tbuckley/cabot-search huggingface dataset:
The methyltransferase NSD3 promotes antiviral innate immunity via direct lysine methylation of IRF3
Authors: Chunmei Wang, Qinlan Wang, Xiaoqing Xu, Bin Xie, Yong Zhao, Nan Li, Xuetao Cao
Journal: The Journal of Experimental Medicine (2017)

Lysine methylation is an important posttranslational modification, implicated in various biological pathological conditions. The transcription factor interferon regulatory factor 3 (IRF3) is essential for antiviral innate immunity, yet the mechanism for methylation control of IRF3 activation remains unclear. In this paper, we discovered monomethylation of IRF3 at K366 is critical for IRF3 transcription activity in antiviral innate immunity. By mass spectrometry analysis of IRF3-associated proteins, we identified nuclear receptor–binding SET domain 3 (NSD3) as the lysine methyltransferase that directly binds to the IRF3 C-terminal region through its PWWP1 domain and methylates IRF3 at K366 via its SET domain. Deficiency of NSD3 impairs the antiviral innate immune response in vivo. Mechanistically, NSD3 enhances the transcription activity of IRF3 dependent on K366 monomethylation, which maintains IRF3 phosphorylation by promoting IRF3 dissociation of protein phosphatase PP1cc and consequently promotes type I interferon production. Our study reveals a critical role of NSD3-mediated IRF3 methylation in enhancing antiviral innate immunity.
NIMG-64. THE POTENTIAL OF 7T ANATOMICAL IMAGING FOR CLINICAL ASSESSMENT OF CONTRAST-ENHANCING AND T2-HYPERINTENSE LESIONS IN PATIENTS WITH GLIOMA
Authors: Angela Jakary, Christopher Hess, Marisa LaFontaine, Peder Larson, Nicholas Butowski, Jennifer Clarke, Susan Chang, Janine Lupo
Journal: Neuro-Oncology (2017)

7 Tesla (7T) MRI scanners can provide novel information to improve the characterization of gliomas. However, patients who receive 7T scans must undergo separate clinical evaluations at lower field strengths due to a lack of clinical validation of 7T anatomical imaging. The purpose of this study was to develop a robust volumetric anatomical imaging protocol for the clinical evaluation of patients with glioma at 7T and compare lesion definition to standard 3T imaging. 3D T2-weighted, T2 FLAIR, and T1-weighted sequences at 7T were optimized to match the contrast, resolution, and scan time of corresponding clinical sequences at 3T. Ten patients with contrast-enhancing glioma (grades II-IV) were scanned with a protocol consisting of pre-contrast anatomical imaging and post-contrast T1-weighted imaging at both field strengths, with the 7T scan occurring in between the pre- and post-contrast 3T imaging. A half-dose of contrast was used at 7T, with an additional half-dose given immediately afterwards at 3T to provide similar lesion contrast given the 2.3-fold difference in field strength. Metrics for comparison between field strengths included volumes of T2 and contrast-enhancing lesions, and Likert-scale ratings (1-5) of lesion definition by a neuro-radiologist. T2 and contrast-enhancing lesion volumes were not significantly different between field strengths, despite the trend in larger enhancing lesion volumes at 3T, which was expected given the protocol design. 7T T2-weighted and post-contrast T1-weighted images received on average half-point higher Likert-scale ratings than corresponding 3T images, whereas the opposite trend was observed with the T2 FLAIR and pre-contrast T1-weighted images. Our pilot study suggests that clinical assessment of contrast-enhancing and T2-hyperintense lesions in glioma is feasible at 7T, which would obviate the need for two scans, allowing patients to take advantage of the increased sensitivity in metabolic and physiologic imaging available at 7T and ultimately improve patient care.
Docetaxel and ifosfamide as salvage treatment in EGFR, ALK wilde type non small cell lung cancer (NSCLC)
Authors: S. Mancarella, M.L. Schirinzi, O. Potì, D. De Giorgi, G. De Maria, C. Olla, G. Imbriglio, A. Martiriggiano, A. Rizzo
Journal: Annals of Oncology (2017)
IMMU-13. PD-L1 EXPRESSION PREDICTS SURVIVAL IN NEWLY DIAGNOSED GLIOBLASTOMA PATIENTS RECEIVING VACCINE IMMUNOTHERAPY BUT NOT STANDARD THERAPY ALONE
Authors: Joseph DiDomenico, Dorina Veliceasa, Winward Choy, Daniel Oyon, Jonathan Lamano, Jason Lamano, Leonel Ampie, Andrew Parsa, Orin Bloch
Journal: Neuro-Oncology (2017)

