tbuckley/cabot-search huggingface dataset:
Association of <i>LPA</i> Variants With Aortic Stenosis
Authors: Hao Yu Chen, Line Dufresne, Hannah Burr, Athithan Ambikkumar, Niko Yasui, Kevin Luk, Dilrini K. Ranatunga, Rachel A. Whitmer, Mark Lathrop, James C. Engert, George Thanassoulis
Journal: JAMA Cardiology (2017)

<h3>Importance</h3> Elevated lipoprotein(a) levels are a risk factor for aortic stenosis (AS). However, a large-scale replication of associations between<i>LPA</i>variants and AS, their interactions with risk factors, and the effect of multiple risk alleles is not well established. <h3>Objective</h3> To replicate the association between<i>LPA</i>variants with AS and identify subgroups who are at higher risk of developing AS. <h3>Design, Setting, and Participants</h3> This case-control study of AS included 44 703 individuals (3469 cases) 55 years or older who were enrolled in the Genetic Epidemiology Research on Aging cohort and who were members of the Kaiser Permanente Northern California health care delivery system. The study leveraged the linkage of administrative health data, electronic medical records, genotypes, and self-reported questionnaire data. The 3469 AS cases were diagnosed between January 1996 and December 2015. Individuals with valvular congenital valvular heart disease were excluded. <h3>Exposures</h3> Two single-nucleotide polymorphisms in the<i>LPA</i>locus,rs10455872andrs3798220, that are known to associate with circulating plasma lipoprotein(a) levels and an<i>LPA</i>risk score. <h3>Main Outcomes and Measures</h3> Aortic stenosis or aortic valve replacement. <h3>Results</h3> The 44 703 participants were of European ancestry, of whom 22 019 (49.3%) were men. The mean (SD) age for the control group was 69.3 (8.3) years and the mean (SD) age for AS cases was 74.6 (8.5) years. Both<i>LPA</i>variants were associated with AS, with a per risk allele odds ratio of 1.34 (95% CI, 1.23-1.47;<i>P</i> = 1.7 × 10<sup>−10</sup>) forrs10455872and 1.31 (95% CI, 1.09-1.58;<i>P</i> = 3.6 × 10<sup>−3</sup>) forrs3798220after adjusting for age, age<sup>2</sup>, and sex. The results remained significant after adjusting for risk factors. The estimates were similar for an<i>LPA</i>risk score. Individuals with 2 risk alleles had a 2-fold or greater odds of AS compared with individuals with no risk alleles (forrs10455872, homozygous odds ratio, 2.05; 95% CI, 1.37-3.07;<i>P</i> = 5.3 × 10<sup>−4</sup>; forrs3798220, homozygous odds ratio, 3.74; 95% CI, 1.03-13.62;<i>P</i> = .05; and for compound heterygotes, odds ratio, 2.00; 95% CI, 1.17-3.44;<i>P</i> = .01). Forrs10455872, the odds ratio for AS was greatest in individuals aged 55 to 64 years and declined with age (interaction<i>P</i> = .03). Eachrs10455872risk allele was also associated with AS that was diagnosed 0.71 years earlier (95% CI, −1.42 to 0;<i>P</i> = .05). <h3>Conclusions and Relevance</h3> We provide a large-scale confirmation of the association between 2<i>LPA</i>variants and AS, reaching genome-wide significance. In addition, individuals with 2 risk alleles have 2-fold or greater odds of developing AS. Age may modify these associations and identify subgroups who are at greater risk of developing AS.
MA 17.10 Toxicity Results from the Randomized Phase III NVALT-11 Study of Prophylactic Cranial Irradiation vs. Observation in Stage III NSCLC
Authors: D. De Ruysscher, A. Dingemans, J. Praag, J. Belderbos, C. Tissing-Tan, J. Herder, T. Haitjema, F. Ubbels, F. Lagerwaard, J. Stigt, E. Smit, H. Van Tinteren, V. Van Der Noort, H. Groen
Journal: Journal of Thoracic Oncology (2017)
P2.02-018 Genomic Profiling of Driver Gene Mutations in 498 Chinese NSCLC Patients
Authors: M. Wang, M. Chen, Y. Shi, Q. Guo, Y. Shang, J. Hu, L. Dai, M. Yao, H. Chen, J. Hu, J. Yao, A. Wang, G. Chirn, K. Wang
Journal: Journal of Thoracic Oncology (2017)
Abstract 17402: Pathological Findings of Takotsubo Cardiomyopathy Relating to Chatecholamine Toxicity: The Study Using Human Left Ventricular Endomyocardial Biopsy Specimens in the Acute Phase
Authors: Tomoya Nakano, Kenji Onoue, Yasuhiro Sakaguchi, Kinta Hatakeyama, Daisuke Kamon, Yoko Dote, Yasuki Nakada, Akihiro Takitsume, Hitoshi Nakagawa, Ayako Seno, Tomoya Ueda, Takuya Kumazawa, Taku Nishida, Tsunenari Soeda, Satoshi Okayama, Yukiji Takeda, Makoto Watanabe, Hiroyuki Kawata, Rika Kawakami, Hiroyuki Okura, Yoshihiko Saito
Journal: Circulation (2015)

