tbuckley/cabot-search huggingface dataset:
INNV-38. THE NEURO-ONCOLOGY BRANCH TRANSLATIONAL RESEARCH IMMERSION PROGRAM: RESULTS FROM TWO YEARS OF DEVELOPMENT AND PARTICIPANT FEEDBACK
Authors: Amber Giles, Amélie Vézina, Alvina Acquaye, María Fletcher Ruiz, Orwa Aboud, Marsha-Kay Hutchinson, Maria Lugo, Caitlin Reid, Heather Sonnemann, Lilian Yang, Mark Gilbert, Terri Armstrong
Journal: Neuro-Oncology (2018)

Integrated, multidisciplinary research collaborations have the potential to transform cancer research by bridging the gap between highly specialized basic research and clinical strategies to target human disease. Training programs that provide opportunities for exposure to this approach will help promote the translation of basic science discoveries into clinical applications. The Neuro-Oncology Branch Translational Research Immersion Program (NOB-TRIP) was designed to immerse students from diverse scientific and cultural backgrounds into an integrated clinically-centered neuro-oncology research platform. Eligible trainees from three separate summer intern programs at the NIH and self-selected for a clinical or basic focus were studied. A trans-disciplinary team developed the NOB-TRIP as a 10-week program consisting of five structured areas of educational focus: didactic lectures; weekly seminars with the NOB Chief on research rigor and career planning; cross-focus observational experiences; integration of wellness; and mentoring in training and public speaking. A post NOB-TRIP survey measured the program’s impact. RESULTS/ Twenty-nine interns (18 female; 11 male) participated in the NOB-TRIP. Education levels included high school (3), undergraduate college (17), post-baccalaureate (2), graduate college (3), medical college (3), and post-doctoral (1). Student evaluations were overwhelmingly positive, with two interns returning for a second internship. Students reported acquiring a greater appreciation for the collaborative science and teamwork in a clinically-focused research branch. Patient-caregiver interactions, professional relationships, and the skills required to navigate a difficult conversation were highlighted as invaluable real-world learning experiences. The NOB-TRIP exemplifies the benefits of cross-disciplinary training to spark enthusiasm, confidence, and collaboration among students with diverse scientific interests. These interpersonal and professional skills can drive a desire for scientific discovery and fuel interest in the challenging field of neuro-oncology.
TMIC-04. NONFUNCTIONAL PITUITARY ADENOMAS DEMONSTRATE TWO SUBTYPES BASED ON MACROPHAGE POLARIZATION STATUS
Authors: Garima Yagnik, Martin Rutkowski, Manish Aghi
Journal: Neuro-Oncology (2018)

Nonfunctional pituitary adenomas (NFPAs), while typically benign, display variable invasiveness, and can present with devastating symptoms of intercranial mass effect. Tumor-associated macrophages (TAMs) have long been accepted as active participants in tumor microenvironments, particularly their M1 and M2 subtypes, correlating with anti- and pro-tumoral effects respectively. We investigated TAMs in NFPA biology and clinical behavior. Patient NFPAs were FACS sorted for total macrophages and M1 and M2 subtypes. Functional assays utilized monocyte cell line THP1. Macrophage isolation from fourteen NFPAs revealed TAMs average 8.5% of dissociated cells (range=0.5%-29.1%), displaying bimodal distribution with most cases clustering below 8% CD11b fraction. Two cases exhibited 18–29% CD11b fractions and were more expansile (size>3.5 cm or MIB1>3%). M2/M1 gene expression ratios assessed by qPCR were above one in NFPAs with cavernous sinus invasion, including the TAM-rich expansile tumors, while M2/M1 ratios were below one in NFPAs without cavernous sinus invasion. Increasing TAM percentage correlated with decreased M2/M1 ratio determined by qPCR of subtype-specific TAM markers. THP1 cells were polarized and used to created media conditioned with M1 and M2 TAMs. Primary cultured NFPA patient cell lines showed that M2 conditioned media induced more invasion (P < 0.01), migration (P < 0.05) and proliferation (P < 10–3). qPCR screening of patient cell lines identified S100A9 and EZH2 as mediators of M2-induced invasion and proliferation, respectively. Our work identified two subtypes of NFPAs based on TAM status: (1) Larger, more proliferative NFPAs exhibited increased TAMs and decreased M2/M1 ratio but sufficient M2-induced EZH2 can drive proliferative expansion with sheer TAM numbers; and (2) NFPAs invading the cavernous sinuses exhibited lower TAMs and higher M2/M1 ratios, with M2-induced S100A9 driving invasion. These results suggest that recruitment of TAMs to the pituitary microenvironment influences tumor development and M2 TAMs promote a more pro-tumoral state.
IMMU-18. TARGETING THE PD1 AND TIGIT CHECKPOINT PATHWAYS FOR ADULT AND PEDIATRIC GLIOMAS
Authors: Karsen Shoger, Lauren McCarl, Ryan Gilbert, Clarence Villanueva, Nicole Levy, Nduka Amankulor, Ian Pollack, Gary Kohanbash
Journal: Neuro-Oncology (2018)

