tbuckley/cabot-search huggingface dataset:
WW and C2 domain–containing proteins regulate hepatic cell differentiation and tumorigenesis through the hippo signaling pathway
Authors: Anke Hermann, Dirk Oliver Wennmann, Sascha Gromnitza, Maria Edeling, Veerle Van Marck, Marius Sudol, Liliana Schaefer, Kerstin Duning, Thomas Weide, Hermann Pavenstädt, Joachim Kremerskothen
Journal: Hepatology (2017)

The Hippo pathway regulates cell differentiation, proliferation, and apoptosis. Upon activation, it inhibits the import of the transcriptional coactivator yes‐associated protein (YAP) into the nucleus, thus suppressing transcription of pro‐proliferative genes. Hence, dynamic and precise control of the Hippo pathway is crucial for organ size control and the prevention of tumor formation. Hippo signaling is controlled by a growing number of upstream regulators, including WW and C2 domain–containing (WWC) proteins, which trigger a serine/threonine kinase pathway. One component of this is the large tumor suppressor (LATS) kinase, which phosphorylates YAP, trapping it in the cytoplasm. WWC proteins have been shown to interact with LATS in vitro and stimulate its kinase activity, thus directly promoting cytoplasmic accumulation of phosphorylated YAP. However, the function of the WWC proteins in the regulation of cell proliferation, organ size control, and tumor prevention in vivo has not yet been determined. Here, we show that loss of hepatic WWC expression in mice leads to tissue overgrowth, inflammation, fibrosis, and formation of liver carcinoma. WWC‐deficient mouse livers display reduced LATS activity, increased YAP‐mediated gene transcription, and enhanced proliferation of hepatic progenitor cells. In addition, loss of WWC expression in the liver accelerates the turnover of angiomotin proteins, which act as negative regulators of YAP activity. Conclusion: Our data define an essential in vivo function for WWC proteins as regulators of canonical and noncanonical Hippo signaling in hepatic cell growth and liver tumorigenesis. Thus, expression of WWC proteins may serve as novel prognostic factors in human liver carcinoma. (Hepatology 2018;67:1546‐1559)
P1.06-023 Spatio-Temporal Distribution of Lung Cancer Mortality Rate in Peru: 2005-2014
Authors: C.J. Flores, J.S. Torres-Roman, L.A. Mas Lopez, R. Ruiz Mendoza, C.A. Samanez, A. Aguilar, C. Vallejos
Journal: Journal of Thoracic Oncology (2017)
OA 08.07 Pazopanib Maintenance for Extensive Disease Small Cell Lung Cancer: a Randomized, Placebo-Controlled Phase II study (KCSG-LU12-07)
Authors: J. Sun, K.H. Lee, B. Kim, H. Kim, Y.J. Min, S.Y. Yi, H.J. Yun, S. Lee, J.S. Ahn, K. Park, M. Ahn
Journal: Journal of Thoracic Oncology (2017)
SCDT-35. UNDERSTANDING TRANSCYTOSIS OF IRON ACROSS THE BBB AS A MODEL FOR DRUG DELIVERY
Authors: James Connor
Journal: Neuro-Oncology (2017)

