tbuckley/cabot-search huggingface dataset:
Abstract 4215: Patient and screening characteristics associated with positive lung cancer screening examinations
Authors: Louise M. Henderson, Samantha Sites, Tina Tailor, Sara C. Bearden, Roger Huamani, Allison Throneburg, Max Nagle, M Patricia Rivera
Journal: Cancer Research (2019)

Abstract Introduction. The likelihood of having a positive low dose computed tomography (LDCT) lung cancer screening (LCS) examination that requires workup may vary according to patients’ characteristics and risk factors. The purpose of this study is to evaluate patient characteristics associated with positive LCS exams. Methods. We utilized data from 1684 LDCT exams conducted for LCS at five academic and community sites from 2015-2018. During the screening visit, patients were asked to complete a comprehensive questionnaire including socio-demographics, smoking history, occupational and environmental exposures, family history of lung cancer, and comorbid conditions. Information on the LCS examination, including the radiologists’ Lung Reporting and Data System (Lung-RADS) assessment, was obtained from the radiologist report. We dichotomized Lung-RADS into negative (Lung-RADS 1 (negative) or 2 (benign appearance or behavior)) and positive (Lung-RADS 3 (probably benign), 4A (suspicious), or 4B (suspicious)) based on the management recommendation of continuing with annual screening in 12 months or requiring follow-up before 12 months. We compared Lung-RADS results (positive versus negative) by patient characteristics using chi-square tests and examined predictors of positive LCS exams using multivariate logistic regression, reporting adjusted odds ratios (aORs) and 95% confidence intervals (95%CI). Results. Screened patients ranged in age from 50-78 years, with 46.7% less than 65 years and 53.3% ages 65 or older. Approximately 53.3% were male and 46.7% were female; 84.5% were White, 11.8% were African American, and 3.7% were other races. The majority (76.5%) of screened patients were overweight or obese. Two-thirds (68.5%) of patients had more than one LCS exam. Most (85.0%) LCS exams were negative while 15.0% were positive. There were no significant differences in Lung-RADS assessment by race, gender, education, or body mass index. Lung-RADS were significantly more likely to be positive in those ages 65 and older versus those ages less than 65 (aOR=1.47, 95%CI: 1.03-2.10) and in baseline versus subsequent screening exams (aOR=0.43, 95%CI: 0.30-0.62). Conclusion. Predictors of having a positive LCS exam requiring work-up before the next recommended annual screening test include being aged 65 and older and having a baseline LCS examination. Citation Format: Louise M. Henderson, Samantha Sites, Tina Tailor, Sara C. Bearden, Roger Huamani, Allison Throneburg, Max Nagle, M Patricia Rivera. Patient and screening characteristics associated with positive lung cancer screening examinations [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 4215.
Abstract 3426: Combining cell barcoding and CRISPR sgRNA libraries with targeted gene expression for single-cell genetic analysis of tumor metastasis
Authors: Alex Chenchik, Paul Diehl, Mikhail Makhanov
Journal: Cancer Research (2019)

Abstract Pooled lentiviral libraries of CRISPR sgRNAs to mediate genome-wide gene knockout have become an invaluable tool for uncovering the functional genetic drivers required for a biological response. Another type of pooled lentiviral library designed with unique DNA sequence tags have also been used to label large populations of cells with unique cell-specific barcodes which allows monitoring changes in sub-populations of cells with distinct phenotypes over time. We have combined cell barcodes with CRISPR sgRNA to construct libraries that enable the identification of multiple occurrences of a common phenotypic response from independent transductions of the same sgRNA effector. Specifically, we demonstrate how this sort of library can be used to identify genes whose activation promotes metastasis of tumors derived from MDA-MB-231 cells engrafted into mice after transduction with a barcoded CRISPR-activation (CRISPRa) sgRNA library. By incorporating multiple barcodes with each sgRNA effector, it is possible to see that, not only are cells in metastatic tumors more likely to have a particular sgRNA targeted to a certain gene, but also that independent transductions of that sgRNA sequence lead to multiple independent metastatic events. With multiple independent clones producing the same phenotype, it is possible to confidently isolate the sgRNA, and by implication, the increased activation of its gene target, as the primary cause of the metastatic phenotype. Citation Format: Alex Chenchik, Paul Diehl, Mikhail Makhanov. Combining cell barcoding and CRISPR sgRNA libraries with targeted gene expression for single-cell genetic analysis of tumor metastasis [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 3426.
Abstract 16901: Exome Sequencing and Haplotype Sharing Analyses Result in the Identification of Novel Genetic Causes of Cardiomyopathies
Authors: Rowida Almomani, J Zhang, Paul A van der Zwaag, Anna PÓsafalvi, Karin Y Van Spaendonck-Zwarts, Maarten P van den Berg, Dirkjan J van Veldhuisen, Birgit Sikkema-Raddatz, Richard J Sinke, Peter van Tintelen, J Wang, Jan D Jongbloed
Journal: Circulation (2012)