High-grade gliomas (HGGs) are the most common and deadliest of malignant primary brain tumors. Additionally, brain and central nervous system tumors are the leading cause of cancer-related morbidity and mortality in infants and children. Tumors, including HGGs, co-opt immune checkpoint molecules to evade T-cell killing, and targeting these pathways has led to cures in some patients with cancers. Immunotherapy trials, including the use of checkpoint blockade therapies, have been conducted with limited success in brain tumor patients. Our analysis of data from The Cancer Genome Atlas identified that of over 30 assessed checkpoint molecules, only expression of the genes coding for PD1 and TIGIT, within the tumor, were associated with shorter overall survival and progression-free survival times. Furthermore, using published pediatric glioma resources, we found that TIGIT expression is elevated in pediatric HGGs compared with lower-grade pediatric gliomas, and TIGIT expression was inversely associated with overall survival in children with HGGs. These data led us to hypothesize that glioma-associated T-cells express PD-1 and TIGIT, which can be targeted to reduce glioma growth. To test this, we assessed whether mono/combination therapies with anti-PD-1 and anti-TIGIT could improve survival and immune function in a syngeneic orthotopic GL261 glioma mouse model. Although anti-TIGIT therapy alone failed to prolong survival, mice treated with both anti-PD1 and anti-TIGIT demonstrated improved survival compared with mice receiving anti-PD1 alone. Immunologic analysis of tumor-infiltrating cells in our mouse model revealed high expression levels of PVR, the TIGIT ligand, on cells resembling myeloid-derived suppressor cells (MDSCs), within the tumor. Additionally, TIGIT treatment led to the reduction of a subset of T-regulatory cells and cells resembling MDSCs. Overall, our data suggest that anti-TIGIT may reduce immunosuppressive cells at the tumor site and improve the efficacy of anti-PD1 trials in adults and children with HGGs.
STEM-04. GLIOMA STEM CELL REGULATOR S100A4 MODULATES GBM IMMUNE LANDSCAPE
Authors: Thomas Gallup, Bikesh Nirala, Nourhan Abdelfatta, Massimo Squatrito, Joshy George, David Baskin, Kyuson Yun
Journal: Neuro-Oncology (2018)