Multiple approaches to optimize drug and neurotrophic delivery across the BBB exist and a number of these approaches have attempted to harness the iron delivery system. Compounds have been conjugated to transferrin, the iron delivery protein, and to antibodies to the transferrin receptor. Ferritin has also been used as a means to transport nanoparticles. These approaches have met with minimal success mainly because they are based on the existing paradigm for iron transport into the brain which is seriously flawed. The existing paradigm holds that the endothelial cells forming the BBB serve as passive conduits transporting a complex of transferrin-iron and the transferrin receptor from the blood to the brain. This paradigm fails to take into account that the endothelial cells have a high iron requirement for maintaining mitochondrial function required for transport of nutrients and also have a high capacity to store iron. We have recently demonstrated that the significant majority of iron that enters an endothelial cell is released in the endothelial cell and transferrin and its receptor are recycled back to the blood. A key component of releasing iron into the cell is the divalent metal transport protein (DMT1). When this protein function is blocked there is a change in the ratio of iron to transferrin that is transcytosed across the BBB. Moreover, we have also demonstrated that ferritin can be transcytosed in a model of the BBB but the movement of this protein and its contents is also dependent upon the activity of DMT1. There is also significant regulation of iron movement across the BBB from feedback mechanisms in the brain. Understanding the mechanisms of movement of iron, transferrin and ferritin, and regulation of those mechanisms is essential to harnessing the iron transport system for drug delivery.
No difference in efficacy of opioids and non-opioid analgesics for arm or leg pain
Authors: Jacqui Wise
Journal: BMJ (2017)

Patients with sprains or fractures appear to get as much pain relief with a combination of ibuprofen and paracetamol as with opioid medications, a study in JAMA concludes.1 The authors say that prescribing non-opioid analgesics first line in emergency departments may help combat the current opioid epidemic in the US.

The double blind randomised clinical trial was conducted at two urban emergency departments in New York. Researchers randomly assigned 416 patients presenting with moderate to …
P3.02-002 Liquid and Solid Rebiopsies in EGFR-Mutated NSCLC Patients
Authors: D. Nunes, E. Dansin, C. Lamblin, E. Wasielewski, C. Descarpentries, V. Grégoire, M.C. Copin, F. Escande, A. Cortot
Journal: Journal of Thoracic Oncology (2017)
CSIG-24. ANDROGEN RECEPTOR IS A POTENTIAL THERAPEUTIC TARGET IN GLIOBLASTOMA
Authors: Nomi Zalsman, Tamar Canello, Haim Ovadia, Hanna Charbit, Bracha Zelikovitch, Anat Mordechai, Yakov Fellig, Stav Rabani, Tal Shahar, Alexander Lossos, Iris Lavon
Journal: Neuro-Oncology (2017)

Androgen receptor (AR) gene is mapped to Xq11-12. It functions as a steroid-hormone-activated-transcription-factor. AR splice variants lacking the Ligand-Binding-Domain (LBD), such as AR-V7/AR3, which arise primarily through exon skipping and cryptic exon inclusion, are activated in a ligand-independent mechanism. The association between sex steroid receptors and brain tumors was described since 1983, but in contrast to the well-established oncogenic role played by androgen receptor (AR) in prostate cancer and the growing evidences on its role in breast cancer, the expression and significance of AR in GBM is controversial and poorly studied. Our previous presented data (Lavon, I. et al. CSIG-13. Neuro-Oncology 18, vi43-vi43 (2016)) and our current results have demonstrated for the first time amplification of AR at the DNA, RNA and protein levels in the majority of GBM samples in patients of both sexes. Our AR-RNA expression results were validated in 703 glioblastomas by analysis of several datasets including the TCGA. We also showed that 30% of glioblastomas express the constitutively active AR-splice-variant AR-V7/AR3. Based on the previously reported activation of AR-V7/AR3 by RTKs, including EGFR, we identified that combination therapy with the AR-antagonist Enzalutamide and EGFR inhibitor is more effective than AR-antagonists alone in cell line expressing AR-V7/AR3. A cell cycle analysis of glioma cells treated with Enzalutamide demonstrated a dose-dependent number of cells in sub-G1 phase suggesting apoptosis as the mechanism for cell death. Enzalutamide given orally (20 mg/kg three time per week) to nude mice bearing human gliomas (U78MG) resulted in reduction of 72% in tumor volume (p=0.0027) as compared to mice treated with vehicle. We hope that the results of this study together with continued laboratory efforts will lead to a new approach for the treatment of human glioblastoma.
DDIS-10. COMPARISON OF CEST AND DWI TO EVALUATE EARLY RESPONSE OF NITROXOLINE TREATMENT IN TEMOZOLOMIDE-RESISTANT GLIOBLASTOMA MODEL
Authors: Nishant Thakur, Nisha Kumari, Hyejin Jeon, Jooyeon Chung, Hye Rim Cho, Seung Hong Choi
Journal: Neuro-Oncology (2017)

