tbuckley/cabot-search huggingface dataset:
P13.06 Transcriptome-wide Mendelian randomization study to identify brain-specific causal genes influencing glioma
Authors: J W Robinson, J Zheng, S Tscavachidis, A E Howell, C L Relton, G N Armstrong, M Bondy, R M Martin, K M Kurian
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND The drug treatment regimen for glioma has remained relatively static since the introduction of temozolomide, although new drugs and drug combinations are being trialled. The human transcriptome can provide promising insights into causal genes as potential drug interventions for glioma treatment and may guide drug discovery methods. MATERIAL AND METHODS We apply two sample Mendelian randomisation and colocalisation to explore the influence of genetically-predicted gene expression across 12 tissue types located in the brain (4,554 genes from GTEx) and whole blood (16,112 genes from eQTLGen) on glioma risk (5,739 cases, 5,501 controls from a meta-analysis of GICC and MDA glioma GWAS). We used the MR-Base R package to conduct these analyses. RESULTS We identify 9 genes whose genetically-predicted expression was strongly associated with glioma risk. Of these genes, 7/9 are shown to have tissue-specific expression while the other two genes showed an association with glioma across multiple brain tissues and whole blood. For example, JAK1, involved in the well-known JAK-STAT pathway, is found in the frontal cortex (OR=1.49 for glioma per standard deviation increase in gene expression; 95% CI: 1.28 to 1.73; P=1.79 × 10−7), the cerebellar hemisphere (OR=1.32; 95% CI: 1.19 to 1.47; P=2.64 × 10−7), the cerebellum (OR=1.27; 95% CI: 1.16 to 1.39; P=2.64 × 10−7) and the cortex (OR=1.38; 95% CI: 1.22 to 1.57; P=2.64 × 10−7). This pathway has been highlighted in previous research as a potential intervention target for glioma therapies. We found that 5/9 of the genes from the MR analysis are expressed in the cerebellum. However malignant cerebellar glioma is a rare tumour (~3% of all malignant gliomas). This suggests that tumourigenesis elsewhere in the brain may be affected by other tissue-specific genes, specifically in the cerebellum, though this will require further research to elucidate. We further triangulate the MR findings with evidence from the OpenTargets platform to strengthen the putative causal associations. OpenTargets aims to “generate evidence on the validity of therapeutic targets based on genome-scale experiments and analysis”. For example, JAK1 receives an overall OpenTargets score of 0.89 out of 1, with most of the evidence for this JAK1-glioma association coming from affected pathways data. CONCLUSION This study has combined genetic epidemiological approaches to the analysis of the human transcriptome on glioma incidence. We provide evidence that these genes may inform putative drug targets for tertiary treatment of glioma. Future research specifically towards this aim will be required to fully elucidate intervention targets.
Five years into the national second-opinion project of the German Testicular Cancer Group (GCTSG): Impact on guideline implementation and the quality of care for testicular cancer patients.
Authors: Friedemann Zengerling, Michael Hartmann, Axel Heidenreich, Susanne Krege, Peter Albers, Alexander Karl, Walter Wagner, Jens Bedke, Hans U. Schmelz, Margitta Retz, Sabine Kliesch, Eva Winter, Markus Kuczyk, Mark Schrader
Journal: Journal of Clinical Oncology (2012)

4530 Background: The diagnosis and therapy of testicular germ cell tumors are subject to constant change. Numerous national and international guidelines have been published since the 1990s in order to meet this challenge. It is questionable, however, whether mere publication of guidelines will lead to their implementation. The aim of the present project of the GTCSG was to establish a national second-opinion network in order to improve the implementation of guidelines and the quality of care. Methods: Before determining the primary therapy, participating urologists could communicate with one of 30 second-opinion centers (SOC) via an internet-based platform. The data set comprised the primary clinical, radiological and pathohistological findings, the therapy planned by the advice seeker (first opinion), the therapy recommended by the SOC (second opinion), and the applied therapy as well as the 2-year follow-up data. Primary end points of the study were congruence between the first and second opinion, treatment changes based on the second opinion, and relapse-free 2-year survival. Results: A total of 1722 SOC requests have been submitted since November 2006. At the time of our data analysis 927 cases were evaluated. The response rate was 75.8% for treatment data and 74.4% for 2-year follow-up data. Advice seekers and SOC had discrepant treatment concepts in 43.3% of the cases; this discrepancy was independent of tumor histology and increased in advanced tumor stages (clinical stage ≥IIa: 52.3% vs. &lt;IIa: 34%; p&lt;0.001, Pearson Χ 2 test). The SOC request led to reduction of the applied therapy in 11.4% and intensification in 9.5% of the cases. Progression-free 2-year survival was 92% (112/122) for stage I, 90% (17/19) for stage IIa-IIb, and 65% (17/26) for stage ≥IIc. Conclusions: Guidelines for the treatment of germ cell tumors are inadequately implemented, particularly in advanced tumor stages. Every fifth second opinion resulted in a relevant change in the scope of therapy. Patients whose treatment was congruent with the second opinion had a relapse rate comparable to that of study results in the literature.