Glioblastoma (GBM) is the most common and aggressive malignant brain tumor in adults and is virtually incurable. Immunotherapy is a promising new approach to treat GBM as it harnesses one’s own immune system to recognize and kill aberrant cancer cells. Unfortunately ongoing trials with immunotherapies show disappointing results in most glioma patients. GBM has highly immune-suppressive microenvironment. Consistently, mesenchymal subtype, the subtype with worst prognosis, has a strong immune signature. We recently reported that S100A4 is necessary for human and mouse glioma initiating cell (GIC) self-renewal and tumor growth, and that S100A4 is a master regulator of mesenchymal transition in GBM. Importantly, we report that S100A4 regulates expression of cytokines that affect TAM infiltration and polarization towards tumor-promoting phenotype. Consistently, TCGA and IVY-GAP data analyses indicate that S100A4 expression is strongly correlated with GBM patient survival, the mesenchymal subtype, and tumor-promoting TAM (tumor-associated macrophage) and MDSC (myeloid-derived suppressor cell) marker expression (such as CD163, CD204/MSR1, IL10, CD11b, S100A8, and S100A9). S100A4 expression and TAM marker expression strikingly overlap in perivascular and perinecrotic regions, previously reported niches for GICs. Interestingly there is no correlation between S100A4 expression and markers of microglia. Through single cell RNA-sequencing analyses of human GBM samples, we now have evidence that S100A4 is expressed in both glioma cells and infiltrating myeloid cells. When S100a4 is knocked down in mouse glioma cells and transplanted into syngeneic mice, tumor promoting myeloid cell numbers are significantly reduced. We are currently testing the role of S100A4 in bone marrow derived myeloid cells and elucidating the molecular mechanism of S100A4 function. Our unpublished observations strongly suggest that S100A4 is a critical regulator of GBM immune landscape and may be key node that links GICs, mesenchymal transition, and the myeloid cell infiltration.
ACTR-51. PHASE 2 STUDY TO EVALUATE THE SAFETY, PHARMACOKINETICS AND CLINICAL ACTIVITY OF PI3K/MTOR INHIBITOR GDC-0084 GIVEN TO GLIOBLASTOMA (GBM) PATIENTS WITH UNMETHYLATED O6-METHYLGUANINE-METHYLTRANSFERASE PROMOTER STATUS
Authors: Patrick Wen, Timothy Cloughesy, John de Groot, James Battiste, James Garner, Jeremy Simpson, Alan Olivero, Elizabeth Gerstner
Journal: Neuro-Oncology (2018)

GDC-0084 is a potent, oral, selective small molecule inhibitor of class I phosphoinositide 3-kinase and mammalian target of rapamycin (PI3K/mTOR) efficacious in GBM models driven by activation of the PI3K pathway. GDC-0084 crosses the blood-brain barrier (BBB) and achieves a brain / plasma ratio of approximately 1.0 in three animal species. GDC-0084 was given as once daily oral dosing in a phase 1 study (Wen et al, J Clin Oncol 34, 2016(15) suppl.2012; NCT01547546) in 47 patients with recurrent high-grade gliomas. The adverse events were generally consistent with the established Class I PI3K/mTOR inhibitor class-effects. GDC-0084 was rapidly absorbed and demonstrated linear- and dose-proportional increases in exposure. The MTD was determined to be 45 mg once daily, with 7/8 patients receiving this dose having drug exposures consistent with anti-tumor activity in pre-clinical models. Fluorodeoxyglucose-positron emission tomography (FDG-PET) scans suggested that GDC-0084 crossed the BBB, with a uniform distribution throughout the brain. The current phase 2 study will investigate the efficacy and safety of GDC 0084 in patients with newly diagnosed GBM, with unmethylated O6-methylguanine-methyltransferase (MGMT) promoter status. This protocol (NCT03522298) has a 2-part design. The phase 1b component consists of an open-label, multicenter dose-escalation study with expansion assess the safety, tolerability, RP2D, PK and clinical activity of GDC 0084 in patients with newly-diagnosed GBM with unmethylated MGMT. The dose-escalation portion of the study will use a standard “3 + 3” design to determine the MTDs for QD, QOD and 3 days on/4 days off schedules. At each of the identified MTDs 10 subjects will be recruited in an expansion cohort. The RP2D will be selected from the three dose schedules being tested. The phase 2 component will evaluate clinical activity of GDC-0084 at the RP2D vs temozolomide as adjuvant therapy following surgical resection and chemoradiation in 224 patients.
Abstract P172: Postural Hand Tremor and Incident Hypertension in Young-to-middle Aged Adults: The Bogalusa Heart Study
Authors: Tian Hu, Jack Guralnik, Jeanette Gustat, Emily Harville, Larry Webber, Wei Chen, Jiang He, Paul K Whelton, Lydia Bazzano
Journal: Circulation (2016)

