tbuckley/cabot-search huggingface dataset:
Abstract 14799: In-vitro Contractile and Echocardiographic Right Ventricular Function in Patients with Tricuspid Regurgitation
Authors: Ravi R Desai, Thomas Marwick, Christine Moravec, Eugene Blackstone, Gosta Pettersson
Journal: Circulation (2012)

Objective:  Right ventricular (RV) dysfunction is often cited as a reason not to intervene in patients with tricuspid regurgitation (TR). We compared quantitative echocardiographic measures of preoperative RV function, and  in vitro  function of RV muscle harvested during cardiac surgery between mild and severe TR patients.    Methods:  43 cardiac surgical patients (19 with TR grade 3+/4+ and 24 with grade 0/1+/2+) underwent trabecular harvest from RV free wall through a right atriotomy during valve repair or replacement. Preoperative echocardiographic RV measurements-- tricuspid anular plane systolic excursion (TAPSE), myocardial performance index (MPI), speckle-derived global longitudinal systolic strain (Strain) and strain rate (SR)--were correlated with isometric contraction of 2 muscle trabeculae, 1-2 mm thick 8-10 mm long. At length of maximal tension development, we measured resting tension, developed tension, and developed tension after isoproterenol administration.    Results:  Correlations were found among echocardiographic measures of RV function: TAPSE with Strain (r= -0.65) (left Fig.), MPI with Strain (r= 0.48), TAPSE with SR (r= -0.47). No strong correlations were seen between isometric contractile variables and these echocardiographic measures. No significant differences in in-vitro muscle contractile function were seen between 0/1+/2+ and 3+/4+ TR patients (right Fig.).    Conclusions:  TAPSE, MPI and deformation parameters are correlated with each other but not with contractile function of RV muscle  in vitro . The preservation of trabecular function in patients with 3+/4+ TR suggests recovery may be possible with normalization of loading conditions. Impairment of noninvasive systolic parameters in TR does not signify irreversible RV dysfunction.
Estimating Improved Partitioning Schemes for Ultraconserved Elements
Authors: Victor A Tagliacollo, Robert Lanfear
Journal: Molecular Biology and Evolution (2018)

Ultraconserved (UCEs) are popular markers for phylogenomic studies. They are relatively simple to collect from distantly-related organisms, and contain sufficient information to infer relationships at almost all taxonomic levels. Most studies of UCEs use partitioning to account for variation in rates and patterns of molecular evolution among sites, for example by estimating an independent model of molecular evolution for each UCE. However, rates and patterns of molecular evolution vary substantially within as well as between UCEs, suggesting that there may be opportunities to improve how UCEs are partitioned for phylogenetic inference. We propose and evaluate new partitioning methods for phylogenomic studies of UCEs: Sliding-Window Site Characteristics (SWSC), and UCE Site Position (UCESP). The first method uses site characteristics such as entropy, multinomial likelihood, and GC content to generate partitions that account for heterogeneity in rates and patterns of molecular evolution within each UCE. The second method groups together nucleotides that are found in similar physical locations within the UCEs. We examined the new methods with seven published data sets from a variety of taxa. We demonstrate the UCESP method generates partitions that are worse than other strategies used to partition UCE data sets (e.g., one partition per UCE). The SWSC method, particularly when based on site entropies, generates partitions that account for within-UCE heterogeneity and leads to large increases in the model fit. All of the methods, code, and data used in this study, are available from https://github.com/Tagliacollo/PartitionUCE. Simplified code for implementing the best method, the SWSC-EN, is available from https://github.com/Tagliacollo/PFinderUCE-SWSC-EN.