CircFOXO3 promotes glioblastoma progression by acting as a competing endogenous RNA for NFAT5
Authors: Shuai Zhang, Keman Liao, Zengli Miao, Qing Wang, Yifeng Miao, Zhongye Guo, Yun Qiu, Binghong Chen, Li Ren, Zilong Wei, Yingying Lin, Xiaojie Lu, Yongming Qiu
Journal: Neuro-Oncology (2019)

Circular RNAs (circRNAs), a newly discovered type of endogenous noncoding RNA, have been proposed to mediate the progression of diverse types of tumors. Systematic studies of circRNAs have just begun, and the physiological roles of circRNAs remain largely unknown. Here, we focused on elucidating the potential role and molecular mechanism of circular forkhead box O3 (circFOXO3) in glioblastoma (GBM) progression.First, we analyzed circFOXO3 alterations in GBM and noncancerous tissues through real-time quantitative reverse transcription PCR (qRT-PCR). Next, we used loss- and gain-of-function approaches to evaluate the effect of circFOXO3 on GBM cell proliferation and invasion. Mechanistically, fluorescent in situ hybridization, RNA pull-down, dual luciferase reporter, and RNA immunoprecipitation assays were performed to confirm the interaction between circFOXO3 and miR-138-5p/miR-432-5p in GBM. An animal model was used to verify the in vitro experimental findings.CircFOXO3 expression was significantly higher in GBM tissues than in noncancerous tissues. GBM cell proliferation and invasion were reduced by circFOXO3 knockdown and enhanced by circFOXO3 overexpression. Further biochemical analysis showed that circFOXO3 exerted its pro-tumorigenic activity by acting as a competing endogenous RNA (ceRNA) to increase expression of nuclear factor of activated T cells 5 (NFAT5) via sponging both miR-138-5p and miR-432-5p. Notably, tumor inhibition by circFOXO3 downregulation could be reversed by miR-138-5p/miR-432-5p inhibitors in GBM cells. Moreover, GBM cells with lower circFOXO3 expression developed less aggressive tumors in vivo.Our data demonstrate that circFOXO3 can exert regulatory functions in GBM and that ceRNA-mediated microRNA sequestration might be a potential strategy for GBM therapy.
Risk of hepatitis B surface antigen seroreversion after corticosteroid treatment in patients with previous hepatitis B virus exposure
Authors: Grace Lai-Hung Wong, Vincent Wai-Sun Wong, Becky Wing-Yan Yuen, Yee-Kit Tse, Terry Cheuk-Fung Yip, Hester Wing-Sum Luk, Grace Chung-Yan Lui, Henry Lik-Yuen Chan
Journal: Journal of Hepatology (2019)
P14.46 SUBEPENDYMAL GIANT CELLS ASTROCYTOMA (SEGA) IN TUBEROUS SCLEROSIS COMPLEX (TSC): A SERIES OF 31 PATIENTS
Authors: F Giordano, C Moscheo, M Lenge, F Mari, M Grandoni, A Buccoliero, I Sardi, L Genitori, M Guidi
Journal: Neuro-Oncology (2019)

Abstract Background Subependymal Giant Cells Astrocytomas (SEGAs) are characteristic of Tuberous Sclerosis Complex (TSC). They are usually benign tumors but may rapidly grow and cause hydrocephalus and raised intracranial pressure. Surgery is mandatory for large and symptomatic SEGAs METHODS 31 patients harboring SEGAs in TSC were admitted for surgery. The main indications for surgery were tumor size and location, tumoral growth and cystization/hemorrhage, and hydrocephalus. In presence of symptomatic hydrocephalus firts surgery aimed to reduce intracranial pressure RESULTS Forty-four surgeries were performed in 31 patients achieving Gross Total and Subtotal Removal in 36 and 8 patients respectively. Recurrences occurred in 11 patients; nine of them were reoperated while two were administered therapy with m-TOR pathway inhibitors. Surgical morbidity and mortality accounted for 22.7% and 2.3% respectively; hydrocephalus was the main complication. After an average follow-up of 5 years, 90% of patients had no evidence of the disease and most (93,3%) had a good clinical status after surgery; 12 out of 30 patients (40%) had a VP-shunt for hydrocephalus Conclusions GTR is feasible and represents the treatment of choice of SEGAs in TSC. Therapy with m-TOR pathway inhibitors is to be considered in selected patients and especially in recurrences of SEGAs
OS8.1 A phase 0/2 clinical trial of a CDK4/6 inhibitor in aggressive meningioma patients
Authors: A Tien, J Li, X Bao, A DeRogatis, Y Fujita, C Pennington-Krygier, S Kim, S Mehta, N Sanai
