tbuckley/cabot-search huggingface dataset:
P08.30 CMV infection influences paracrine interactions in the glioblastoma microenvironment and amplifies the angiogenic phenotype.
Authors: H. Krenzlin, K. Grauwet, P. Behara1, M. Griessl, M. Gutknecht, C. H. Cook, A. E. Chiocca, S. Lawler
Journal: Neuro-Oncology (2017)

Objective: Cytomegalovirus (CMV) is a ubiquitous member of the herpes virus family with a prevalence of between 50-100% in the human population and lifelong persistence. While usually clinically benign, severe cases are observed in neonates and immunocompromised patients. CMV has been associated with various tumors, including glioblastoma (GBM). The aim of this study is to clarify the interrelationship between CMV and GBM, as to elucidate its contribution to GBM progression. Methods: Pericytes, proneural (PN) and mesenchymal (MES) human GBM cell lines were assessed via flow cytometry for permissiveness to CMV (Towne Strain) infection. The transcriptome of infected cells was assessed using RT-qPCR and RNA-Seq analysis. Transwell migration and endothelial tube formation were evaluated in co-culture experiments. C57BL/6 mice were infected with murine CMV (MCMV-Δm157) at P2 and syngeneic GL261 tumor cells were implanted at week 14 after latency was established. Tumor composition was analyzed using flow cytometry. Murine and human brain sections were analyzed by immunofluorescence staining. Results: CMV was found to closely co-localize with tumor vessels in patient derived GBM specimens. In vitro studies confirmed a high permissiveness of pericytes for CMV infection. GBM cells, permissive for CMV infection had a proneural, rather than a mesenchymal signature. The transcription of pro-angiogenic cytokines such as IL-6, TGF-beta and angiogenesis inducing receptor PAR-1 were up-regulated upon CMV infection. Transwell assays revealed increased migration towards CMV infected cells after 48h (GBM cells towards infected pericytes: 1.5-fold (p=0.07); pericytes towards infected GBM cells: 1.48-fold (p=0.009)). Further, co-culture of human brain microvascular endothelial cells (HBMEC) and infected PN cells led to the establishment of larger (160%, p=<.0001) and more complex (number of junctions 9.5 (-) vs. 21 (+), p<.0001)) tube formations on Matrigel. In vivo, tumors formed by GL261 cells in MCMV infected mice (n=10) showed significantly higher numbers of infiltrating pericytes and were better vascularized compared to those of uninfected animals (n=10). Tumor cell infiltrates showed profound changes in CMV latent mice. Conclusion: In this study, we showed that tumor associated pericytes and GBM cells with a proneural signature are prone to CMV infection, which induces a distinct cytokine production. Enhanced tube formation of HBMEC in vitro and the increased migration of tumor cells and pericytes towards infected cells suggests a contribution of CMV to shape a distinct tumor microenvironment. Moreover, higher pericyte infiltration and increased angiogenesis was found in vivo. We conclude that CMV may cause GBM progression by increasing diffuse infiltration and angiogenesis via paracrine signaling.
Detection of circulating thyroid cancer cells by quantitative RT-PCR for TSH receptor mRNA: Role of pre and post surgery levels in monitoring patients with thyroid cancer
Authors: Manjula Gupta, Su-Ynn Chia, Mira Milas, Allan Siperstein
Journal: Clinical Cancer Research (2007)

B18  Introduction: Thyroid cancer accounts for 90% of all endocrine malignancies, and is responsible for more deaths than all other endocrine cancers combined. Current management of differentiated thyroid cancer (DTC) relies on the fine-needle aspiration biopsy (FNA) for the pre-operative evaluation of thyroid nodules, and on serum thyroglobulin (Tg) measurement for monitoring recurrent disease post-operatively. Both methods while useful have well-recognized limitations. Detection of circulating thyroid cancer cells by analysis of thyroid-specific proteins/genes has been proposed as the most promising method to solve these problems.  Methods: Detection of thyroid cancer cells in circulation by measuring preoperative TSH receptor mRNA expression using quantitative RT-PCR provides high diagnostic sensitivity and specificity. It distinguished normal, benign, and malignant, (p 46 ng/mL and positive WBS. Overall concordance with stimulated Tg was 81% and with WBS was 96%.  Conclusions: Our results suggest that TSHR-mRNA levels immediately post-op are predictictive of residual/metastatic disease and correlate with disease activity in long term monitoring of patients with thyroid cancer.