Introduction Inherited cardiomyopathies are genetically heterogeneous diseases that can be caused by mutations in many different genes. To identify novel genetic causes of cardiomyopathy, exome seq...
Abstract LB-103: Defining oncogenic SWI/SNF complex mediated immune reprogramming in squamous cell carcinoma
Authors: SrinivasVinod Saladi, Robert Morris, Kenneth Ross, mihriban Karaayvaz, Purushothama Rao Tata, hongmei mou, Jayaraj Rajagopal, Michael Lawrence, Leif Ellisen
Journal: Cancer Research (2019)

Abstract Squamous cell carcinoma (SCC) remains among the most treatment-refractory of human cancers, reflecting in part a limited understanding of the key pathways and mechanisms that drive this disease. The p53-related transcription factor p63 is a central tumor maintenance factor subject to overexpression and/or genomic amplification in a high fraction of SCCs. Loss-of-function mutations in SWI/SNF chromatin remodeling subunit genes are observed in many cancers, but an oncogenic role for SWI/SNF is not well established. We reveal that ACTL6A, encoding a SWI/SNF subunit linked to stem and progenitor cell function, is frequently co-amplified and highly expressed together with p63 in head and neck, and lung squamous cell carcinoma (HNSCC &amp; LUSC). ACTL6A and p63 physically interact and cooperatively control a transcriptional program that promotes proliferation and suppresses differentiation, in part through activation of the Hippo-YAP pathway via regulators including WWC1. Consequently, loss of ACTL6A or p63 in tumor cells induces YAP phosphorylation and inactivation, associated with growth arrest and terminal differentiation, all phenocopied by WWC1 overexpression. In vivo, ectopic ACTLC6A/p63 expression promotes tumorigenesis, while ACTL6A expression and YAP activation are highly correlated in primary HNSCC and predict poor patient survival. More recently, we show the major cell-autonomous pathway repressed by ACTL6A is the interferon response in vitro, while we find ACTL6A amplification in HNSCC is associated with immunologically “cold” tumors despite a high mutation burden in vivo. Collectively, these findings reveal that ACTL6A orchestrates a tumor cell-intrinsic mechanism of immune evasion and define ACTL6A as a potent driver of human SCC.These findings establish a fundamental mechanism for ACTL6A and p63 to alter epigenetic states, and uncover a critical oncogenic function for SWI/SNF, which has been largely viewed as a tumor suppressor in human cancer. Furthermore, by revealing the Hippo-YAP pathway as a major target of ACTL6A/p63 linked to tumor behavior, this work suggests potential therapeutic approaches for refractory HNSCC cases. Citation Format: SrinivasVinod Saladi, Robert Morris, Kenneth Ross, mihriban Karaayvaz, Purushothama Rao Tata, hongmei mou, Jayaraj Rajagopal, Michael Lawrence, Leif Ellisen. Defining oncogenic SWI/SNF complex mediated immune reprogramming in squamous cell carcinoma [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 LB-103.
Abstract 867: EGFR kinase domain duplication (EGFR-KDD) is activated by asymmetric intra-molecular dimerization
Authors: Zhenfang Du, Jean-Nicolas Gallant, Monica Red-Brewer, Benjamin Brown, Jonathan Sheehan, Jens Meiler, Christine M. Lovly
Journal: Cancer Research (2019)

