tbuckley/cabot-search huggingface dataset:
P14.02 Influence of individual CpG methylation status on outcome in adult patients with glioblastoma multiforme receiving alkylating agent treatment
Authors: S Siller, M Lauseker, A Giese, J Tonn, K Niyazi, N Thon, B Suchorska, F Kreth
Journal: Neuro-Oncology (2019)

Abstract Background: Methylation of the O-6-methylguanine-DNA methyltransferase (MGMT) promotor causes gene silencing and has been associated with a favourable prognosis in patients with glioblastoma multiforme (GBM) receiving alkylating chemotherapy. However, analysis of MGMT promotor methylation is usually reported as a cut-off depending on the results of the correspondent CpG site testing. This approach disregards a possible heterogeneity concerning the methylation status within the individual CpG sites and its possible association with prognosis in GBM patients. The current study aimed at elucidating the association between methylation of CpG sites 74–98 within the MGMT promotor region and outcome in GBM patients receiving alkylating agents. Material and Methods: Individual methylation status of 230 patients with histologically proven GBM following concomitant radio-chemotherapy with TMZ after stereotactic biopsy or open tumor resection (OTR) was assessed by the Sanger sequencing (Sseq) approach. Methylation of CpG sites 74–98 within the MGMT promotor region was defined according to a ratio of cytosine /thymine peak &gt;50%. The total number of methylated CpG sites as well as clinical factors such as age, Karnofsky Performance Score (KPS) and mode of surgical procedure were correlated with outcome using proportional hazards models. In a subset of 34 patients, a correlation between individual CpG methylation and MGMT mRNA expression was performed. Results: Median progression-free (PFS) and overall survival (OS) were 7.8 and 14.6 months, respectively. Alongside younger age, KPS&gt; 80 and OTR, the cumulative total number of methylated loci within the CpG sites 74–98 was strongly associated with both PFS and OS and retained its prognostic influence on outcome in multivariate models (p &lt;0.001). Furthermore, a linear coherence between the total number of methylated CpG sites 74–98 and survival parameters could be observed. Moreover, low number of methylated CpG sites was observed in tumor specimen with a high mRNA expression and vice versa (Spearman correlation coefficient: -0.62). Conclusion: In contrast to the concept of dichotomizing the MGMT promotor status into ‘methylated’ and ‘non-methylated’, our approach shows a clear heterogeneity within the methylation status of the CpG sites 74–98 within the GBM tumor specimens. Our data suggest a strong correlation between outcome and the total number of methylated CpG sites, thus an up-front analysis of the individual GpC site methylation status prior to initiation of alkylating chemotherapy might help to improve treatment response in GBM patients.
P14.94 Mitochondrial DNA copy number in new onset and recurrent glioblastoma and its effect on radiation resistance and patient survival
Authors: P Sravya, V P Nimbalkar, N N Kanuri, S Rao, A Arivazhagan, S Somanna, P Kondaiah, V Santosh
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Recent evidence shows that mitochondrial DNA (mtDNA) content is responsible for radiation resistance in various cancers, but not evaluated in glioblastoma(GBM).Hence,we studied the role of mtDNA content in GBM pathogenesis and treatment response. MATERIAL AND METHODS Archived FFPE tissues of newly diagnosed GBM(n=130), recurrent GBM (n=32 pairs) and non-neoplastic control brain(n=30) with available clinical details were utilized for the study. Immunohistochemistry, Sanger’s sequencing, methylation specific PCR and fluorescent in-situ hybridization were used to study IDH, ATRX and TERT promoter mutations, MGMT promoter methylation and EGFR amplification. mtDNA content was analyzed using quantitative real time PCR (relative quantification) and was calculated using the formula 2- ΔΔCTx100. Malignant glioma cell lines U87 and LN229 were used to study the difference in mtDNA content following radiation exposure.LN229 cell line was subjected to mtDNA depletion by incubation with ethidium bromide for 4 days.The parent and mtDNA depleted LN229 cell lines were then assessed for sensitivity to radiation and Temozolomide(TMZ) therapy using MTT assay. RESULTS