tbuckley/cabot-search huggingface dataset:
CBMT-21. ALTERATIONS OF CYSTEINE METABOLISM IN GENETIC VARIANTS OF HIGH GRADE GLIOMAS
Authors: Mirna Lechpammer, Zachary Rabow, Taryn Morningstar, Jean-Pierre Gagner, Kiarash Shahlaie, Fady Girgis, Ralph Green, Evgeny Nudler, David Zagzag
Journal: Neuro-Oncology (2018)

Isocitrate dehydrogenase (IDH) mutation have been reported to impose in gliomas a shortage of NADPH required to maintain a redox state and may rely on cysteine (Cys) availability for biosynthesis of glutathione (GSH) to ensure antioxidant levels. Cys may be replenished via extracellular intake or by de novo intracellular synthesis via transsulfuration (TS) pathway. The aim of this study was to investigate alterations of Cys metabolism in genetic variants of high-grade gliomas (HGG). Seventeen tumor samples from 15 adult patients (11 M / 4 F; average age 57 years, range 25 – 81 years), who underwent surgical resection for newly diagnosed or recurrent HGG were analyzed by HPLC. Levels of Cys, homocysteine and GSH were correlated with the genetic signature of HGG (wild-types vs. IDH1 mutation, PTEN deletion, EGFR amplification and MGMT methylation). Cys levels were significantly higher (2.1 fold increase; p=0.0038) in IDH1-mut (n=4) vs. IDH1-wt HGG (n=13), with comparable homocysteine and GSH levels. PTEN deletion and EGFR amplification did not significantly alter Cys metabolites with comparable levels of Cys, homocysteine and GSH detected in PTEN-del (n=7) and PTEN-intact (n=6) HGG, as well as in EGFR-amp (n=7) and EGFR-non amp (n=9) HGG. Significantly higher Cys levels (3.2 fold increase; p=0.0186) were also found in MGMT methylated (n=4) vs. non-methylated (n=3) HGG, with comparable levels of homocysteine and GSH. Increased Cys levels detected in IDH1-mut and MGMT methylated HGG support the hypothesis that these tumors may preferentially use the TS pathway for GSH synthesis. These findings are consistent with our report of increased TS pathway enzyme cystathionine B-synthase (CBS) in HGG, but concurrent increased intake of Cys cannot be excluded. Our results suggest utilizing Cys metabolites as potential markers and/or therapeutic targets in some genetic variants of HGG, a hypothesis that should be further explored in larger translational trials.
Abstract P033: Impact of Empathetic Touch Therapy on Reducing Feelings of Stress, Anxiety, Pain and Depression
Authors: Donna Arz, Michael McClain, Kathy Quach, Joseph Sky, David Steinhorn, Sachin A Shah
Journal: Circulation (2018)

Introduction: The association between post-traumatic stress disorder (PTSD) and cardiovascular disease has been established. Complementary and integrative medicine (CAM) modalities are commonly underutilized due to their mixed results and need further evaluation. Empathetic Touch therapy is a holistic healing tool, which incorporates integrative medicine techniques such as energy healing, acupressure, craniosacral therapy, shamanic healing, aspects of Chinese medicine and spiritual care to promote wholeness in the body, mind, and spirit. The purpose of this study is to analyze symptoms of stress, anxiety, pain, and depression in a primarily veterans affairs population suffering from PTSD and voluntarily undergoing Empathetic Touch therapy sessions at a non-profit organization called the Forgotten Soldier Program. Hypothesis: We assessed the hypothesis that Empathetic Touch therapy will reduce feelings of anxiety, stress, pain, and depression. Methods: This is a retrospective analysis of 424 participants from the Forgotten Soldier Program who completed surveys before and after an approximately 1-hour session of Empathetic Touch therapy (November 7, 2013 through August 11, 2017). Self-reported scores on a scale of 0 to 10 for feelings of stress, anxiety, pain, and depression were collected before and after every therapy session. The change from baseline was determined and analyzed using a paired t-test. Results: Across a cohort of 424 individual patients, a total of 1,359 individual sessions were included for analysis. Self-reported feelings of stress (n=1267), anxiety (n=1223), pain (n=1275), and depression (n=416) were reduced by 3.27±3.34, 2.98±3.53, 2.44±3.66 and 1.46±3.7 (all p-values &lt;0.001), respectively. No significant adverse events related to Empathetic Touch therapy were reported. Conclusion: Empathetic Touch therapy significantly reduces feelings of stress, anxiety, pain, and depression. Alternative and integrative modalities need to be further incorporated in a holistic treatment of patients. Assessing the impact of Empathetic Touch therapy on cardiovascular endpoints is warranted.
Pharmacologic inhibition of hypoxia‐inducible factor (HIF)‐hydroxylases ameliorates allergic contact dermatitis
Authors: Mario C. Manresa, Leila Smith, Laura Casals‐Diaz, Raphael R. Fagundes, Eric Brown, Praveen Radhakrishnan, Stephen J. Murphy, Bianca Crifo, Moritz J. Strowitzki, Doug N. Halligan, Ellen H. van den Bogaard, Hanna Niehues, Martin Schneider, Cormac T. Taylor, Martin Steinhoff
Journal: Allergy (2018)

