tbuckley/cabot-search huggingface dataset:
We Can Learn From the Past, but We Must Pave the Future of Congenital Heart Disease Research—Reply
Authors: Clayton A. Smith, Matt Oster, Lazaros Kochilas
Journal: JAMA Cardiology (2019)

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Antigen Receptor Function in the Context of the Nanoscale Organization of the B Cell Membrane
Authors: Michael R. Gold, Michael G. Reth
Journal: Annual Review of Immunology (2019)

The B cell antigen receptor (BCR) plays a central role in the self/nonself selection of B lymphocytes and in their activation by cognate antigen during the clonal selection process. It was long thought that most cell surface receptors, including the BCR, were freely diffusing and randomly distributed. Since the advent of superresolution techniques, it has become clear that the plasma membrane is compartmentalized and highly organized at the nanometer scale. Hence, a complete understanding of the precise conformation and activation mechanism of the BCR must take into account the organization of the B cell plasma membrane. We review here the recent literature on the nanoscale organization of the lymphocyte membrane and discuss how this new information influences our view of the conformational changes that the BCR undergoes during activation.
Is Progression of Pulmonary Fibrosis due to Ventilation-induced Lung Injury?
Authors: Richard K. Albert, Bradford Smith, Carrie E. Perlman, David A. Schwartz
Journal: American Journal of Respiratory and Critical Care Medicine (2019)

If VILI contributes to pulmonary fibrosis, then cyclical and/or permanent alveolar collapse must be part of the pathology.Burkhardt and Cottier (2) date the first discussion of alveolar collapse in pulmonary fibrosis to a German textbook of pathology published in 1922 in which Kaufmann (3), under the heading "Collapse Induration," noted that "if collapse of alveoli persists for some time, expansion may no longer be possible.The denuded alveolar walls stick together and coalesce.The alveoli are obliterated.In the interstitial tissue proliferation of fibrous tissue ensues resulting in cicatricial induration."Burkhardt (4) and Burkhardt and Cottier (2) also cited multiple papers in the German literature dating to the 1950s that described collapse induration as an important mechanism in the development of pulmonary fibrosis.Heppleston's 1956 publication (5) seems to have been the first to suggest that
Abstract 18427: Dysregulation of the miR143/145 Cluster and Mir133a During Progression of Vein Graft Neointima Formation
Authors: Robert A McDonald, Katie M White, Keith E Robertson, Jia Hu, Ruifaug Lu, Sarah J George, Son Wan, Andrew H Baker
Journal: Circulation (2012)

Background: The late failure of autologus human saphenous vein bypass grafts due to neointimal formation carries a major clinical burden. Therefore, identifying novel strategies to prevent neointimal formation is desirable. The principal cell type responsible for the neointimal lesion are smooth muscle cells (SMC), which are activated in response to injury leading to accelerated rates of proliferation and migration. MicroRNAs (miRs) are small non-coding RNAs that play an important role in modulating vascular phenotypes through regulation of gene expression. Methods and results: We undertook a microarray profiling approach to identify miRs which may be modulated during the development of neointimal lesions in the setting of vein graft disease. Profiling experiments revealed several miRs (miR133a, miR143 and miR145) which have been previously implicated in SMC de-differentiation and activation. These results were validated by q-PCR which demonstrated that miR-133a and miR-143 were down-regulated 4-5 fold and miR-145 was down regulated between 7-11 fold in the human saphenous vein ex vivo culture model and the porcine interposition model of vein graft neoinitma formation (both models, n=6). Treatment of isolated SMC harvested from human saphenous veins with TGF-β 1 (10ng/ml), to induce differentiation to a more quiescent and contractile phenotype, up-regulated miR-145 by 2.2+0.2 fold (n=3) but miR-133a levels were unaffected . A wounding assay was utilised to determine whether miR levels were elevated during SMC migration. Following quiescence, SMC were subjected to multiple scratch wounds and placed in serum to induce migration for a period of 16 hours. Quantification of miR-145 levels in migrating SMC revealed a 5-fold reduction in miR-145 levels following induction of migration. Conclusion: These results suggest that the miR-143/145 cluster plays an important role in the dedifferentiation of SMCs during neointimal formation following vein grafting. We also demonstrate that TGF-β 1, an established modulator of SMC differentiation and proliferation, increased miR-143/145 levels suggesting that elevation of miR-143/145 in vein grafts may prevent SMC de-differentiation and elevated rates of SMC proliferation and migration.
Abstract 16865: Declining Population Blood Pressure During the Rise of Obesity: Is Blood Lead Implicated?
Authors: Justin P Zachariah, Yunfei Wang, Daniel J Penny, Thomas Baranowski
Journal: Circulation (2017)

