tbuckley/cabot-search huggingface dataset:
Abstract 12177: Important Roles of Endothelial Caveolin-1/eNOS Complex in Maintaining Microvascular Homeostasis Through Endothelium-dependent Hyperpolarization Mediated Mechanism
Authors: Hiroki Saito, Saori Sato, Yousuke Ikumi, Shuhei Tanaka, Shigeo Godo, Hiroaki Shimokawa
Journal: Circulation (2015)

Background: The endothelium plays important roles in maintaining cardiovascular homeostasis by synthesizing and releasing several vasodilators, including prostacyclin (PGI2), nitric oxide (NO) and endothelium-dependent hyperpolarization (EDH) factor. It is widely accepted that EDH plays important roles especially in microcirculation. We have previously demonstrated that endothelial NO synthase (eNOS) plays diverse roles depending on vessel size, as a NO generating system in conduit arteries and an EDH-mediated system in resistance arteries. Recently, we also have reported that caveolin-1 is involved in enhanced EDH-mediated mechanisms in resistance arteries through functional inhibition of eNOS. However, the detailed functions of caveolin-1 in the endothelium remain to be elucidated. Material and Results: We newly generated endothelium-specific caveolin-1-knockout mice (eCav-1-KO) under the control of Tie2 promoter. We confirmed that caveolae is absent in endothelial cells of those mice. Co-immunoprecipitation experiments showed the eNOS/Cav-1 complex formation in control mice, but not in eCav-1-KO mice. Western blot experiments demonstrated that the extent of eNOS phosphorylation at Ser1177 (stimulatory site) was comparable, whereas that at Thr495 (inhibitory site) was significantly reduced in mesenteric arteries from eCav-1-KO mice as compared with control mice, demonstrating hyperactivation of eNOS. Isometric tension experiments and Langendorff experiments showed that NO-mediated responses were significantly enhanced, whereas EDH-mediated responses were significantly reduced in microcirculations in eCav-1-KO mice. Importantly, eCav-1-KO mice showed altered endothelial functions and cardiac hypertrophy despite normal blood pressure level. Furthermore, the hearts from eCav-1-KO mice showed enhanced staining for nitrotyrosine, a marker of nitrosative stress in microvessels and epicardial arteries, whereas those from control mice only showed mild staining in epicardial arteries alone. Conclusions: These results indicate that endothelial Cav-1/eNOS complex plays important roles in maintaining microvascular homeostasis through EDH-mediated mechanisms in mice in vivo.
Do subjects with mild or moderate atrophic gastritis or intestinal metaplasia confined to the antrum benefit from gastric cancer surveillance?
Authors: Duc Trong Quach, Toru Hiyama, Takuji Gotoda
Journal: Gut (2019)

We read with interest the paper by Rugge et al which reported that Operative Link on Gastritis Assessment (OLGA) staging reliably predicted the risk for development of gastric epithelial neoplasia.1 No neoplastic lesions were found in low-risk OLGA stages (ie, stages 0–II) where they developed exclusively in high-risk stages (ie, stages III–IV) when followed for 55 months. This study also showed that Helicobacter pylori eradication in subjects with high-risk OLGA stages did not abolish the risk for neoplastic progression. These results are quite convincing. However, two concerns would be raised.

First, whether endoscopy surveillance …
MEDU-16. MYC BUT NOT MYCN GENERATES AGGRESSIVE GROUP 3 MEDULLOBLASTOMA THROUGH ARF SUPPRESSION
Authors: Oliver Mainwaring, Holger Weishaupt, Sonja Hutter, Gabriela Rosen, Karl Annusver, Maria Kasper, Fredrik Swartling
Journal: Neuro-Oncology (2019)