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND New approaches are urgently needed for aggressive meningiomas, which remain largely incurable. Forkhead Box M1 (FOXM1) has been identified as a master transcription factor in aggressive meningiomas and Cyclin D-dependent Kinases (CDK) are positive regulators of cell-cycle entry, promoting tumorigenesis through FOXM1 activation. We evaluated the tumor pharmacokinetics (PK), tumor pharmacodynamics (PD), and preliminary clinical response of ribociclib, a selective CDK4/6-inhibitor, in aggressive meningioma patients. MATERIAL AND METHODS Eight aggressive WHO Grade II/III meningioma patients with intact RB expression were enrolled and administered oral ribociclib daily (900mg) for 5 days prior to tumor resection. Plasma, tumor, and cerebrospinal fluid (CSF) samples were collected at 2, 8, or 24 h after the last dose. Total and unbound drug concentrations were determined using a validated LC-MS/MS method. PD effects, including RB and FoxM1 phosphorylation, were compared to matched archival tissue. Patients with PK and PD responses in tumor tissue, defined as unbound ribociclib concentration &gt; 5-fold in vitro IC50 (0.04µM) and &gt;20% decrease in pRB levels, respectively, were enrolled into an exploratory Phase 2 cohort. RESULTS The median CSF concentration of ribociclib was 0.25 µM. In tumor tissue, the median unbound ribociclib concentration was 1.36 µM and the median unbound tumor-to-plasma ratio was 5.34. Suppression of G1-to-S phase was inferred in tumors with declining FoxM1 phosphorylation (50%), RB phosphorylation (38%), and cellular proliferation (75%). Four patients demonstrated concurrent PK and PD responses and were graduated to continuous ribociclib therapy. At one year, two of these patients (one Grade II and one Grade III) demonstrate partial responses per RANO criteria. CONCLUSION Ribociclib achieves pharmacologically-active concentrations in aggressive meningioma tissue. Target modulation was demonstrated by a decrease in FOXM1-mediated tumor proliferation. Further investigation of ribociclib as a therapeutic strategy for aggressive meningiomas is warranted.
Teleoncology: Prospects and challenges for cost effective cancer care.
Authors: Ammara Majeed, Midhat Lakhani, Afia Ashraf, Udhayvir Singh Grewal, Prem Thirunagari, Ahsan Wahab, Hamza Hassan, Muhammad Salman Faisal, Fazal I Raziq, Faiz Anwer
Journal: Journal of Clinical Oncology (2019)

e23182 Background: An estimated 20.3 million cancer survivors are expected to be around by 2026. Estimated national expenditure for cancer care in 2017 were $147.3 billion and expected to increase every year. Cancer treatment is complex and requires management decisions, counselling, psychological support to be made by multidisciplinary teams. For rural and remote patients, these teams may be composed of local clinicians, and experts from distant urban centers using telemedicine (TeleMed). Methods: We used 2 databases to study Teleoncology (TelOnc) since 2002. Results: Scope of TelOnc includes cancer Telegenetics, Telepathology, remote supervision, symptom management, survivorship care, palliative care, and increase access to cancer clinical trials. Mobile applications support symptom management, lifestyle modification, and medication adherence. TeleMed can support the oncologist with interactive tele-education. Future TelOnc models would include web-based tools, mobile technologies and remote chemotherapy supervision. TeleMed had a high patient satisfaction rate. In a survey 82.21% participants were satisfied with their TeleMed experience, only 2.14% was not satisfied. Challenges: Despite an area of growing need, few studies have prospectively evaluated its efficacy in cancer. Even fewer data is available in young adults (group with liking for technology) with cancer. Lack of uniform model for reimbursement and hurdles of interstate practice license for providers are unique challenges. Conclusions: TeleMed / TelOnc can improve access to medical care, reduce healthcare costs, (Table) and reduce geographic health disparities. [Table: see text]
Functional diversification of IgGs through Fc glycosylation
Authors: Taia T. Wang, Jeffrey V. Ravetch
Journal: Journal of Clinical Investigation (2019)