P16.29 Malignant craniopharyngioma
Authors: E. Unal, K. Kilic, N. Ozdemir, F. Gunver, S. Isik, S. Can
Journal: Neuro-Oncology (2017)

Introduction: Malignant transformation of craniopharyngioma has rarely been described. In this article, we report a case of 28th malignant craniopharyngioma ever mentioned in English literature. Materials and Methods: We performed a PUBMED, HUBMED, BAU Library Database and Ovid search on malignant craniopharyngiomas and identified 27 reported cases. CASE DESCRIPTION: 44 years old female patient was diagnosed with craniopharyngioma two years ago and underwent surgical resection of a typical craniopharyngioma, the histopathological result was adamantinomatous craniopharyngioma of Grade I. There was no malignancy. One year ago cavernous sinus invasion has been detected and gamma knife irradiation has been made. At admission she was blind in the right eye for the last six months and the vision was diminished in the left eye for a month. The MRI showed that nasal cavity was full of tumor, that the clivus was almost completely destructed and that orbita and maxillary sinus were also invaded. Firstly the ENT surgeons debulked the tumor via transmaxillary route and then the transcranial approach allowed only a subtotal removal due to a profuse bleeding. The histopatological examination showed malignant tumoral infiltration rich in cells with many mitoses. The patient died two years later. CONCLUSION: The relevant literature of malignant craniopharyngioma is reviewed and discussed. The surgeon must be aware that total removal of a malignant craniopharyngioma can be hazardous because of intractable bleedings occurring during surgery.
Systematic literature review (SLR) of clinical and real-world observational studies of octreotide LAR for treatment of neuroendocrine tumors (NETs).
Authors: Rachael Sorg, Maureen Neary, Cassie Tang, Cherry Song, Jipan Xie
Journal: Journal of Clinical Oncology (2015)

e15190 Background: Octreotide LAR is indicated by the FDA for severe diarrhea/flushing episodes associated with metastatic carcinoid tumors and recommended in NCCN guidelines for tumor control and treatment of carcinoid syndrome in NET. This study reviewed clinical and observational studies of octreotide LAR in treatment of NET relative to clinical and symptom outcomes. Methods: SLR was performed to identify articles evaluating octreotide LAR in NET published through 2014 in MEDLINE, EMBASE, and Cochrane Library and the most recent 3 years for 3 conferences (ASCO, ESMO, NANETS). Studies reporting efficacy (overall survival [OS], time to progression [TTP], progression-free survival [PFS], response rate, symptom control, rescue therapy, quality of life [QoL]) or adverse events (AEs) of octreotide LAR in NET were included. Results: SLR identified 20 full-text articles and 7 conference abstracts reporting efficacy or safety of octreotide LAR in NET, across 7 clinical and 19 observational studies. Studies included a total of 2,316 patients receiving octreotide LAR; sample sizes in these studies ranged from 8-392. Tumor origin included pancreas, midgut, hindgut, and lung. Follow-up duration ranged from 1-307.4 months; octreotide LAR treatment duration varied from 1-81 months. Twelve reported OS (median from 25.3-112 months in 6 studies, median not reached in 6); 6 reported TTP (median from 12-30 months in 5 studies, median not reached in 1) and 5 reported PFS (median from 6.8-41 months). Thirteen reported symptom control with varying definitions. Among studies with available data, symptom resolution/improvement rates ranged from 33-91% for diarrhea (N = 5), 53-100% for flushing (N = 5), and 50-100% for abdominal pain (N = 3). Additionally, 16 reported response rates, 11 reported AEs, 1 reported rescue therapy, and 1 reported QoL. Conclusions: This SLR provided a detailed review of literature for octreotide LAR in NET in clinical and observational studies. Studies had large variation in design, patient populations, and outcome definitions. Many patients were treated with octreotide LAR across these studies, with some having long follow-up and extended treatment duration.