Glioblastoma multiforme (GBM) is the most common malignant primary brain tumor with often recurrence. The currently available imaging parameters often are not adequate to make the final decision for treatment. As alterations in metabolism in GBM occur earlier than other variation during chemotherapy so, it would be advantageous to identify early biomarkers for response prediction to chemotherapy. Here, we evaluate the capability of chemical exchange saturation transfer (CEST) magnetic resonance imaging (MRI) to predict the early therapeutic effects of nitroxoline in a temozolomide (TMZ) resistant GBM model. In our study, we prepared TMZ-resistant GBM mouse model treated with 100 mg/kg of nitroxoline for 7 days that resulted in dramatical decreased in amide proton transfer (APT) value, while increased in non-treated group as assessed by CEST. In addition, nitroxoline slow down the tumor progression as compared to non-treated group, in which tumor volume was significantly increased further confirmed by histological examination. Furthermore, to compare the CEST, we investigated DWI for the same step of nitroxoline treatment in which, apparent diffusion coefficient (ADC) value was not increased significantly. Our study suggests that CEST can successfully predict the early response of nitroxoline treatment as compared to DWI and may serve as a biomarker. This would have a major impact on the clinical management of patients with TMZ-resistant GBM.
NIMG-33. CORRELATION BETWEEN IDH MUTATION STATUS, PATIENT SURVIVAL, AND BLOOD VOLUME ESTIMATES IN DIFFUSE GLIOMAS: A TCGA/TCIA PROJECT
Authors: Rajan Jain, Laila M Poisson, Ingrid Littig, Lucidio Neto, Chih-Chun Wu, Victor Ng, Sohil H Patel, Matija Snuderl, David Zagzag, John Golfinos, Andrew S Chi
Journal: Neuro-Oncology (2017)

Prior studies have shown correlation between relative cerebral blood volume (rCBV) and patient survival as well as with tumor genomics. The purpose of this study was to determine whether rCBV values correlate with isocitrate dehydrogenase (IDH) mutation status and patient overall survival in diffuse gliomas. 96 treatment naive gliomas (62 patients from TCGA/TCIA dataset and 34 patients from our institute) (WHO grades II=26, grade III=30, grade IV=40) with DSC T2* perfusion data were included. IDH mutation status (IDHmut-codel, IDHmut-non-codel, and IDHwt) and survival data were assayed by the TCGA, and pre-surgical imaging collected by the TCIA (The Cancer Imaging Archive). rCBV was obtained from 4 regions of interests within the highest perfusion areas including enhancing and non-enhancing segments of each tumor, utilizing Olea Sphere software (Olea Medical, LaCiotat). Mean differences in rCBV are compared by ANOVA and t-test. Associations with overall survival, defined as the time from diagnosis to death or last follow-up, are estimated by Cox regression models and Kaplan-Meier methods. IDHwt gliomas (n=40) demonstrated higher rCBV (rCBV=6.36 ± 3.05) values than IDHmut gliomas (n=46) (rCBV=2.07 ± 1.83; t-test p<0.0001). Gliomas with rCBV <2.0 showed better survival (n=14, median 117.3 months) than gliomas with rCBV >2.0 (n=48, median 15.4 months; log-rank (p<0.0001). Among the IDH mutated tumors, the group with rCBV values >2.0 (n=8) showed poorer survival (36.5% surviving at 3 years) than IDHmut gliomas (n=11) with lower rCBV (87.5% surviving at 3 years; log-rank p=0.0299). IDHwt gliomas have higher rCBV than IDHmut gliomas irrespective of the glioma grade. Higher CBV measurements are associated with poor survival in the entire cohort, and rCBV higher than 2.0 within IDHmut gliomas may identify a subset of IDHmut patients with decreased survival.
Early‐life antibiotic exposure increases the risk of developing allergic symptoms later in life: A meta‐analysis
Authors: F. Ahmadizar, S. J. H. Vijverberg, H. G. M. Arets, A. de Boer, J. E. Lang, J. Garssen, A. Kraneveld, A. H. Maitland‐van der Zee
Journal: Allergy (2017)