Background: Population-based child and adult studies around the globe show decreasing blood pressure (BP) despite rising obesity. While these conflicting trends may be the effect of treating hypertensive persons, children offer a window into this conundrum because very few children are treated with BP medicine. Decomposing BP into pulse pressure (PP) and mean arterial pressure (MAP) allows for the localization of the BP trends into large versus small artery function, respectively. As our previous work has shown obesity and tobacco exposure do not account for the BP trends, we hypothesized that changes in lead exposure may have contributed to PP and MAP trends over this period. Methods and Results: We analyzed anthropometric, BP, and laboratory data on 8-17 year old children from the cross-sectional National Health and Nutrition Examination Surveys (NHANES) 1976 through 2008(N= 13,886). Using either PP or MAP as outcome of interest in separate models, stepwise multivariable adjusted survey regression was u...
THER-02. TARGETING DNA DAMAGE REPAIR IN MYC-DRIVEN PEDIATRIC BRAIN TUMORS
Authors: Sonja Krausert, Sander Lambo, Sebastian Brabetz, Norman Mack, Benjamin Schwalm, Stefan Pfister, Marcel Kool
Journal: Neuro-Oncology (2019)

Pediatric brain tumors frequently harbor MYC- or MYCN-amplification or show high overexpression and are associated with poor outcome. Examples for which current treatments are unsuccessful are for instance the medulloblastoma (MB) subgroups SHH (MYCN-amplified), Group 3 (MYC amplified) and embryonal tumors with multilayered rosettes (ETMR). Since MYC(N) is normally expressed in rapidly dividing cells but not in quiescent tissue stem cells, amplification or high expression in tumors leads to increased transcription, which can be in conflict with DNA replication and subsequently can cause replication stress and DNA damage. We hypothesized that high expression or amplification of MYC(N) in tumors makes them vulnerable to DNA damage response inhibitors (DDRi) and even more vulnerable to combinations of DDRi and chemotherapeutics. To test this hypothesis we performed in vitro drug experiments using different Group 3 MB cell lines and the BT183 ETMR cell line. We evaluated the IC50-values of the topoisomerase inhibitor Topotecan and the DDRi BGB-290, a PARP-inhibitor, in monotherapy. All cell lines were sensitive for Topotecan and showed IC50-values in the low nM-range but PARP-inhibitors were ineffective (for MB) or showed only slight effects (for ETMR cells). However, a significant decrease in IC50 can be observed when Topotecan and BGB-290 are used in combination. For in vivo treatments, we injected NSG mice with luciferase labelled ETMR cells, monitored tumor growth via IVIS and started the non-toxic single and combination treatments when a predefined threshold of tumor growth was reached. When effective in this ETMR in vivo model, we will repeat the experiments with additional ETMR and MB models. In vivo treatments are ongoing and results will be presented at the conference.
A new social sciences network for infectious threats
Authors: Tamara Giles-Vernick, Ruth Kutalek, David Napier, David Kaawa-Mafigiri, Michel Dückers, John Paget, Syed Masud Ahmed, Phaik Yeong Cheah, Alice Desclaux, Daniel De Vries, Anita Hardon, Hayley MacGregor, Christopher Pell, Sabina F Rashid, Roman Rodyna, Constance Schultsz, Khoudia Sow, Annie Wilkinson
Journal: The Lancet Infectious Diseases (2019)
Abstract 14271: Over 35 Years Trend in the Clinical and Pathological Characteristics of Cardiac Rupture in Patients With Acute Myocardial Infarction
Authors: Satoshi Honda, Yasuhide Asaumi, Takafumi Yamane, Toshiyuki Nagai, Tadayoshi Miyagi, Hiroki Sakamoto, Toshihisa Anzai, Kengo Kusano, Masaharu Ishihara, Hisao Ogawa, Satoshi Yasuda
Journal: Circulation (2013)