Abstract Recently, we identified a novel oncogenic EGFR exon 18 - 25 Kinase Domain Duplication (EGFR-KDD) in patients with lung cancer (PMID: 26286086). This novel EGFR alteration contains two tandem, in-frame EGFR TKDs. Computational modeling suggested that the linker between the two TKDs may support the formation of an asymmetric intra-molecular dimer. In this study, we sought to provide experimental support for the model that EGFR-KDD could form ligand-independent asymmetric intra-molecular dimers. We constructed point mutations (Table 1) disrupting the potential intra- (C1, N2) and inter-molecular dimer interfaces (N1 and C2) between each TKD of EGFR-KDD. We also introduced catalytically inactivating mutation into each TKD individually (Dead1 and Dead2). We stably expressed these mutants in YAMC and NR6, two cell lines lacking endogenous wild-type EGFR expression. In the absence of ligand, ‘wild-type’ EGFR-KDD was phosphorylated on known EGFR auto-phosphorylation sites, Y992, Y1068, and Y1173. However, mutations of the intra-molecular dimer interface (C1, N2) abrogated EGFR-KDD auto-phosphorylation, which is an accepted surrogate for EGFR enzymatic activity. In support of these data, expression of EGFR-KDD, but not the intra-molecular dimer interface mutants (C1, N2), supported growth in soft agar, an assay utilized in support of oncogenic phenotypes. Interestingly, phosphorylation of the dimer interface mutants (C1, N2) was rescued by ligand stimulation, suggesting the formation of EGFR-KDD multimers. Our structural modeling by Rosetta suggests that EGFR-KDD can form high order multimers with itself or with wild-type EGFR, and we observed co-precipitation of EGFR-KDD with itself and wild-type EGFR in vitro. Collectively, our findings define a previously unrecognized model of asymmetric intra-molecular dimers for EGFR, which provides important insights for the understanding of EGFR activation mechanisms and shed light on the exploration of therapeutic benefit. Table 1:Kinase domain mutations constructed for these studiesLobeMutationFunctionsN1I706QDisruption of the 1st N-lobe interfaceDead1D837NKinase dead mutation of the 1st kinase domainC1V948RDisruption of the 1st C-lobe interfaceN2I1057QDisruption of the 2nd N-lobe interfaceDead2D1188NKinase dead mutation of the 2nd kinase domainC2V1299RDisruption of the 2nd C-lobe interface Citation Format: Zhenfang Du, Jean-Nicolas Gallant, Monica Red-Brewer, Benjamin Brown, Jonathan Sheehan, Jens Meiler, Christine M. Lovly. EGFR kinase domain duplication (EGFR-KDD) is activated by asymmetric intra-molecular dimerization [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 867.
Abstract 3962: Chemotherapy induces alteration of programmed death ligand-1 expression in gastric cancer
Authors: Kohei Yamashita, Masaaki Iwatsuki, Shiro Iwagami, Kojiro Eto, Yuki Koga, Yuki Kiyozumi, Yoshifumi Baba, Naoya Yoshida, Hideo Baba
Journal: Cancer Research (2019)