52PD EGFR clonality and tumor mutation burden (TMB) analysis based on circulating tumor DNA (ctDNA) sequencing in advanced non-small cell lung cancer (NSCLC)
Authors: X. Ai, Y. Lin, A. Liu, C. Xie, X. Hu, Q. Zhao, Y. Zang, C. Rao, X. Yi, S. Lu
Journal: Journal of Thoracic Oncology (2018)
Abstract 20184: Cardiac MRI Feature Tracking in Duchenne Muscular Dystrophy Patients More Frequently Demonstrates Decreased Myocardial Strain Associated With Late Gadolinium Enhancement Positive Segments Compared to Echocardiographic Speckle Tracking
Authors: Bryan Siegel, Laura Olivieri, Heather Gordish-Dressman, Christopher Spurney
Journal: Circulation (2016)

Introduction:  Duchenne muscular dystrophy (DMD) is an inherited X-linked disorder with an incidence of 1 in 3,500 male births and cardiomyopathy is becoming the leading cause of death. While Cardiac MRI (CMR) and late gadolinium enhancement (LGE) are important tools in recognizing myocardial involvement, myocardial strain imaging may demonstrate early changes and allow patients to avoid gadolinium contrast.   Methods:  We performed CMR feature tracking (FT) and echo based speckle tracking (ST) strain measures on DMD patients and age/sex matched controls who had received a CMR with contrast and transthoracic echocardiogram. Data was collected for longitudinal strain/strain rate in the apical 4 chamber view and circumferential strain/strain rate in the mid-papillary parasternal short axis. Segmental wall analysis was performed and compared with the presence of LGE. Data was analyzed using student’s t-test and one-way ANOVA adjusting for multiple comparisons.   Results:  We measured 22 subjects with DMD (mean age 14; EF 57%) and 9 controls (mean age 14; EF 59%). In 12 of 22 subjects with DMD LGE was positive only in the lateral segments in short axis. Average circumferential strain (CS) measured by FT was significantly decreased in DMD compared to controls (-18.6±6 vs. -25.1±3; p   Conclusions:  CMR FT derived myocardial strain was better than ST in demonstrating differences between subjects with DMD and controls. FT was also able to demonstrate differences in LGE positive and negative segments within patients with DMD. FT may be able to predict LGE positive segments in DMD without the use of gadolinium contrast.
First-line Systemic Therapy for Metastatic Renal Cell Carcinoma: A Systematic Review and Network Meta-analysis
Authors: Christopher J.D. Wallis, Zachary Klaassen, Bimal Bhindi, Xiang Y. Ye, Thenappan Chandrasekar, Ann M. Farrell, Hanan Goldberg, Stephen A. Boorjian, Bradley Leibovich, Girish S. Kulkarni, Prakesh S. Shah, Georg A. Bjarnason, Daniel Y.C. Heng, Raj Satkunasivam, Antonio Finelli
Journal: European Urology (2018)
Genetic risk for Alzheimer’s disease is concentrated in specific macrophage and microglial transcriptional networks
Authors: Katherine E. Tansey, Darren Cameron, Matthew J. Hill
Journal: Genome Medicine (2018)

Genome-wide association studies of Alzheimer's disease (AD) have identified a number of significant risk loci, the majority of which lie in non-coding regions of the genome. The lack of causal alleles and considerable polygenicity remains a significant barrier to translation into mechanistic understanding. This includes identifying causal variants and the cell/tissue types in which they operate. A fuller understanding of the cell types and transcriptional networks involved in AD genetic risk mechanisms will provide important insights into pathogenesis. We assessed the significance of the overlap between genome-wide significant AD risk variants and sites of open chromatin from data sets representing diverse tissue types. We then focussed on macrophages and microglia to investigate the role of open chromatin sites containing motifs for specific transcription factors. Partitioned heritability using LDscore regression was used to investigate the contribution of specific macrophage and microglia transcription factor motif-containing open chromatin sites to the heritability of AD. AD risk single nucleotide polymorphisms (SNPs) are preferentially located at sites of open chromatin in immune cells, particularly monocytes (z score = 4.43; corrected P = 5.88 × 10− 3). Similar enrichments are observed for macrophages (z score = 4.10; corrected P < 2.40 × 10− 3) and microglia (z score = 4.34, corrected P = 0.011). In both macrophages and microglia, AD risk variants are enriched at a subset of open chromatin sites that contain DNA binding motifs for specific transcription factors, e.g. SPI1 and MEF2. Genetic variation at many of these motif-containing sites also mediate a substantial proportion of AD heritability, with SPI1-containing sites capturing the majority of the common variant SNP-chip heritability (microglia enrichment = 16.28, corrected enrichment P = 0.0044). AD risk alleles plausibly operate in immune cells, including microglia, and are concentrated in specific transcriptional networks. Combined with primary genetic association results, the SPI1 and MEF2 transcriptional networks appear central to AD risk mechanisms. Investigation of transcription factors targeting AD risk SNP associated regulatory elements could provide powerful insights into the molecular processes affected by AD polygenic risk. More broadly, our findings support a model of polygenic disease risk that arises from variants located in specific transcriptional networks.