Introduction: Increased sympathetic nervous activity is a feature of postural hand tremor and increases blood pressure. Beta-blocker therapy is effective in managing postural hand tremor and hypertension. However, the relationship between postural hand tremor and hypertension has not been examined in a population-based cohort study. Methods: We prospectively examined the association between postural hand tremor and incident hypertension in a community-based cohort of 715 (184 Black, 531 White) American adults without hypertension and not using medications to control tremor (e.g., beta-blockers). At a baseline examination in 2000-2002, postural hand tremor was measured by having participants in a darkened room use their outstretched arms to point a laser beam for 8 seconds at a sheet of Polaroid film 8 feet away. Hand tremor was characterized by the width of the circular diameter that encompassed all laser beam exposures and enumeration of exposure dots in the contained area. Both hands were assessed sequentially. Incident hypertension was defined as new elevation of blood pressure (systolic ≥ 140 mmHg or diastolic ≥ 90 mmHg, based on an average of six readings over two visits), or self-report of hypertension, or antihypertensive medication use. Results: During a median follow-up of 6.4 years, 198 (69 Black and 129 White) participants developed hypertension. Tremor measurements (by quartile) were positively associated with incident hypertension after adjustment for demographics, lifestyle and metabolic risk factors at baseline. There was significant interaction by race (P: 0.01). Among Whites, tremor was positively associated with incident hypertension (Hazard ratio highest vs. lowest quartile: 2.35 [95% CI: 1.35 - 4.09], P - linear trend: 0.007 for the dot numeration method; and 3.02 [95% CI: 1.69 - 5.38], P - linear trend: 0.002 for the circular method). Among Blacks, tremor was not associated with hypertension risk. Conclusions: In this community-based cohort, postural hand tremor was strongly associated with the risk of incident hypertension among Whites, and merits further study as a potential indicator of risk for hypertension.
Metering the METEOR in methotrexate failure: is propensity score a falling star?
Authors: Sakir Ahmed
Journal: Annals of the Rheumatic Diseases (2018)

The debate on the preferred treatment of rheumatoid arthritis (RA) after methotrexate (MTX) failure has always been fascinating. Sytske Anne Bergstra and associates have analysed data from patients in the METEOR cohort who had failed MTX monotherapy.1 It was absorbing to see how they used multiple propensity score (PS) to control for bias in non-randomised data collected from an international registry (‘METEOR’). They have pragmatically outlined how the PS was analysed.

The analysis has demonstrated clear superiority of biological disease-modifying anti-rheumatoid drugs (b-DMARDs) over conventional synthetic DMARDs (cs-DMARDs) in both unadjusted and PS-adjusted results at 6 months and at 1 year. There is already plenty of evidence that addition of a bDMARD to MTX (on failure of monotherapy) is better in the short term than addition of a cs-DMARD. A network meta-analysis of 33 trials has shown the superiority of b-DMARDs at 6 months in achieving …
PATH-31. GIANT CELL GLIOBLASTOMAS: ANALYSIS OF MISMATCH-REPAIR (MMR) PROTEINS EXPRESSION, POLIMERASE ε (POLE) MUTATIONS AND THEIR ROLE IN TUMOR IMMUNORESPONSE
Authors: Bianca Pollo, Monica Patanè, Chiara Calatozzolo, Rosina Paterra, Mariangela Farinotti, Sonia Spinello, Francesco DiMeco, Antonio Silvani, Gaetano Finocchiaro
Journal: Neuro-Oncology (2018)

