tbuckley/cabot-search huggingface dataset:
P08.56 Autocrine activation of the IFN signaling pathway modulates the immunogenicity of glioma cells
Authors: M. Silginer, S. Nagy, C. Happold, H. Schneider, M. Weller, P. Roth
Journal: Neuro-Oncology (2017)

Introduction: Interferons (IFN) are cytokines that are typically induced upon viral infection, but can be constitutively expressed also in the absence of acute infection to regulate various processes. Alterations in IFN signaling have been observed in numerous malignancies, however the physiological role of autocrine and paracrine IFN signaling remains poorly understood. Methods: Here, we aimed at characterizing autocrine IFN-β signaling and its functional impact in glioma cells in vitro using RNA interference-mediated gene silencing. Results: Exposure to recombinant IFN-β led to the induction of the classical IFN-response gene Myxovirus A (MxA) in a panel of glioma cell lines, whereas some glioma-initiating cells showed basal MxA protein expression even in the absence of exogenous IFN-β, indicating the presence of constitutive IFN signaling. Silencing of the type I IFN receptors IFNAR1 or IFNAR2, or the ligands IFN-α or IFN-β, decreased MxA levels, providing evidence for the existence of an autocrine type I IFN signaling loop. On a functional level, we observed reduced PD-L1, MHC class I and class II expression and increased susceptibility to NKL cell-mediated lysis upon IFNAR silencing, suggesting that constitutive IFN signaling in glioma cells plays an immunomodulatory role. Conclusion: Our findings point to an important role of constitutive IFN signaling in the immune evasion of glioma cells.
Engineering Cardiac Muscle Tissue
Authors: Florian Weinberger, Ingra Mannhardt, Thomas Eschenhagen
Journal: Circulation Research (2017)

Twenty years after the initial description of a tissue engineered construct, 3-dimensional human cardiac tissues of different kinds are now generated routinely in many laboratories. Advances in stem cell biology and engineering allow for the generation of constructs that come close to recapitulating the complex structure of heart muscle and might, therefore, be amenable to industrial (eg, drug screening) and clinical (eg, cardiac repair) applications. Whether the more physiological structure of 3-dimensional constructs provides a relevant advantage over standard 2-dimensional cell culture has yet to be shown in head-to-head-comparisons. The present article gives an overview on current strategies of cardiac tissue engineering with a focus on different hydrogel methods and discusses perspectives and challenges for necessary steps toward the real-life application of cardiac tissue engineering for disease modeling, drug development, and cardiac repair.
P18.03 Active coping strategies are associated with improved overall survival in newly diagnosed glioblastoma. A prospective study
Authors: S. Kebir, M. Niessen, A. Kellner, V. Tschuschke, U. Herrlinger, M. Glas
Journal: Neuro-Oncology (2017)

Background: The impact of psychosocial variables on the survival of cancer is discussed controversially. In a prospective study, we investigated whether the quality of coping strategies are of prognostic value in newly diagnosed glioblastoma. Methods: In a prospective study, patients with newly diagnosed glioblastoma underwent audiotaped interviews immediately following surgery and before initiating radiochemotherapy. The patients’ coping strategies were then identified from each interview using the Ulm Coping Manual that describes 34 different coping strategies. An exploratory factor analysis was conducted to assess patterns of coping strategies that reflect the same underlying general coping mechanism (also known as factor). These factors are characterized by a set of highly correlated coping strategies. Patients who are highly associated (loaded highly on) with a specific factor were compared against those with low loadings. In a Kaplan-Meier analysis, we compared overall survival (OS) between patients loading highly on a specific factor and those with negative loadings. A Cox regression analysis served to detect independent prognostic variables. Results: Eighteen patients were eligible for interviewing. Six factors have been retained based on the amount of variation they explain in all coping strategies. Among those, factor 1 (F1) explained the overall highest amount of variation and was characterized almost exclusively by high loadings of active coping strategies, including taking the initiative, problem analysis, emotional support, optimism/hope, and active compliance with factor loadings ranging from 54%-92%. The top two-thirds of patients with the highest loadings on F1 were compared against the lower third with poor loadings. Canonical prognostic factors were balanced between those groups. The high F1 loadings group had a particularly high median OS (24.1 months) as compared to the one with low F1 loadings (median OS, 10.6 months, p=0.0002). In a multivariable Cox regression analysis, F1 emerged as a prognostic factor (p<0.001) independent of canonical prognostic markers including age, Karnofsky performance score, extent of resection, and O6-methylguanin-DNA-methyltransferase (MGMT). Conclusions: Patients adopting positive coping strategies share a highly improved OS independent of known prognostic factors as compared to those with predominantly negative coping mechanisms. Exploitation of coping mechanisms may offer a possible novel avenue for glioblastoma treatment. Further exploration in a larger trial is warranted.
OS08.4 NF2 Disruption by Genomic Rearrangements Drives A Subset of Radiation Induced Meningiomas
Authors: S. Suppiah, P. Tonge
Journal: Neuro-Oncology (2017)