While PD-L1 expression on tumors and immune cells can mediate immunosuppression, limited data exists about the correlation of PD-L1 to clinical outcomes in GBM. Here we evaluate outcomes of GBM patients treated with standard radiation and temozolomide therapy alone, or with concurrent vaccine immunotherapy, stratified by PD-L1 expression on tumor and circulating myeloid cells. Newly diagnosed GBM patients treated with standard chemoradiation (n=71) or a clinical trial of heat shock protein vaccination (n=32) had tumor PD-L1 expression evaluated by immunohistochemistry (SP142 clone) and characterized as negative-low (0-5%), medium (5-50%), or high (>50%) expression. PD-L1 expression on circulating myeloid cells (CD11b+) was evaluated by flow cytometry at surgery, and patients were divided into PD-L1hi/PD-L1lo subsets relative to the median. Radiographic progression and overall survival were recorded. Among patients treated with standard chemoradiation, significant tissue PD-L1 expression (medium-high) was observed in 36%. Myeloid cell PD-L1 expression ranged from 3-81% with a median of 21%. No correlation between tumor and myeloid PD-L1 expression was observed (R2=0.008; p=0.53). PFS for the peripheral PD-L1hi vs. PD-L1lo groups was 9.5 vs. 8.8 months (HR =0.76; p=0.37). No difference was observed in OS for these groups (HR = 0.75; p=0.40). By comparison, in patients treated with vaccine therapy, PFS for the peripheral PD-L1hi vs. PD-L1lo groups was 11.3 vs. 27.2 months (HR=3.1, p=0.009), and OS was 18.0 vs. 44.7 months (HR 3.3, p=0.007). Tumor characterization as PD-L1 negative-low vs. medium-high did not impact PFS (HR=0.84, p=0.69) or OS (HR=0.89, p=0.56). Expression of PD-L1 on tumor and circulating myeloid cells in GBM patients receiving standard chemoradiation did not significantly impact survival. In patients treated with concurrent vaccine immunotherapy, only myeloid cell PD-L1 expression correlated with survival. These results suggest that checkpoint inhibition for GBM may only be effective when combined with other immunotherapeutic strategies.
P3.16-010 Preoperative Six-Minute Walk Distance Is Associated with Complications of Pneumonia after Lung Resection
Authors: K. Hattori, T. Matsuda, Y. Takagi, M. Nagaya, T. Inoue, Y. Mizuno, H. Nakajima, Y. Nishida, Y. Hasegawa, K. Kawaguchi, T. Fukui, N. Ozeki, K. Yokoi, S. Ito
Journal: Journal of Thoracic Oncology (2017)
CSIG-03. PROLINE GLUTAMIC ACID AND LEUCINE RICH PROTEIN 1 (PELP1) PROMOTES GLIOBLASTOMA PROGRESSION VIA β-CATENIN PATHWAY
Authors: Gangadhara Reddy Sareddy, Mei Zhou, Jinyou Liu, Suryavathi Viswanadhapalli, Aleksandra Gruslova, Darrell Brann, Andrew Brenner, Ratna Vadlamudi
Journal: Neuro-Oncology (2017)