Clonality of T-cell repertoire in the tumor microenvironment (TME) and peripheral blood of metastatic melanoma patients treated with CTLA4 blockade and interferon-α (IFN).
Authors: Ahmad A. Tarhini, Aya Agha, Zahra Rahman, Sharon Benzeno, Erik Yusko, Priyanka Vallabhaneni
Journal: Journal of Clinical Oncology (2017)

9 Background: Patients with metastatic melanoma were treated with tremelimumab and IFN in a previously reported study (Tarhini. J Clin Oncol. 2012). Clonality of T-cell repertoire was analyzed in terms of clinical response both in TME and in peripheral blood. Methods: Patients received tremelimumab 15 mg/kg I.V. every 12 weeks. High dose IFN (HDI) was administered concurrently. Responses were assessed by RECIST as complete (CR) or partial (PR), stable disease (SD) or progression (PD). T-cell receptor beta chain (TCRB) repertoire was immunosequenced in peripheral blood mononuclear cells (PBMC) (N=33 patients) and tumor (N=18) utilizing Adaptive Biotechnologies immunoSEQ platform to determine repertoire clonality and T-cell fractions at pre-treatment (tumor, PBMC), one month (PBMC), and 3 months (PBMC). The clonality metric quantitates, the extent of mono- or oligo-clonal expansion by measuring the shape of the clone frequency distribution. Values range from 0 to 1; values approaching 1 indicate a nearly monoclonal population. Results: In pretreatment TME, T-cell clonality was significantly (p = 0.0008) different and greater in patients who achieved disease control (CR, PR, SD) versus those with PD. Further, there was a significant (p = 0.044) difference between the increased TCR fraction in TME in responders (CR, PR) and non-responders (SD, PD). There was a trend towards association between pretreatment TME T-cell clonality and overall survival (OS) (p = 0.24) and progression free survival (PFS) (p = 0.18) not reaching significance. Within the circulation (PBMC), no significant associations were found by examining the pretreatment samples. However, early on-treatment (day 29) there was significant association and decrease in T-cell clonality and OS (p = 0.005) and PFS (p = 0.003). Conclusions: T-cell clonality in the TME pretreatment is a promising biomarker of immunotherapeutic benefit in our study. While baseline PBMC clonality was not associated with clinical benefit, early on-treatment (day 29) was significantly associated. These findings require validation in an independent cohort and exploration in relation to other immunotherapeutics. Clinical trial information: NCT00610857.
