tbuckley/cabot-search huggingface dataset:
TMOD-30. R206H ACVR1 SIGNIFICANTLY ACCELERATES DIFFUSE INTRINSIC PONTINE GLIOMA PATHOGENESIS
Authors: Christine Hoeman, Guo Hu, Francisco Cordero, Oren Becher
Journal: Neuro-Oncology (2016)

Diffuse intrinsic pontine gliomas (DIPGs) comprise 15% of pediatric brain tumors and are the leading cause of death for children with brain tumors. In spite of numerous clinical trials, little progress has been made in prolonging the survival of DIPG patients. As there are currently no effective treatments, it is important to develop mouse models in order to understand the biology of these tumors. Recently we, and others have discovered activating bone morphogenic protein (BMP) pathway mutations in ACVR1, which encodes for the Activin A receptor (ALK-2). ACVR1 mutations are found in 25% of DIPG patients and commonly co-occur with the H3.1 K27M mutation. In order to study how these two mutations co-operate and affect tumor biology, our lab has developed the first genetically engineered mouse model (GEMM) driven by both mutations through the use of the RCAS/t-va retroviral system. Preliminary results show that brainstem progenitor cells grown as neurospheres and infected with R206H-ACVR1 virus had increased pSMAD1/5/8 and Id1 expression in vitro, indicating increased BMP signaling. In vivo, infection of brainstem progenitors in nestin tv-a (Ntv-a); p53 floxed (p53fl) mice with R206H-ACVR1, H3.1 K27M, PDGFA, and Cre had significantly decreased survival relative to mice infected with WT ACVR1, WT H3.1, PDGFA, and Cre, or H3.1K27M; PDGF-A; and Cre suggesting that the BMP pathway is pro-tumorigenic. Additionally the combination of ACVR1 R206H and H3.1 K27M enhanced angiogenesis as evidenced by CD31 staining and western blot, providing a possible mechanism of co-operation. Finally, PDGF-A; ACVR1 R206H; H3.1 K27M; p53-deficient tumor derived neurospheres were tested in vitro with the ACVR1 inhibitor LDN 212854 and were found to have significantly decreased proliferation and survival. Based on these results, LDN 212854 is currently being evaluated in vivo in our model with the hopes that it will be a new therapeutic agent for treating DIPG.
Delayed differentiation of potent effector CD8 <sup>+</sup> T cells reducing viremia and reservoir seeding in acute HIV infection
Authors: Hiroshi Takata, Supranee Buranapraditkun, Cari Kessing, James L. K. Fletcher, Roshell Muir, Virginie Tardif, Pearline Cartwright, Claire Vandergeeten, Wendy Bakeman, Carmen N. Nichols, Suteeraporn Pinyakorn, Pokrath Hansasuta, Eugene Kroon, Thep Chalermchai, Robert O’Connell, Jerome Kim, Nittaya Phanuphak, Merlin L. Robb, Nelson L. Michael, Nicolas Chomont, Elias K. Haddad, Jintanat Ananworanich, Lydie Trautmann
Journal: Science Translational Medicine (2017)

CD8+ T cells play a critical role in controlling HIV viremia and could be important in reducing HIV-infected cells in approaches to eradicate HIV. The simian immunodeficiency virus model provided the proof of concept for a CD8+ T cell-mediated reservoir clearance but showed conflicting evidence on the role of these cells to eliminate HIV-infected cells. In humans, HIV-specific CD8+ T cell responses have not been associated with a reduction of the HIV-infected cell pool in vivo. We studied HIV-specific CD8+ T cells in the RV254 cohort of individuals initiating ART in the earliest stages of acute HIV infection (AHI). We showed that the HIV-specific CD8+ T cells generated as early as AHI stages 1 and 2 before peak viremia are delayed in expanding and acquiring effector functions but are endowed with higher memory potential. In contrast, the fully differentiated HIV-specific CD8+ T cells at peak viremia in AHI stage 3 were more prone to apoptosis but were associated with a steeper viral load decrease after ART initiation. Their capacity to persist in vivo after ART initiation correlated with a lower HIV DNA reservoir. These findings demonstrate that HIV-specific CD8+ T cell magnitude and differentiation are delayed in the earliest stages of infection. These results also demonstrate that potent HIV-specific CD8+ T cells contribute to the reduction of the pool of HIV-producing cells and the HIV reservoir seeding in vivo and provide the rationale to design interventions aiming at inducing these potent responses to cure HIV infection.