Purpose: Majority of pediatric cancers require the irradiation of the central nervous system (CNS), and as more patients survive into adulthood from improved oncological therapy the sequelae of brain radiation are increasing in prevalence. Radiation-induced meningiomas (RIMs), one such secondary effect, demonstrate a clinically more aggressive behaviour than sporadic meningiomas (SMs). We aimed to describe the genomic mutational landscape of RIMs. Methods: We analyzed a principal cohort of 18 RIMs, with 31 RIMs overall, from patients who received childhood radiation therapy and 30 SMs, as a comparator population. We performed a multiplatform integrative genomic analysis; including methylation, whole exome and RNA sequencing. Results: RIMs exhibited a five-fold increase in copy number alterations, commonly the loss of chromosome 1p (17/18 RIMs) and 22q (17/18 RIMs), which was significantly more than observed in SMs. In contrast to sporadic meningiomas, we identified only one focal NF2 mutation in a single RIM case within the splice donor site of intron 11 predicted to adversely affect RNA splicing between exons 11 and 12. Furthermore, RNA sequencing data revealed an NF2 gene fusion event in 35.3% of RIMs. In all 6 cases, there was a complete NF2 exon spliced into a complete exon of a reciprocal gene, suggesting that the breakpoints of genomic rearrangement are intronic. All tumours with the NF2 fusion also possessed monosomy of chromosome 22q, rendering the cells with homozygous disruption of NF2. Also, targeted sequencing panel confirmed that RIMs had fewer nonsynonymous NF2 mutations (6.5% vs. 30% in SM) and absence of mutations in TRAF7, SMO, KLF4, PIK3CA and AKT1, genes traditionally involved in SMs. Unsupervised clustering demonstrated two distinct methylation subgroups, with subgroup 1 having a male predominance and the two groups were distinguished by 600 differently methylated probes. Clinically, RIMs with the NF2 fusion exhibited ill-defined borders and a tendency to develop in anatomic frontal location.Conclusion: Our study demonstrates that RIMs have distinct genomic drivers of oncogenesis as compared to SMs, specifically NF2 inactivation through fusion event. Radiation therapy possibly triggers genomic structural rearrangements through error-prone repair of double-stranded DNA breaks.
MiR-155 Promotes FLT3-ITD-Induced Myeloproliferative Disease through Inhibition of Interferon Signaling
Authors: Jared Wallace, Dominique Kagele, Ruozhen Hu, Marah Runtsch, Margaret Alexander, Thomas Huffaker, Timothy Mosbruger, Dinesh S. Rao, Rodney R. Miles, June Round, Ryan M. O'Connell
Journal: Blood (2016)
P11.04 A single center experience in pediatric high grade gliomas (a retrospective observational study)
Authors: M. S. Elnaggar, K. F. Riad, A. A. Abdelhakeem, A. F. Elsherif
Journal: Neuro-Oncology (2017)