Glioblastomas (GBM) have dismal survival rates (1 year-34.6% and 5 year-4.75%) and affect 13,000 patients per year. Standard treatment consists of surgical resection, external beam radiation therapy, adjuvant chemotherapy with temozolomide and tumor treating fields. Nonetheless, despite a heavy investment in therapy, all patients will eventually succumb to their disease. Delineating the molecular pathways and mechanisms that contribute to the GBM development is clinically significant and provide novel therapeutic options for GBM. In the present study, we examined the significance of coregulator protein Proline Glutamic acid and Leucine rich Protein 1(PELP1) in GBM. Immunohistochemical analysis of glioma tissue microarrays revealed that PELP1 is overexpressed in the glial tumors compared to normal brain, with the highest expression in GBM and TCGA analysis revealed that patients with high PELP1 expression have shorter survival. Knockdown of PELP1 using specific siRNA and shRNA has a dramatic effect on cell proliferation, cell migration and invasion of established and patient-derived GBM cells. Global transcriptomic analysis revealed that PELP1 knockdown significantly downregulated the pathways related to cell survival, migration, and invasion including β-catenin pathway. Further gene set enrichment analysis (GSEA) confirmed that the PELP1-downregulated genes correlated well with signatures of β-catenin pathway. Mechanistic studies showed that PELP1 interacts with β-catenin and PELP1 increases β-catenin reporter gene activation. Accordingly, PELP1 knockdown significantly reduced the expression of β-catenin target genes and chromatin immunoprecipitation assays demonstrated that knockdown of PELP1 attenuated the recruitment of β-catenin to the target genes promoter. Further, knockdown of PELP1 significantly reduced in vivo tumor progression in orthotopic models and improved the overall mice survival. Taken together these results provide the evidence that PELP1 could be a potential therapeutic target for therapeutic intervention in GBM.
P1.07-041 CD47 Expression and Prognosis in a Cohort of Patients with Lung Adenocarcinoma (NSCLC)
Authors: O. Arrieta, M. Orozco-Morales, A. Cardona, A. Avilés, N. Hernandez-Pedro, L. Cabrera-Miranda, G. Soca-Chafre, P. Barrios, G. Cruz-Rico
Journal: Journal of Thoracic Oncology (2017)
P2.16-026 Surgical Treatment for Metastatic Lung Tumors from Various Sarcomas
Authors: H. Yamamoto, K. Namba, K. Takahashi, J. Soh, K. Shien, T. Kurosaki, S. Ohtani, S. Sugimoto, M. Yamane, T. Oto, S. Toyooka
Journal: Journal of Thoracic Oncology (2017)
OA 13.07 Contraction of T Cell Clonality in Lung Cancer Metastases
Authors: A. Mansfield, H. Ren, S. Sutor, R. Dronca, S. Park, S. Markovic, W. Nevala, J. Jen, M.C. Aubry, H. Dong
Journal: Journal of Thoracic Oncology (2017)
Prevenzione della infezione da rosolia congenita: una sfida per ogni paese europeo
Authors: N Crowcroft, R G Pebody
Journal: Eurosurveillance (2004)

Questo numero di Eurosurveillance e dedicato all'epidemiologia e al controllo della infezione da rosolia congenita (IRC) in tutta Europa. Mostra che nonostante la disponibilita da molti anni di un vaccino sicuro ed efficace, la IRC - conseguenza dell'infezione da rosolia durante la gravidanza - rimane un problema di sanita pubblica importante sia nell'Unione Europea sia nella piu ampia Regione Europea dell'OMS. Gli articoli che seguono fanno un quadro delle sfide che si trovano ad affrontare i vari programmi nazionali di immunizzazione in Europa. Essi illustrano le grandi differenze in termini di morbosita e di accessibilita ai servizi sanitari preventivi sia all'interno di ciascun paese che tra un paese e l'altro.
DRES-12. SINGLE CELL CLONAL ANALYSIS OF GBM TUMOR HIERARCHIES USING OPTICAL BARCODING
Authors: Cecile Maire, Malte Mohme, Kristoffer Riecken, Antonio Failla, Katharina Kolbe, Marlena Helms, Boris Fehse, Manfred Westphal, Katrin Lamszus
Journal: Neuro-Oncology (2017)