mtDNA content was lower than control brain tissue(mean mtDNA content 19.6) in all cases studied,with significantly lower content in older patients(p=0.04).Lower mean mtDNA content was seen in IDH wild type, MGMT unmethylated and EGFR amplified tumors when compared to their counterparts(p=1.06).Survival analysis using Cox regression showed that lower mtDNA copy number is associated with higher risk and hence poorer prognosis(p=0.047).Paired tumor analysis was performed in 32 patients with recurrence of whom only 19 had received radiation therapy (RT).The mean mtDNA content was higher at recurrence as compared to the primary tumor in those who received RT(mean at diagnosis 20.1; mean at recurrence 49.3, p=0.02) while no significant difference was observed in those who did not receive RT. U87 and LN229 cell lines exposed to radiation (0, 2, 4 and 6Gy) showed an increase of 8% and 25% in mtDNA content, respectively, after 6Gy radiation exposure.LN229 parent cells showed a radiation dose dependent decline in cell viability(86% at 2Gy, 68% at 4Gy and 50% at 6Gy).The mtDNA depleted LN229 cells were 100% viable at 0, 2 and 4 Gy and 82% viable at 6Gy.The IC50 of TMZ in parent LN229 cells was 69.3 µM while in the mtDNA depleted cells,it was 100.8 µM. Conclusion:Our study shows that lower mtDNA content is associated with poorer survival in GBM.RT increased the mtDNA content in both patient samples and malignant glioma cell lines.mtDNA depleted LN229 lines are more radio-chemo resistant than parent LN229 lines,thus showing that lower mtDNA content leads to treatment resistance.Hence,we establish the significant role of mtDNA content in the pathogenesis and treatment resistance of GBM.
Using machine learning to predict mortality in older patients with cancer: Decision tree and random forest analyses from the ELCAPA and ONCODAGE prospective cohorts.
Authors: Etienne Audureau, Pierre-Louis Soubeyran, Claudia Martinez-Tapia, Carine A. Bellera, Sylvie Bastuji-Garin, Pascaline Boudou-Rouquette, Muriel Rainfray, Anne Chahwakilian, Thomas Grellety, Olivier Hanon, Simone Mathoulin-Pélissier, Elena Paillaud, Florence Canoui-Poitrine
Journal: Journal of Clinical Oncology (2019)

11516 Background: Accurate prognosis is crucial to decision making in oncology, but remains challenging in older patients due to the heterogeneity of this population and the lack of ability of current models to capture complex interactions between oncological and geriatric predictors. We aimed to develop new predictive algorithms based on machine learning to refine individualized prognosis in older patients with cancer. Methods: Data were collected from 3409 patients ≥70 years referred to geriatric oncology clinics for completion of a geriatric assessment (GA), including 2012 and 1397 patients from the ELCAPA (training set) and ONCODAGE (validation set) French prospective cohorts, respectively. Candidate predictors included baseline oncological and geriatric parameters, G-8 score and routine biological data (CRP/albumin ratio). Prognostic models for 12-months mortality were built using Cox regression model, single decision tree (DT) and random survival forest (RSF). Models performance was compared based on externally validated Harrell’s C-indexes. Results: During the 1-year study period, 875 (43%) and 219 (16%) patients died in the training and validation sets, respectively (mean age: 81±6 / 78±5, women 47% / 70%, metastasis 50% / 34%). Cox model identified 9 independent predictors of mortality: tumor site/metastatic status, anticancer treatment, weight loss &gt; 3kg, drugs &gt; 5, renal failure, increased CRP/Albumin, ECOG-PS≥2, ADL≤5 and altered TGUG. DT identified more complex combinations between features, yielding 16 patient groups with highly differentiated survival, notably depending on the G-8 ( &lt; 10 vs. ≥10 as the root node). RFS had the highest C-index (0.86 [RFS], 0.82 [Cox], 0.81 [DT]), identifying the G-8, CRP/albumin and tumor site/metastasis as the most important features. Conclusions: While Cox modeling confirmed known independent prognostic factors, DT revealed more complex interactions between them and random forest achieved superior prognostic performance by better capturing patient’s complexity. The latter model has been implemented into an interactive web interface for easy and direct use in clinical practice. Clinical trial information: NCT02884375.