Abstract Background When an immune cell migrates from the bloodstream to a site of chronic inflammation, it experiences a profound decrease in microenvironmental oxygen levels leading to a state of cellular hypoxia. The hypoxia‐inducible factor‐1α ( HIF ‐1α) promotes an adaptive transcriptional response to hypoxia and as such is a major regulator of immune cell survival and function. HIF hydroxylases are the family of oxygen‐sensing enzymes primarily responsible for conferring oxygen dependence upon the HIF pathway. Methods Using a mouse model of allergic contact dermatitis ( ACD ), we tested the effects of treatment with the pharmacologic hydroxylase inhibitor DMOG , which mimics hypoxia, on disease development. Results Re‐exposure of sensitized mice to 2,4‐dinitrofluorobenzene ( DNFB ) elicited inflammation, edema, chemokine synthesis (including CXCL 1 and CCL 5) and the recruitment of neutrophils and eosinophils. Intraperitoneal or topical application of the pharmacologic hydroxylase inhibitors dymethyloxalylglycine ( DMOG ) or JNJ 1935 attenuated this inflammatory response. Reduced inflammation was associated with diminished recruitment of neutrophils and eosinophils but not lymphocytes. Finally, hydroxylase inhibition reduced cytokine‐induced chemokine production in cultured primary keratinocytes through attenuation of the JNK pathway. Conclusion These data demonstrate that hydroxylase inhibition attenuates the recruitment of neutrophils to inflamed skin through reduction of chemokine production and increased neutrophilic apoptosis. Thus, pharmacologic inhibition of HIF hydroxylases may be an effective new therapeutic approach in allergic skin inflammation.
Abstract P025: Left Atrial Dilatation Predicts The Incidence Of Persistent Atrial Fibrillation In Japanese General Population; The Suita Study
Authors: Aya Higashiyama, Makoto Watanabe, Yoshihiro Kokubo, Tomonori Okamura, Akira Okayama, Yoshihiro Miyamoto
Journal: Circulation (2018)

Objective: Atrial fibrillation (AF) is an important risk factor for cardiovascular disease (CVD). Left atrial (LA) dilatation detected by ultrasonic cardiography (UCG) has been reported to be associated with the incidence of AF in Western countries. However, the relationship between LA dilatation and the AF incidence has not been well investigated in Asian countries, with lower incidence of AF and obesity and with higher incidence of hypertension and stroke. To investigate the relationship between LA dilatation and the AF incidence in Japanese general population, we estimated the multivariate-adjusted hazard ratios (HR) of LA dilatation assessed by UCG for the incidence of AF. Methods: Participants were 1,585 individuals without AF (665 men, 920 women) who are the participants of a prospective cohort study for CVD incidence in urban Japanese general population (the Suita study). The mean±SD age of the participants were 67.8±7.0 years. Transthoracic UCG was performed from July in 2007 to June in 2013, and LA dimension was determined in accordance with American Society of Echocardiography recommendations by M-mode echocardiograms. After the UCG, the electrocardiograms (ECG) were repeatedly performed until March in 2016. The physicians coded the ECG using Minnesota Code (MC), and AF code is defined as 8-3-1. The HRs of LA dilatation for the incidence of AF with 95% confidence interval (CI) were estimated by Cox proportional hazard model with the adjustment for the followings at the UCG test; age, sex, systolic blood pressure, body mass index, the presence of heavy drinking (more than 2 drinks/day), non-HDL cholesterol, and the presence of the moderate or severe mitral or aortic valve abnormality detected by UCG. Results: The mean follow-up period from UCG to the last ECG was 4.6±1.8 years, and 19 AF incidences were detected. The multivariate-adjusted HR of the LA dilatation (&gt;40 mm) for the incidence of AF was 8.19 (95% CI: 2.47-27.14). And the multivariate-adjusted HR of 5 mm increment of LA dimension was 2.95 (1.65-5.29), and that of the highest quartile of LA dimension compared to the lowest was 3.37 (0.64-17.78). Among 674 participants with left atrial volume index (LAVI) data (5 AF cases), the multivariate-adjusted HR of LAVI ≥ 32 (ml/m 2 ) for AF incidence was 3.93 (95%CI: 0.34-45.86), and it showed the highest HR among the co-adjusted factors. Conclusion: LA diameter assessed by UCG is a simple and non-invasive clinical data, and could be a useful factor for the prediction of AF incidence among Japanese general population. Although the follow-up period was not enough compared to the previous studies in Western population, the present study might indicate that individuals with LA dilation detected by UCG are the important candidate for careful and continuous check-ups about CVD risk factors, ECG and UCG in Asian population.
STEM-20. Spt6 REGULATES TRANSCRIPTION BY STABILIZING RNA Pol II AND SO DRIVES GLIOBLASTOMA CANCER STEM-LIKE CELL MAINTENANCE
Authors: Rikke Rasmussen, Elisabeth Anne Adanma Obara, Alex Frias, Diana Aguilar-Morante, Kristoffer Vitting-Seerup, Petra Hamerlik
Journal: Neuro-Oncology (2018)

