tbuckley/cabot-search huggingface dataset:
Increased Synthesis of MCL-1 Protein Underlies Initial Survival of <i>EGFR</i>-Mutant Lung Cancer to EGFR Inhibitors and Provides a Novel Drug Target
Authors: Kyung-A Song, Yasuyuki Hosono, Crystal Turner, Sheeba Jacob, Timothy L. Lochmann, Yoshiko Murakami, Neha U. Patel, Jungoh Ham, Bin Hu, Krista M. Powell, Colin M. Coon, Brad E. Windle, Yuko Oya, Jennifer E. Koblinski, Hisashi Harada, Joel D. Leverson, Andrew J. Souers, Aaron N. Hata, Sosipatros Boikos, Yasushi Yatabe, Hiromichi Ebi, Anthony C. Faber
Journal: Clinical Cancer Research (2018)

Purpose: EGFR inhibitors (EGFRi) are effective against EGFR-mutant lung cancers. The efficacy of these drugs, however, is mitigated by the outgrowth of resistant cells, most often driven by a secondary acquired mutation in EGFR, T790M We recently demonstrated that T790M can arise de novo during treatment; it follows that one potential therapeutic strategy to thwart resistance would be identifying and eliminating these cells [referred to as drug-tolerant cells (DTC)] prior to acquiring secondary mutations like T790MExperimental Design: We have developed DTCs to EGFRi in EGFR-mutant lung cancer cell lines. Subsequent analyses of DTCs included RNA-seq, high-content microscopy, and protein translational assays. Based on these results, we tested the ability of MCL-1 BH3 mimetics to combine with EGFR inhibitors to eliminate DTCs and shrink EGFR-mutant lung cancer tumors in vivoResults: We demonstrate surviving EGFR-mutant lung cancer cells upregulate the antiapoptotic protein MCL-1 in response to short-term EGFRi treatment. Mechanistically, DTCs undergo a protein biosynthesis enrichment resulting in increased mTORC1-mediated mRNA translation of MCL-1, revealing a novel mechanism in which lung cancer cells adapt to short-term pressures of apoptosis-inducing kinase inhibitors. Moreover, MCL-1 is a key molecule governing the emergence of early EGFR-mutant DTCs to EGFRi, and we demonstrate it can be effectively cotargeted with clinically emerging MCL-1 inhibitors both in vitro and in vivoConclusions: Altogether, these data reveal that this novel therapeutic combination may delay the acquisition of secondary mutations, therefore prolonging therapy efficacy. Clin Cancer Res; 24(22); 5658-72. ©2018 AACR.
Abstract 19142: Short Telomeres Induce p53 and Autophagy to Regulate Cardiac Progenitor Cell Fate
Authors: Collin Matsumoto, Jacqueline Emathinger, Minyoung Shin, Aimee Levinson, Pearl Quijada, Nathalie Nguyen, Mark A Sussman, Nirmala Hariharan
Journal: Circulation (2017)

Aging severely limits myocardial regeneration. Delineating the impact of age-associated factors such as short telomeres is critical to enhance the regenerative potential of cardiac progenitor cells...
Epigenetic prediction of response to anti-PD-1 treatment in non-small-cell lung cancer: a multicentre, retrospective analysis
Authors: Michäel Duruisseaux, Anna Martínez-Cardús, Maria E Calleja-Cervantes, Sebastian Moran, Manuel Castro de Moura, Veronica Davalos, David Piñeyro, Montse Sanchez-Cespedes, Nicolas Girard, Marie Brevet, Etienne Giroux-Leprieur, Coraline Dumenil, Monica Pradotto, Paolo Bironzo, Enrica Capelletto, Silvia Novello, Alexis Cortot, Marie-Christine Copin, Niki Karachaliou, Maria Gonzalez-Cao, Sergio Peralta, Luis M Montuenga, Ignacio Gil-Bazo, Iosune Baraibar, Maria D Lozano, Mar Varela, Jose C Ruffinelli, Ramon Palmero, Ernest Nadal, Teresa Moran, Lidia Perez, Immaculada Ramos, Qingyang Xiao, Agustin F Fernandez, Mario F Fraga, Marta Gut, Ivo Gut, Cristina Teixidó, Noelia Vilariño, Aleix Prat, Noemi Reguart, Amparo Benito, Pilar Garrido, Isabel Barragan, Jean-François Emile, Rafael Rosell, Elisabeth Brambilla, Manel Esteller
Journal: The Lancet Respiratory Medicine (2018)
Abstract 1141: A novel regulatory gene subnetwork of glioma stem-like cells
Authors: Changwang Deng, Son B. Le, David D. Tran
Journal: Cancer Research (2018)