The impact of PD-L1 on survival and value of the immune check point inhibitors in non-small-cell lung cancer; proposal, policies and perspective
Authors: Helmy M. Guirgis
Journal: Journal for ImmunoTherapy of Cancer (2018)

Background: The impact of programmed death receptor-ligand1 (PD-L1) on costs and value of the immune check point inhibitors (ICPI) has received minimal attention.Objectives: 1-Design a sliding scale to grade survival in 2nd-line non-small-cell lung cancer (NSCLC).2-Compare costs and value of Nivolumab (Nivo), Atezolizumab (Atezo) and Pembrolizumab (Pembro) vs. Docetaxel (Doc).Methods: Previously reported median overall survival (OS) and prices posted by parent company were utilized.The OS gains over controls in days were graded (gr) from A+ to D. Docetaxel costs were calculated for 6-12 cycles and the ICPI for 1 year.Adverse events treatment costs (AEsTC) were reported separately.The cost/life-year gain (C/LYG) was computed as drug yearly-cost/OS gain over control in days × 360 days.The relative value of the ICPI were expressed as $100,000/C/LYG.Results: Costs of Doc 6 cycles were $23,868, OS/gr 87/C, AEs gr ¾ > 20%, AEsTC $1978 and 6-12 cycle C/LYG $98,764 -$197,528.Nivo, Atezo and Pembro gr ¾ were < 20% at average costs of $1480.In non-squamous NSCLC, Nivo demonstrated OS/g 84/C and C/LYG $558,326 as compared with 264/A and $177,645 in PD-L1 > 10%.Atezolizumab OS/g were 87/B and C/LYG $551,407 improving in enriched PD-L1 to 162/A and $332,020 respectively.Pembrolizumab in PD-L1 > 1.0% demonstrated OS/g 57/C and C/LYG $659,059 improving in > 50% PD-L1 to 201/A and $186,897.PD-L1 enrichment increased RV of Nivo from 0.18 to 0.56, Atezo from 0.16 to 0.66 and Pembro from 0.15 to 0. 53.Conclusions: Simplified methodology to grade OS and weigh value of anticancer drugs was proposed.In 2nd-line non-squamous NSCLC, value of Doc, Nivo, Atezo and Pembro regardless of PDL-1 expression were limited and modest.Enrichment of PD-L1 resulted in unprecedented OS, improved grades and enhanced value at seemingly justifiable costs.
114P Evaluation of pulmonary function parameters after moderate hypofractionated image-guided thoracic irradiation in locally advanced node-positive non-small cell lung cancer patients with very limited lung function
Authors: F. Manapov, O. Roengvoraphoj, J. Taugner, M. Dantes, C. Wijaya, C. Belka, C. Eze
Journal: Journal of Thoracic Oncology (2018)
35PD Magnitude of exposure to biomass fuel smoke and risk of lung cancer in women: Cases and controls study
Authors: R. Baez-Saldana, U. Rumbo-Nava, A. Canseco-Raymundo, P. Castillo-Gonzalez, S. Leon-Duenas, R. Rivera-Rosales, C. Luna-Rivero
Journal: Journal of Thoracic Oncology (2018)
Abstract #191: Characterization of putative lymphoma-initiating (cancer stem) cells in canine lymphoma
Authors: Daisuke Ito, Timothy O'Brien, Jaime Modiano
Journal: Cancer Research (2009)

The cancer stem cell theory postulates that tumors arise from, are maintained by, and metastasize from a rare cell population that has stem cell features, including self-renewal and multipotential for differentiation. Recently, evidence supporting the existence of cancer stem cells has been demonstrated in many types of cancers. However, a lymphoma-initiating (stem) cell (Ly-IC) has not been conclusively identified. The objective of this study was to investigate naturally occurring canine lymphoma for the presence of cancer stem cells. Canine lymphoma has strong similarities in both basic and clinical aspects to human lymphoma. In addition, lymphoma is more common in dogs than in people, and the disease progression follows a more rapid course. This provides exceptional opportunities to obtain case materials and follow outcomes in a relatively short period of time. We used flow cytometry to examine expression of hematopoietic progenitor antigens, CD34, c-Kit, and CD133, as well as the common leukocyte antigen CD45, on single cell suspensions isolated from canine lymphoma biopsies. Our data suggest there is an inverse correlation between the percentage of putative Ly-IC in a tumor and the length of disease-free survival. Furthermore, we consistently found a rare population of CD34+ and/or c-Kit+ cells in canine diffuse large B cell lymphoma (DLBCL) that also resided within the B-cell phenotypic group (CD21+ or CD22+) comprising the malignant population. Two populations of CD34+ cells with either intermediate expression of CD45 (CD45-int) or high expression of CD45 (CD45-high) were detected. Light scatter properties of CD34+CD45-int cells were similar to small-lymphocytes, whereas CD34+CD45-high cells were larger and more similar to the cells that made up the bulk of tumor. The expression and distribution of CD34, c-Kit and CD45 were variable, suggesting that, in addition to the bulk of the large tumor cell population (>97% of all cells) DLBCL includes Ly-IC at different stages of maturation or differentiation. These results suggest there is a population of cells in canine lymphoma that exhibit stem cell-like phenotypes, and which may represent the putative Ly-IC that is responsible for maintenance, progression and recurrence of tumors. This project establishes a useful large animal (canine) model to test the cancer stem cell theory in lymphoma, which will enable us to carry out effective translational lymphoma studies. Supported by grants R01 CA112211 and P30 CA77598 from the NCI, grant #615 from the AKC Canine Health Foundation, and by the Comparative Oncology Research Fund from the University of Minnesota College of Veterinary Medicine and the Minnesota Medical Foundation.  Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 191.