Thioredoxin reductase modulates NFkB signaling at the nuclear compartment
Authors: Jacqueline Heilman, Walter Watson
Journal: Cancer Research (2008)

5268  Nuclear factor-kappa-B (NFκB) promotes cell survival, proliferation, and inflammation, and is recognized as a promising target for chemotherapeutics. Some inhibitors of NFκB have also been shown to inhibit thioredoxin reductase (TR1), which is itself a focus of anticancer therapies. One of the major substrates of TR1 is thioredoxin (Trx1). It has been assumed, but never tested, that the effects of TR1 inhibition on the NFκB pathway are mediated through a buildup of oxidized Trx1. The purpose of the present study is to test the hypothesis that TR1 regulates NFκB activity through effects on the redox state of Trx1. In order to address this question, we treated HeLa cells with siRNA for TR1, and stimulated the NFκB pathway with TNFα. We then confirmed TR1 protein knockdown by western blot and performed an insulin reduction assay to confirm decreased enzymatic activity. IκB degradation was analyzed by western blot, and p50 and p65 localization were determined by western blot and gel shift assay. A luciferase reporter construct was used to measure NFκB activity. The redox status of Trx1 was measured by a redox western blot technique, and reactive oxygen species (ROS) were detected by FACS analysis of DCF fluorescence. Following knockdown of TR1 and stimulation with TNFα, IκB degradation, and p50/p65 translocation occurred as expected, however expression of the NFκB reporter gene decreased by 40%. Surprisingly, even at a 95% knock-down of TR1 activity, Trx1 was not oxidized and no ROS were detected. From this we conclude that active TR1, and not the redox status of the total cellular pool of Trx1, is important for maximal NFκB signaling in the nuclear compartment.
Randomized, Double-Blind, Placebo-Controlled, Multicenter Phase II Study of Onartuzumab Plus Bevacizumab Versus Placebo Plus Bevacizumab in Patients With Recurrent Glioblastoma: Efficacy, Safety, and Hepatocyte Growth Factor and O
Authors: Timothy Cloughesy, Gaetano Finocchiaro, Cristóbal Belda-Iniesta, Lawrence Recht, Alba A Brandes, Estela Pineda, Tom Mikkelsen, Olivier L Chinot, Carmen Balana, David R Macdonald, Manfred Westphal, Kirsten Hopkins, Michael Weller, Carlos Bais, Thomas Sandmann, Jean-Marie Bruey, Hartmut Koeppen, Bo Liu, Wendy Verret, See-Chun Phan, David S Shames
Journal: Journal of Clinical Oncology (2017)
OS10.6 Infigratinib (BGJ398) in patients with recurrent gliomas with fibroblast growth factor receptor (FGFR) alterations: a multicenter phase II study
Authors: A B Lassman, J M Sepúlveda-Sánchez, T Cloughesy, J M Gil-Gil, V K Puduvalli, J Raizer, F Y De Vos, P Y Wen, N Butowski, P Clement, M D Groves, C Belda-Iniesta, K Steward, S Moran, Y Ye, P Roth
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND FGFR mutations and translocations occur in approximately 10% of glioblastomas (GBMs). FGFR3-TACC3 fusion has been reported as predictive of response to FGFR tyrosine kinase inhibitor therapy both pre-clinically and clinically. Infigratinib (BGJ398) is a selective small-molecule pan-FGFR kinase inhibitor that has demonstrated anti-tumor activity in several solid tumors with FGFR genetic alterations. Therefore, we conducted a phase II trial to test the efficacy of infigratinib in FGFR-altered recurrent GBM (NCT01975701). METHODS This open-label trial accrued adults with recurrent high-grade gliomas following failure of initial therapy that harbored FGFR1-TACC1 or FGFR3-TACC3 fusions; activating mutations in FGFR1, 2 or 3; or FGFR1, 2, 3, or 4 amplification. Oral infigratinib was administered 125 mg on days 1–21 every 28 days. Prophylaxis for hyperphosphatemia, a common toxicity, was recommended. The primary endpoint was the 6-month progression-free survival (6mPFS) rate by RANO (locally assessed, estimated by K-M method), with