Most of the genomic and epigenetic alterations in GBM have been described thanks to the effort of the Tumor Cancer Genome Atlas and others, highlighting the highly heterogeneous and complex genomic landscape of GBM. Our understanding of how such heterogeneity is maintained is however still limited, and tumor growth driven by micro-environmental selective pressure follows a clonal-evolution model that leads to the emergence of new subpopulation and regional heterogeneity. We established GBM-patient derived cell lines (PDCL) and mouse xenografts from tissue resections and followed the growth progression of multiple clones in vivo by using optical barcoding to track and quantify the clonal evolution. We isolated single cells out of GBM-PDCL and tagged them with specific combinations of two out of six different fluorescent proteins, thus generating 21 optically barcoded (OBC) clones. These clones were then grown either separately or as a mix in vitro and in vivo after intracranial injection. Using this innovative technique, we were able to track the fate of individual clones and analyzed their growth dynamics in different microenvironments. We discovered that fast growing clones in vitro are not necessarily the ones that are responsible for most of the tumor growth in vivo. Interestingly, the clones that do not have the capacity to overgrow other clones when injected in the brain as a mix, are still tumorigenic when injected alone. Moreover, we discovered that distinct clones were more resistant to radiotherapy than others, opening the possibility to identify specific clonal subpopulations in the tumor that are resistant to treatment and will probably develop into the major resistant clone when the tumor will recur. Understanding how tumor heterogeneity is shaped by the microenvironment and how the different clonal population react to treatment will help predicting drug treatment efficiency and potential resistance.
P1.02-001 SLFN11 Expression in Early Stage Non-Small Cell Lung Cancer Predicts Benefit from Adjuvant Chemotherapy with Taxane and Platinum
Authors: V. Velcheti, S. Schwartz, F. Cecchi, Y. Tian, S. Sellappan, C. Rudin, J. Poirier, T. Hembrough
Journal: Journal of Thoracic Oncology (2017)
Medical regulators could merge in government shake-up
Authors: Abi Rimmer
Journal: BMJ (2017)

Plans to overhaul the way doctors, nurses, and other healthcare professionals are regulated have had a mixed response. 

A key aim of the Department of Health’s plans to reform medical regulation is to ensure that organisations have a “consistent and flexible range of powers that allow them to take a prompt and proportionate approach to concerns about an individual’s fitness to practise.”

To meet that objective, the department has proposed shrinking the number of medical regulators from the current nine to three or four.

Consultation documents on upgrading the regulation of healthcare professions were launched at the end of October,1 with a remit for the four UK governments to look into which professions needed statutory regulation.

Other proposals include promoting more joint working among regulators and having a single database …
P3.01-029 Transient Asymptomatic Pulmonary Opacities (TAPOs) during Osimertinib Treatment and Its Clinical Implication
Authors: H. Lee, H. Lee, J. Sun, S. Lee, Y. Kim, S.E. Park, J.S. Ahn, K. Park, M. Ahn
Journal: Journal of Thoracic Oncology (2017)
Targeting the T cell receptor β-chain constant region for immunotherapy of T cell malignancies
Authors: Paul M Maciocia, Patrycja A Wawrzyniecka, Brian Philip, Ida Ricciardelli, Ayse U Akarca, Shimobi C Onuoha, Mateusz Legut, David K Cole, Andrew K Sewell, Giuseppe Gritti, Joan Somja, Miguel A Piris, Karl S Peggs, David C Linch, Teresa Marafioti, Martin A Pule
Journal: Nature Medicine (2017)
We are all Jews of somebody: migration and genetic. The story of Jewish settlements in Italian Salento
Authors: L. Orlando, M. Caloro, E.S. Lutrino, D. Loparco, C. Caliolo, P. Schiavone, A. Quaranta, P. Fedele, P. Rizzo, M. D'Amico, M.C. Chetrì, A. Marino, E. Mazzoni, N. Calvani, A. Nacci, F. Sponziello, M. Cinefra, P. Ferrara, L.L. Falcone, S. Cinieri
Journal: Annals of Oncology (2017)
EXTH-52. EGFRvIII: A NEW PREDICTIVE BIOMARKER FOR TEMOZOLOMIDE RESPONSE IN MGMT PROMOTOR METHYLATED GLIOBLASTOMA PATIENTS
Authors: Nina Struve, Tim Brend, Lucy Stead, Zev A Binder, Leonie Ott, Justus Muller-Goebel, Konstatin Hoffer, Jennifer J D Morrissette, Cordula Petersen, Kai Rothkamm, Donald O’Rourke, Susan C Short, Malte Kriegs
Journal: Neuro-Oncology (2017)