P18.15 Associations between seizure control and cognition in tumour associated epilepsy compared with non-tumoural epilepsy
Authors: A. Twenhöfel, L. Rankin, H. Ingle, D. Gillespie, R. Grant
Journal: Neuro-Oncology (2017)

Introduction: Epilepsy is associated with adverse effects on cognition and psychological functioning. Polytherapy and poor seizure control have been associated with poor cognition. Little research has been carried out on the impact of epileptic seizures and anti-epileptic drugs (AED) on cognition in patients with brain tumours (BT). We have compared cognitive abilities in patients with tumour associated epilepsy (TAE) (“controlled” and “active”) and compared this with non-tumoural epilepsy (NTE) with active epilepsy to look at the effect of polytherapy and seizure frequency on cognition. METHODS: We studied cognition, mood and fatigue in patients with epilepsy attending the Edinburgh Centre for Neuro-Oncology clinic with TAE (n = 32 “controlled” and n = 36 “active”) and patients attending a hospital epilepsy service with NTE (n = 29). Consented patients completed the following neuro-cognitive tests (Hopkins Verbal Learning Test–Revised, Brain Injury Rehabilitation Trust - Memory and Information Processing, the Trail Making Test, the Controlled Oral Word Association Test, the Hospital Anxiety and Depression Scale (HADS) and the Brief Fatigue Inventory. Results: The two TAE groups did not significantly differ in any tumour variables (type, location, site, lateralisation, therapy). Patients with “controlled” TAE were significantly more often taking AED monotherapy compared with patients with “active” TAE and NTE. Most patients (78%) were on “new generation” AEDs. Levetiracetam was the most common prescribed drug (monotherapy and first-drug polytherapy). Patients with “controlled” TAE (M = -0.6, SD = 0.8) scored significantly higher on a composite memory (verbal and visual) z-score than those with “active” TAE (M = -1.13, SD = 1.09) and NTE (M = -1.35, SD = 0.85) [F (2,94)= 11.69, p= 0.001]. Multinomial Logistic Regression Analysis showed that even when controlled for the cognitive effect of AED polytherapy the relative risk of having memory impairment was 98% higher for patients with “active” compared to “controlled” TAE, p = .03, 95% CI [6%, 270%]) (and even higher for NTE). Furthermore NTE patients (M = 9.26, SD = 3.77) were significantly more anxious than “controlled” TAE patients (M = 6, SD = 4.91) [F (1,78)= 8.82, p= .003] as measured on the HADS (7 items scored from 0-3; caseness cut-off 8). CONCLUSION: Seizure control is associated with better cognitive memory abilities and psychological functioning in TAE patients. AED polytherapy with newer agents does not necessarily lead to an additional cognitive burden. Whereas previous studies stressed the negative influence of AED (poly-) therapy on cognition in BT patients, the present study suggested a cognitive impact of “active” TAE beyond the influence of AEDs. The prominent cognitive impact of AED therapy in previous studies may have been be related to the type of drugs prescribed, if patients were taking AEDs of the “old generation”.