Abstract Glioblastoma (GBM) is the most common and deadliest malignant brain tumor in adults. GBM is enriched in glioma stem-like cells (GSCs) that contribute to tumor initiation and treatment resistance and thus a natural focus for therapeutic development. However, targeting GSCs has been a challenge because of a lack of master regulators specific to GSCs and not to normal brain cells. Therefore, systematic identification of the GSC-specific common regulatory program will improve our understanding of GSCs and provide an opportunity to develop GSC-specific therapeutics that are efficacious and safe. To accomplish these objectives, we have recently developed two innovative tandem computational platforms, GeneRep and nSCORE, which were subsequently experimentally validated. The tandem platforms complement each other and allow us to 1) interrogate large-scale gene expression profiles of GSCs, GBM-differentiated cells, normal neuronal precursor cells (NPCs) and astrocytes (NAs) to extract candidate GSC-specific gene regulatory networks; and 2) functionally rank GSC-specific core master regulators, respectively. A cluster of 8 interrelated master subnetworks emerged, which were functionally grouped into the stemness and cancer pathways, some of which belonged to the Sox, Olig and Myc families. By enforcing the expression of this cluster in NAs, we were able to reprogram these normal cells into GSCs as measured by the neurosphere formation and in vivo tumorigenesis assays, confirming the critical requirement of this cluster for the GSC identity. Furthermore, this network cluster was present and functioned cooperatively to maintain GSCs in several patient-derived GSC lines examined to date. Survival and neurosphere formation rates of GSCs were profoundly suppressed when at least two nodes in this cluster were depleted by siRNA compared to depletion of the individual nodes. Our data establish a novel gene regulatory cluster controlling GSCs and provide a compelling rationale for its therapeutic targeting to reduce tumor recurrence. Citation Format: Changwang Deng, Son B. Le, David D. Tran. A novel regulatory gene subnetwork of glioma stem-like cells [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 1141.
Abstract 19109: Low PCSK9 and LDL Cholesterol and Risk of Dementia, Parkinson’s Disease, and Epilepsy - A Mendelian Randomization Study
Authors: Marianne Benn, Børge G Nordestgaard, Ruth Frikke-Schmidt, Anne Tybjærg-Hansen
Journal: Circulation (2015)

Introduction: Low levels of low-density-lipoprotein cholesterol(LDL-C) due to statin use has been associated with reduced cognitive function. We aimed to assess whether low LDL-C due to genetic variation in the 3-hydroxy-3-methylglutaryl-CoA reductase(HMGCR; rs17238484) and proprotein convertase subtilisin kexin 9(PCSK9; rs11591147, rs148195424, rs562556, rs505151) genes, involved in LDL-C biosynthesis and metabolism, respectively, is associated with risk of Alzheimer’s dementia, vascular dementia, all dementia, Parkinson’s disease, and epilepsy in a general population off and on lipid lowering medication. Methods: We examined associations of plasma LDL-C with observational risk of disease; genetic variants with plasma LDL-C levels; and genetic variants and risk of disease as an indication of causality using a Mendelian randomization design in 92,068 participants off and 11,519 participants on lipid lowering medication from the Copenhagen General Population Study and the Copenhagen City Heart Study. Results: In observational analysis, risk of epilepsy was 98%(95% confidence interval: 32%-297%) higher in participants with an LDL-C &lt;1.5mmol/L versus ≥3.0mmol/L. Low LDL-C was not associated with risk of Alzheimer’s dementia, vascular dementia, all dementia, and Parkinson’s disease. In causal genetic analyses, PCSK9 and HMGCR variants associated with 7.8% and 2.9% lower LDL-C. Genotypes were not associated with risk of Alzheimer’s dementia, vascular dementia, all dementia, Parkinson’s disease, or epilepsy. Conclusions: Using 103,587 individuals from the general population, we found that observationally low LDL-C level was associated with increased risk of epilepsy. Low LDL-C due to PCSK9 and HMGCR variants was not associated with Alzheimer’s dementia, vascular dementia, all dementia, Parkinson’s disease or epilepsy, and results does not support a causal role of low LDL-C in these diseases.
Colorectal Cancer Screening
Authors: Randall W. Burt, James S. Barthel, Kelli Bullard Dunn, Donald S. David, Ernesto Drelichman, James M. Ford, Francis M. Giardiello, Stephen B. Gruber, Amy L. Halverson, Stanley R. Hamilton, Mohammad K. Ismail, Kory Jasperson, Audrey J. Lazenby, Patrick M. Lynch, Edward W. Martin, Robert J. Mayer, Reid M. Ness, Dawn Provenzale, M. Sambasiva Rao, Moshe Shike, Gideon Steinbach, Jonathan P. Terdiman, David Weinberg
Journal: Journal of the National Comprehensive Cancer Network (2010)
Abstract 2296: STAR-SEQR: Accurate fusion detection and support for fusion neoantigen applications
Authors: Jeff Jasper, Jason G. Powers, Victor J. Weigman
Journal: Cancer Research (2018)