Introduction: Takotsubo Cardiomyopathy (TTC) is characterized by transient hypokinesis of the left ventricular (LV) apex and mid-ventricular regions, and hyperkinesis of the LV base, without significant coronary artery stenosis. The precise pathogenic mechanism of TTC remains unknown. Earlier reports assumed that catecholamine excess is involved in the pathogenesis of TTC, from the elevation of plasma catecholamine concentration or by 123I-metaiodobenzylguanidine myocardial scintigraphy. However, there have been no pathological findings that directly support this scenario in human, so far. In this study, we investigated clinical and pathological features in TTC heart including expression of G-protein receptor kinase 2 (GRK2), which is a marker for acute desensitization of β-adrenergic receptors (β-ARs), and compared with those in non-TTC heart. Methods and Results: The clinical and pathological features from 20 TTC patients (TTC group) and non-TTC patients (non-TTC group) were analyzed. In TTC patients, LV biopsy was performed at the acute phase. Non-TTC group of patients consisted of 14 patients with ventricular tachycardia or conduction disorder, who underwent LV biopsy to rule out primary myocardial diseases. Pathological data showed that the contraction band was more frequently observed in TTC than in non-TTC group (p=0.017) (Figure A), and the percentage of interstitial fibrosis area of TTC was higher than that of non-TTC group (12.1±7.7% vs 7.4±3.0%, p=0.036) (Figure B). Moreover, the percentage of GRK2 positive stained area in TTC was greater than in non-TTC group (49.0±17.8% vs 15.7±11.9%, p&lt;0.001) (Figure C). Conclusions: The present study demonstrates up-regulation of GRK2 for the first time in human TTC, and supports the involvement of catecholamine toxicity in the pathogenesis of TTC.
NIMG-102. APPLICATION OF CALCITRIOL TO ENHANCE THE QUALITY OF IMAGING WITH 5-ALA FLUORESCENCE-GUIDED RESECTION OF GLIOMA
Authors: Shiguang Zhao, Xiaofeng Chen, Lei Teng, Chunlei Wang
Journal: Neuro-Oncology (2017)

Recurrence of glioma frequently occurs within the marginal area of the surgical cavity as a result of residual infiltrating glioma cells. It has been demonstrated that more extensive surgical resection appears to be associated with longer life expectancy for patients with high grade glioma. Fluorescence-guided surgery with 5-aminolevulinic acid (ALA) for resection of glioma has been used as an effective therapeutic modality to improve recognition of brain tumor margin and patient prognosis. However, the marginal area of glioma usually shows vague or no fluorescence, which makes tumor identification difficult. To be able to understand how to overcome these issues, we assessed the intracellular levels of PpIX and quality of 5-aminolevulinic acid metabolic imaging in human glioma cell lines and rat cortical astrocytes preconditioned with calcitriol for 48 hours by flow cytometry and fluorescence microscopy. Furthermore, expression of porphyrin synthetic enzymes in pretreated glioma cells was analyzed by RT-PCR and changes in ALA-induced PpIX ﬂuorescence and cell survival after light exposure were assessed. Calcitriol pretreated glioma cells showed higher level of ALA-induced PpIX than control group. Interestingly, this study revealed that pretreatment of normal astrocytes with calcitriol followed by ALA did not result in increased intracellular concentrations of ALA-induced PpIX. Furthermore, mechanistic studies demonstrated that calcitriol enhanced the accumulation of ALA-induced PpIX via upregulation of CPOX. This finding suggests that the combined treatment of glioma cells with calcitriol, a simple, non-toxic and highly effective preconditioning regimen, may provide an effective and selective therapeutic modality to enhance ALA-induced PpIX fluorescent quality and improve recognition of tumor tissue.
PDTM-12. THE ONCOLYTIC ADENOVIRUS DELTA-24-RGD MEDIATES AN EFFICIENT ANTITUMOR RESPONSE IN VIVO IN SUPRATENTORIAL PRIMITIVE NEUROECTODERMAL TUMORS
Authors: Marc Garcia-Moure, Naiara Martínez-Vélez, Marisol González-Huarriz, Monsterrat Puigdelloses, Miguel Angel Idoate, Ricardo Diez Valle, Sonia Tejada, Candelaria Gomez-manzano, Juan Fueyo, Ana Patiño-Garcia, Marta M Alonso
Journal: Neuro-Oncology (2017)