Abstract 426: A Novel Method to Study Viral Cardiomyopathy
Authors: Millie Shah, Cheryl Borgman, Kevin Janes
Journal: Circulation Research (2015)

Latent coxsackievirus B3 (CVB3) cardiac infections are implicated in the development of DCM with persistent enteroviral RNA found in up to 66% (30/45) of DCM patient biopsies who are at a 6-fold higher risk of fatality. Current treatments aim at delaying heart failure but none address the viral etiology of the disease. Viral protein presence is thought to disrupt normal cellular signaling leading to tissue dysfunction. The downstream effects of viral perturbations are complex and wide-ranging; especially in proinflammatory contexts seen clinically. Thus, comprehensively understanding the molecular mechanisms of CVB3-mediated disease is key in developing treatments for viral DCM patients. In this study we built a novel in vitro model of chronic CVB3 infection to facilitate high-throughput, systems-level studies of viral cardiomyopathy. Current methods of studying CVB3 rely on animals or animal derived cardiac cells, making large-scale intracellular signaling studies difficult, time intensive, and expensive. To facilitate high-throughput studies we used immortalized human cardiomyocytes to engineer single-cell derived cell lines that express a maturation deficient CVB3 genome. CVB3 RNA expression was validated in each line by two independent methods: gene-specific nested qRT-PCR and single molecule RNA fluorescence in situ hydridization (smFISH). Plaque-assay verified that viral RNA expression did not result in live virus release. Microarray analysis shows that CVB3 expressing cell lines have altered immune cytokine, extracellular matrix protein, and stress-signaling protein expression. Further, differences between CVB3 expressing lines suggest differential responses to viral RNA expression which may identify a set of beneficial adaptations. Future studies will include high-throughput signaling protein activity assays we have developed specifically for phosphatase and kinase activity quantification with the aim of linking immune cytokine signaling dysregulation to pathogenic gene expression. These studies will deepen our knowledge of CVB3-mediated DCM and identify proteins whose targeted modulation could offer new treatment strategies to patients whose current options are either palliative care or heart transplantation.
Abstract P063: BMP-2 Upregulates PTEN Expression and Induces Apoptosis of Pulmonary Artery Smooth Muscle Cells Under Hypoxia
Authors: Weifeng Pi, LiPing Su, Jian Zhu, Weiguo Xu
Journal: Circulation Research (2011)

Background: Primary pulmonary hypertension is mainly caused by increased proliferation and decreased apoptosis in pulmonary artery smooth muscle cells (PASMCs). Aim: To investigate the role of BMP-2 in regulation of PTEN and apoptosis of PASMCs under hypoxia. Methods: Normal human PASMCs were cultured in basal medium (BM) or growth medium (GM) and treated with BMP-2 from 5–80 ng/ml under hypoxia (5% CO 2 + 94% N 2 +1% O 2 ) for 72 hours. Gene expression of PTEN, caspase−3, −8, and −9, AKT-1 and -2 were determined by quantitative RT-PCR (QRT-PCR). Protein expression levels of PTEN, AKT and phosph-AKT (pAKT) were determined. Apoptosis of PASMCs were determined by measuring activities of caspases-3, -8 and -9. siRNA-smad-4 was used to determine whether Smad signaling pathway was involved in the regulation of PTEN expression by BMP-2. bpV(HOpic) (PTEN inhibitor) and GW9662 (PPAR-r antagonist) were also used. Results: Proliferation of PASMCs showed dose dependence of BMP-2, the lowest proliferative rate was achieved at 40–60ng/ml under hypoxia (BM=77.2±4%, GM=80±2.8%). Increased gene expression levels of PTEN, caspases−3, −8 and −9 were found, while AKT-1, and -2 did not change. Consistently, the PTEN protein expression also showed dose dependence of BMP-2. Though AKT was unchanged in all treated samples, reduced pAKT was found in BMP-2 treated PASMCs. Increased activities of caspase-3, -8 and -9 of PASMCs were found after cultured with BMP-2 in both mediums. PTEN expression was unchanged when Smad-4 expression was inhibited. However pre-treat PASMCs with bpV(HOpic) and GW9662 (PPAR-r inhibitor) inhibited PTEN protein expression and recovered PASMCs proliferation rate. Conclusion: BMP-2 can increase PTEN expression under hypoxia in a dose dependent pattern. BMP-2 can increase apoptosis of PASMCs under hypoxia. The increased PTEN expression may be mediated through PPAR-r signalling pathway, instead of BMP/Smad signalling pathway.