Introduction: Pediatric high grade glioma is an uncommon type of Pediatric central nervous system (CNS) tumors as it represents only 8-12 % of these tumors. These tumors still represent challenges in their treatment. Survival rates are higher in Pediatric tumors than in adults, which can be partially explained by more chemotherapy protocols or difference in the tumor biology. In 2005 the introduction of temozolamide change the way of practice in treatment of these tumors in adult patients. But no data was available for Pediatric tumors at that time. The use of temozolamide in pediatric gliomas has different results in studies and still it is not a standard of care in pediatric patients. Materials and Methods: We perform a retrospective analysis for Pediatric high grade glioma patients. We collect all data of Patients aged less than 18 years old having high grade glioma, from the period of 2010-2016 in Assuit university, and Comparing the results of patients received temozolamide with radiotherapy and adjuvant temozolamide to patients received radiotherapy alone or with other lines of chemotherapy and we analyze prognostic factors and results of the treatment. Results: 22 Patients with high grade glioma was found from the period of 2010 till 2016, and were surgically operated at Assiut university hospital, and was diagnosed pathologically as glioblastoma multiform. The median age was 9 years (range 3.5-17). The male-to-female ratio was 2:1. 16 patients have near total resection and 6 of them have only biopsy. All the patients received radiation therapy 6000 CGy over 30 setting for 6 weeks.10 patients received temozolamide concomitant with radiotherapy followed by adjuvant temozolamide and 2 patients received radiotherapy alone and the remaining 10 patients received cisplatin, vepside and vencristine as adjuvant treatment after radiotherapy. At 3 years median progression free survival (PFS) to all patients was 11.91 months (95% CI 9.35-14.46) and overall survival (OS) was 17.55 months (95% CI 14.15 -20.94). The patients receiving Temozolamide had better PFS 15.40 months (95% CI 12.48-18.32) and OS 21.20 months (95% CI 18.09-24.31) than the other patients receiving other adjuvant treatment were their PFS 9 months (95% CI 5.55- 12.45) and OS 14.50 months (95% CI 9.02-19.98). Subtotal resection of the tumor and temozolamide treatment was found to be a statistically significant prognostic factor in both univariate and multivariate analysis (P value<0.05).Conclusions: High grade glioma is an aggressive uncommon pediatric tumor. In our analysis optimal surgical resection and use temozolamide were found to be significant prognostic factors. Further prospective studies and more patients number are needed to confirm these results.
Interim Results from a Phase 1/2 Clinical Study of Lentiglobin Gene Therapy for Severe Sickle Cell Disease
Authors: Julie Kanter, Mark C. Walters, Matthew M. Hsieh, Lakshmanan Krishnamurti, Janet Kwiatkowski, Rammurti T Kamble, Christof von Kalle, Frans A. Kuypers, Marina Cavazzana, Philippe Leboulch, Marcelyne Joseney-Antoine, Mohammed Asmal, Alexis A. Thompson, John F. Tisdale
Journal: Blood (2016)
Erratum: TGF-β is responsible for NK cell immaturity during ontogeny and increased susceptibility to infection during mouse infancy
Authors: Jeffrey P Marcoe, James R Lim, Keri L Schaubert, Nassima Fodil-Cornu, Marsel Matka, Alexandra L McCubbrey, Alexander R Farr, Silvia M Vidal, Yasmina Laouar
Journal: Nature Immunology (2013)
Inferior Survival Rates After Chemoradiation for Rectal Cancer Without Surgery
Authors: Angelita Habr-Gama, Guilherme Pagin São Julião, Rodrigo O. Perez
Journal: JAMA Oncology (2017)

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Phase II study of single-agent cetuximab in <i>KRAS</i> G13D mutant metastatic colorectal cancer (mCRC).
Authors: Marta Schirripa, Sara Lonardi, Chiara Cremolini, Fotios Loupakis, Lisa Salvatore, Francesca Bergamo, Carlotta Antoniotti, Anna Roma, Roberta Bertorelle, Gianluca Masi, Federica Marmorino, Daniele Rossini, Giulia Pasquini, Federica Zoratto, Vittorina Zagonel, Alfredo Falcone
Journal: Journal of Clinical Oncology (2014)