Primitive Neuroectodermal Tumors of the central nervous system (sPNET) are very rare aggressive malignant pediatric tumors characterized by the presence of poorly differentiated tumor cells. Despite the formidable advances in medical oncology, the low incidence of sPNET has hindered the development of appropriate therapies to treat this malignancy. Therefore, the outcome for children affected with sPNET still remains dismal since the current treatments are ineffective. Thus, it is critical to implement novel and radically different therapeutic approaches to improve the survival and quality of life of these children. Delta-24-RGD oncolytic adenovirus has been modified to confer it a tumor restricted replication and an expanded tropism to cancer cells. Altogether, these modifications lead to an optimized antitumor effect mediated by the viruses which have been already tested in preclinical and clinical models of different cancers, including brain cancers, obtaining very promising results. Here we describe the antitumor effect mediated by Delta-24-RGD in sPNET models (PFSK-1 and SK-PN-DW cells), as well as a in a new unpublished cell line (PBT-25) we have generated from tumor biopsy. First, we demonstrate in vitro that Delta-24-RGD transduces efficiently sPNET cells, and then the virus replicates in producing as a result high titers of new infectious particles. The infection and replication of the virus promote cell death of sPNET cells, obtaining IC50 values ranging from 7 to 18 MOIs. In vivo, Delta-24-RGD showed a safety profile since no signs of toxicity were observed upon their administration. Finally, the antitumor effect of Delta-24-RGD was assessed in vivo in orthotopic models of sPNET. Delta-24-RGD treatment resulted in a significant increase in overall survival of the animals (19 and 21 days for PFSK-1 and SK-PN-DW, respectively) compared to vehicle treated animals (14 days). In combination, these results demonstrate the potential therapeutic benefit of Delta-24-RGD for the treatment of sPNET.
P2.01-032 A Randomized Phase Ii Trial of Selumetinib + Platinum-pemetrexed (Pem-c) in Kras Wildtype (Wt)/Unknown NSCLC: CCTG Ind219
Authors: P. Bradbury, B. Melosky, D. Tu, G. Nicholas, P. Wheatley-Price, S. Laurie, G. Goss, M. Florescu, N. Basappa, A. Reiman, A. Tan, D. Hao, J. Rotherstein, N. Leighl, J. Goffin, C. Kollmannsberger, P. Kaurah, P. Brown-Walker, L. Seymour
Journal: Journal of Thoracic Oncology (2017)
IMMU-01. TEMOZOLOMIDE-RESISTANT CAR-T ENHANCES GLIOBLASTOMA CLEARANCE BY CONCURRENT CHEMOTHERAPY AND IMMUNOTHERAPY
Authors: Prakash Sampath, Sadhak Sengupta, Sudarshana Sengupta, Richard Junghans
Journal: Neuro-Oncology (2017)