Glioblastoma (GBM) is the most advanced and lethal tumor with epigenetically distinct cancer stem-like cells (CSCs) resistant to chemo- and radio-therapy. Spt6 is a histone chaperon involved in nucleosome assembly and regulates RNA polymerase II-mediated transcription. Our preliminary data identified Spt6 to be crucial for glioblastoma stem cells (GSCs) genomic stability and survival. Spt6 depletion in GSCs decreased global transcription rates and cell cycle entry. Cycloheximide and proteasome inhibitor (MG132) experiments confirmed that Spt6 stabilizes RNA polymerase II and so regulates GSC maintenance at a transcriptional level. Spt6 loss impaired GSC survival in vitro and tumor initiating capacity in vivo, thereby making it an attractive target for glioblastoma therapy.
Abstract 16314: The Obesity Paradox in Critical Limb Ischemia Patients (From J BEAT Registry)
Authors: Naotaka Murata, Yoshimitu Soga, Osamu Iida, Norihiko Kamioka, Yohei Kobayashi, Kei Ichihashi, Yusuke Tomoi
Journal: Circulation (2013)

Background: Previous reports indicate that the body mass index (BMI) is inversely related with mortality in peripheral arterial disease. However, such a relationship is unclear in critical limb isc...
RTHP-09. DYSREGULATION OF Wnt SIGNALING PATHWAY CORRELATES WITH TREATMENT OUTCOME IN GLIOBLASTOMA MULTIFORME
Authors: Eric Weterings, Christopher Morrison, Nicholas Gravbrot, Michael Hammer, Daruka Mahadevan, Baldassarre Stea
Journal: Neuro-Oncology (2018)

Glioblastoma multiforme (GBM) is the most common and most aggressive primary brain cancer with a median life expectancy of 13–15 months after surgery and chemo-radiation treatment. GBM is hallmarked by a poor response to radiation therapy (RT), which is generally attributed to upregulation of several DNA repair pathways. To identify pathways which predict poor chemo-radiation treatment outcome, we conducted a retrospective clinical-genetic study in which we evaluated the mRNA expression profiles of 24 GBM tumor samples, stratified on the basis of patient survival post chemo-radiation treatment. All patients were treated at our institution by surgical resection and intensity-modulated RT with concurrent and adjuvant temozolomide. Expression profiles were obtained utilizing a commercially available PanCancer Pathways Panel (NanoString Technologies, Inc.). Our data analysis shows a distinctly significant correlation between 5 members of the Wnt pathway and overall patient survival. A 2- to 9-fold higher expression of negative regulators of the Wnt pathway and a 2- to 3-fold lower expression of positive Wnt regulators was observed in tumor material of patients with a longer than median survival. We conclude that upregulation of the Wnt pathway correlates with poor chemo-radiation treatment outcome in GBM. In vitro experimentation by other groups has recently demonstrated a role for Wnt signaling in activation of Non-Homologous End-Joining mediated DNA double-strand break repair and the subsequent onset of radio-resistance. These preliminary findings support the hypothesis that the Wnt pathway may be used as a predictive marker for RT outcome in GBM and suggest new strategies to increase the radiation sensitivity of GBM.
QOLP-11. QUALITY OF LIFE IN HIGH-GRADE GLIOMA PATIENTS ON A PHASE I VIROTHERAPY STUDY
Authors: Lauren Kloeppinger, Christina Amidei, Maciej Lesniak, Roger Stupp, James Chandler, Matthew Tate, Adam Sonabend, Orin Bloch, Rimas Lukas, Sean Sachdev, Priya Kumthekar, Karen Dixit
Journal: Neuro-Oncology (2018)