Abstract This study systematically reviewed and quantified the relationship between exposure to antibiotics during the first 2 years of life and the risk of allergies/atopies including hay fever, eczema, food allergy, positive skin prick testing ( SPT ), or elevated allergen‐specific serum/plasma immunoglobulin (Ig) E levels later in life. PubMed and Web of Science databases were searched for observational studies published from January 1966 through November 11, 2015. Overall pooled estimates of the odds ratios ( OR s) were obtained using fixed or random‐effects models. Early‐life exposure to antibiotics appears to be related to an increased risk of allergic symptoms of hay fever, eczema, and food allergy later in life. The summary OR for the risk of hay fever (22 studies) was 1.23, 95% confidence interval ( CI ):1.13‐1.34; I 2 : 77.0%. The summary OR for the risk of eczema (22 studies) was 1.26, 95% CI : 1.15‐1.37; I 2 : 74.2%, and the summary OR for food allergy (3 studies) was 1.42, 95% CI : 1.08‐1.87; I 2 : 80.8%. However, no association was found for antibiotics exposure early in life and objective atopy measurements including positive SPT or elevated allergen‐specific serum/plasma IgE levels.
HOUT-10. RISK FACTORS FOR PLATELET TRANSFUSION IN GLIOBLASTOMA SURGERY
Authors: John Sheppard, Carlito Lagman, Prasanth Romiyo, Thien Nguyen, Giyarpuram Prashant, Joel Beckett, Alexander Tucker, Daniel Nagasawa, Isaac Yang
Journal: Neuro-Oncology (2017)

The role of platelet transfusion in glioblastoma surgery is not well-defined. The objective of this study was to identify risk factors for platelet transfusion in glioblastoma surgery and to compare outcomes of prophylactic versus therapeutic transfusion strategies. The records of adult patients who underwent craniotomy for tumor resection at a single academic medical center between March 2013 and January 2017 were retrospectively reviewed to identify patients diagnosed with glioblastoma and who were transfused at least 1 unit of platelets within seven days of surgery or were not transfused platelets. We performed stepwise, multivariate regressions to identify risk factors for platelet transfusion. Through the use of a 1:1 matched case-control study, we compared outcomes of transfusion and no-transfusion groups. Subgroup analyses were performed for the comparisons of transfusion strategies. One hundred and five adult patients who underwent craniotomies for tumor resection and had histopathologic diagnoses of glioblastoma were analyzed. Prior antiplatelet therapy (OR 8.21, 95% CI: 2.36, 28.58), preoperative platelet count less than 188,000/µL (OR 4.48, 95% CI: 1.35-14.91), and operative time (OR 1.73, 95% CI: 1.10-2.72) were significant risk factors for platelet transfusion in glioblastoma surgery. Patients transfused prophylactically were in the hospital longer when compared with patients transfused for active bleeding (9.34 days vs 3.92 days, p < 0.001) and also had an increased risk of experiencing at least one in-hospital complication (OR 30, 95% CI: 1.47, 611.80). No adverse transfusion reactions were observed. We identified several risk factors for platelet transfusion in adult patients having undergone craniotomy for resection of glioblastoma. Prophylactic platelet transfusion was associated with poorer outcomes compared with therapeutic platelet transfusion.
Abstract 15465: Influence of Ejection Fraction on the Prognostic Value of Sympathetic Innervation Imaging with Iodine-123 Meta-iodobenzylguanidine (123I-mIBG) in Heart Failure: An Echocardiography Sub-analysis from the ADMIRE-HF Trial
Authors: Amil M Shah, Mikhail Bourgoun, Arnold F Jacobson, Scott D Solomon
Journal: Circulation (2010)