Group 3 medulloblastoma (MB) carry the worst prognosis of all MB. The transcription factors MYC and MYCN are suggested drivers for a subset of these tumours; with MYC amplifications (17–20%) representing the most common genetic alteration in Group 3 tumours, while MYCN amplifications (4–6%) are less frequent. To improve current treatment options for these patients, it is of crucial importance to decipher differential features of MYCN- and MYC-driven MB and to establish accurate animal models for these patients. By driving MYC from the hindbrain-specific Glutamate transporter 1 (Glt1) promoter using a Tet-OFF system, we have established a novel murine model of MYC-driven MB (GMYC) which accurately recapitulates aggressive Group 3 MB. GMYC tumours develop without any p53 mutations and with ~70% penetrance. Tumour-prone GMYC mice can further be cured by MYC-depletion through dox treatment. Comparison of transcriptional profiles between GMYC and our MYCN-driven GTML tumours revealed that both models accurately represent Group 3 MB, while showing differential expression of key features of MYC- or MYCN-driven tumours. CDKN2A was identified as one of the top upregulated genes in our GTML model as compared to our GMYC model. CDKN2A encodes two tumour suppressors, p16INK4A and p14ARF, which are key regulators of cell cycle progression and activation of p53. Similar enhancement of CDKN2A is observed in MYCN-amplified as compared to MYC-amplified Group 3/4 patients. Tumour formation following partial or complete knockout of CDKN2A significantly increased tumour penetrance in GTML as compared to GMYC animals. Similarly, CDKN2A levels significantly correlate with poor prognosis in MYCN amplified MB patients, while CDKN2A levels are low in MYC amplified patients. This suggests that MYC is regulating and suppressing CDKN2A during MB formation and further advocates that pharmacological restoration of CDKN2A would be a potential future therapy for this group of high-risk MB patients.
Xeroderma pigmentosum in South Africa: Evidence for a prevalent founder effect
Authors: M. Kgokolo, F. Morice‐Picard, H. R. Rezvani, F. Austerlitz, F. Cartault, A. Sarasin, M. Sathekge, A. Taieb, C. Ged
Journal: British Journal of Dermatology (2019)
DIPG-11. ACTIVATION OF RAS SIGNALING AND DISTINCT MITOGEN-ACTIVATED PROTEIN KINASES (MAPKs) PROVIDES UNIQUE THERAPEUTIC VULNERABILITIES IN MUTANT HISTONE DIPG
Authors: Robert Koncar, Ann-Catherine Stanton, Brittany Dey, Nishant Agrawal, Michelle Wassell, Lauren McCarl, Abigail Locke, Lauren Sanders, Olena Morozova Vaske, Gary Kohanbash, James Felker, C David James, Rintaro Hashizume, Alberto Broniscer, Ian Pollack, Sameer Agnihotri
Journal: Neuro-Oncology (2019)

Diffuse intrinsic pontine gliomas (DIPGs) are incurable pediatric brain tumors with an aggressive onset. Apart from irradiation, there are currently no effective therapies available for DIPG patients, who have a median survival time of less than one year. DIPG cells possess a mutation in histone H3 (H3K27M) that results in a reduction of H3K27 trimethylation and activation of oncogenic signaling pathways. We show that the H3K27M mutation induces RAS pathway signaling which is augmented by additional RAS activators including PDGFRA. We observed that the H3K27M mutation leads to silencing of GTPase-activating proteins, namely RASAL1, which when ectopically expressed, reduced proliferation and RAS activation. An siRNA screen of RAS pathway effectors identified ERK5, but not ERK1/2, as important for DIPG growth. Suppression of ERK5, which is highly expressed in DIPG, decreased DIPG cell proliferation and induced apoptosis both in vitro and in vivo. Mechanistically, we show that ERK5 directly activates and stabilizes the proto-oncogene MYC. ERK5 overexpression fully rescued ERK5-depleted cells and partial rescue was achieved by expression of ERK5 mutants lacking kinase activity or the transactivation domain (ΔTAD). However, no rescue was achieved with kinase-dead, ΔTAD double mutants. Additionally, ERK5 knockdown or treatment with ERK5 inhibitors significantly increased survival of mice intracranially engrafted with DIPG cells. TG02, a pan-CDK and ERK5 inhibitor currently in phase II trials for various cancers, was the most effective treatment, extending median survival time nearly two-fold. Collectively, our data demonstrate DIPG reliance on RAS and MYC activities, and in so doing reveal novel therapeutic targets for treating these tumors.
HGG-10. HISTONE H3G34V MUTATION IS SUFFICIENT TO DRIVE DISTINCT GENOMIC H3K36 METHYLATION PATTERNS IN PEDIATRIC GLIOMA
Authors: Tina Huang, Andrea Piunti, Patrick Ozark, Elizabeth Bartom, Jin Qi, Rintaro Hashizume, Ali Shilatifard, Amanda Saratsis
Journal: Neuro-Oncology (2019)