The therapeutic potential of virotherapy for malignant glioma has sparked much interest recently, however, little is known about its effect on quality of life (QOL). We sought to explore patients QOL before and after treatment with a neural stem cell (NSC) driven oncolytic adenovirus (CRAd-S-pk7) plus standard of care therapy using the FACT-Brain. Patients with pathologically confirmed high-grade glioma at the time of resection received an intratumoral injection of CRAd-S-pk7. Concurrent radiotherapy to 60Gy with daily temozolomide (75mg/m2) followed, beginning within 7–10 days after surgery. Patients then received 6 cycles of adjuvant temozolomide (150–200 mg/m2) for the first 5 days every 28 days, and then were followed until progression. FACT-Brain was collected at baseline, day 14, day 56 (end of concurrent period), and then every 8 weeks during the adjuvant period. 7 patients have been enrolled to date, all with glioblastoma. Mean FACT-Brain Total and TOI scores at baseline were 162.0 (SD=19.1) and 115.3 (SD=23.8), consistent with expected baseline QOL scores in the newly diagnosed population. Mean scores declined significantly (p=.05 and p<0.01 respectively) by the end of concurrent treatment to 142.7 (SD=31.4) and 99.0 (SD=23.8), rebounded after adjuvant Cycle 1, and were similar to baseline by cycle 2. HGG patients treated with NSC virotherapy have declines in QOL after completing concurrent chemoradiation followed by improvement. This QOL pattern is similar to patients receiving standard treatment and may help clinicians discuss the impact of virotherapy with future patients. In addition, information may assist in evaluating net clinical benefit in future virotherapy studies.
CADD-03. A VERSATILE AND MODULAR TARGETED NANOPARTICLE PLATFORM FOR DELIVERY OF COMBINATION THERAPIES TO ADULT AND PEDIATRIC CNS TUMORS
Authors: Fred Lam, Stephen Morton, Jeffrey Wyckoff, Tu-Lan Vu Han, Mun Hwang, Amanda Maffa, Elena Balkanska-Sinclair, Michael Yaffe, Scott Floyd, Paula Hammond
Journal: Neuro-Oncology (2018)

Effective treatment of CNS tumors is limited by the presence of the blood-brain barrier (BBB) and rapid resistance to single agent therapies. To address these issues, we developed nanoparticles (NPs) that can be functionalized with ligands, such as transferrin (Tf-NPs), for delivery across the BBB to deliver multiple cargo to CNS tumors. In vitro uptake studies in U87MG and GL261 GBM cell lines demonstrate increased intracellular uptake of Tf-NPs compared to non-functionalized NPs in a time-dependent manner. Using intravital imaging through a cranial window, we show the ability of Tf-NPs to traverse the intact BBB in non-tumor bearing mice as well as achieve direct and durable tumor binding in intracranial orthotopic models of U87MG and GL261 GBM. Treatment of tumor-bearing mice with Tf-NPs loaded with temozolomide (TMZ) and the bromodomain inhibitor JQ1 leads to superior therapeutic effects with increased DNA damage and apoptosis that correlates with a 1.5- to 2-fold decrease in tumor burden and corresponding increase in survival compared to mice treated with drugs packaged in non-functionalized NPs or mice treated with equivalent free-drug dosing. Immunocompetent mice treated with Tf-NP-loaded drugs also show relative protection from the effects of systemic drug toxicity due to TMZ and JQ1. Preliminary intravital imaging further shows the ability of our NPs to target pediatric tumors such as medulloblastoma, demonstrating the preclinical potential of this nanoscale platform to deliver novel combination therapies to adult and pediatric CNS tumors.
RARE-03. CHARACTERISTICS OF PATIENTS WITH NEUROCUTANEOUS MELANOSIS: THE MSK EXPERIENCE FROM 2003–2018
Authors: Elsie Ennin, Kevin De Braganca, Sofia Haque, Ashfaq Marghoob, Yasmin Khakoo
Journal: Neuro-Oncology (2018)