3524 Background: RAS mutant metastatic colorectal cancer (mCRC) patients (pts) are excluded from treatment with anti-EGFR monoclonal antibodies. Nevertheless, retrospective data from large phase III trials led to hypothesize a potential benefit from cetuximab in KRAS G13D mutant pts both in first and advanced lines of treatment (De Roock JAMA 2010, Tejpar JCO 2012). In the refractory setting, KRAS G13D mutant pts achieved a superior progression free survival (PFS) (4.0 vs. 1.9 months, HR=0.51, p=0.004) and overall survival (OS) (7.6 vs. 5.7 months, HR=0.50, p=0.005) compared to pts with other KRAS mutations. We conducted the present trial in order to prospectively confirm those findings and to evaluate the clinical relevance of single agent cetuximab in KRAS G13D mutant mCRC pts. Methods: According to previously reported results, using a phase 2 Fleming single-stage design, with 90% power and alpha 0.05, setting p0=10% and p1=50%, the study required the inclusion of 12 pts. The alternative hypothesis would have been rejected if 3 or less pts would have been progression-free at four months after treatment start. We prospectively enrolled mCRC patients to receive treatment with cetuximab monotherapy (500 mg/mq bi-weekly). Main eligibility criteria were the following: KRAS G13D mutant, measurable metastatic disease, progression after treatment with fluoropyrimidine, oxaliplatin, irinotecan, and bevacizumab or no other valid therapeutic option. Pts were re-evaluated according to RECIST 1.1 criteria. Results: Twelve consecutive KRAS G13D mutant eligible pts were enrolled. Main pts’ characteristics were the following: Male/Female, 6/6; median age, 74 years (range 26-79); Eastern Cooperative Oncology Group performance status 0/1-2, 6/6; synchronous/metachronous disease, 8/4; median number of previous CT lines, 2 (range 0-5). Three patients (25%) showed disease stabilization at four months after treatment start and no RECIST responses were observed. Disease control rate at six months was 0%. Median PFS and OS were 1.9 and 7.2 months, respectively. Grade 3 rash was observed in two (17%) patients and no unexpected toxicities occurred. Conclusions: The hypothesis of a clinically relevant benefit with cetuximab monotherapy in KRAS G13D mutant mCRC pts was rejected. KRAS G13D mutant mCRC pts should not be treated with cetuximab and alternative strategies should be adopted.
Hepatic metal ion transporter ZIP8 regulates manganese homeostasis and manganese-dependent enzyme activity
Authors: Wen Lin, David R. Vann, Paschalis-Thomas Doulias, Tao Wang, Gavin Landesberg, Xueli Li, Emanuela Ricciotti, Rosario Scalia, Miao He, Nicholas J. Hand, Daniel J. Rader
Journal: Journal of Clinical Investigation (2017)

Genetic variants at the solute carrier family 39 member 8 (SLC39A8) gene locus are associated with the regulation of whole-blood manganese (Mn) and multiple physiological traits. SLC39A8 encodes ZIP8, a divalent metal ion transporter best known for zinc transport. Here, we hypothesized that ZIP8 regulates Mn homeostasis and Mn-dependent enzymes to influence metabolism. We generated Slc39a8-inducible global-knockout (ZIP8-iKO) and liver-specific-knockout (ZIP8-LSKO) mice and observed markedly decreased Mn levels in multiple organs and whole blood of both mouse models. By contrast, liver-specific overexpression of human ZIP8 (adeno-associated virus-ZIP8 [AAV-ZIP8]) resulted in increased tissue and whole blood Mn levels. ZIP8 expression was localized to the hepatocyte canalicular membrane, and bile Mn levels were increased in ZIP8-LSKO and decreased in AAV-ZIP8 mice. ZIP8-LSKO mice also displayed decreased liver and kidney activity of the Mn-dependent enzyme arginase. Both ZIP8-iKO and ZIP8-LSKO mice had defective protein N-glycosylation, and humans homozygous for the minor allele at the lead SLC39A8 variant showed hypogalactosylation, consistent with decreased activity of another Mn-dependent enzyme, β-1,4-galactosyltransferase. In summary, hepatic ZIP8 reclaims Mn from bile and regulates whole-body Mn homeostasis, thereby modulating the activity of Mn-dependent enzymes. This work provides a mechanistic basis for the association of SLC39A8 with whole-blood Mn, potentially linking SLC39A8 variants with other physiological traits.
Abstract P290: RhoA Protects Against Myocardial Ischemia/Reperfusion Injury
Authors: Sunny Y Xiang, Shigeki Miyamoto, Davy Vanhoutte, Jeffery D Molkentin, Gerald W Dorn, Joan Heller Brown
Journal: Circulation Research (2011)