Abstract Genomic structural variation and associated RNA fusions are a common clinical feature known to be involved in the initiation and pathogenesis of cancer. This complex class of variants also has significant implications on therapeutic decisions and has emerging roles in evidence-based clinical applications. Consequently, fusion detection is an emerging aspect of precision medicine that enables clinical utility of fusions as a therapeutically-relevant target which includes small molecules, biologics, and neoantigen-directed approaches.Here we present STAR-SEQR, an algorithm that uses multiple levels of evidence to detect and quantify fusions from RNA-Seq data. STAR-SEQR is a fast and accurate tool that goes beyond fusion detection and also provides rich annotation and useful reporting features to aid in the adoption of fusions in clinical diagnostics. Notably the software produces fusion expression values, PCR primers, fusion RNA sequence, and predicted peptide sequence to facilitate downstream applications.To address the analytical performance of STAR-SEQR to existing tools, we utilized previously characterized synthetic datasets and real-world sample data with matching DNA sequencing. Of note, in a dataset of 50 synthetic fusions, STAR-SEQR had the highest accuracy of all tools tested and called 49/50 events with no false positives. STAR-SEQR has also been run on several large clinical datasets and the fusion events identified have displayed strong overlap with identified DNA structural variants. STAR-SEQR also performed well in the ongoing ICGC-TCGA DREAM SMC-RNA Challenge and achieved the highest F1 score in the simulated data round with an overall average of 0.96. Analytical lab testing has also been performed using the Seracare Fusion RNA Mix V2 sample containing 15 clinically significant fusions with known concentrations in the low range of detectability. STAR-SEQR accurately called 13/15 events with the other events having no identifiable read alignments. We have also benchmarked methods comparing FFPE material, range of read lengths, and library methods where STAR-SEQR demonstrated excellent tradeoff between sensitivity and precision and generally outperformed other tools.In summary, STAR-SEQR has excellent analytical performance that surpasses existing fusion detection tools. It is broadly applicable to RNA-Seq methods, computationally efficient, and robust across sample characteristics. Lastly, STAR-SEQR is explicitly designed to enable fusion-directed clinical diagnostics and support cancer immunotherapy approaches that utilize fusion neoantigens. Citation Format: Jeff Jasper, Jason G. Powers, Victor J. Weigman. STAR-SEQR: Accurate fusion detection and support for fusion neoantigen applications [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 2296.
Suppression of Phosphoinositide 3-Kinase Prevents Cardiac Aging in Mice
Authors: YasutakaInuzuka, JunjiOkuda, TsuneakiKawashima, TakaoKato, ShinichiroNiizuma, YodoTamaki, YoshitakaIwanaga, YukiYoshida, RieKosugi, KayoWatanabe-Maeda, YojiMachida, ShingoTsuji, HiroyukiAburatani, TohruIzumi, ToruKita, TetsuoShioi
Journal: Circulation (2009)

Background— Heart failure is a typical age-associated disease. Although age-related changes of heart are likely to predispose aged people to heart failure, little is known about the molecular mechanism of cardiac aging. Methods and Results— We analyzed age-associated changes in murine heart and the manner in which suppression of the p110α isoform of phosphoinositide 3-kinase activity modified cardiac aging. Cardiac function declined in old mice associated with the expression of senescence markers. Accumulation of ubiquitinated protein and lipofuscin, as well as comprehensive gene expression profiling, indicated that dysregulation of protein quality control was a characteristic of cardiac aging. Inhibition of phosphoinositide 3-kinase preserved cardiac function and attenuated expression of the senescence markers associated with enhanced autophagy. Suppression of target of rapamycin, a downstream effector of phosphoinositide 3-kinase, also prevented lipofuscin accumulation in the heart. Conclusions— Suppres...
Immunotherapy targeting toll-like receptor 2 alleviates neurodegeneration in models of synucleinopathy by modulating α-synuclein transmission and neuroinflammation
Authors: Changyoun Kim, Brian Spencer, Edward Rockenstein, Hodaka Yamakado, Michael Mante, Anthony Adame, Jerel Adam Fields, Deborah Masliah, Michiyo Iba, He-Jin Lee, Robert A. Rissman, Seung-Jae Lee, Eliezer Masliah
Journal: Molecular Neurodegeneration (2018)