Background: In systolic heart failure (HF), abnormal myocardial sympathetic innervation imaging by 123I-mIBG and reduced LV ejection fraction (EF) are both associated with increased risk of cardiov...
CSIG-07. INVASIVENESS OF GLIOMA PROMOTED BY C-C MOTIF LIGAND 5 CORRELATES WITH CAMKII SIGNALLING PATHWAY
Authors: Pin-Yuan Chen, Chiung-Yin Huang, Yu-Ju Wu, Kuo-Chen Wei
Journal: Neuro-Oncology (2017)

The microenvironment of malignant glioma is characterized by a series of reactive stromal cells with an abundance of inflammatory mediators, and proteolytic enzymes. Chemokine C-C motif ligand 5 (CCL5) has been reported to facilitate angiogenesis, and migration in serval cancers including glioma. However, the mechanism of how CCL5 facilitate glioma invasion has largely remained unresolved. In this study, firstly, we found higher level of CCL5 expression displayed in tumors than in adjacent brain tissues of glioblastoma patients according to the results from cytokine array. To further identified the effect of CCL5 on glioma cells, the increasing migratory activities of U87MG and A172 glioma cell lines after CCL5 stimulation were revealed by wound healing assay and transwell invasion assay. In addition, CCL5 stimulation increased matrix metalloproteinase (MMP), AKT and p-CaMKII protein expressions. Furthermore, inhibition of CaMKII led to downregulation of CCL5-incuded MMP expression. Our results suggest that modulation of glioma CaMKII may restrict the effect of CCL5 on glioma migration and could be a potential therapeutic strategy for alleviating glioma invasion. Whether CCL5 in tumor microenvironment is secreted by tumor cells or by other neighboring cells that promote glioma invasiveness requires future investigation.
Abstract 21345: Diastolic Blood Pressure is the Predictors of Left Ventricular Myocardial Relaxation in Healthy Postmenopausal Women
Authors: Haruki Sekiguchi, Makiko Kimura, Nobuhisa Hagiwara
Journal: Circulation (2017)