The small GTPase RhoA has established effects on cytoskeletal dynamics and gene expression but its role in regulating cardiac physiology and disease remains elusive. To characterize the in vivo role of RhoA signaling in cardiomyocytes, we generated conditional cardiac-specific RhoA transgenic mice (CA-RhoA) with 2–5 fold increases in RhoA activation in the adult heart. CA-RhoA mice show no overt cardiomyopathy but when challenged by in vivo or ex vivo I/R, these mice exhibit strikingly increased tolerance to injury. Compared to control mice, myocardial infarct size in CA-RhoA mice is reduced by 60–70% (20% vs. 50%, ex vivo; 10% vs. 37%, in vivo) and recovery of contractile function is significantly improved. Protein kinase D (PKD) is robustly activated in CA-RhoA hearts and inhibiting PKD reverses the cardioprotection afforded by RhoA. Both RhoA and PKD are also activated during I/R and blocking PKD augments I/R injury in WT mouse hearts. To further confirm that RhoA and PKD play a protective role during I/R, cardiac-specific RhoA knockout mice generated in the Molkentin laboratory were tested and demonstrated to show decreased tolerance to I/R injury, manifests as increased infarct size (42% vs. 23%) and lactate dehydrogenase release relative to control mice. This was accompanied by attenuated PKD activation during I/R. Taken together, our data indicates that RhoA signaling in adult cardiomyocytes promotes survival and reveals an unexpected role of PKD as a downstream mediator of RhoA and on cardioprotection against I/R.
Proteomic analysis of filaggrin deficiency identifies molecular signatures characteristic of atopic eczema
Authors: Martina S. Elias, Heather A. Long, Carla F. Newman, Paul A. Wilson, Andrew West, Paul J. McGill, Keith C. Wu, Michael J. Donaldson, Nick J. Reynolds
Journal: Journal of Allergy and Clinical Immunology (2017)

Atopic eczema (AE) is characterized by skin barrier and immune dysfunction. Null mutations in filaggrin (FLG), a key epidermal barrier protein, strongly predispose to AE; however, the precise role of FLG deficiency in AE pathogenesis remains incompletely understood.We sought to identify global proteomic changes downstream of FLG deficiency in human epidermal living skin-equivalent (LSE) models and validate findings in skin of patients with AE.Differentially expressed proteins from paired control (nontargeting control short hairpin RNA [shNT]) and FLG knockdown (FLG knockdown short hairpin RNA [shFLG]) LSEs were identified by means of proteomic analysis (liquid chromatography-mass spectrometry) and Ingenuity Pathway Analysis. Expression of key targets was validated in independent LSE samples (quantitative RT-PCR and Western blotting) and in normal and AE skin biopsy specimens (immunofluorescence).Proteomic analysis identified 17 (P ≤ .05) differentially expressed proteins after FLG knockdown, including kallikrein-7 (KLK7; 2.2-fold), cyclophilin A (PPIA; 0.9-fold), and cofilin-1 (CFL1, 1.3-fold). Differential protein expression was confirmed in shNT/shFLG LSEs; however, only KLK7 was transcriptionally dysregulated. Molecular pathways overrepresented after FLG knockdown included inflammation, protease activity, cell structure, and stress. Furthermore, KLK7 (1.8-fold) and PPIA (0.65-fold) proteins were differentially expressed in lesional biopsy specimens from patients with AE relative to normal skin.For the first time, we show that loss of FLG in the absence of inflammation is sufficient to alter the expression level of proteins relevant to the pathogenesis of AE. These include proteins regulating inflammatory, proteolytic, and cytoskeletal functions. We identify PPIA as a novel protein with levels that are decreased in clinically active AE skin and show that the characteristic upregulation of KLK7 expression in patients with AE occurs downstream of FLG loss. Importantly, we highlight disconnect between the epidermal proteome and transcriptome, emphasizing the utility of global proteomic studies.
Response to: ‘2016 update of the EULAR recommendations for the management of rheumatoid arthritis: no utopia for patients in low/middle-income countries?’ by Misra <i>et al</i>
Authors: Josef S Smolen, Robert B M Landewé, Désirée van der Heijde
Journal: Annals of the Rheumatic Diseases (2017)

We appreciate the comments provided by Misra et al 1 on the 2016 update of the European League Against Rheumatism (EULAR) recommendations for the management of rheumatoid arthritis (RA).2 They raise a very good point by stating that the use of biologic (b) and targeted synthetic (ts) disease-modifying antirheumatic drugs (DMARDs) in countries like India and many others, is limited by unjustifiable drug prices that are the consequence of various policies by drug manufacturers. Therefore, highly effective drugs are not widely accessible to patients in many countries. While EULAR is highly concerned by this reality, the recommendations are not primarily meant to improve accessibility of drugs worldwide. The EULAR recommendations provide what is regarded to be the optimal therapeutic approach according to the evidence derived from systematic literature reviews (SLRs)3–5 and expert opinion. If the best therapeutic approach may not be feasible in some countries, alternatives have to be sought. Of course such alternatives would be to switch to another conventional synthetic DMARD (csDMARD) or to add a csDMARD, rather than to add a bDMARD or tsDMARD. Misra et al try to imply, though, that such an alternative is as efficacious as adding a bDMARD, and this is a comment that the task force did not agree with.

Misra et al refer to the tumour necrosis factor inhibitors …