Abstract Background Cancer immunotherapy targeting the programmed cell death 1 (PD-1) / programmed death ligand 1 (PD-L1) pathway have been demonstrated favorable therapeutic effect in gastric cancer (GC). However, it remains unclear that PD-L1 expression in GC tissue can be a biomarker to predict the therapeutic effect of immune checkpoint inhibitors. We hypothesize that prior therapy, including chemotherapy and radiation therapy can lead to the alteration of PD-L1 status, resulting in imprecise evaluation of PD-L1 expression. The aim of this study is to clarify the effect of cytotoxic agents on PD-L1 expression in GC cells in time and dose depending manner. Methods PD-L1 expression of GC cell lines were confirmed by quantitative PCR and western blotting. Two gastric cancer cell lines, which have low PD-L1 expression, are selected and used in subsequent in vitro experiment. We evaluated the expression of PD-L1 in these cell lines by quantitative PCR and western blotting after exposure to cytotoxic agents at various concentrations and exposure times. Furthermore, we examined whether the expression of PD-L1 induced by cytotoxic agents was maintained after ceasing the 5-FU exposure. The gene pathway regulating PD-L1 induction was also examined. Results The PD-L1 expression of the selected GC cell lines were upregulated, depending on the concentration and exposure time of cytotoxic agents. Furthermore, the PD-L1 expression induced by cytotoxic agents was maintained even after cessation of exposure. We clarify that the upregulation of PD-L1 expression was induced via p38 MAPK activation. Conclusion We demonstrated that cytotoxic agent can alter the expression of PD-L1 in GC cells through the activation of p38 MAPK pathway in dose and time depending manner. Our findings suggested that the modified administration of immune checkpoint inhibitors can improve the antitumor response, leading to promising new treatment strategy against GC. Citation Format: Kohei Yamashita, Masaaki Iwatsuki, Shiro Iwagami, Kojiro Eto, Yuki Koga, Yuki Kiyozumi, Yoshifumi Baba, Naoya Yoshida, Hideo Baba. Chemotherapy induces alteration of programmed death ligand-1 expression in gastric cancer [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 3962.
Abstract 13930: Culprit Lesion in Patients With ST-elevation Myocardial Infarction is Severely Narrowed With Large Plaque Burden: A Combined Intravascular Ultrasound and Optical Coherence Tomography Study
Authors: Takumi Higuma, Tsunenari Soeda, Masahiro Yamada, Hiroaki Yokoyama, Kei Izumiyama, Fumie Nishizaki, Jay Lee, Yoshiyasu Minami, Daniel S. Ong, Hang Lee, Ken Okumura, Ik-Kyung Jang
Journal: Circulation (2015)

Background: There have been controversies on the degree of stenosis of the culprit lesion in patients with ST-elevation myocardial infarction (STEMI). In the past it was thought the culprit lesion for STEMI had only mild to moderate stenosis. However, recent studies suggested that in fact the degree of the luminal narrowing might be severe at the culprit site. Aim: The aim of the current study was to investigate the severity and the detailed morphologic characteristics of the culprit lesion in patients with STEMI using intravascular ultrasound (IVUS) and optical coherence tomography (OCT). Methods and Results: A total of 111 STEMI patients (67.8±11.2 years, 89 male) who underwent percutaneous coronary intervention within 12 hours from symptom onset were included. TIMI flow grade 2 or 3 was achieved in 108 (97%) patients after thrombectomy. Both OCT and IVUS were performed. Minimum lumen cross-sectional area (MLA) and plaque burden (PB) were 3.14±1.45 mm 2 and 83.0±7.24% by IVUS. Patients were divided into 2 groups on the basis of MLA by IVUS: Group A (MLA &lt;4 mm 2 , n=104) and Group B (MLA &gt;4 mm 2 , n=7). Group A had a higher incidence of PB &gt;70% compared to Group B (99.0% vs 28.6%, p&lt;0.001). OCT revealed that lipid plaque, microchannel and macrophage were more frequent in Group A than in Group B. The incidence of plaque rupture tended to be higher in Group A than in Group B (Figure). Conclusions: Among STEMI patients, more than 90% of culprit lesions have a small MLA (&lt;4.0 mm 2 ) with large plaque burden. Severely narrowed culprit lesion had more features of vulnerability.
Vaccination for the Prevention of Group B <i>Streptococcus</i> Infection in Nonpregnant Adults—Reply
Authors: Miriam Baron Barshak
Journal: JAMA Internal Medicine (2019)

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Abstract 14126: Novel KCNQ1 Missense Mutation Associated with Juvenile-Onset Atrial Fibrillation
Authors: Kanae Hasegawa, Seiko Ohno, Hideki Itoh, Tetuhisa Hattori, Takeru Makiyama, Futoshi Toyoda, Wei-Guang Ding, Masaomi Chinushi, Hiroshi Matsuura, Minoru Horie
Journal: Circulation (2012)