Background: Early reperfusion by thrombolysis or primary percutaneous coronary intervention has improved the survival following acute myocardial infarction (AMI), in which cardiac rupture (CR) incl...
PREDIMED authors respond to Agarwal and Ioannidis
Authors: Miguel A Martinez-Gonzalez
Journal: BMJ (2019)

Most of the issues mentioned by Agarwal and Ioannidis regarding our recent publication of the PREDIMED trial were covered in the paper, including the 99 page appendix, which is freely available at www.nejm.org/doi/suppl/10.1056/NEJMoa1800389/.1

We have also published corrections of minor aspects …
Abstract 16607: Shift Workers Have Higher Blood Pressure Medication Use, but Only When They Are Short Sleepers Who Prefer Mornings: A Uk Biobank Study
Authors: Marguerite Daus, Alicia Lozano, Barbara Riegel, Freda Patterson, Susan Malone, Alexandra Hanlon
Journal: Circulation (2018)

Shift workers have higher blood pressure medication use, but only when they are short sleepers who prefer mornings: A UK Biobank Study Introduction: Poor sleep quality is a risk factor for cardiovascular disease (CVD). Shift work influences sleep patterns and duration, but this study examines how shift work and sleep influence cardiovascular health. Methods: Baseline (BL) and 5-year follow-up (5YFU) data from the UK Biobank cohort study (N=11,259) were used to generate separate logistic regression models of shift workers and non-shift workers to examine the moderating effects of shift work on the relationship between sleep duration (short ≤6hrs; adequate 7-8hrs; long ≥9hrs) and chronotype (morning; evening) at BL with incident blood pressure (BP) medication (med) use from BL to 5YFU. All models were adjusted for family history of CVD, depression status, insomnia, narcolepsy, and alcohol intake. Results: The sample was predominately female (57.6%), White (97.8%), had not attended college (50.4%) and reported a mean age of 55.2 ± 7.4 years. Most were adequate sleepers (7-8hrs) (72.1%), morning chronotype (60.4%), and currently employed (66.5%) with 8.2% identifying as shift workers at BL. Only 7.7% reported incident BP med use from BL to 5YFU. Analysis demonstrated significant moderation for both sleep duration (p=0.02) and chronotype (p=0.04) in those working shifts. Among shift workers, short sleepers (≤6hrs) had a 2-fold increased odds of incident BP med use compared to adequate sleepers (OR=2.14, 95% CI=1.24-3.67, p=0.006); those with morning chronotype had a 78% increased odds of incident BP med use compared to evening chronotype (OR=1.78, 95% CI=1.03-3.12, p=0.04). Among non-shift workers, short versus adequate sleepers and those reporting morning versus evening chronotype had only a 3% increased (OR=1.03, 95% CI=0.85-1.25, p=0.76) and a 5% decreased (OR=0.95, 95% CI=0.81-1.13, p=0.60) odds of incident BP med use, respectively. Conclusions: The relationship between sleep duration and chronotype with incident BP med use was significant among shift workers and not in non-shift workers. Shift workers who are short sleepers or of morning time preference have increased incident blood pressure medication use.
Abstract A15: Modeling sporadic gastrointestinal stromal tumor with BRAFV600E mutation
Authors: Leili Ran, Devan Murphy, Jessica Sher, Zhen Cao, Shangqian Wang, Edward Walczak, Youxin Guan, Yuanyuan Xie, Shipra Shukla, Yu Zhan, Cristina R. Antonescu, Yu Chen, Ping Chi
Journal: Clinical Cancer Research (2018)