a goal of &gt;40%. RESULTS As of the Sep 2017 data cut-off, 26 patients (16 men, 10 women; median age 55 years, range 20–76 years; 50% with ≥2 prior regimens) were treated, and 24 (92.3%) discontinued for disease progression (n=21) or other reasons (n=3). All patients had FGFR1 or FGFR3 gene alterations, and 4 had &gt;1 gene alteration. The estimated 6mPFS rate was 16% (95% CI 5.0–32.5%); median PFS was 1.7 months (95% CI 1.1–2.8 months); median OS was 6.7 months (95% CI 4.2–11.7 months); ORR was 7.7% (95% CI 1.0–25.1%). The best overall response was: partial response 7.7% (FGFR1 mutation n=1; FGFR3 amplification n=1); stable disease 26.9%; progressive disease 50.0%; missing/unknown 15.3%. The most common (&gt;15%) all-grade treatment-related adverse events (AEs) were hyperphosphatemia, fatigue, diarrhea, hyperlipasemia, and stomatitis. There were no grade 4 treatment-related AEs. Eleven patients (42.3%) had treatment-related AEs requiring dose interruptions or reductions (most commonly hyperphosphatemia). CONCLUSIONS Infigratinib induced partial response or stable disease in approximately one-third of patients with recurrent GBM and/or other glioma subtypes harboring FGFR alterations. Most AEs were reversible and manageable. Further potential combinations are being explored in patients with proven FGFR-TACC fusion genes and analysis of biomarker data is ongoing.
Marked Re-Expansion of Chimeric Antigen Receptor (CAR) T Cells and Tumor Regression Following Nivolumab Treatment in a Patient Treated with Axicabtagene Ciloleucel (axi-cel; KTE-C19) for Refractory Diffuse Large B Cell Lymphoma (DLBCL)
Authors: Brian T. Hill, Zachary J. Roberts, John M. Rossi, Mitchell R. Smith
Journal: Blood (2017)
Impaired dopamine metabolism in Parkinson’s disease pathogenesis
Authors: Anna Masato, Nicoletta Plotegher, Daniela Boassa, Luigi Bubacco
Journal: Molecular Neurodegeneration (2019)

A full understanding of Parkinson's Disease etiopathogenesis and of the causes of the preferential vulnerability of nigrostriatal dopaminergic neurons is still an unsolved puzzle. A multiple-hit hypothesis has been proposed, which may explain the convergence of familial, environmental and idiopathic forms of the disease. Among the various determinants of the degeneration of the neurons in Substantia Nigra pars compacta, in this review we will focus on the endotoxicity associated to dopamine dyshomeostasis. In particular, we will discuss the relevance of the reactive dopamine metabolite 3,4-dihydroxyphenylacetaldehyde (DOPAL) in the catechol-induced neurotoxicity. Indeed, the synergy between the catechol and the aldehyde moieties of DOPAL exacerbates its reactivity, resulting in modification of functional protein residues, protein aggregation, oxidative stress and cell death. Interestingly, αSynuclein, whose altered proteostasis is a recurrent element in Parkinson's Disease pathology, is considered a preferential target of DOPAL modification. DOPAL triggers αSynuclein oligomerization leading to synapse physiology impairment. Several factors can be responsible for DOPAL accumulation at the pre-synaptic terminals, i.e. dopamine leakage from synaptic vesicles, increased rate of dopamine conversion to DOPAL by upregulated monoamine oxidase and decreased DOPAL degradation by aldehyde dehydrogenases. Various studies report the decreased expression and activity of aldehyde dehydrogenases in parkinsonian brains, as well as genetic variants associated to increased risk in developing the pathology. Thus, we discuss how the deregulation of these enzymes might be considered a contributing element in the pathogenesis of Parkinson's Disease or a down-stream effect. Finally, we propose that a better understanding of the impaired dopamine metabolism in Parkinson's Disease would allow a more refined patients stratification and the design of more targeted and successful therapeutic strategies.