Synucleinopathies of the aging population are an heterogeneous group of neurological disorders that includes Parkinson's disease (PD) and dementia with Lewy bodies (DLB) and are characterized by the progressive accumulation of α-synuclein in neuronal and glial cells. Toll-like receptor 2 (TLR2), a pattern recognition immune receptor, has been implicated in the pathogenesis of synucleinopathies because TLR2 is elevated in the brains of patients with PD and TLR2 is a mediator of the neurotoxic and pro-inflammatory effects of extracellular α-synuclein aggregates. Therefore, blocking TLR2 might alleviate α-synuclein pathological and functional effects. For this purpose, herein, we targeted TLR2 using a functional inhibitory antibody (anti-TLR2). Two different human α-synuclein overexpressing transgenic mice were used in this study. α-synuclein low expresser mouse (α-syn-tg, under the PDGFβ promoter, D line) was stereotaxically injected with TLR2 overexpressing lentivirus to demonstrate that increment of TLR2 expression triggers neurotoxicity and neuroinflammation. α-synuclein high expresser mouse (α-Syn-tg; under mThy1 promoter, Line 61) was administrated with anti-TLR2 to examine that functional inhibition of TLR2 ameliorates neuropathology and behavioral defect in the synucleinopathy animal model. In vitro α-synuclein transmission live cell monitoring system was used to evaluate the role of TLR2 in α-synuclein cell-to-cell transmission. We demonstrated that administration of anti-TLR2 alleviated α-synuclein accumulation in neuronal and astroglial cells, neuroinflammation, neurodegeneration, and behavioral deficits in an α-synuclein tg mouse model of PD/DLB. Moreover, in vitro studies with neuronal and astroglial cells showed that the neuroprotective effects of anti-TLR2 antibody were mediated by blocking the neuron-to-neuron and neuron-to-astrocyte α-synuclein transmission which otherwise promotes NFκB dependent pro-inflammatory responses. This study proposes TLR2 immunotherapy as a novel therapeutic strategy for synucleinopathies of the aging population.
Expression of Proto-oncogenes and Gene Mutation of Sarcomeric Proteins in Patients With Hypertrophic Cardiomyopathy
Authors: HisashiKai, AkihikoMuraishi, YujiSugiu, HirohumiNishi, YukihikoSeki, FumitakaKuwahara, AkinoriKimura, HirohisaKato, TsutomuImaizumi
Journal: Circulation Research (1998)

Abstract—Several mutations of cardiac β-myosin heavy chain (β-MHC) gene were reported in patients with hypertrophic cardiomyopathy (HCM). Involvement of proto-oncogenes has been shown in the mechanism of experimental cardiac hypertrophy. This study sought to examine the effects of c-H-ras and c-myc expression in the steady-state myocardium on hypertrophic changes and to evaluate the possible interaction between β-MHC mutation and proto-oncogene expression in HCM. Endomyocardial biopsy was performed in 17 HCM patients (5 β-MHC mutations and 1 troponin T mutation) and 7 control subjects (no mutation). Reverse transcription–polymerase chain reaction analysis revealed c-H-ras expression in all members of both groups. Cardiomyocyte size was correlated with the expression level of c-H-ras (P<0.001), and c-H-ras expression was upregulated in HCM patients (P<0.01). HCM patients with a β-MHC mutation had the higher c-H-ras expression than did control subjects or patients without a mutation (P<0.01). c-myc mRNA was...
Abstract 19256: Predicting Exercise Systolic Blood Pressure and Heart Rate at 20 Years of Follow-up: Correlates in the Framingham Heart Study
Authors: Nicole L Spartano, Asya Lyass, Martin G Larson, Gregory D Lewis, Ramachandran S Vasan
Journal: Circulation (2015)