Larger Numbers of Donor Naïve CD8+ T-Cells and Plasmacytoid Dendritic Cell Precursors In Allogeneic BM Grafts From Unrelated Donors Are Associated with Improved Survival: Results From BMT CTN 0201
Authors: Edmund K Waller, Wayne A.C. Harris, Steven Devine, David L. Porter, Shin Mineishi, John M. McCarty, Corina E Gonzalez, Thomas R Spitzer, Oleg I. Krijanovski, Michael L. Linenberger, Ann Woolfrey, Alan Howard, Cathy Gurgol, Brent R. Logan, Dennis L Confer, Claudio Anasetti
Journal: Blood (2011)
GENT-17. SEX-SPECIFIC GENOME-WIDE ANALYSIS FOR LOCI ASSOCIATED WITH GLIOMA RISK
Authors: Quinn Ostrom, Margaret Wrensch, Yanwen Chen, Beatrice Melin, John Wiencke, Georgina Armstrong, Terri Rice, Lucie McCoy, Helen Hansen, Melissa Bondy, Jill Barnholtz-Sloan
Journal: Neuro-Oncology (2016)

Incidence of glioma varies significantly by sex in the US, and most glioma histologies occur with significantly higher incidence in males. Previous analyses have examined the impact of estrogen exposure as a potential environmental risk factor for these tumors, but have found results of minimal significance and low effect sizes. There may be differences in genetic architecture that contribute to sex differences in incidence. Using data collected for previous glioma GWAS from MD Anderson Cancer Center, and the University of California, San Francisco we assessed 17 previously identified glioma risk SNPs by sex, overall and for glioblastoma (GBM) and non-GBM tumors separately. There were 1,160 male cases (64% GBM) and 2,247 male controls, and 669 female cases (63% GBM) and 3,529 female controls. Odds ratios (OR) and 95% confidence intervals (95%CI) were calculated using an additive genetic logistic regression model. For non-GBM, rs55705857 (CCDC26) had a larger effect size in females (OR=5.45, 95%CI=3.18-9.34, p=6.47x10-10) as compared to males (OR=3.06, 95%CI=2.23-4.22, p=6.23x10-12). This SNP also conferred risk for GBM but only among females (OR=1.79, 95%CI=1.26-2.59, p=2.15x10-3). Among GBM cases, rs78378222 (TP53) had an effect size nearly twice as high in females (OR=5.13, 95%CI=2.52-10.42, p=6.25x10-6) as compared to males (OR=2.49, 95% CI=01.5-4.12, p=4.23x10-4). This SNP also had increased effect in non-GBM (Female OR=4.56, 95%CI=1.77-11.76, p=1.71x10-3; Male OR=3.37, 95%CI=1.83-6.20, p=1.00x10-4). Sex differences and other demographic differences in cancer susceptibility provide important clues to etiology, and these differences can be leveraged for discovery in genetic association studies. Discovery of sex-related variation in heritability and risk for glioma may further explain significant differences in incidence by sex for these tumors in the absence of environmental risk factors that explain a substantial portion of risk.