The incidence of large congenital melanocytic nevi (LCMN) is 1/20,000 with 25% of children diagnosed with neurocutaneous melanocytosis (NCM), characterized by excessive proliferation of melanocytes in the leptomeninges and brain parenchyma. Specifically the disorder represents abnormal migration of melanocyte precursors due to abnormal melanin-producing genes in primitive leptomeningeal cells. While NCM can transform to melanoma, the molecular drivers involved in NCM related melanoma are different from the drivers in patients with non-NCM related melanoma. Children who become symptomatic from NCM may have a poor prognosis overall with 25–60% developing melanoma. While melanoma typically harbors mutations in the BRAF gene, NCM has a distinct molecular signature comprised primarily of mutations in the NRAS gene. We reviewed our institutional database from 2003–2018 and identified 47 patients with large congenital melanocytic nevi (LCMN) and NCM. Fifteen were female and 16/47 died. Five had molecular testing which revealed an NRAS mutation in the affected tissues. Four patients who developed melanoma, received targeted therapy including off label trametinib, nivolumab and/or ipilumumab. While none of these patient were longterm survivors, one patient lived for 12 months after receiving radiation therapy, nivolumab and ipilumumab. One patient with a VP shunt developed intraperitoneal melanoma, malignant ascites and subsequently died. CONCLUSIONS: While NCM which transforms to melanoma is typically fatal, new targeted therapies may offer prolonged survival. Further efforts to identify which patients are high risk are needed in an attempt to offer earlier treatment.
DRES-05. MOLECULAR EVOLUTION OF DIFFUSE GLIOMAS AND THE GLIOMA LONGITUDINAL ANALYSIS CONSORTIUM
Authors: Roel Verhaak, GLASS Consortium, Kenneth Aldape, Samirkumar Amin, David Ashley, Jill Barnholtz-Sloan, Amanda Bates, Rameen Beroukhim, Christoph Bock, Daniel Brat, Elizabeth Claus, Joseph Costello, John de Groot, Gaetano Finocchiaro, Pim French, Hui Gan, Brent Griffith, Christel Herold-Mende, Craig Horbinski, Antonio Iavarone, Steven Kalkanis, Konstantina Karabatsou, Hoon Kim, Mathilde Kouwenhoven, Kerrie McDonald, Hrvoje Miletic, Do-Hyun Nam, Ho Keung Ng, Simone Niclou, Houtan Noushmehr, David Ormond, Laila Poisson, Guido Reifenberger, Federico Roncaroli, Jason K. Sa, Peter Sillevis Smitt, Marion Smits, Camila F. Souza, Ghazaleh Tabatabai, Erwin Van Meir, Colin Watts, Pieter Wesseling, Adelheid Woehrer, W K Alfred Yung, Christine Jungk, Eric van Dyck, Bart A. Westerman, Olajide Abiola, Nikolaj Zeps, Sean Grimmond
Journal: Neuro-Oncology (2018)

A comprehensive characterization of the somatic alterations and molecular subtypes of glioma at diagnosis has been established. However, gliomas undergo significant molecular changes over time, some of these causing malignant progression or associated with therapy. Understanding this molecular evolution may uncover therapeutic vulnerabilities and facilitate development of more effective systemic therapies. The Glioma Longitudinal Analysis (GLASS) Consortium is an international effort to systemically catalogue the longitudinal changes in gliomas through multi-platform characterization. GLASS has developed computational and clinical infrastructure to enable its mission of establishing a well annotated longitudinal molecular dataset of 1500 gliomas including 500 gliomas per each of the IDHwt/IDH-mut-non-codel/IDH-mut-codel subtypes. An initial dataset comprising 150 cases with exome sequencing at multiple timepoints has been constructed, including cases diagnosed as IDHwt (55%), IDH-mut-non-codel (38%) and IDH-mut-codel (6%). Treatment regimens followed the expected combinations of chemo- and radiation therapy while survival was more favorable than reported in literature, suggested a bias in our dataset towards better performing cases. This is possibly explained by the need for two consecutive surgical procedures to be included in the analysis. While more than half of mutations in IDHwt primary tumors were recovered in their matching recurrences, this fraction was less than 30% in the other two subtypes. The disparity in mutations between primary and recurrences may reflect intratumoral heterogeneity in both primary and recurrence, and clonal selection patterns. We observed temozolomide treatment-associated hypermutation in up to 13 of our cohort. A more detailed analysis of mutational and DNA copy number data is underway. A cohort of 75 additional patients with multi-timepoint exome data is being processed and, through several funded projects, multi-platform characterization of 250 gliomas is in progress. In summary, GLASS will provide a rich resource to the glioma community with the potential for paradigm shifting discoveries.
Treatment of latent tuberculosis with 12 weeks isoniazid/rifapentine in clinical practice
Authors: Gabrielle Fröberg, Lena Jansson, Judith Bruchfeld
Journal: European Respiratory Journal (2018)

<b>Completion rate with 12 weeks isoniazid/rifapentine for latent tuberculosis was high. Direct observed therapy was solved with flexibility. Adverse events were mostly mild, except one case of suspected nephrotoxicity, which calls for heightened attention.</b>http://ow.ly/DRE430mw5QQ