Introduction: Blood pressure (BP) and heart rate (HR) responses to exercise may add prognostic information beyond their resting values. Many cardiovascular disease (CVD) risk factors are associated with exercise BP and HR cross-sectionally, but factors influencing exercise hemodynamics over the life-course are unknown. Methods: We assessed BP and HR in response to treadmill tests (6 minutes of the Bruce protocol) in a sample of 1231 Framingham Offspring participants who performed the treadmill test during two routine examinations: 1979-1983 (baseline) and 1998-2001 (follow-up). We included participants (55% women, mean age 39±8 years at baseline, 58±8 years at follow up) free of CVD and not taking beta-blockers or anti-hypertension medications at either exam. Baseline diabetes mellitus (DM) cases and individuals taking lipid-lowering medications at baseline were excluded due to small numbers. We related exercise hemodynamics at follow-up to baseline CVD risk factors and their interim changes, also adjusting for baseline exercise hemodynamics. Results: Compared with men, women experienced greater change in exercise hemodynamics at 20 y follow-up, relative to baseline exercise hemodynamics (see Table 1). Baseline blood lipid levels, resting SBP and HR, and smoking status were associated with greater exercise SBP at follow-up. Baseline BMI did not independently influence follow-up exercise hemodynamics, but weight gain across exams (the effect of 1 kg/m2 increase in BMI) was associated with higher exercise SBP and higher exercise HR. New-onset DM was associated with ~6 mm Hg higher exercise SBP, independent of weight gain, compared to those who remained free of DM across exams. Conclusions: CVD risk factors and their worsening over time were associated with higher exercise SBP and HR on follow-up. Our findings suggest that maintaining an optimal risk factor profile over the lifecourse will favorably impact exercise hemodynamic responsesover time.
Abstract 1706: Inhibition of fibulin-3 reverses macrophage polarization in glioblastoma and increases anti-tumor inflammatory responses
Authors: Sharon L. Longo, Prajna Behera, Mariano S. Viapiano, Mohan Sobhana Nandhu
Journal: Cancer Research (2018)

Abstract Glioblastomas (GBMs) are the most common primary tumors of the Central Nervous System and one of the most aggressive and difficult to treat forms of cancer. Our laboratory was the first to identify the extracellular protein fibulin-3 (EFEMP1) in GBMs and demonstrate the pro-tumoral functions of this protein in solid tumors. We have recently developed a function-blocking antibody ("mAb428.2") against fibulin-3, which inhibits the enhancing effect of this protein on ADAM17 activity and NFkB signaling (Nandhu et al., Clin Cancer Res, 2017). Using mAb428.2 we observed a significant anti-tumor effect and prolongation of survival in nude mice carrying patient-derived GBM xenografts implanted subQ or intracranially (antibody treatment: 8x 30 mg/kg, q24h, IV). Interestingly, reduction of tumor growth during mAb428.2 treatment was accompanied with significant tumor necrosis and increased infiltration of Iba1-positive tumor-associated macrophages (TAMs) both in subQ and orthotopic tumors. Remarkably, TAMs in mAb428.2-treated GBMs showed very low co-expression of Arginase-I, a bona-fide marker of M2 ("tumor promoting") TAM polarization. Further analysis of mouse-specific gene expression in the tumor mass and in recovered macrophages (CD11b-positive cells) showed that TAMs in mAb428.2-treated GBMs had significantly increased expression of inflammatory cytokines (IFN-gamma, IL-1b, IL-10) and downregulation of M2 markers (CD163, CD206, ARG1), suggesting that our anti-fibulin-3 treatment prevented the expected M2 polarization of TAMs. Accordingly, mAb428.2-treated tumors showed drastically decreased expression of CSF-1a, an M2-inducing cytokine that may be regulated by fibulin-3. Co-culture experiments of PMA-activated U937 macrophages with GBM stem-like cells did not affect tumor cell viability when a control IgG1 was added to the cultures. However, addition of mAb428.2 caused significant decrease of GBM cell viability, suggesting that anti-fibulin-3 treatment enables TAMs to attack tumor cells. Taken together, our results strongly suggest that anti-fibulin-3 and possibly other anti-ECM approaches may induce a marked inflammatory reaction driven by innate immune cells, potentiating anti-tumor therapy. Citation Format: Sharon L. Longo, Prajna Behera, Mariano S. Viapiano, Mohan Sobhana Nandhu. Inhibition of fibulin-3 reverses macrophage polarization in glioblastoma and increases anti-tumor inflammatory responses [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 1706.
Power of a Trial Investigating a Low-Intensity PSA-Based Screening Intervention
Authors: Paul F. Pinsky
Journal: JAMA (2018)

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