DRES-01. BONE MARROW RESPONSE AS A POTENTIAL BIOMARKER OF OUTCOMES IN GLIOBLASTOMA PATIENTS
Authors: Eugene Vaios, Brian Nahed, Alona Muzikansky, Amir Fathi, Jorg Dietrich
Journal: Neuro-Oncology (2016)

Glioblastoma (GBM) is a highly aggressive malignancy which requires a multi-disciplinary therapeutic approach of surgery, chemotherapy and radiation therapy. Treatment-related side-effects can be challenging to patient management. The most common adverse effect of chemotherapy with temozolomide (TMZ) is myelosuppression. It remains unclear whether the degree of bone marrow suppression might serve as a biomarker for outcome. The aim of the current study was to investigate whether the pattern of the degree of bone-marrow toxicity in patients treated with TMZ correlates with overall survival (OS) and MRI-based time to progression (PFS). Complete blood counts, clinical and radiographic information were collected retrospectively from 86 malignant glioma patients who had completed both radiation therapy and at least 6 monthly cycles of chemotherapy with TMZ. Using a multivariate cox proportional hazard model, it was observed that treatment-induced decreases in white blood cell counts, MGMT promotor methylation, wild-type EGFR, IDH mutation, and younger patient age at diagnosis were associated with improved OS. The 2-year survival rate was 25% and 58% for patients with increases and decreases, respectively, in white blood cell counts from baseline over 6 months of TMZ treatment (p = 0.0019). Consistent with the literature, IDH mutation and MGMT promotor methylation were associated with improved PFS and OS. IDH mutation and MGMT promotor methylation were not correlated with changes in white blood cell counts. Decreases in white blood cell counts might serve as a potential biomarker for OS and PFS in malignant glioma patients treated with standard chemoradiation. It remains unclear whether treatment induced changes in white blood cell counts correlate with drug induced anti-tumor activity or represent an independent factor of altered systemic and tumor microenvironment. Additional studies will be needed to identify chemotherapy associated dose-dependent effects and to characterize the white blood cell subpopulations that might account for the observed effects.
Impact of depth of response (DpR) on survival in patients (pts) with RAS wild-type (WT) metastatic colorectal cancer (mCRC) receiving first-line panitumumab + FOLFOX4 vs FOLFOX4
Authors: S. Siena, F. Rivera Herrero, J.-Y. Douillard, J. Taieb, R. Koukakis, G. Demonty, M. Peeters
Journal: Annals of Oncology (2016)
CBIO-21. STAT3 REGULATES AN SL/PL TRANSITION IN BTICs THROUGH AN EMT-LIKE PROCESS MEDIATED BY SLUG
Authors: Charles Chesnelong, H. Artee Luchman, J. Gregory Cairncross, Samuel Weiss
Journal: Neuro-Oncology (2016)

The Signal Transducer and Activator of Transcription 3 (STAT3) is essential for GBM progression and crucial for invasion, proliferation and survival of Brain Tumor Initiating Cells (BTICs). STAT3 may drive a putative Proneural to Mesenchymal transition (PMT) associated with a more aggressive GBM phenotype at recurrence. Interestingly, the previously identified Stem–Like (SL) BTICs associate with the Proneural subtype while Progenitor-Like (PL) BTICs resemble the Mesenchymal subtype. This finding suggests a possible shift from slower growing SL-BTICs towards a more aggressive PL phenotype, mirroring the PMT observed in GBM. We thus propose that STAT3 may regulate an SL/PL transition in BTICs and a PMT in GBM through an Epithelial to Mesenchymal Transition (EMT)-like process. Here, we confirm that STAT3 and EMT pathways are strongly over-activated in PL-BTICs. We further highlight SLUG as the main mediator of this transition as it is the most highly expressed EMT regulator in BTICs and its expression is strikingly correlated with both STAT3/EMT pathways and the SL/PL state. Further, we show that SLUG expression is decreased after STAT3 inhibition, increased following STAT3 activation and confirm by ChIP that SLUG is a novel direct transcriptional target of STAT3. We also confirm that SLUG over-expression leads to E-cadherin down-regulation and promotes migrative abilities. Finally, using The Cancer Genome Atlas (TCGA) transcriptomic data, we demonstrate that STAT3 and EMT activity scores are tightly correlated, enriched in mesenchymal GBM samples and predict poorer survival. Most importantly, SLUG expression also correlates with STAT3 and EMT scores, is enriched in mesenchymal samples and is associated with poor patient outcome. The STAT3/EMT axis may regulate stem-like characteristics, proliferation, invasion and resistance, promoting a more aggressive mesenchymal GBM phenotype via an EMT-like process mediated by SLUG. Blocking this process represents a novel actionable therapeutic strategy in GBM with clinically relevant JAK2 and STAT3 inhibitors.