Abstract Gastrointestinal stromal tumor (GIST) is the most common subtype of sarcoma, characterized by activating mutations in KIT, PDGFRA, BRAF, N/H/KRAS, and loss of function genetic/epigenetic alterations in NF1, SDH-complex. Despite clinical advances for KIT/PDGFRA-mutant GIST, the scientific and clinical advances for KIT/PDGFRA-wild type GISTs have remained extremely limited due to the lack of model systems. Due to the lack of ICC-lineage specific cre system, modeling for sporadic GIST has not been feasible. ETV1 has recently been described as an ICC and GIST-lineage specific master regulator. Here, using the cre-activated Rosa26CAGGS-LSL-EYFP system, we demonstrate that Etv1CREERT2 preferentially activates cre in the Etv1-expressing ICC lineage by tamoxifen. Using the BrafCA conditional allele for cre-activated BrafV600E, we observed that BrafV600E alone, while leading to development of ICC hyperplasia, is not sufficient to drive GIST tumorigenesis. Combination of BrafV600E activation and Trp53 loss not only gives rise to ICC hyperplasia, but also leads to multifocal GIST-like tumors in mouse GI tract with 100% penetrance. We further demonstrate that the BrafV600E; Tp53-/- sporadic GIST mouse models are amenable for therapeutic intervention and recapitulate clinical responses to RAF inhibitors in human GIST. Our observations provide the first in vivo model for understanding the pathogenesis and therapeutic responses in BRAF-mutant GISTs. Importantly, these observations provide the proof of principle for modeling sporadic GIST in adult mice using the Etv1CREERT2 system and establish the feasibility and utility of establishing model systems for human GISTs that do not have any model systems available for mechanistic studies and therapeutic development. Citation Format: Leili Ran, Devan Murphy, Jessica Sher, Zhen Cao, Shangqian Wang, Edward Walczak, Youxin Guan, Yuanyuan Xie, Shipra Shukla, Yu Zhan, Cristina R. Antonescu, Yu Chen, Ping Chi. Modeling sporadic gastrointestinal stromal tumor with BRAFV600E mutation [abstract]. In: Proceedings of the AACR Conference on Advances in Sarcomas: From Basic Science to Clinical Translation; May 16-19, 2017; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(2_Suppl):Abstract nr A15.
HGG-02. EVOLUTION OF GENOMIC ARCHITECTURE IN PEDIATRIC GLIOBLASTOMA RELIES ON CANCER STEM CELL HIERARCHIES
Authors: Marco Gallo
Journal: Neuro-Oncology (2019)

Pediatric glioblastoma (pGBM) invariably recurs even following aggressive treatment. Because of the relative rarity of pGBM and the paucity of patient-derived models to study this malignancy, we investigated molecular principles underlying tumor growth ad recurrence using longitudinally collected surgical resections. The genetic architecture of each diagnostic and recurrent sample was assessed with whole-genome sequencing with linked read technology, which allowed the assembly of Mbp-range haplotype blocks and the resolution of maternal and paternal chromosomes. Our analyses show that each pGBM sample has a complex genetic architecture defined by coexisting subclones. At each recurrence, new subclones emerge and they become progressively more diverged from the subclones at diagnosis. The overall outcome of these clonal dynamics is that although the overall mutational burden remains constant at recurrence, only about 7% of deleterious single nucleotide variants are shared between longitudinal samples. Interestingly, we observed a significant enrichment of mutations in genes linked to hereditary disorders. To follow up on developmental origins of this class of mutations, we did whole genome sequencing of the germlines of both parents of two of our pGBM patients. Trio analysis revealed three routes by which potentially deleterious variants arise: (i) inheritance from a healthy parent; (ii) de novo germline events; (iii) somatic events. The identification of de novo germline events suggested that the mutagenic processes leading to overt tumorigenesis might start during early development in a snowball effect that culminates with somatic events. In order to better understand the processes that lead to the observed patterns of tumor evolution, we generated mathematical models of tumor growth using variant allele frequency information for each sample. Our results show that pGBM is organized according to a cancer stem cell model. Our data therefore highlight a high degree of genetic and cellular complexity that underlies tumor growth and evolution of pGBM.
DIPG-21. ELECTRICAL INTEGRATION OF GLIOMA INTO NEURAL CIRCUITRY
Authors: Humsa Venkatesh, Wade Morishita, Anna Geraghty, Dana Silverbush, Marlene Arzt, Lydia Tam, Anitha Ponnuswami, Shawn Gillespie, Amit Agarwal, Aviv Regev, Hannes Vogel, Dwight Bergles, Mario Suva, Robert Malenka, Michelle Monje
Journal: Neuro-Oncology (2019)

