards. This review discusses recent neuropharmacological findings from studies using these models and discusses future directions and clinical implications.
Abstract 1304: AbYlinkTM: A site-selective labeling method for preclinical imaging of therapeutic antibodies
Authors: Viktoriia Postupalenko, Léo Marx, David Viertl, Natalia Gasilova, Mathilde Plantin, Nadège Gsponer, Alexandre Johanssen, Thibaut Denoel, Gerrit Hagens, Jean-Manuel Segura, Frédéric Levy, Patrick Garrouste, John Prior, Margret Schottelius, Niklaus Schaefer, Origene Nyanguile
Journal: Cancer Research (2021)

Abstract Clinical development of therapeutic antibodies relies on robust and thorough preclinical evaluation of multiple pharmacodynamic and pharmacokinetic parameters of antibody candidates. While current methods are available for in vitro characterization of antibodies, in vivo determination of tissue distribution, tumor accumulation and retention and potential off-target effects cannot be performed non-invasively in vivo over a prolonged period of time. Here, we used AbYlinkTM, a novel site-selective labeling method of native antibodies, enabling the single-step covalent conjugation of a radionuclide chelator to the Fc domain of any IgG antibody isotype. Given the selectivity of this reaction for the Fc region of the immunoglobulin, labeling of the antibody at this location should not compromise binding to the antigen. Chelators that are covalently attached to the antibody allows for the labeling with radioisotopes such as 68Ga, 177Lu, 111In and 89Zr, and for the sensitive and quantitative molecular in vivo measurement by Positron Emission Tomography (PET) or Single Photon Emission Computed Tomography (SPECT). AbYlinkTM also permits the conjugation of fluorescent dyes to antibodies with the aim to measure antibody pharmacodynamic parameters by intravital microscopy. In this work, we have validated the technology by labeling several antibodies and ADCs with different payloads. Importantly, antibodies conjugated with AbYlinkTM retained the same affinity to the antigen as the original, unconjugated antibodies, contrary to the randomly labelled antibodies. We will also present data on the specific radiolabeling of commercially available trastuzumab with 111Indium and the SPECT images obtained after injection of mice bearing HER2-positive tumors with 111In-trastuzumab. The present data suggest that AbYlinkTM can be used to support preclinical drug discovery tools to assist in the selection of therapeutic antibody candidates and/or for pharmacodynamic assessment of commercial antibodies. Furthermore, the specificity of the chemical conjugation suggests that AbYlinkTM can help to control the chelator distribution on the antibody drug conjugates. Citation Format: Viktoriia Postupalenko, Léo Marx, David Viertl, Natalia Gasilova, Mathilde Plantin, Nadège Gsponer, Alexandre Johanssen, Thibaut Denoel, Gerrit Hagens, Jean-Manuel Segura, Frédéric Levy, Patrick Garrouste, John Prior, Margret Schottelius, Niklaus Schaefer, Origene Nyanguile. AbYlinkTM: A site-selective labeling method for preclinical imaging of therapeutic antibodies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1304.