BACKGROUND: Mutations in genes encoding Histone protein isoforms H3.3 (H3F3A and H3F3A) and H3.1 (HIST1H3B) are detected at high frequency in pediatric high-grade glioma (pHGG). Up to 50% of cortical pHGGs bear a point mutation in H3F3A, resulting in replacement of glycine 34 with arginine or valine (G34R/V). H3G34V mutation is known to impair SETD2 activity (H3K36-specific trimethyltransferase). Reduced K36me3 is observed on nucleosomes bearing H3G34V protein relative to wild-type, contributing to genomic instability and driving a distinct gene expression signature associated with tumorigenesis. However, it is not known if this differential H3K36me3 enrichment is due to H3G34V mutant protein alone. We therefore set to elucidate the effect of H3G34V mutant protein on genomic H3K36me3 enrichment in vitro. METHODS: A doxycycline-inducible short hairpin RNA (shRNA) against G34V mutant H3F3A was delivered via lentivirus to an established G34V mutant pediatric glioma cell line (KNS42). H3G34V mutation was introduced into H3.3 wild type normal human astrocytes (NHA). Mutation knockdown / knockin was confirmed by sequencing and western blot. H3.3WT, H3K36me3, and H3G34V ChIP-Seq was performed to determine relative genomic distribution in transfected and unperturbed KNS42 cells and NHAs, and also compared to a H3WT glioma cell line. RESULTS: shRNA-induced knockdown of H3G34V restored the pattern of genomic H3K36me3 enrichment to that observed in H3.3 wild-type glioma cells and NHAs. In turn, introducing H3G34V to NHAs was sufficient to drive the distinct K36 methylation profile seen in H3G34V glioma cells. H3G34V mutation was also associated with a global increase in overall H3.3WT genomic enrichment, representing a heightened state of active transcription relative to wild-types. CONCLUSIONS: Our study is the first to demonstrate H3G34V mutation is sufficient to induce differential H3K36me3 enrichment patterns associated with genomic instability and increased transcription. Gene expression analysis is currently underway to further evaluate these effects on transcription regulation.
MEDU-23. IMPROVING IMMUNOTHERAPEUTIC POTENTIAL IN GROUP 3 MEDULLOBLASTOMA USING LOW DOSE RADIATION FOLLOWED BY 4-1BB MONOCLONAL ANTIBODY ADMINISTRATION
Authors: Mohammed Alshareef, Ramin Eskandari, Daniel McDonald, Kenneth Vanek, Joseph Jenrette, Sunil Patel, Samuel Cheshier, David Cachia, Arabinda Das
Journal: Neuro-Oncology (2019)