Giant cell glioblastoma (gcGBM) is a rare (<1%) variant glioblastoma (GBM), in younger patients. Unlike the IDH-wild type GBM, they have a better prognosis. Mutations in the POLE and in MMR genes accelerate tumorigenesis, generating in some tumours an ultra-mutated phenotype. The lack of proofreading activity generates production of neoantigens, recalling tumour infiltrating lymphocytes, and immune-checkpoint ligands exposition. Aim of our study was to investigate MMR proteins expression, POLE mutations, related checkpoint molecules and the tumor immune-microenvironment in a group of gcGBMs compared to IDH-wild type GBMs. We performed a molecular and immunohistochemical analysis on 60 primary gcGBMs. All tumours where characterized for EGFR, PTEN, p53, IDH1, MGMT status by immunohistochemistry and/or molecular analysis. We investigated MMR protein (MSH6, MSH2, PML2 and MLH1), PD-L1, CTLA-4 and CD28 expression by immunohistochemistry in gcGBMs and in a group of standard GBMs. POLE mutations have been studied by direct sequencing of exons encoding its exonuclease activity. Then we assess the immunological status investigating the presence of lymphocytic infiltrates, microglia and macrophages, by CD3, CD4, CD8, CD68, CD163, MHC class II and IBA1. All the results obtained have been related to clinical data. The median survival time was 21 months, with 4 patients long survivors (>5 years), higher than in the standard group. The main findings where partial loss of expression of MMR proteins (overall MSH2 and MSH6) on 30% of cases, mostly related to presence of inflammatory infiltrates, also showing CD28 immunostaining. Microglia IBA1+ was significantly present in patients with longer survival. Correlation with PD-L1 and CTLA4 was found only in 2 cases. POLE sequencing displays mutation F367S on 20% of cases. Our results show that gcGBMs are an histological variant with increased tendency to ultra-mutated phenotype with a better prognosis and suggesting these patients as candidates for immunotherapy.
Abstract 18926: Metformin is Associated With Improved Skeletal Muscle Glucose Uptake and Improves Skeletal Muscle Energetics. There is Limited Data of the Impact of Metformin Us on Need for Repeat Revascularization in Patients With Symptomatic Peripheral Artery Disease (pad) Treated With Endovascular Revascularization
Authors: Avantika Banerjee, Atif Mohammad, Denizen Kocak, Kyle Planchard, Thomas Das, Emmanouil Brilakis
Journal: Circulation (2015)

Background: Metformin is associated with improved skeletal muscle glucose uptake and improves skeletal muscle energetics. There is limited data of the impact of metformin us on need for repeat revascularization in patients with symptomatic peripheral artery disease (PAD) treated with endovascular revascularization. Methods: We compared need for vessel revascularization (TLR) rates in patients with diabetes mellitus (DM) treated with metformin and without, to non-DM enrolled in the Excellence in Peripheral Artery Disease (XLPAD) registry (NCT01904851) between 2006 and 2015. Results: In the study cohort of 2140 interventional procedures, 57.4% were performed in DM (n=268 on metformin and n=961 not on metformin). Frequency of hypertension, hyperlipidemia and chronic kidney disease was higher in DM not on metformin compared to DM on metformin (p&lt;0.001 for all comparisons). Lesion and stent lengths were similar in both groups. Revascularization free survival compared to the non-DM (control) was similar for DM on metformin (HR=0.95, 95%CI: 0.56-1.60; p=0.85) compared to DM not on metformin (HR=1.84, 95%CI: 0.98-3.45; p=0.06; Figure 1A). Overall survival compared to non-DM (control), was similar for DM on metformin (HR=1.70, 95%CI: 0.64-4.54; p=0.29) and significantly worse for DM not on metformin (HR=4.55, 95%CI: 2.44-8.48; p&lt;0.001; Figure 1B). Conclusions: Metformin therapy in symptomatic PAD patients with DM following endovascular revascularization is associated with improved survival and lower need for repeat revascularization compared to diabetics not treated with metformin.
GENE-28. METHYLOMES AND TRANSCRIPTOMES VARY ACROSS IDH1 MUTANT CANCERS
Authors: Denise Scholtens, Makda Zewde, Adam Buss, David James, Dusten Unruh, Craig Horbinski
Journal: Neuro-Oncology (2018)