A novel role of astrocyte elevated gene‐1 (AEG‐1) in regulating nonalcoholic steatohepatitis (NASH)
Authors: Jyoti Srivastava, Chadia L. Robertson, Kareem Ebeid, Mikhail Dozmorov, Devaraja Rajasekaran, Rachel Mendoza, Ayesha Siddiq, Maaged A. Akiel, Nidhi Jariwala, Xue‐Ning Shen, Jolene J. Windle, Mark A. Subler, Nitai D. Mukhopadhyay, Shah Giashuddin, Shobha Ghosh, Zhao Lai, Yidong Chen, Paul B. Fisher, Aliasger K. Salem, Arun J. Sanyal, Devanand Sarkar
Journal: Hepatology (2017)

Nonalcoholic steatohepatitis (NASH) is the most prevalent cause of chronic liver disease in the Western world. However, an optimum therapy for NASH is yet to be established, mandating more in‐depth investigation into the molecular pathogenesis of NASH to identify novel regulatory molecules and develop targeted therapies. Here, we unravel a unique function of astrocyte elevated gene‐1(AEG‐1)/metadherin in NASH using a transgenic mouse with hepatocyte‐specific overexpression of AEG‐1 (Alb/AEG‐1) and a conditional hepatocyte‐specific AEG‐1 knockout mouse (AEG‐1 ΔHEP ). Alb/AEG‐1 mice developed spontaneous NASH whereas AEG‐1 ΔHEP mice were protected from high‐fat diet (HFD)‐induced NASH. Intriguingly, AEG‐1 overexpression was observed in livers of NASH patients and wild‐type (WT) mice that developed steatosis upon feeding HFD. In‐depth molecular analysis unraveled that inhibition of peroxisome proliferator‐activated receptor alpha activity resulting in decreased fatty acid β‐oxidation, augmentation of translation of fatty acid synthase resulting in de novo lipogenesis, and increased nuclear factor kappa B–mediated inflammation act in concert to mediate AEG‐1‐induced NASH. Therapeutically, hepatocyte‐specific nanoparticle‐delivered AEG‐1 small interfering RNA provided marked protection from HFD‐induced NASH in WT mice. Conclusion : AEG‐1 might be a key molecule regulating initiation and progression of NASH. AEG‐1 inhibitory strategies might be developed as a potential therapeutic intervention in NASH patients. (H epatology 2017;66:466–480).
A shared statement of ethical principles for those who shape and give health care
Authors: S. R. Benatar, D. M. Berwick, M. Bisognano, J. Dalton, F. Davidoff, J. Frenk, H. Hiatt, B. Hurwitz, P. Janeway, M. H. Marshall, R. Norling, M. R. Rocklage, H. Scott, A. Sen, R. Smith, A. Sommerville
Journal: BMJ (1999)
OS04.3 Extent of resection and overall survival in risk adjusted and exact matched analyses of 22,928 glioblastoma (all molecular subtypes) patients
Authors: B. Iorgulescu
Journal: Neuro-Oncology (2017)

Background: Maximal tumor resection, chemo- and radiotherapy are the standard of care for glioblastoma (GBM), of which robust assessment by clinical trial methodology has been limited by GBM's severely abridged survival and relatively rare prevalence. Methods: The United States National Cancer Database was queried for GBM patients newly-diagnosed from 2004–2014. Overall survival (OS) was assessed by Cox proportional hazards, stratified by extent of resection, and risk adjusted for age, sex, race, Charlson's comorbidity index, insurance, facility location, facility annual case volume, chemotherapy, radiotherapy, tumor location, tumor laterality, and tumor size; and estimated by Kaplan-Meier methods. Subgroup analyses included MGMT methylation or Karnofsky Performance Score, in the risk adjustment. Coarsened exact matching was used to simulate allocation in an interventional trial. Results: 82,960 adult GBM (all molecular subtypes) patients remained after exclusion, 22,928 with complete data for extent of resection and risk adjustment variables, 83% (n=19,007) of which reached endpoint for OS. Median OS for gross total resection (GTR) was 15.5 mos. (95%CI: 15.2–15.9), compared to 11.7 mos. for subtotal resection (STR; 95%CI: 11.3–12.0; HR 1.29, p<0.001) and 5.9 mos. for those who