Pediatric high-grade gliomas (pHGGs) are a lethal group of cancers whose progression is robustly regulated by neuronal activity. Activity-regulated release of growth factors into the tumor microenvironment represents part of the mechanism by which neuronal activity influences pHGG growth, but this alone is insufficient to explain the magnitude of the effect that activity exerts on glioma progression. Here, we report that neuron-glioma interactions include bona fide synaptic communication. Single cell transcriptomic analyses of primary pediatric and adult glioma samples reveal unambiguous expression of synaptic genes by malignant glioma cells. Whole cell patch clamp recordings from xenografted, pediatric patient-derived glioma cells revealed the existence of AMPAR-mediated excitatory neurotransmission between pre-synaptic glutamatergic neurons and post-synaptic glioma cells. Millisecond timescale excitatory post-synaptic currents (EPSCs) that are depolarizing were observed in a subpopulation of pHGG cells and are associated with activity-induced glioma cell calcium transients. These excitatory axon-glioma synapses are reminiscent of the axon-glial synapses formed between neurons and oligodendrocyte precursor cells. A second electrophysiological response characterized by a prolonged (>1 sec) depolarization in response to neuronal activity was also observed. These longer duration currents are blocked by gap junction inhibitors, supporting the concept that gap junction-mediated tumor interconnections, such as observed with tumor microtubes, can function as an electrically coupled network. As neurotransmitter-mediated depolarization of normal neural precursor cells can profoundly affect precursor cell proliferation, differentiation and survival, we tested the hypothesis that depolarizing currents in pediatric glioma cells promote tumor growth. Using in vivooptogenetic techniques to depolarize xenografted pHGG cells expressing channelrhodopsin-2 (ChR2), we found that glioma depolarization robustly promoted proliferation, while expression of a dominant-negative AMPAR subunit (GluA2) that blocks neuron-glioma signaling inhibited pHGG xenograft growth and extended mouse survival. These findings suggest that integration of pediatric glioma into neural circuits promotes tumor progression.
Mogamulizumab Treatment Elicits Autoantibodies Attacking the Skin in Patients with Adult T-Cell Leukemia-Lymphoma
Authors: Yui Suzuki, Masato Saito, Toshihiko Ishii, Itaru Urakawa, Asuka Matsumoto, Ayako Masaki, Asahi Ito, Shigeru Kusumoto, Susumu Suzuki, Masanori Hiura, Takeshi Takahashi, Akimichi Morita, Hiroshi Inagaki, Shinsuke Iida, Takashi Ishida
Journal: Clinical Cancer Research (2019)

Abstract Purpose: The anti-CCR4 mAb, mogamulizumab, offers therapeutic benefit to patients with adult T-cell leukemia-lymphoma (ATL), but skin-related adverse events (AE) such as erythema multiforme occur frequently. The purpose of this study was to determine the mechanisms by which mogamulizumab causes skin-related AEs in patients with ATL. Experimental Design: We investigated whether autoantibodies were present in patients’ sera using flow cytometry to determine binding to keratinocytes and melanocytes (n = 17), and immunofluorescence analysis of tissue sections. We analyzed the IgM heavy chain repertoire in peripheral blood mononuclear cells before and after mogamulizumab or other chemotherapy by next-generation sequencing (NGS; n = 16). Results: Autoantibodies recognizing human keratinocytes or melanocytes were found in the sera of 6 of 8 patients suffering from mogamulizumab-induced erythema multiforme. In one patient, complement-dependent cytotoxicity (CDC) mediated by autoantibodies against keratinocytes or melanocytes was proportionally related to the severity of the erythema multiforme. The presence of autoantibodies in the epidermis was confirmed in all biopsy specimens of mogamulizumab-induced erythema multiforme (n = 12). Furthermore, colocalization of autoantibodies and C1q, suggesting the activation of CDC, was observed in 67% (8/12). In contrast, no autoantibody or C1q was found in ATL tumor skin lesions (n = 13). Consistent with these findings, NGS demonstrated that IgM germline genes had newly emerged and expanded, resulting in IgM repertoire skewing at the time of erythema multiforme. Conclusions: Mogamulizumab elicits autoantibodies playing an important role in skin-related AEs, possibly associated with regulatory T-cell depletion. This is the first report demonstrating the presence of skin-directed autoantibodies after mogamulizumab treatment.