TMIC-28. HETEROGENEOUS GLIOBLASTOMA CELL RESPONSES TO TNF DEPEND ON MOLECULAR SUBTYPE
Authors: Michael Barish, Alicia Mizes, Blake Brewster, Negin Baghdadchi, Christine Brown
Journal: Neuro-Oncology (2016)

Glioblastoma multiforme (GBM), which displays wide variation between patients, has been stratified into subtype classifications that are anchored at two ends by proneural (PN) and mesenchymal (Mes) subtypes. PN tumors are associated with preferential expression of neural stem and progenitor cell markers, and Mes tumors with mesenchymal markers and markers of epithelial-to-mesenchymal transition (EMT). Regions within a tumor may vary in subtype, and for GBM up to one-third of total cells may be microglia and tumor associated macrophages. We examined how GBM molecular subtype and differentiation status influence invasive behaviors. The microglia/macrophages associated with GBM secrete a number of proinflammatory cytokines including tumor necrosis factor (TNF). In vitro, TNF up-regulates expression of the adhesion molecule VCAM-1 (Mahadev et al., PLoS One 9: e95123; 2014). We utilized a cohort of patient-derived primary glioma cell lines characterized by TCGA signature gene expression as PN or Mes (Brown et al., PLoS One 8: e7769; 2013), grown in culture with stem-like or differentiated cell properties (Brown et al., Cancer Res 69: 8886-8893; 2009), in a “dot migration assay” that recapitulates in vivobrain tumor dissemination along blood vessels and associated ECM (Baghdadchi et al., in preparation). We measured by immunofluorescence spatial dependence of tumor cell morphology and physical interactions with other tumor cells, migration, and expression of tumor adhesion molecules and other markers. VCAM-1 expression responses to TNF by proneural (PBT003) and mesenchymal (PBT017) GBM cell lines differed markedly. Specifically, VCAM-1 immunoreactivity was initially low on (PN) PBT003 cells and markedly enhanced by exposure (6 days) to TNF (10 ng/ml). In contrast, VCAM-1 immunoreactivity was initially higher on (Mes) PBT017 cells and decreased on chronic exposure to TNF. While preliminary, these observations suggest that within patient tumors, responses to activated microglia and macrophages may be regionally disparate depending on local molecular subtype
Long-term treatment with evolocumab added to conventional drug therapy, with or without apheresis, in patients with homozygous familial hypercholesterolaemia: an interim subset analysis of the open-label TAUSSIG study
Authors: Frederick J Raal, G Kees Hovingh, Dirk Blom, Raul D Santos, Mariko Harada-Shiba, Eric Bruckert, Patrick Couture, Handrean Soran, Gerald F Watts, Christopher Kurtz, Narimon Honarpour, Lihua Tang, Sree Kasichayanula, Scott M Wasserman, Evan A Stein
Journal: The Lancet Diabetes & Endocrinology (2017)
Iron Overload and Cytokine Serum Levels in Congenital Hemolytic Anemias
Authors: Wilma Barcellini, Anna Ines Gregorini, Giulia Soverini, Anna Zaninoni, Juri A Giannotta, Cristina Vercellati, Valeria Ferri, Paola Bianchi, Agostino Cortelezzi, Maria Domenica Cappellini
Journal: Blood (2016)
GENT-33. EPIGENETIC ALTERATIONS AT INTERGENIC REGIONS ASSOCIATED WITH PROGRESSION IN A SUBSET OF IDH MUTANT GLIOMAS
Authors: Thais Sarraf Sabedot, Tathiane Malta, Michele Ceccarelli, Huy Dihn, Benjamin Berman, Houtan Noushmehr
Journal: Neuro-Oncology (2016)

Malignant gliomas are heterogeneous brain tumors characterized by progression and recurrence with variable patterns. Generally, IDH mutant gliomas are associated with favorable clinical outcome and higher DNA methylation at CpG islands (G-CIMP). However, our group reported a subclassification for G-CIMP (Ceccarelli et al. 2016). We termed these novel subtypes as ‘G-CIMP-low’, with lower DNA methylation profile and significantly worse survival, and ‘G-CIMP-high’, with higher levels of DNA methylation and better clinical outcome. Also, in matched primary and recurrent glioma cases, potential progression from G-CIMP-high to G-CIMP-low was observed. We aimed to understand potential epigenomic mechanisms leading to progression. To evaluate this, we