2O MET activation in lung cancer up-regulates PD-L1 expression independently of JAK-STAT pathway, promoting an immunosuppressive phenotype
Authors: M. Saigí, J.J. Alburquerque-Béjar, A. Mc Leer-Florin, C. Pereira, E. Pros, O.A. Romero, N. Baixeras, E. Nadal, E. Brambilla, M. Sánchez-Céspedes
Journal: Journal of Thoracic Oncology (2018)
Somatic mutation burden in cancer samples determined by targeted next generation sequencing.
Authors: Dinesh Cyanam, Adam Broomer, David Mandelman, Ruchi Chaudhary, Paul D Williams, Goutam Nistala, Rajesh Gottimukkala, Kate Rhodes, John Bishop, Fiona Hyland, Seth Sadis
Journal: Journal of Clinical Oncology (2017)

15 Background: High somatic mutation burden in tumor tissues is associated with the presentation of neoantigens that promote immune responses particularly in the context of immune checkpoint therapies. Herein, we characterize the ability of targeted cancer research panels to generate estimates of somatic mutation burden. Methods: Somatic mutation data from &gt; 8000 cancer samples obtained from The Cancer Genome Atlas (TCGA) was curated and standardized, and the number of single nucleotide variants (SNVs) in exonic regions of each sample determined. Next, the number of SNVs associated with target regions of two Ion AmpliSeq cancer panels (Oncomine Comprehensive Assay [OCA, 146 genes, 0.35 MB]; Comprehensive Cancer Panel [CCP, 409 genes, 1.7 MB]) was likewise determined and the frequency of mutation counts in the exome and the panel target regions was compared. Mutation counts of samples containing truncating mutations in mismatch repair (MMR) and other DNA repair genes were characterized. A facile workflow with less than 60 minutes of hands-on time was developed to estimate mutation counts for a batch of 8 samples using the Ion Chef for automated library preparation and templating followed by sequencing on the Ion S5. Results: The sensitivity of targeted panels in estimating somatic mutation burden was positively correlated with panel size. The area under the Receiver Operating Characteristic (ROC) curve showed that CCP had &gt; 90% sensitivity and &gt; 95% specificity to differentiate high and low mutation burden based on informatics analysis of TCGA data. As expected, truncating mutations in MMR genes were associated with higher somatic mutation counts in colorectal tumor tissue. Using data generated from OCA and CCP, we characterized a set of filters that provided a good estimate of somatic mutation counts when applied to a tumor-only workflow. Conclusions: A simple workflow was developed on the Ion Torrent sequencing platform to estimate somatic mutation burden in cancer samples. The methods described herein will help advance research in immuo-oncology.