Treosulfan, Fludarabine and Cytarabine As Conditioning before Allogeneic Hematopoietic Stem Cell Transplantation
Authors: Inken Hilgendorf, Nils Winkelmann, Jochen J Frietsch, Friederike Hunstig, Ulf Schnetzke, Sebastian Scholl, Andreas Hochhaus, Jochen Casper
Journal: Blood (2018)
The potential of cerebrospinal fluid–based liquid biopsy approaches in CNS tumors
Authors: Austin K Mattox, Hai Yan, Chetan Bettegowda
Journal: Neuro-Oncology (2019)

Cerebrospinal fluid (CSF) may be the best hope for minimally invasive diagnosis and treatment monitoring of central nervous system (CNS) malignancies. Discovery/validation of cell-free nucleic acid and protein biomarkers has the potential to revolutionize CNS cancer care, paving the way for presurgical evaluation, earlier detection of recurrence, and the selection of targeted therapies. While detection of mutations, changes in RNA and miRNA expression, epigenetic alterations, and elevations of protein levels have been detected in the CSF of patients with CNS tumors, most of these biomarkers remain unvalidated. In this review, we focus on the molecular changes that have been identified in a variety of CNS tumors and profile the approaches used to detect these alterations in clinical samples. We further emphasize the importance of systemic collection of CSF and the establishment of standardized collection protocols that will lead to better cross-study biomarker validation and hopefully FDA-approved clinical markers.
An open-label phase 1 clinical trial of the anti-α <sub>4</sub> β <sub>7</sub> monoclonal antibody vedolizumab in HIV-infected individuals
Authors: Michael C. Sneller, Katherine E. Clarridge, Catherine Seamon, Victoria Shi, Marek D. Zorawski, Jesse Shawn Justement, Jana Blazkova, Erin D. Huiting, Michael A. Proschan, Jorge Rodrigo Mora, Michael Shetzline, Susan Moir, Henry Clifford Lane, Tae-Wook Chun, Anthony S. Fauci
Journal: Science Translational Medicine (2019)

Despite the substantial clinical benefits of antiretroviral therapy (ART), complete eradication of HIV has not been possible. The gastrointestinal tract and associated lymphoid tissues may play an important role in the pathogenesis of HIV infection. The integrin α4β7 facilitates homing of T lymphocytes to the gut by binding to the mucosal addressin cell adhesion molecule-1 (MAdCAM-1) expressed on venules in gut-associated lymphoid tissue. CD4+ T cells with increased expression of α4β7 are susceptible to HIV infection and may be key players in subsequent virus dissemination. Data from nonhuman primate models infected with simian immunodeficiency virus (SIV) have suggested that blockade of the α4β7/MAdCAM-1 interaction may be effective at preventing SIV infection and may have beneficial effects in animals with established viral infection. To explore whether these findings could be reproduced in HIV-infected individuals after interruption of ART, we conducted an open-label phase 1 clinical trial of vedolizumab, a monoclonal antibody against α4β7 integrin. Vedolizumab infusions in 20 HIV-infected individuals were well tolerated with no serious adverse events related to the study drug. After interruption of ART, the median time to meeting protocol criteria to restart therapy was 13 weeks. The median duration of plasma viremia of <400 copies/ml was 5.4 weeks. Only a single subject in the trial experienced prolonged suppression of plasma viremia after interruption of ART. These results suggest that blockade of α4β7 may not be an effective strategy for inducing virological remission in HIV-infected individuals after ART interruption.