INTRODUCTION: Group 3 Medulloblastoma (MB) subtype has the worst prognosis amongst the MB subtypes. Despite aggressive treatments, survival of patients with Group 3 MB remains below 50% over 5 years. A limitation of therapeutic success is cancer cellular mechanisms suppressing immune responses, enabling escape of detection. We previously identified tumor-associated micoglias (TAMs) as important in T-cell-excluded tumor phenotype. The goal of our study was to reprogram intratumoral TAMs to allow T-cell infiltration into Group 3 MB tumor, improving efficacy of immunotherapy. We examine the immunobiologic rationale for treating with low-dose radiation treatment (LDRT) followed by 4-1BB monoclonal antibody (mAB) treatment. METHODS: Brain tissue was obtained from patients with Group 3 MB at MUSC and Group 3 MB cell line MP1 and were implanted over the occipital bone in C57BL/J mice. We examine treatment with 1 Gy LDRT followed by 4-1BB-targeting mAB and evaluate conversion of M2 microglia into the M1 phenotype, enhancement of MB cell death in ex vivo human and mice. We evaluate post-treatment tumoral size, cell death, and survival in mice. RESULTS: TAMs were activated with LDRT followed by 4-1BB antibody and converted from M2-like to M1-like microglia. Total number of tumor infiltrate leukocytes (TILs) following treatment was significantly increased. In vivo mice models reacted similarly, with increased tumoral cell death in response to LDRT and 4-1BB mAb. There was reduction of tumor size by 60% and increased survival when compared to untreated controls. We also determined that cell death occurred within malignant tumor cells but not healthy neuronal cells following LDRT plus 4-1BB mAb treatment. CONCLUSIONS: We propose a novel treatment using LDRT followed by 4-1BB antibody to increase TAMs activation, conversion of T-cells and result in significant increase in intra-tumoral cell death, reduction in in vivo tumor size and increased overall survival in a mouse model.
GENE-19. DEEP PROTEOMIC SURVEY ACROSS SEVEN CHILDHOOD BRAIN TUMORS
Authors: Pei Wang, Nicole Tignor, Steven Gygi, Richard Ivey, Amanda Paulovich, Alexey Nescizhskii, Sanjukta Guha Thakurta, Jeffery Whiteaker, Jacob Kennedy, Uliana Voytovich, Li Ding, Liang Bo Wang, Pichai Raman, Yuankun Zhu, Tara Hiltke, Adam Resnick, Brian Rood
Journal: Neuro-Oncology (2019)

Genomic characterization has allowed for the differentiation of different tumor types based upon the abundance of gene transcripts. However, owing to the many layers of regulation between transcript and the post-translationally modified protein, the functional moiety of the cell, it has been challenging to extrapolate biology from these transcriptional differences. We hypothesized that a comparative analysis of the proteome and phosphoproteome across 7 childhood brain tumors would yield a deeper understanding of the differences in their functional biology. We performed tandem mass tag labeling and triple mass spectrometry of 226 fresh frozen tumor samples collected in a single institution representing the histologic diagnoses of: high grade astrocytoma (27), low grade astrocytoma (97), ganglioglioma (20), ependymoma (32), medulloblastoma (22), atypical teratoid rhabdoid tumor (12), and craniopharyngioma (16). Among these samples were 22 pairs from pre/post recurrence. Across this sample set, we quantified 9155 proteins and 13632 phospho sites. After data preprocessing including normalization, batch correction and missing value imputation, we performed consensus clustering and showed that protein profiles can effectively distinguish major histology types. Additional regression based differential analyses revealed groups of proteins and pathways showing distinct activity patterns across different histologic types. Further leveraging the WGS data, we characterized the functional impact of mutation and fusion features of the glial tumors. Specifically, focusing on the largest cohort, low grade glioma, we analyzed the proteomic ramifications of BRAF status: V600E, BRAF-fusion and wild type. Moreover, from the primary and recurrent tumor pairs, we discovered the upregulation of proteins associated with immune evasion in more advanced LGG tumors. The incorporation of the proteomic dimension into large scale efforts at tumor characterization adds functional insight that can help drive translational efforts.
Abstract 21007: Post-Transcriptional Regulation of Hsp70.3 Expression in Late Ischemic Preconditioning by Alternative Polyadenylation
Authors: Michael Tranter, Myc McGuinness, Xiaoping Ren, Lauren Haar, Robert N Helsley, Waltke R Paulding, W. Keith Jones
Journal: Circulation (2010)

Introduction: Recent results from our lab have demonstrated that NF-κB-dependent expression of heat shock protein 70.3 (Hsp70.3) is required for late ischemic preconditioning (IPC). We have also sh...
Abstract 274: Expression and Phosphorylation States of Eukaryotic Elongation Factor 2 (EEF2) and EEF2 Kinase in Cardiomyocytes From Hypertrophy Models
Authors: Satoshi Kameshima, Muneyoshi Okada, Shiro Ikeda, Yuki Watanabe, Hideyuki Yamawaki
Journal: Circulation Research (2016)