Despite refinements in multimodal management of glioblastoma (GBM) patients, long-term problem-free survival is still dismal. Post resection GBM patients who are concurrently treated with radiation and chemotherapy had a modest median survival of 14. 6 months. Immunotherapy for GBM has often been considered as the fourth arm of GBM therapy. After recent clinical success of chimeric antigen receptors expressing T cells (CAR-T) in GBM patients, interest in tumor-directed immunotherapy has been reinvigorated. However as per standard care, immunotherapy must be concurrent with or following the standard care protocol for glioma therapy, which includes Temozolomide (TMZ) chemotherapy. Concurrent chemotherapy with TMZ reduces the efficacy of adoptive T cell immunotherapy by inducing severe lymphopenia. Waiting for post-chemotherapy treatment minimizes the window of opportunity for effective immunotherapy because recurrent tumors often have a different antigenic profile than the primary diagnosis because of inherent tumor heterogeneity in GBM. To address this, we have created a TMZ-resistant CAR-T cell directed against IL13Rα2+ GBM tumors by introducing a mutated O6-methylguanine-DNA methyltransferase (MGMT) moiety in the existing IL13CAR backbone. This specific mutation in MGMT (P140KMGMT) blocks the interaction of TMZ to MGMT and therefore protects the rapidly proliferating anti-GBM CAR-T cells from TMZ-induced lymphopenia. Activated P140KMGMT-IL13CAR-T cells were protected from TMZ-induced cytotoxicity in vitro without any loss of anti-tumor effects of these modified CAR-T cells. Experimental xenograft animals treated with P140KMGMT-IL13CAR-T cells and concurrent TMZ therapy showed two-fold increase in median survival over groups that were treated with TMZ alone, and 2.8-fold increase in overall survival over groups that were treated with TMZ-sensitive second generation IL13CAR-T cells and concurrent TMZ. These encouraging results point us strongly in the direction of developing this technology clinically towards a promising future of concurrent chemotherapy and immunotherapy for GBM management.
STEM-43. GSK3β PROMOTES THE BMX-MEDIATED STAT3 ACTIVATION TO MAINTAIN GLIOBLASTOMA STEM CELLS
Authors: Zhi Huang, Susan Ke, Wenchao Zhou, Qiulian Wu, Xiaoguang Fang, Qi Xie, Xiuxing Wang, Jeremy Rich, Shideng Bao
Journal: Neuro-Oncology (2017)

Glioblastoma (GBM) is the most lethal brain cancer containing highly tumorigenic glioma stem cells (GSCs). As GSCs contribute to malignant behaviors including tumor angiogenesis, cancer invasion, therapeutic resistance and tumor recurrence, targeting GSCs may significantly improve GBM treatment. Here we demonstrate that the glycogen synthase kinase 3β (GSK3β) promotes the BMX-mediated STAT3 signaling to maintain GSCs and thus targeting GSK3β impairs GBM tumor growth. GSK3β is preferentially activated in GSCs relative to matched non-stem tumor cells (NSTCs) and neural progenitor cells (NPCs). Functional inhibition of GSK3β by its inhibitors or shRNA reduced activating phosphorylation of BMX kinase and STAT3 in GSCs but not in NPCs that express little BMX. Disrupting GSK3β inhibited GSC tumorsphere formation and induced cell death in GSCs but showed little effect on NPCs. Importantly, disruption of GSK3β potently suppressed GSC-driven tumor growth in vivo. Ectopic expression of a constitutively active STAT3 (STAT3-C) rescued the effects caused by GSK3β disruption, supporting that GSK3β mediates through STAT3 activation to maintain the GSC phenotype. Collectively, these data indicate that GSK3β is a potential therapeutic target of GSCs. Thus, pharmacological inhibition of GSK3β may potently disrupt GSCs to overcome therapeutic resistance and improve GBM treatment.
CSIG-29. THE PROGNOSTIC VALUE OF FAS AND FASL IN WHO GRADE II GLIOMA PROGRESSION
Authors: Marco Timmer, Gabriele Röhn, Roland Goldbrunner, Jan Werner
Journal: Neuro-Oncology (2017)