Abstract 2092: Effects of Yi Sui Granules, an herbal medicine, on MDS/AML: Similar to decitabine or other mechanisms
Authors: Jing Wang, Chong Gao, Elizabeth Gullen, Jieya Wu, Xiaoyuan Zhang, Xinyi Chen
Journal: Cancer Research (2021)

Abstract Objective Yi Sui Granules (YSG) has been clinically used and proved efficacious in patients with myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) for 25 years, however, its mechanism remains unclear. This study is to evaluate the effects of YSG on DNA methylation of AML/MDS. Methods and Results From cytotoxicity assays using CCK-8 method, we found out YSG inhibited SKM-1, HL-60, K-562 and CEM cells in a dose-dependent manner with an IC50 of 1.173±0.165 mg/ml, 1.70±0.2 mg/ml, 2.85±0.05 mg/ml, 1.70±0.2 mg/ml respectively. In vivo, decitabine inhibited tumor growth in terms of tumor volume and tumor weight but led to significant weight loss of SKM-1 xenographed BALB/c-nu mice. While YSG (50.69%) showed similar tumor weight inhibition rate to decitabine (56.64%) without side effects including body weight loss. To explore its mechanism, we discovered that DNA methyltransferase 1 (DNMT1) expression was significantly down-regulated(P&amp;lt;0.05) and SFRP5 gene was demethylated(P&amp;lt;0.01) after treated with either YSG or decitabine using RT-PCR, western blot and bisulfite amplicon sequencing methods. Furthermore, we found significant up-regulation of SFRP5 expression(P&amp;lt;0.05), down-regulation of Wnt3a protein(P&amp;lt;0.05) and β-catenin expression(P&amp;lt;0.05), as well as down-regulation of C-myc(P&amp;lt;0.05) and CyclinD1 expression(P&amp;lt;0.05) in decitabine group and YSG group. Equally interestingly, survival benefits were observed in YSG high-dose group but not in Decitabine group(P&amp;lt;0.05). Conclusion Similar to decitabine, YSG's suppression of SKM1 tumor may be related to the inhibition of DNMT1 expression, de-methylation of SFRP5 and up-regulation of SFRP5 expression, preventing Wnt3a from binding to Frizzled receptors, therefore inhibiting the abnormal activation of Wnt signaling, and down-regulating its target gene expression including C-myc and CyclinD1. Unlike decitabine, YSG prolong overall survival though other mechanisms, which will be further investigated in our future research. Corresponding Author: Jing Wang and Xinyi Chen, Address: No.5 Haiyuncang, Dongcheng District, Beijing, 100700, China; Email: Jing.Wang@bucm.edu.cn and chenxinyi0729@126.comAcknowledgement: This work was supported by the Young Scientist Fund (81503575) and Key Program (81630080) of National Natural Science Foundation of China, the Golden Bridge Project of Beijing Association for Science and Technology(ZZ20059) and the Elite Program of Dongcheng district of Beijing (2020-dchrcpyzz-38). Citation Format: Jing Wang, Chong Gao, Elizabeth Gullen, Jieya Wu, Xiaoyuan Zhang, Xinyi Chen. Effects of Yi Sui Granules, an herbal medicine, on MDS/AML: Similar to decitabine or other mechanisms [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2092.
Abstract 373: Advancing precision oncology by synergizing ddPCR with microdissection
Authors: Donald J. Johann, Ikjae Shin, Erich Peterson, Mathew Steliga, Jason Muesse, Katy Marino, Sarah Laun, Adam Roberge, Robert Weigman, Michael Emmert-Buck, Michael Tangrea
Journal: Cancer Research (2021)

Abstract Background - The domain of precision oncology includes improving patient treatment outcomes based on the application of advanced molecular profiling methodologies to pathological specimens. To this end, optimal utilization of tumor tissue from diagnostic biopsies is an unmet medical need. This is especially relevant today since precision oncology is a rapidly evolving field where timely tumor genotyping is essential for the indication of many advanced and targeted therapies. National Comprehensive Cancer Network (NCCN) guidelines now mandate molecular testing for clinically actionable targets in certain malignancies. Patients diagnosed with advanced non-small cell lung cancer (NSCLC) are commonly of an older age and have significant co-morbidities. This frequently causes clinical dilemmas regarding the ability to obtain adequate amounts of tissue for tumor genotyping. In these cases, the tumor tissue may have been obtained by an image-guided biopsy, and the diagnosis of NSCLC proper determined via cytology. In certain instances, adequate tissue for tumor genotyping and/or a more advanced mutational analysis to identify oncogenic drivers may not be available. Methods - Formalin fixed paraffin embedded (FFPE) specimens were examined using advanced immuno-based laser capture microdissection (LCM), following a formal pathology review. In preparation for droplet digital PCR (ddPCR), DNA was extracted from samples and run with a series of positive and negative controls. Results - Utilizing lung cancer as an example, an improved genotyping approach for NSCLC solid tumors was developed and tested. The strategy involves optimization of the microdissection process and analysis of a large number of identical target cells from FFPE specimens sharing similar characteristics, in other words, single-cell subtype analysis. Immunostaining status, cell phenotype, and spatial location within a histological section are examples of shared characteristics that can guide cell procurement. Conclusions - Synergy between microdissection and ddPCR enhances molecular analysis. Demonstrated is a methodology that illustrates genotyping of a solid tumor from a small tissue biopsy sample in a time and cost-efficient manner, using immunohistochemistry directed LCM and ddPCR detection. Citation Format: Donald J. Johann, Ikjae Shin, Erich Peterson, Mathew Steliga, Jason Muesse, Katy Marino, Sarah Laun, Adam Roberge, Robert Weigman, Michael Emmert-Buck, Michael Tangrea. Advancing precision oncology by synergizing ddPCR with microdissection [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 373.