Effects of 3D culturing conditions on the transcriptomic profile of stem-cell-derived neurons
Authors: Halil Tekin, Sean Simmons, Beryl Cummings, Linyi Gao, Xian Adiconis, Cynthia C. Hession, Ayan Ghoshal, Danielle Dionne, Sourav R. Choudhury, Volkan Yesilyurt, Neville E. Sanjana, Xi Shi, Congyi Lu, Matthias Heidenreich, Jen Q. Pan, Joshua Z. Levin, Feng Zhang
Journal: Nature Biomedical Engineering (2018)
Utility of glycated hemoglobin screening in patients undergoing elective coronary artery surgery: Prospective, cohort study from the E-CABG registry
Authors: Francesco Nicolini, Giuseppe Santarpino, Giuseppe Gatti, Daniel Reichart, Francesco Onorati, Giuseppe Faggian, Magnus Dalén, Sorosh Khodabandeh, Theodor Fischlein, Daniele Maselli, Saverio Nardella, Antonino S Rubino, Marisa De Feo, Antonio Salsano, Riccardo Gherli, Giovanni Mariscalco, Eeva-Maija Kinnunen, Vito G Ruggieri, Karl Bounader, Matteo Saccocci, Sidney Chocron, Juhani Airaksinen, Andrea Perrotti, Fausto Biancari
Journal: International Journal of Surgery (2018)
Physician Prescribing of Opioids to Patients at Increased Risk of Overdose From Benzodiazepine Use in the United States
Authors: Joseph A. Ladapo, Marc R. Larochelle, Alexander Chen, Melissa M. Villalon, Stefanie Vassar, David Y. C. Huang, John N. Mafi
Journal: JAMA Psychiatry (2018)

<h3>Importance</h3> Recent increases in US opioid-related deaths underscore the need to understand drivers of fatal overdose. The initial prescription of opioids represents a critical juncture because it increases the risk of future opioid use disorder and is preventable. <h3>Objective</h3> To examine new opioid prescribing patterns in US patients at increased risk of overdose from benzodiazepine use. <h3>Design, Setting, and Participants</h3> This study used publicly available data from the National Ambulatory Medical Care Survey and National Hospital Ambulatory Medical Care Survey from January 1, 2005, through December 31, 2015, to identify adults 20 years or older receiving new opioid prescriptions and concurrently using a benzodiazepine. <h3>Main Outcomes and Measures</h3> Population-based rates of new opioid prescriptions stratified by use of benzodiazepines. <h3>Results</h3> This study analyzed 13 146 visits, representing 214 million visits nationally, with a new opioid prescription. Rates of new opioid prescriptions among adults using a benzodiazepine increased from 189 to 351 per 1000 persons between 2005 and 2010 (rate difference, 162; 95% CI, 29-295;<i>P</i> = .02) and decreased to 172 per 1000 persons by 2015 (rate difference, −179; 95% CI, −310 to −48;<i>P</i> = .008). New opioid prescriptions in the general population not using benzodiazepines increased nonsignificantly from 78 to 93 per 1000 US persons between 2005 and 2010 (rate difference, 15; 95% CI, −3 to 33;<i>P</i> = .10) and decreased nonsignificantly to 79 per 1000 persons by 2015 (rate difference, −14; 95% CI, −38 to 11;<i>P</i> = .28). The likelihood of receiving a new opioid prescription during an ambulatory visit remained higher for patients concurrently using benzodiazepines compared with the general population after adjusting for demographic characteristics, comorbidities, and diagnoses associated with pain (adjusted relative risk, 1.83; 95% CI, 1.56-2.15;<i>P</i> &lt; .001). Naloxone was coprescribed in less than 1% of visits when a patient concurrently used a benzodiazepine. <h3>Conclusions and Relevance</h3> In 2010, new opioid prescriptions for US adults stopped increasing and began to decrease among higher-risk patients who used benzodiazepines. These patterns suggest that the recent increase in opioid-related deaths may be associated with factors other than physicians writing new opioid prescriptions. Nevertheless, prescribing among higher-risk patients still occurred at rates higher than rates in the general population, representing an important opportunity to improve quality of care for patients experiencing pain.