The cell surface receptor Fas plays an important role in the mechanisms of induced cell death. Targeting Fas with an antibody or its ligand FasL (CD95L, CD178) drives the cell into apoptosis. The aim of this study was to evaluate the value of Fas/FasL in WHO grade II glioma progression. As low-grade gliomas do evolve and proceed towards glioblastomas, the question was whether there is a possible use for Fas/FasL as biomarkers regarding the malignant progression and progression free survival (PFS). Quantitative real-time PCR was performed with Cycler Rotor Gene Q and the Rotor-Gene SYBR Green PCR Kit (Qiagen). SDHA was used as a housekeeping gene. Data analysis was performed with Graphpad Prism 7. Statistical tests used: Log-rank test for Kaplan Meier analysis. The significance level (α) was set on 0.05. The ImmPACT DAB substrate Kit (SK-4105) was used for staining with Diaminobenzidine (DAB). 44 patients with primary grade II gliomas (22 astrocytomas, 16 oligoastrocytomas and 6 oligodendrogliomas) were included. The patients were divided in two groups according to whether the Fas or the FasL value was higher or lower as the mean value of all patients. The two groups were compared regarding their PFS, which was set as the time in months between first resection and tumor-recurrence operation. Patients with a high FasL expression level had a significantly longer time to progression (median PFS: FasL-high 42.93 vs. FasL-low 29.93; Log-rank p<0.05). The level of Fas did not show significant difference in the median PFS (Fas-high 44.07 vs. Fas-low 35.89). Fas-L may be of value as a low-grade biomarker regarding progression free survival.
P3.02-007 Circulating miRNAs as Prognostic Biomarkers in Resected Early-Stages Non-Small-Cell Lung Cancer
Authors: P. Ulivi, E. Petracci, V. Ludovini, G. Marisi, S. Baglivo, R. Chiari, A. Delmonte, N. De Luigi, L. Crinò, D. Amadori, F. Grignani
Journal: Journal of Thoracic Oncology (2017)
PATH-30. GENOMIC LANDSCAPE OF CENTRAL NERVOUS SYSTEM TUMORS
Authors: Wenya Linda Bi, Noah Greenwald, Adrian Dubuc, Sandro Santagata, Keith Ligon, Azra Ligon, Laura MacConnail, Rameen Beroukhim, Ian Dunn
Journal: Neuro-Oncology (2017)

Molecular taxonomy augments traditional histopathology in defining tumor subclasses and improves clinical risk stratification. We investigated the molecular signatures of over 2,000 central nervous system (CNS) tumors using a clinical multiplexed next-generation sequencing assay, to investigate cardinal mutations, copy number alterations, and rearrangements. These included over 1000 gliomas, 170 meningiomas, 150 pituitary adenomas, 25 vestibular schwannomas, and other less common pathologies. Machine learning clustering analysis partitioned CNS tumors into four robust categories, with critical contribution from the extent of copy number alterations within tumors. An unbiased decision tree constructed based on the entropic contribution of the molecular features in our dataset recapitulated the known histological subtypes among gliomas and suggests a rank order of significance in molecular signatures. We further correlated the genomic data with clinical annotation and survival outcomes to provide prognostic guidance in the interpretation of molecular signatures. Lastly, we described the role of targetable oncogenic pathways in specific cancers to postulate potential therapeutic venues in CNS tumors. This analysis of a large series of CNS tumors from a clinical setting confirms previously identified molecular subclasses for diverse tumors, describe the incidence of genomic alterations in specific tumors, and present potential novel signatures that emerge with large-scale profiling of tumors.
BSE: o contexto legislativo Europeu
Authors: T Chalus, I Peutz
Journal: Eurosurveillance (2000)