Formulation strategies for bacteriophages to target intracellular bacterial pathogens
Authors: Wei Yan, Parikshit Banerjee, Miao Xu, Subhankar Mukhopadhyay, Margaret Ip, Nicholas B. Carrigy, David Lechuga-Ballesteros, Kenneth Kin Wah To, Sharon S.Y. Leung
Journal: Advanced Drug Delivery Reviews (2021)
Abstract 2278: Analysis of primary and secondary EGFR-TKI resistance mutations evolution in 835 EGFR-mutant Chinese lung cancers
Authors: Xiaorong Dong, Dongqiang Zeng, Xinyi Liu, Mengli Huang
Journal: Cancer Research (2021)

Abstract Background: EGFR gene is the most frequent mutated gene in lung cancer. EGFR-Ex19del and EGFR-L858R mutations account for 90% mutations in EGFR mutations and these two kinds of genomic alterations are both sensitive to EGFR-TKIs. However, resistance to EGFR-TKIs would always happen after a period of treatment. EGFR-T790M and EGFR-ex20ins alterations had been identified as alterations result in resistance. The evolution of EGFR-T790M and EGFR-ex20ins in lung cancers with EGFR-mutant baseline features have not been systemically investigated. Method: We analyzed 835 EGFR-mutant Chinese lung cancers. Each patient had received treatment containing EGFR-TKIs and at least two longitudinal follow-up evaluations based on NGS testing. The median follow-up time was 278 days. We systemically analyzed the evolution of EGFR primary and secondary mutations as previously defined. Result: EGFR-Ex19del, EGFR-L858R, EGFR-G719X, EGFR-L861Q and EGFR-Ex20ins were basically mutually exclusive. Out of 835 cases, 401 were with EGFR-Ex19del, 348 were with EGFR-L858R, 27 were with EGFR-G719X, 22 were with EGFR-L861Q and 9 were with EGFR-Ex20ins at baseline time. EGFR-T790M were co-mutated in 16.6% EGFR-19del population and in 11.3% EGFR-L858R population. In EGFR-G719X, EGFR-L861Q and EGFR-Ex20ins population, the proportion of patients with EGFR-T790M co-mutations were all about 10%. EGFR-S768I was the most frequent co-occurring EGFR mutation in EGFR-G719X subgroup while was not occur in EGFR-L861Q subgroup. In follow-up time, 26.8% EGFR-Ex19del patients loss the T790M mutation and 51.4% EGFR-L858R patients loss the T790M mutation. Interestingly, the EGFR-T790M and the driver EGFR mutation in EGFR-G719X, EGFR-L861Q and EGFR-Ex20ins subgroups keep all the time in EGFR-TKI treatment. Conclusion: We investigated the resistance EGFR alterations evolution longitudinally in a large Chinese lung cancer cohort. We found that EGFR-T790M was a common co-mutation in lung cancers with different baseline EGFR driver mutations. Although the co-mutant frequency of T790M was similar (about 10%) in each subgroup, it was most likely to disappear in EGFR-L858R baseline subgroup after EGFR-TKI treatment. Citation Format: Xiaorong Dong, Dongqiang Zeng, Xinyi Liu, Mengli Huang. Analysis of primary and secondary EGFR-TKI resistance mutations evolution in 835 EGFR-mutant Chinese lung cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2278.