extracted publicly available whole-genome bisulfite sequencing (WGBS) and RNAsequencing/Microarray data for G-CIMP-low (n=1), G-CIMP-high (n=2) and non-tumor brain (n=2) samples. We assess DNA methylation levels at single CpG level (~25 million) and integrated with chromHMM, epigenomic histone modification and transcriptomic data. We observed high concordance between Infinium-CpG-microarray and WGBS data (n=25,516 CpG, p-value<0.05, cor=0.95) suggesting our sample size is sufficient for exploratory analysis. At known intergenic regions and potential regulatory elements, G-CIMP-high and non-tumor brain samples show similar DNA methylation profile whereas G-CIMP-low presents with lower levels of DNA methylation. A significant number of CTCF insulator binding sites (n=24, p-value<0.05) showed DNA methylation differences between G-CIMP-low and G-CIMP-high and deregulated genes near these sites were found to be associated with cell cycle pathways (n=23). Also, there were DNA methylation changes near nuclear lamina domains, usually associated with deregulation of genes at boundaries, suggesting that chromatin accessibility may be affected in G-CIMP-low. Together these results suggest that most of epigenetic alterations in G-CIMP-low are at intergenic regions, specially candidate functional regulatory elements, which may alter 3D structure of chromatin in G-CIMP-low, allowing specific tumor suppressor genes to be deregulated and thereby leading to more aggressive phenotype for G-CIMP-low.
Identification of patients at risk for severe toxicity under PD1 inhibitors: role of sarcopenic overweight
Authors: P. Boudou Rouquette, A. Jouinot, O. Huillard, J. Arrondeau, C. Tlemsani, V. Heidelberg, J. Chapron, N. Kramkimel, D. Damotte, F. Batteux, L. Dehghani, B. Terrier, L. Groussin, N. Dupin, B. Blanchet, M. Alifano, K. Leroy, M.-P. Revel, J. Alexandre, F. Goldwasser
Journal: Annals of Oncology (2016)
EXTH-32. COMBINATION OF RAS INHIBITOR AND DOXORUBICIN IN LIPOSOMES ENHANCES THERAPEUTIC EFFICACY IN GLIOBLASTOMA MOUSE MODEL
Authors: A.B. Madhankumar, Becky Slagle-Webb, Oliver Mrowczynski, Russell Payne, Brad Zacharia, Elias Rizk, James Connor
Journal: Neuro-Oncology (2016)

Ras is activated in majority of high grade astrocytomas including GBM tumors. Certain Ras inhibitors were previously demonstrated to act in synergy with doxorubicin, a topoisomerase II inhibitor for a variety of malignant tumors. When Ras inhibitor is delivered via the liposomal membrane, its cytotoxicity will be enhanced. When doxorubicin (DXR) is encapsulated in the liposome core, in addition to Ras inhibitor, their synergistic cytotoxicity on the tumor cells will be enhanced. To enhance the specificity of the Ras inhibition on the tumor cells the liposomes were also conjugated to interleukin-13 (IL-13), a cytokine which has its receptor overexpressed in GBM tumors. The liposomes were formulated as described in our previous reports with a slight modification including farnesyl thiosalicylic acid (FTS), a Ras inhibitor. The particle size and the surface morphology were verified using a particle size analyzer. The cytotoxicity assay was performed on human glioma initiating cells, T3691 and an established human glioma cell line, U87. The cytotoxicity assay on these cells confirmed an enhanced cytotoxicity of FTS-LIP(DXR) compared to LIP-DXR. Subcutaneous tumors were developed in the mouse models after injecting the U87 glioma cells in athymic nude mice. Subcutaneous tumor bearing mice were injected with FTS-LIP (DXR) weekly once for 7 weeks at a dose of 7 mg/kg dose. The tumor volume and the weight of the mice were monitored once a week. The tumor progression in the mice treated with FTS-LIP(DXR) was slower than in the LIP(DXR) group. In the untreated control mice, the tumor volume increased steadily compared to control mice. In vivo study in a group of mice treated with IL13-FTS-LIP(DXR) indicated a similar trend of lower tumor progression in the treatment group. Experiments are in progress to demonstrate the therapeutic efficacy of these liposomes in patient derived xenograft (PDX) models.