Eukaryotic elongation factor 2 (eEF2) kinase (eEF2K, also known as calmodulin (CaM)-dependent protein kinase III) is regulated by both CaM-dependent and -independent mechanisms. Activated eEF2K phosphorylates and inactivates a specific substrate, eEF2. eEF2 activation facilitates protein translation. It is recognized that increased protein synthesis is one of the primary factors for cardiomyocyte hypertrophy. In fact, angiotensin II, which induces cardiomyocyte hypertrophy, was reported to facilitate eEF2 dephosphorylation (activation) and protein synthesis in rat isolated cardiomyocytes. We have previously demonstrated that protein expression of eEF2K was increased specifically in left ventricles (LV) of spontaneously hypertensive rats (SHR). However, expression and phosphorylation states of eEF2K and eEF2 in LV of other cardiac hypertrophy models are unknown. The aim of this study was to explore it. Male C57BL/6NJcl mice and Wistar rats received transverse aortic constriction (TAC) and isoproterenol (5 mg/kg; ISO) injection, respectively, which induced cardiac hypertrophy. After 3 and 28 days from TAC operation and 7 days from ISO injection, LV were isolated and used for Western blotting (WB) and immunohistochemistry (IHC). Echocardiography was done in TAC mice before LV isolation. In TAC-induced hypertrophied LV (3 days), eEF2K expression was significantly increased (p&lt;0.01 vs. SHAM) and its phosphorylation at Ser366 was significantly decreased (p&lt;0.05 vs. SHAM). Consistently, eEF2 phosphorylation was significantly increased (p&lt;0.01 vs. SHAM). In LV from ISO rats, eEF2K phosphorylation at Ser366 was significantly decreased as determined by WB (p&lt;0.01 vs. control). In addition, eEF2K- and phosphorylated eEF2-positive cardiomyocytes were increased as determined by IHC. These changes were also confirmed in LV from SHR. At 28 days after TAC, fractional shortening was significantly decreased (from 56.6±1.6% to 44.4±2.3%, p&lt;0.01). Interestingly, eEF2 phosphorylation in LV was significantly decreased (p&lt;0.05 vs. SHAM). The present results suggest the potential role of eEF2K/eEF2 signals in the pathogenesis of cardiac hypertrophy/failure.
Spatiotemporal distribution and determinants of measles incidence during a large outbreak, Italy, September 2016 to July 2018
Authors: Xanthi D Andrianou, Martina Del Manso, Antonino Bella, Maria Fenicia Vescio, Melissa Baggieri, Maria Cristina Rota, Patrizio Pezzotti, Antonietta Filia
Journal: Eurosurveillance (2019)

BackgroundMeasles is still endemic in Italy and outbreaks are frequent. From 2016 to 2018, more than 7,000 measles cases were reported to the national integrated measles and rubella surveillance system, the largest outbreak since implementation of this system.AimWe aimed to describe the characteristics and spatiotemporal distribution of measles cases in Italy and explore determinants of incidence at municipality level.MethodsWe performed a retrospective observational study, mapping by municipalityall measles cases reported to the national surveillance system with symptom onset between 1 September 2016 and 31 July 2018. We also analysed measles-mumps-rubella (MMR) vaccination coverage (VC) data (2000-2017) for the first and second dose, collected from the Ministry of Health. We used regression analysis to explore factors associated with measles incidence at municipality level.ResultsWe analysed 7,854 cases, 3,927 (50%) female. Median age was 26 years; 475 cases (6%) were younger than 1 year. The outbreak occurred in two epidemic waves. The first started in central/northern regions (end of 2016), the second (mostly within 2018) was concentrated in southern regions. In 2016 and 2017, national VC was below 95% for both MMR doses. In 2017, only one region reported VC above 95% for the first dose. At municipality level, incidence was associated with higher urbanisation, less deprivation and fewer adults.ConclusionThe spread of measles between September 2016 and July 2018 in Italy indicates the need to improve VC and to explore further how societal and other parameters might be linked to incidence.
DIPG-20. DIFFUSE INTRINSIC PONTINE GLIOMA IN CHILDREN. RESULTS OF ANALYSES IN THE MULTICENTER RETROSPECTIVE STUDY
Authors: Ella Kumirova, Victoria Emtsova, Sergey Ozerov, Galina Tereschenko, Anton Artemov, Aleksey Nechesnyuk, Marina Mushinskaya, Olga Nikonova, Ludmila Minkina, Inna Gerbek, Andrey Karmanov, Elena Erega, Aleksander Shapochnik, Zhanna Kumikova, Heda Khasmagomadova, Elena Bogatyreva, Vladimir Makhonin, Natalia Yudina, Ludmila Privalova, Galina Kudentsova, Dmitry Pogorelov, Nadegda Golovkina, Margarita Belogurova, Aleksander Rumyantsev
Journal: Neuro-Oncology (2019)