Xpert bladder monitor: Longitudinal clinical performance for avoiding un-necessary cystoscopies in patients under active surveillance for recurrent bladder cancer (BIAS project)
Authors: V. Fasulo, M. Lazzeri, M. Paciotti, N. Frego, C. Roberto, P.P. Avolio, A. Uleri, P. Casale, A. Saita, G. Lughezzani, N. Buffi, G. Guazzoni, R. Hurle
Journal: European Urology (2021)
Abstract 2331: Metabolic evasion of mCRPC immunotherapy by ACOD1 production of itaconate
Authors: James H. Schofield, Mark A. Hawk, Sharif Rahmy, Ryan D. Sheldon, Casey Leimbach, Seunghoon Sun, Xin Lu, Russell G. Jones, Zachary T. Schafer
Journal: Cancer Research (2021)

Abstract The use of immune checkpoint blockade (ICB) therapies in the form of αPD-1 &amp; αCTLA-4 monoclonal antibodies (mAb) have made great strides in the battle against melanoma, lung, and breast cancers. However, these strategies are not universally effective. Roadblocks occur as certain cancers cannot be targeted by these therapies or may develop resistance to ICB. How resistance to ICB therapy arises represents a crucial barrier to more effective use of these therapies. Recent studies have demonstrated that the metabolic milieu of the tumor microenvironment (TME) plays a role in regulating the anti-tumor immune response. However, the specific mechanisms by which cancer cell secreted metabolites in the TME impact the responsiveness of cancer cells to ICB remain poorly understood. In order to better understand the factors that influence the effectiveness of ICB, we utilized a mouse model (Smad4-/-/Pten-/-/Trp53-/-) of male castration resistant prostate cancer (mCRPC) that is responsive to αCTLA-4 and αPD-1 ICB. Using serial culture and injection of residual tumor cells that survive ICB, we generated cell lines that had developed resistance to ICB. Unbiased metabolomic screening of these cell lines revealed a stark increase in the production of the anti-inflammatory metabolite itaconate in the resistant cell lines. This observation was supported by the increased abundance of the enzyme responsible for itaconate production, aconitate decarboxylase 1 (ACOD1) among the resistant lines. Reduction of this enzyme through shRNA compromises the viability of ICB resistant cells but not sensitive cells. Interestingly, conditioned media from the resistant cell lines restricts the in vitro activation of naïve CD8+ T cells. Furthermore, the reduction of ACOD1 among the resistant population results in increased activation of CD8+ T cells when treated with conditioned media from these resistant cells. These observations also extend to other, more established cell lines like the Lewis lung carcinoma (LLC). Taken together, these results indicate that cancerous epithelial cell production of itaconate, through the activity of ACOD1, may represent a mechanism that antagonizes T cell activation and thus promotes ICB evasion. Citation Format: James H. Schofield, Mark A. Hawk, Sharif Rahmy, Ryan D. Sheldon, Casey Leimbach, Seunghoon Sun, Xin Lu, Russell G. Jones, Zachary T. Schafer. Metabolic evasion of mCRPC immunotherapy by ACOD1 production of itaconate [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2331.
Therapeutic Plasma Exchange in Vaccine-Induced Immune Thrombotic Thrombocytopenia
Authors: Christopher J Patriquin, Vincent Laroche, Rita Selby, Jacob Pendergrast, David Barth, Benoit Côté, Nathalie Gagnon, Guillaume Roberge, Marc Carrier, Lana A Castellucci, Dimitrios Scarvelis, Johnathan P Mack
Journal: New England Journal of Medicine (2021)

Therapeutic Plasma Exchange in Refractory VITT Three patients with severe manifestations of VITT after Covid-19 vaccination had a poor response to initial therapy with anticoagulants and intravenou...