Since their discovery in gliomas, mutations in isocitrate dehydrogenases 1 and 2 (collectively referred to as “IDH1mut”) have been discovered in a variety of cancers, including acute myeloid leukemia (AML), melanoma, and cholangiocarcinoma. While IDH1mut promotes genomic hypermethylation in all these cancers, glioma remains the only tumor in which IDH1mut is a consistently favorable prognostic marker, for reasons that are unclear. We therefore hypothesized that the pattern of DNA methylation, the resultant transcriptomic profiles, and specific genes suppressed, would all vary among IDH1mut cancers according to tissue of origin. We analyzed Illumina 450K and RNA-Seq data from The Cancer Genome Atlas, including WHO grade II-IV gliomas (N=647; 427 IDH1mut, 220 IDH1wt), AML (N=194; 15 IDH1mut, 179 IDH1wt), melanoma (N=475; 23 IDH1mut, 452 IDH1wt), and cholangiocarcinoma (N=45; 7 IDH1mut, 38 IDH1wt). Using the tcgaWorkflow R package, we compared CpG methylation using Wilcoxon tests on beta values and transcriptomic read counts using negative binomial generalized log-linear models for IDH1mut versus IDH1wt tumors. A CpG site was considered hypermethylated if its mean beta value in IDH1mut cancer was >0.15 relative to the matching IDH1wt cancer. P-values were false discovery rate (FDR)-corrected. Of 264,735 analyzed CpG sites, 70,591 (19%) were hypermethylated in IDH1mut gliomas compared to IDH1wt gliomas. In contrast, only 3%, 2%, and 4% of CpG sites were hypermethylated in IDH1mut AML, melanoma, and cholangiocarcinoma, relative to each of their IDH1wt counterparts. Methylation-associated transcriptome differences were also more pronounced in IDH1mut gliomas. Key promalignant genes that were uniquely hypermethylated and downregulated in IDH1mut gliomas, relative to other IDH1mut cancers, included ERBB2 (HER2), LGALS1 (galectin-1), and PDPN (podoplanin), among others. These data suggest that the extent and targets of IDH1mut-induced genomic hypermethylation vary greatly according to the cellular context, and may help explain why IDH1mut is only a favorable prognostic marker in gliomas.
Genetic Analysis Reveals AMPK Is Required to Support Tumor Growth in Murine Kras-Dependent Lung Cancer Models
Authors: Lillian J. Eichner, Sonja N. Brun, Sébastien Herzig, Nathan P. Young, Stephanie D. Curtis, David B. Shackelford, Maxim N. Shokhirev, Mathias Leblanc, Liliana I. Vera, Amanda Hutchins, Debbie S. Ross, Reuben J. Shaw, Robert U. Svensson
Journal: Cell Metabolism (2018)
Single bead investigation of a clinical drug delivery system – A novel release mechanism
Authors: E. Ahnfelt, J. Gernandt, Y. Al-Tikriti, E. Sjögren, H. Lennernäs, P. Hansson
Journal: Journal of Controlled Release (2018)

Microgels, such as polymeric hydrogels, are currently used as drug delivery devices (DDSs) for chemotherapeutics and/or unstable drugs. The clinical DDS DC bead® was studied with respect to loading and release, measured as relative bead-volume, of six amphiphilic molecules in a micropipette-assisted microscopy method. Theoretical models for loading and release was used to increase the mechanistic understanding of the DDS. It was shown that equilibrium loading was independent of amphiphile concentration. The loading model showed that the rate-determining step was diffusion of the molecule from the bulk to the bead surface ('film control'). Calculations with the developed and applied release model on the release kinetics were consistent with the observations, as the amphiphiles distribute unevenly in the bead. The rate determining step of the release was the diffusion of the amphiphile molecule through the developed amphiphile-free depletion layer. The release rate is determined by the diffusivity and the tendency for aggregation of the amphiphile where a weak tendency for aggregation (i.e. a large cacb) lead to faster release. Salt was necessary for the release to happen, but at physiological concentrations the entry of salt was not rate-determining. This study provides valuable insights into the loading to and release from the DDS. Also, a novel release mechanism of the clinically used DDS is suggested.