A crise da Encefalopatia Espongiforme Bovina (BSE) levou a importantes reconsideracoes sobre a forma como a Comunidade Europeia aborda as questoes de seguranca alimentar. Entre 28 de Julho de 1989, quando as restricoes ao transporte de alguns bovinos vivos provenientes do RU comecaram, e 29 de Junho de 2000, data da proibicao da utilizacao de alguns tecidos que apresentavam um risco de BSE, denominado Material de Risco Especificado (MRE) em toda a Uniao Europeia, todas as Decisoes adoptadas foram baseadas em clausulas de salvaguarda, conforme e definido nas directivas veterinarias. No fim do prazo e de acordo com o Tratado de Amsterdao, todas estas Decisoes devem ser substituidas por uma legislacao primaria elaborada pelo Parlamento, o Conselho e a Comissao Europeus.
P1.02-049 Detection of CDKN2A Gene Mutations in Patients with Non-Small Cell Lung Cancer Patients
Authors: S. Wang, C. Xu, W. Wang, W. Zhuang, Z. Song, Y. Zhu, R. Chen, Y. Guan, X. Yi, Y. Chen, G. Chen, M. Fang, T. Lv, Y. Song
Journal: Journal of Thoracic Oncology (2017)
PUB035 CONFIRM: A Phase III Randomized Trial to Evaluate the Efficacy of Nivolumab versus Placebo in Relapsed Mesothelioma
Authors: D. Fennell, E. Kirkpatrick, K. Cozens, S. Danson, G. Hanna, J. Lester, J. Lord, M. Nye, C. Ottensmeier, P. Szlosarek, N. Steele, M. Kalevras, T. Maishman, G. Griffiths
Journal: Journal of Thoracic Oncology (2017)
P1.03-010 Efficacy and Safety of Anaplastic Lymphoma Kinase (ALK) Tyrosine Kinase Inhibitors in ALK-Positive Non-Small Cell Lung Cancer
Authors: R. Imase, S. Endo, Y. Sasahara, T. Shinmura, T. Ozawa, H. Majima, T. Hara, H. Shimada, S. Yamauchi, Y. Sakakibara, A. Kobayashi, K. Yamazaki, Y. Jin, K. Yamanaka, O. Matsubara
Journal: Journal of Thoracic Oncology (2017)
P1.17-013 Prognostic Impact of Programmed Cell Death-1 (PD-1) and PD-Ligand 1 (PD-L1) Expression in Thymic Cancer
Authors: S. Funaki, Y. Shintani, N. Ose, T. Kawamura, R. Kanzaki, M. Minami, M. Okumura
Journal: Journal of Thoracic Oncology (2017)
NHS should be “first port of call” for potential Brexit savings, says Hunt
Authors: Abi Rimmer
Journal: BMJ (2017)

The NHS should be first in line to receive any financial savings that come about as the result of Britain leaving the European Union, England’s health secretary has said.

Speaking at the NHS Providers conference in Birmingham on 8 November, Jeremy Hunt said that, despite no government commitment to increase NHS funding because of Brexit, this should happen if possible.

Referring to a proposal by the Vote Leave campaign to increase NHS funding by £350m (€396m; $458m) a week if Britain left the EU, Hunt said, “As you know, it wasn’t a government promise; it was a promise by the Leave campaign, but what I very much agree with is [that] if there is a Brexit dividend [and] if we end up having less pressure on public finance because of not making contributions to the EU, I believe that the NHS should be the first port of …
QLIF-45. ASSOCIATIONS AMONG MEANING OF ILLNESS, SYMPTOM BURDEN, QUALITY OF LIFE AND DEPRESSION IN PATIENTS WITH LEPTOMENINGEAL METASTASIS
Authors: Julie Walker, Barbara J O’Brien, Terri S Armstrong, Mark R Gilbert, Rebecca Casarez, Geri Wood
Journal: Neuro-Oncology (2017)

Patients with leptomeningeal metastasis (LM) have symptoms related to disease within the neuroaxis, cancer sites outside the neuroaxis and treatment toxicities. The meaning ascribed to advanced cancer has been shown to impact the perceived severity of symptoms as well as quality of life (QoL) and depression. Our aim was to explore and describe relationships among meaning of illness (MoI), depression, QoL and symptom burden in LM patients and to explore whether adding spine-related items from the MD Anderson Symptom Inventory-Spine (MDASI-SP) to the MDASI-Brain Tumor (BT) enhanced understanding of symptom burden in LM patients. Thirty participants with LM were consented and enrolled into one of two groups: Newly-diagnosed (n=15) and on active treatment (n=15). Five items unique to the MDASI-SP were added to the MDASI-BT and the difference between the mean scores of the MDASI-BT and modified MDASI-BT was analyzed. The relationships among variables were assessed with correlational analysis. The sample was primarily white (73%), female (63%) with a median age of 54 years. Breast cancer was the most common primary cancer (50%) with the brain being the most common site of metastasis (23%). There were no associations between MoI and symptom burden (p=.12). Higher MoI was associated with better QoL (p<.01) and less depression (p<.01). Though there was no significant difference between the original and modified MDASI-BT (p=.33), there was a wide range of responses to the spine related items with some considered to be severe. Depressive symptoms and QoL in LM patients were related to better MoI indicating a need for further exploration. The wide range of responses to spine-related items on the modified MDASI-BT indicate the need for an instrument to measure symptoms anywhere along the neuroaxis. Longitudinal studies exploring the relationship of MoI with symptom burden may clarify non-significant associations.