Despite many clinical efforts, the prognosis of GBM patients has not improved in the last 10 years. Epigenetic silencing of the O6-methylguanine-DNA-methyltransferase (MGMT) gene is the only predictive biomarker that is associated with temozolomide (TMZ) response. The establishment of new biomarkers, for personalized treatment is of significant interest. The epidermal growth factor receptor (EGFR) variant III (EGFRvIII) is expressed in approximately 20–30% of GBM. The aim of this study was to investigate if EGFRvIII is a predictive biomarker for TMZ response by analyzing the TMZ sensitivity of isogenic cell cultures and tumour xenografts with/without endogenous EGFRvIII expression. Using two, unique isogenic pairs of MGMT deficient GBM cells we observed that endogenous EGFRvIII expression was associated with a significant increase in TMZ sensitivity in vitro and in vivo. Knockdown of EGFRvIII restored TMZ resistance, confirming EGFRvIII dependence. We observed prolonged accumulation in S/G2-phase in EGFRvIII+ cells after TMZ treatment, indicating increased replication stress induced by TMZ and a significantly higher number of DNA double strand breaks. Because TMZ sensitivity in MGMT negative cells is predominantly determined by functional mismatch repair (MMR), we next analyzed MMR protein expression. We observed that EGFRvIII expression was associated with upregulated MMR proteins and that conversely, even a moderate decrease in MSH6 and MLH1 expression yielded a pronounced increase in TMZ resistance. In accordance with our findings, analysis of clinical data revealed that EGFRvIII positive GBM patients displaying MGMT promotor methylation have significantly better outcomes than EGFRvIII negative patients. In summary, we have shown that MGMT negative EGFRvIII expressing GBM cells and tumours are significantly more sensitive to TMZ compared to isogenic EGFRvIII negative counterparts due to upregulated MMR. Our data highlight a new mechanism of TMZ sensitivity and we conclude that EGFRvIII is a predictive biomarker for response to TMZ in MGMT methylated GBM patients.
P2.03-035 Osimertinib in Relapsed EGFR-Mutated Non-Small Cell Lung Cancer Patients with Brain Metastases: Results from the TREM-Study
Authors: I.J. Eide, Å. Helland, S. Borrisova, S. Ekman, S. Cicenas, J. Koivunen, B.H. Grønberg, O.T. Brustugun
Journal: Journal of Thoracic Oncology (2017)
MA 13.07 A Randomized Trial of SABR vs Conventional Radiotherapy for Inoperable Stage I Non-Small Cell Lung Cancer: TROG09.02 (CHISEL)
Authors: D. Ball, T. Mai, S. Vinod, S. Babington, J. Ruben, T. Kron, B. Chesson, A. Herschtal, A. Rezo, C. Elder, M. Skala, A. Wirth, G. Wheeler, A. Lim, M. Vanevski, M. Shaw
Journal: Journal of Thoracic Oncology (2017)
JCES 01.26 Circulating Cell-Free DNA of Cerebrospinal Fluid May Function as Liquid Biopsy for Leptomeningeal Metastases of ALK Rearrangement NSCLC
Authors: Y. Li, B. Jiang, J.-. Yang, X. Zhang, Z. Zhang, Q. Zhou, H. Tu, Z. Wang, H. Chen, C. Xu, B. Wang, Y. Wu
Journal: Journal of Thoracic Oncology (2017)
Surveillance de la résistance aux antibiotiques en Bulgarie – une synopsis de BulSTAR 2003
Authors: M Petrov, N Hadjieva, T Kantardjiev, Tz Velinov, A Bachvarova
Journal: Eurosurveillance (2005)