Predictors of Mortality in Patients Undergoing Autologous Stem Cell Transplant (ASCT) Admitted to the Intensive Care Unit: An Institutional Review of 1013 Transplant Patients over Five Years.
Authors: Martina A. Trinkaus, Stephen E. Lapinsky, David C. Hallett, Norman Franke, Andrew Winter, Michael Crump, Donna E. Reece, Christine Chen, Suzanne Trudel, Ian Quirt, Armand Keating, Joseph R. Mikhael
Journal: Blood (2007)
Dendritic cell vaccination in combination with docetaxel for patients with prostate cancer – a randomized phase II study
Authors: P. Kongsted, E. Ellebæk, T.H. Borch, T.Z. Iversen, R. Andersen, Ö Met, M. Hansen, L. Sengeløv, I.M. Svane
Journal: Annals of Oncology (2016)
Pathology of BRCA1- and BRCA2-associated breast cancers: known and less known connections
Authors: F. Fostira, E. Fountzila, A. Vagena, P. Apostolou, I. Konstanta, C. Papadimitriou, E. Razis, C. Christodoulou, E. Timotheadou, V. Mollaki, M. Papamentzelopoulou, I.S. Vlachos, D. Yannoukakos, I. Konstantopoulou
Journal: Annals of Oncology (2016)
MERIBEL study: Single-agent eribulin as first-line therapy for taxane-resistant HER2[-] metastatic breast cancer (MBC) patients (pts)
Authors: V. Ortega, J. Lao, I. Garau, N. Afonso, L. Calvo, Y. Fernández, M. Martinez-Garcia, E. Blanco, P. Zamora, M. García, J.J. Illarramendi, C. Rodríguez, E. Aguirre, J. Pérez, J. Cortes Castan, A. Llombart-Cussac
Journal: Annals of Oncology (2016)
Corrigendum re: “Serum Levels of MicroRNA miR-371a-3p: A Sensitive and Specific New Biomarker for Germ Cell Tumours” [Eur Urol 2017;71:213–20]
Authors: Klaus-Peter Dieckmann, Arlo Radtke, Meike Spiekermann, Thomas Balks, Cord Matthies, Pascal Becker, Christian Ruf, Christoph Oing, Karin Oechsle, Carsten Bokemeyer, Johannes Hammel, Sebastian Melchior, Werner Wosniok, Gazanfer Belge
Journal: European Urology (2017)
Ultraradical surgery and heated intraperitoneal chemotherapy (HIPEC) as multimodal treatment of advanced colorectal cancer.
Authors: S. Nikolic, M. Zegarac, M. Inic, A. Martinovic
Journal: Journal of Clinical Oncology (2011)

585 Background: Examin does agressive surgical treatment in combination with HIPEC (oxaliplatin) could increase median survial in patients with advanced stage of colorectal cancer. Methods: Ultraradical surgery and HIPEC was applied in patients who were initialy with peritoneal carcinomatosis or infiltration in around organs. We evaluated the patients during the period 2000-2010 in this retrospective study. Results: During 2000 and 2010 we peformed 132 ultraradical surgical procedure. All patients were treated with HIPEC (40C) using oxaliplatin (410mg/m 2 ) in 3l of perfusat during 90 minutes. The average duration of the procedure was 5h 57 minutes.The follow up period was 72 months. 120 had Ro and 12 had R1 resection. One year survival rate was 81.25% and three year survival rate was 56.25%, six year survival rate is 40.6%. Conclusions: Ultraradical surgery combined with HIPEC prolongs patient's survival and is considered to be a safe procedure if performed by the experience team of oncological surgeons. No significant financial relationships to disclose.