Introduction; Atrial fibrillation (AF) is the most common cardiac arrhythmia occurring in the general population. Recently, several gene mutations associated with ion channels were reported to caus...
Increasing childhood vaccination coverage of the refugee and migrant population in Greece through the European programme PHILOS, April 2017 to April 2018
Authors: Kassiani Mellou, Chrysovalantis Silvestros, Eirini Saranti-Papasaranti, Athanasios Koustenis, Ioanna D. Pavlopoulou, Theano Georgakopoulou, Chryssoula Botsi, Agapios Terzidis
Journal: Eurosurveillance (2019)

After the 2016 Balkan route border closures, vaccination of refugee children in Greece was mainly performed by non-governmental organisations. Activities varied between camps, resulting in heterogeneity of vaccination coverage (VC). In April 2017, the European programme ‘PHILOS - Emergency health response to refugee crisis’ took over vaccination coordination. Interventions were planned for the first time for refugee children in the community and unaccompanied minors at safe zones. From April 2017–April 2018, 57,615 vaccinations were performed against measles-mumps-rubella (MMR) (21,031), diphtheria-tetanus-pertussis (7,341), poliomyelitis (7,652), pneumococcal disease (5,938), Haemophilus influenzae type b (7,179) and hepatitis B (8,474). In April 2018, the vaccination status of children at camps (reception and identification centres and community facilities such as hostels/hotels were excluded) was recorded and VC for each disease, stratified by dose, nationality and camp size, was calculated. More than 80% of the children received the first MMR dose, with VC dropping to 45% for the second dose. For all other vaccines, VC was &lt; 50% for the first dose in children aged 0–4 years and &lt; 25% for the second dose. Despite challenges, PHILOS improved planning and monitoring of vaccination activities; however, further efforts towards improving VC in refugee children are needed.
Abstract 868: Epigenomic profiling of primary hepatocellular carcinoma reveals super-enhancer-associated chromatin regulator network
Authors: Liangliang XU, Feng WU, Otto K.W. CHEUNG, Lemuel L.M. SZETO, Myth T.S. MOK, Kevin Y.L. Yip, Ka F. To, Alfred S.L. CHENG
Journal: Cancer Research (2019)

Abstract Hepatocellular carcinoma (HCC) is the second most common cause of cancer mortality worldwide. Parallel with the growing epidemics of obesity and diabetes, non-alcoholic fatty liver disease (NAFLD) has become the predominant cause leading to HCC in a dysregulated metabolic background. Recent HCC genomics studies present only a paucity of recurrent gene mutations, which lead to a sparkling interest in the epigenetic regulation of hepatic carcinogenesis. Chromatin modifications convert the metabolic insults from NAFLD to transcriptional program that contributes to HCC development. Super-enhancers (SEs) are subclass of regulatory elements with unusually strong enrichment for the binding of transcriptional coactivators to fulfill cell identity. Currently, it has been proposed that dysregulation of SEs underlies the development of diseases including cancers, but the role of SEs in NAFLD-associated HCC is still unknown. In order to investigate the alterations of histone modifications in NAFLD-associated HCC development, nanoscale chromatin immunoprecipitation sequencing of multiple histone marks were performed. By integrating multiple epigenomic profiles from primary NAFLD-associated HCCs and matched non-tumor tissues, we identified recurrent SEs enriched that contribute to fatty liver, lipid metabolism and metabolic syndrome. Interestingly, we observed significant enrichment of recurrent active SEs in a number of target genes. Notably, through CRISPR/Cas9-induced knockout liver cell lines, we showed that deletion of two distinct SE regions significantly reduced the expression of a candidate target gene and attenuated the tumorigenic potential of HCC cells. In summary, our results show that the dysregulation of SEs contributes to human hepatic carcinogenesis, thus representing novel therapeutic targets for NAFLD-associated HCCs. Citation Format: Liangliang XU, Feng WU, Otto K.W. CHEUNG, Lemuel L.M. SZETO, Myth T.S. MOK, Kevin Y.L. Yip, Ka F. To, Alfred S.L. CHENG. Epigenomic profiling of primary hepatocellular carcinoma reveals super-enhancer-associated chromatin regulator network [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 868.