L’article suivant presente le systeme de surveillance de la resistance antimicrobienne en Bulgarie (Bulgarian Surveillance Tracking Antimicrobial Resistance, BulSTAR) et presente les donnees de surveillance de 2003. Ce programme de surveillance longitudinal controle l’isolement et la sensibilite aux antibiotiques de tous les micro-organismes d’importance clinique isoles par les laboratoires de microbiologie participants. Ces micro-organismes sont isoles a partir d’echantillons sanguins, de liquide cephalo-rachidien, des voies respiratoires hautes et basses, d’urine et de prelevements de plaies. Vingt huit laboratoires publics, 45 laboratoires hospitaliers et six prives repartis dans les 28 districts de la Republique de Bulgarie ont participe a BulSTAR 2003. Le nombre total d’isolats provenant de sources recensees pendant la periode de l’etude s’elevait a 98 929. Sept micro-organismes representaient 72% des bacteries isolees : Escherichia coli, Staphylococcus aureus, le groupe Proteus-Providencia-Morganella, Klebsiella spp., Pseudomonas spp, Streptococcus pneumoniae et Streptococcus pyogenes. La resistance aux antibiotiques des bacteries cliniques Gram positif et Gram negatif en Bulgarie a ete estimee de niveau moyen comparee a d’autres sources de surveillance dans le monde. Une experience unique sur la population et sur une periode de 32 ans consistant a traiter toutes les infections severes avec une combinaison d’ampicilline et de gentamicine a conduit a des taux de resistance aux aminoglycosides deux fois plus eleves compares a d’autres pays du monde. Ceci est le resultat de schemas therapeutiques extremement conservateurs utilises dans les ex-pays socialistes, issus de directives nationales et d’une production interne a bas cout de gentamicine et d’ampicilline. La mise en place prochaine d’un reseau informatise et les ameliorations apportees pour la detection des erreurs devraient augmenter la sensibilite et de l’impact du systeme de surveillance BulSTAR – un outil indispensable dans la lutte contre le phenomene mondial de la resistance antimicrobienne.
Abstract 20279: A Bioinformatics Approach Reveals Mechanism of Pericardial Fluid Exosome Action in Promoting Ischemia in Diabetic Patients
Authors: Maryam Anwar, Jaimy Saif, Sezin Aday, Giovanni Biglino, Kate Heesom, Gianni Angelini, Enrico Petretto, Costanza Emanueli
Journal: Circulation (2017)

Type 2 diabetes mellitus (T2DM) impairs endogenous reparative angiogenic processes thus leading to ischaemic heart disease (IHD). Recently, it has come to light that extracellular vesicles (EVs) e....
EXTH-03. ENHANCED IN VIVO EFFICACY AND SAFETY OF COMBINATION TEMOZOLOMIDE AND BROMODOMAIN INHIBITOR THERAPY FOR GLIOMAS USING A TARGETED DUAL DRUG-LOADING STEALTH LIPOSOMAL CARRIER
Authors: Fred Lam, Stephen Morton, Jeffrey Wyckoff, Amanda Maffa, Elena Balkanska-Sinclair, Scott Floyd, Paula Hammond
Journal: Neuro-Oncology (2017)

Effective treatment for glioblastoma (GBM) is limited by the presence of the blood-brain barrier (BBB) and rapid resistance to single agent therapies. To address these issues, we developed a transferrin-functionalized nanoparticle (Tf-NP) that can deliver dual combination therapies. Using intravital imaging, we show the ability of Tf-NPs to traverse the intact BBB in mice as well as achieve direct tumor binding in two intracranial orthotopic models of GBM. Treatment of tumor-bearing mice with Tf-NPs loaded with temozolomide and the bromodomain inhibitor JQ1 led to increased DNA damage that correlated with decreased tumor burden and significant survival benefits compared to equivalent free-drug dosing. Immunocompetent mice treated with Tf-NP-loaded drugs also showed protection from the effects of systemic drug toxicity, demonstrating the preclinical potential of this platform to deliver novel combination therapies for gliomas and other central nervous system tumors.
Observations on a 2-Step Approach to Screening for Parkinson Disease
Authors: Alastair J. Noyce, Andrew Lees
Journal: JAMA Neurology (2017)

To the Editor We read with interest the report from Jennings et al.1 The study showed that, among hyposmic individuals, a dopamine transporter (DAT) deficit at baseline identified those with a high relative risk of conversion to clinical Parkinson disease (PD) after 4 years of follow-up.1