Plasma sRAGE Acts as a Genetically Regulated Causal Intermediate in Sepsis-associated Acute Respiratory Distress Syndrome
Authors: Tiffanie K. Jones, Rui Feng, V. Eric Kerchberger, John P. Reilly, Brian J. Anderson, Michael G. S. Shashaty, Fan Wang, Thomas G. Dunn, Thomas R. Riley, Jason Abbott, Caroline A. G. Ittner, David C. Christiani, Carmen Mikacenic, Mark M. Wurfel, Lorraine B. Ware, Carolyn S. Calfee, Michael A. Matthay, Jason D. Christie, Nuala J. Meyer
Journal: American Journal of Respiratory and Critical Care Medicine (2019)

Acute respiratory distress syndrome (ARDS) lacks known causal biomarkers. Plasma concentrations of sRAGE (soluble receptor for advanced glycation end products) strongly associate with ARDS risk. However, whether plasma sRAGE contributes causally to ARDS remains unknown.
Community Health Workers Improve Linkage to Hypertension Care in Western Kenya
Authors: Rajesh Vedanthan, Jemima H. Kamano, Allison K. DeLong, Violet Naanyu, Cynthia A. Binanay, Gerald S. Bloomfield, Stavroula A. Chrysanthopoulou, Eric A. Finkelstein, Joseph W. Hogan, Carol R. Horowitz, Thomas S. Inui, Diana Menya, Vitalis Orango, Eric J. Velazquez, Martin C. Were, Sylvester Kimaiyo, Valentin Fuster
Journal: Journal of the American College of Cardiology (2019)
Heparanase Accelerates Obesity-Associated Breast Cancer Progression
Authors: Esther Hermano, Rachel Goldberg, Ariel M. Rubinstein, Amir Sonnenblick, Bella Maly, Daniela Nahmias, Jin-Ping Li, Marinka A.H. Bakker, Johan van der Vlag, Israel Vlodavsky, Tamar Peretz, Michael Elkin
Journal: Cancer Research (2019)

Obese women have higher risk of bearing breast tumors that are highly aggressive and resistant to therapies. Tumor-promoting effects of obesity occur locally via adipose inflammation and related alterations to the extracellular matrix (ECM) as well as systemically via circulating metabolic mediators (e.g., free fatty acids, FFA) associated with excess adiposity and implicated in toll-like receptor-mediated activation of macrophages-key cellular players in obesity-related cancer progression. Although the contribution of macrophages to proneoplastic effects of obesity is well documented, the role of ECM components and their enzymatic degradation is less appreciated. We show that heparanase, the sole mammalian endoglucuronidase that cleaves heparan sulfate in ECM, is preferentially expressed in clinical/experimental obesity-associated breast tumors. Heparanase deficiency abolished obesity-accelerated tumor progression in vivo. Heparanase orchestrated a complex molecular program that occurred concurrently in adipose and tumor tissue and sustained the cancer-promoting action of obesity. Heparanase was required for adipose tissue macrophages to produce inflammatory mediators responsible for local induction of aromatase, a rate-limiting enzyme in estrogen biosynthesis. Estrogen upregulated heparanase in hormone-responsive breast tumors. In subsequent stages, elevated levels of heparanase induced acquisition of procancerous phenotype by tumor-associated macrophages, resulting in activation of tumor-promoting signaling and acceleration of breast tumor growth under obese conditions. As techniques to screen for heparanase expression in tumors become available, these findings provide rational and a mechanistic basis for designing antiheparanase approaches to uncouple obesity and breast cancer in a rapidly growing population of obese patients. SIGNIFICANCE: This study reveals the role of heparanase in promoting obesity-associated breast cancer and provides a mechanistically informed approach to uncouple obesity and breast cancer in a rapidly growing population of obese patients.
Membrane-associated mucins of the ocular surface: New genes, new protein functions and new biological roles in human and mouse
Authors: M. Elizabeth Fini, Shinwu Jeong, Haiyan Gong, Rafael Martinez-Carrasco, Nora M.V. Laver, Minako Hijikata, Naoto Keicho, Pablo Argüeso
Journal: Progress in Retinal and Eye Research (2019)