Introduction: Previous studies that indicate metabolic syndrome (MetS) might be at risk for left ventricular (LV) diastolic dysfunction. However, little is known about which metabolic factors contribute to the development of LV dysfunction in postmenopausal women without obesity or overweight, diabetes mellitus, and/or cardiovascular disease. Methods: Participants without diabetes mellitus, systolic dysfunction, or other heart diseases underwent a thorough physical examination including tissue Doppler echocardiography. A peak early mitral annular velocity (e′) of &lt;5.0 was designated as indicating abnormal LV myocardial relaxation (LVMR). We performed single and multiple logistic regression analyses of e′ and cardiovascular risk factors, including MetS factors and indicators of major organ dysfunction. Normal-weight subjects (body mass index &lt;25 kg/m2) were also analyzed. Results: A total of 269 postmenopausal women (mean age, 70 ± 7 years) participated, of which 29 (10.8%) had MetS and 67 (23.8%) had abnormal LVMR. Multiple logistic regression analysis revealed high diastolic blood pressure: DBP (odds ratio [OR] 5.3, 95% confidential interval [CI] 1.89 - 15.0, P &lt; 0.01), abnormal waist circumference (OR 2.4, CI 1.15 - 5.01, P &lt; 0.01) and age (OR 1.1, CI 1.05 - 1.16, P &lt; 0.01) to be predictors of abnormal LVMR. In normal-weight subjects (n = 232), high DBP (OR 5.1, CI 1.65 - 15.89, P &lt; 0.01), and aging (OR 1.1, CI 1.06 - 1.17, P &lt; 0.01) were predictors of abnormal LVMR. Conclusions: In postmenopausal women, only diastolic blood pressure was the independent risk factors for abnormal LVMR in both normal-weight and over-weight individuals, and therefore might be useful for predicting diastolic heart failure during routine physical checkups.
P1.01-037 Circulating Tumor DNA Clearance During Treatment Associates with Improved Progression-Free Survival
Authors: S. Lu, Y. Song, Z. Xie, Z. Zhu, L. Liu, M. Li, X. Dong, M. Jin, J. Hu, C. Rao, G. Tong, D. Zheng, W. Zhao, Y. Chen, H. Han-Zhang, H. Xu, X. Mao, L. Zhang, H. Liu, J. Ye
Journal: Journal of Thoracic Oncology (2017)
IL-17A improves the efficacy of mesenchymal stem cells in ischemic-reperfusion renal injury by increasing Treg percentages by the COX-2/PGE2 pathway
Authors: Ming Bai, Li Zhang, Bo Fu, Jiuxu Bai, Yingjie Zhang, Guangyan Cai, Xueyuan Bai, Zhe Feng, Shiren Sun, Xiangmei Chen
Journal: Kidney International (2017)
PDTM-28. TARGETED INHIBITION OF EZH2 AND BET BROMODOMAIN PROTEINS FOR THE TREATMENT OF DIFFUSE INTRINSIC PONTINE GLIOMAS
Authors: Andrea Piunti, Marc Morgan, Elizabeth Bartom, Nundia Louis, Xingyao He, Ali Zhang, Craig Horbinski, Stacy Marshall, Emily Rendleman, Yoh-hei Takahashi, Alexander Misharin, Nebiyu Abshiru, Rishi Lulla, Amanda Saratsis, Neil Kelleher, C David James, Ali Shilatifard, Rintaro Hashizume
Journal: Neuro-Oncology (2017)

Recent discovery of somatic histone gene mutations, resulting in replacement of lysine 27 by methionine (K27M) in the encoded histone H3.3 proteins, in diffuse intrinsic pontine glioma (DIPG) has dramatically improved our understanding of disease pathogenesis, and stimulated the development of novel therapeutic approaches targeting epigenetic regulators for disease treatment. K27M mutant DIPG shows a dramatic reduction in global methylation at K27 residues on all 16 H3 proteins. This reduction in H3K27 methylation is believed to modify cellular gene expression in a way that favors tumor development. We have shown that inhibition of the H3K27 demethylase JMJD3 acts to restore K27 methylation in DIPG cells, while demonstrating potent anti-tumor activity, in vitro and in vivo. In addition to H3K27 methylation, H3K27 can also be acetylated (K27ac), which requires bromo- and extra-terminal domain (BET) protein activity. We have recently identified H3K27M-K27ac nucleosomes co-localize with BET bromodomain proteins at actively transcribed genes, whereas a polycomb repressive complex 2 (PRC2) is excluded from these regions, demonstrating that H3K27M and PRC2 occupy distinct chromatin regions in DIPG cells. Despite a major loss of H3K27 methylation, PRC2 activity is still detected in H3K27M DIPG cells, and the residual PRC2 activity is required to maintain DIPG proliferative potential by repressing neuronal differentiation and function. Small molecule inhibitor of EZH2 inhibited cell growth through the upregulation of gene that are normally repressed by PRC2 in DIPG. We also tested the anti-tumor activity of BET bromodomain containing protein 4 (BRD4) inhibitor, JQ1, and EZH2 inhibitor, GSK126, in our human DIPG xenograft model, and JQ1 and GSK126 treatment results in a significant delay of tumor progression and prolonged animal survival. Our findings suggest EZH2 inhibition could be a potential combinatorial strategy with BRD4 inhibition in treating K27M DIPG, that could counteract the development of resistance to single-agent epigenetic therapy.