BACKGROUND/OBJECTIVES. We present the results of multicenter retrospective study in children with diffuse intrinsic pontine glioma (DIPG). DESIGN/METHODS. From January 2010 to October 2018 142 patients with DIPG were observed/treated in Rogachev’s center from 16 regional hospitals of Russia. All details of follow-up were available in 57 pts (40%). MRI was the main confirmation of diagnosis, 1 pt was biopsied, 2 – received partial resection. Histological types: 1 - DIPG, 1 - HGG, in 1 patient the biopsy wasn’t informative. The distribution on the age in 57 pts (median 60 mths, 17–180 m): 9 (15,8%) patients was younger than 3 years, 48 (84,2%) patients were older than 3 years. There were 29 (50.8%) girls and 28 (49.1%) boys. 48 patients (84%) who received RT/CHT, and 9 (15,7%) patients were not treated. RT was performed in 47 patients, among them 20 (42%) – with parallel Temozolomid (TMZ), in 1 - with Valproic acid. 27 patients (47%) showed positive response to the therapy. 16 patients (28%) received TMZ after radiation therapy, 8 (50%) of them had positive answer. 19 pts (33%) are alive. The median to the first progression after RT was 9 m (1–57 m). The median of OS 12 m (1–63 m). Among 20 pts, who received TMZ during RT 17 pts died (85%). Among 26 pts, who did not receive TMZ 15 pts died (57,7%). Salvage (second) RT was performed in 17 children (29%) among them only 2 pts (11,8%) are alive. CONCLUSIONS: It is well know that not any therapy of DIPG can provide long-term survival. Adding TMZ to RT and salvage RT does not improve the effect of primary and relapse treatment also in our cohort. Further research is needed in this area for the development of new treatment strategies.
Surface Immobilized E‐Cadherin Mimetic Peptide Regulates the Adhesion and Clustering of Epithelial Cells
Authors: Jie Li, Jacopo Di Russo, Ximeng Hua, Zhiqin Chu, Joachim P. Spatz, Qiang Wei
Journal: Advanced Healthcare Materials (2019)

Abstract Cadherin mimetic peptides are widely used in synthetic biomaterials to mimic cell–cell adhesion in cell microniches. This mimicry regulates various cell behaviors. Although the interaction between immobilized cadherin and cells is investigated in numerous studies, the exact manner of functioning of cadherin mimetic peptides is yet to be fully understood. Cadherin mimetic peptides mimic only the critical amino acid sequence of cadherin and are not equal to these proteins in function. Compared to the cadherin proteins, mimetic peptides are more stable, easier to fabricate, and exhibit a precise chemical composition. In this study the E‐cadherin mimetic peptide His‐Ala‐Val (HAV) on material surfaces is immobilized and epithelial cell adhesion and clustering are studied. The results suggest that immobilized HAV peptides specifically interact with E‐cadherin on the cell membrane, resulting in an increased expression of E‐cadherin and its downstream signaling protein β‐catenin. This interaction relocates E‐cadherin‐based adhesion from the cell–cell interface to the cell–materials interface, which promotes cell adhesion via mechanosensing and initiates a transition in the cell cluster from a solid‐like to a fluid‐like state. The study presents an overview of the interactions between E‐cadherin mimetic peptide and epithelial cells to aid in the design of novel biomaterials.