did not undergo resection (NR; 95%CI: 5.7–6.2; HR 1.56, p<0.001). Estimated 2yr OS rates were GTR 30.7% (95%CI: 29.7–31.8), STR 22.1% (95%CI: 21.1–23.0), and NR 14.8% (95%CI: 14.1–15.5). Notably, in the risk-adjustment adjuvant chemotherapy (HR 0.63, 95%CI: 0.60–0.66), radiotherapy (HR 0.71, 95%CI: 0.68–0.75), unilateral tumor (HR 0.66 vs. bilateral, 95%CI: 0.58–0.76), and supratentorial tumors (HR 0.77 vs. infratentorial, 95%CI: 0.71–0.86) were associated with significantly (p<0.001) improved OS. Additionally, coarsened exact matched (5,867 GTR: 5,867 STR) cohorts demonstrated similar outcomes, (GTR HR vs. STR: 0.74, 95%CI: 0.71–0.78). Median OS for patients with these favorable characteristics was 24.2 mos. vs. 1.5 mos. for those with unfavorable characteristics. In subgroup analyses, GTR significance remained after including MGMT (n=2,776) status in the risk-adjustment (HR vs. STR: 0.74) and MGMT methylation was associated with improved OS (HR 0.66, 95%CI: 0.60–0.72). Compared to STR, GTR was associated with reduced rates of 30- and 90-day mortality (OR 0.71 and 0.64, respectively). Conclusion: In the largest prospectively collected dataset of its kind, GTR for GBM was associated with significantly improved OS compared to STR or NR, in risk adjusted and exact matched analyses. Adjuvant chemotherapy, radiotherapy, unilaterality, supratentorial location, and MGMT methylation in the risk adjusted analysis were also associated with significantly improved OS.
Characterisation of eppin function: expression and activity in the lung
Authors: Aaron Scott, Arlene Glasgow, Donna Small, Simon Carlile, Maelíosa McCrudden, Denise McLean, Ryan Brown, Declan Doherty, Fionnuala T. Lundy, Umar I. Hamid, Cecilia M. O'Kane, Daniel F. McAuley, Malcolm Brodlie, Michael Tunney, J. Stuart Elborn, Chris R. Irwin, David J. Timson, Clifford C. Taggart, Sinéad Weldon
Journal: European Respiratory Journal (2017)

Eppin is a serine protease inhibitor expressed in male reproductive tissues. The aim of this study was to investigate the localisation and regulation of eppin expression in myeloid and epithelial cell lines, and explore its potential role as a multifunctional host defence protein. Using immunohistochemistry and Western blotting, eppin was detected in the lungs of patients with acute respiratory distress syndrome and cystic fibrosis lung disease. Expression of eppin in monocytic cells was unaffected by stimulation with Toll-like receptor agonists, cytokines and hormone receptor agonists. However, upregulated expression and secretion of eppin was observed following treatment of monocytes with epidermal growth factor. Incubation of recombinant eppin with monocytic cells resulted in significant inhibition of lipopolysaccharide-induced chemokine production. Furthermore, eppin inhibited lipopolysaccharide-induced NF-κB activation by a mechanism which involved accumulation of phosphorylated IκBα. In an in vivo model of lung inflammation induced by lipopolysaccharide, eppin administration resulted in decreased recruitment of neutrophils to the lung with a concomitant reduction in the levels of the neutrophil chemokine macrophage inflammatory protein-2. Overall, these results suggest a role for eppin outside of the reproductive tract and that eppin may have a role in the innate immune response in the lung.
A novel framework to account for ecological drivers in the control and elimination of environmentally transmitted disease: a modelling study
Authors: Giulio A De Leo, Susanne H Sokolow, Andres Garchitorena, Calistus N Ngonghala, Andrea Lund, Michele Barry, Katherine S Burke, Erin A Mordecai, Gretchen C Daily, James H Jones, Jason R Andrews, Eran Bendavid, Stephen P Luby, A Desiree LaBeaud, Krish Seetah, Jean-François Guégan, Kevin Lafferty, Chelsea L Wood, Isabel J Jones, Matthew H Bonds
Journal: The Lancet (2017)