IgG antibodies are secreted from B cells and bind to a variety of pathogens to control infections as well as contribute to inflammatory diseases. Many of the functions of IgGs are mediated through Fcγ receptors (FcγRs), which transduce interactions with immune complexes, leading to a variety of cellular outcomes depending on the FcγRs and cell types engaged. Which FcγRs and cell types will be engaged during an immune response depends on the structure of Fc domains within immune complexes that are formed when IgGs bind to cognate antigen(s). Recent studies have revealed an unexpected degree of structural variability in IgG Fc domains among people, driven primarily by differences in IgG subclasses and N-linked glycosylation of the CH2 domain. This translates, in turn, to functional immune diversification through type I and type II FcγR–mediated cellular functions. For example, Fc domain sialylation triggers conformational changes of IgG1 that enable interactions with type II FcγRs; these receptors mediate cellular functions including antiinflammatory activity or definition of thresholds for B cell selection based on B cell receptor affinity. Similarly, presence or absence of a core fucose alters type I FcγR binding of IgG1 by modulating the Fc's affinity for FcγRIIIa, thereby altering its proinflammatory activity. How heterogeneity in IgG Fc domains contributes to human immune diversity is now being elucidated, including impacts on vaccine responses and susceptibility to disease and its sequelae during infections. Here, we discuss how Fc structures arising from sialylation and fucosylation impact immunity, focusing on responses to vaccination and infection. We also review work defining individual differences in Fc glycosylation, regulation of Fc glycosylation, and clinical implications of these pathways.
Association of Use of the Neonatal Early-Onset Sepsis Calculator With Reduction in Antibiotic Therapy and Safety
Authors: Niek B. Achten, Claus Klingenberg, William E. Benitz, Martin Stocker, Luregn J. Schlapbach, Eric Giannoni, Robin Bokelaar, Gertjan J. A. Driessen, Petter Brodin, Sabita Uthaya, Annemarie M. C. van Rossum, Frans B. Plötz
Journal: JAMA Pediatrics (2019)

The neonatal early-onset sepsis (EOS) calculator is a clinical risk stratification tool increasingly used to guide the use of empirical antibiotics for newborns. Evidence on the effectiveness and safety of the EOS calculator is essential to inform clinicians considering implementation.To assess the association between management of neonatal EOS guided by the neonatal EOS calculator (compared with conventional management strategies) and reduction in antibiotic therapy for newborns.Electronic searches in MEDLINE, Embase, Web of Science, and Google Scholar were conducted from 2011 (introduction of the EOS calculator model) through January 31, 2019.All studies with original data that compared management guided by the EOS calculator with conventional management strategies for allocating antibiotic therapy to newborns suspected to have EOS were included.Following PRISMA-P guidelines, relevant data were extracted from full-text articles and supplements. CHARMS (Checklist for Critical Appraisal and Data Extraction for Systematic Reviews of Prediction Modeling Studies) and GRADE (Grades of Recommendation, Assessment, Development and Evaluation) tools were used to assess the risk of bias and quality of evidence. Meta-analysis using a random-effects model was conducted for studies with separate cohorts for EOS calculator and conventional management strategies.The difference in percentage of newborns treated with empirical antibiotics for suspected or proven EOS between management guided by the EOS calculator and conventional management strategies. Safety-related outcomes involved missed cases of EOS, readmissions, treatment delay, morbidity, and mortality.Thirteen relevant studies analyzing a total of 175 752 newborns were included. All studies found a substantially lower relative risk (range, 3%-60%) for empirical antibiotic therapy, favoring the EOS calculator. Meta-analysis revealed a relative risk of antibiotic use of 56% (95% CI, 53%-59%) in before-after studies including newborns regardless of exposure to chorioamnionitis. Evidence on safety was limited, but proportions of missed cases of EOS were comparable between management guided by the EOS calculator (5 of 18 [28%]) and conventional management strategies (8 of 28 [29%]) (pooled odds ratio, 0.96; 95% CI, 0.26-3.52; P = .95).Use of the neonatal EOS calculator is associated with a substantial reduction in the use of empirical antibiotics for suspected EOS. Available evidence regarding safety of the use of the EOS calculator is limited, but shows no indication of inferiority compared with conventional management strategies.
Dynamic CD8 T-cell responses to tumor-associated Epstein-Barr virus (EBV) antigens in patients with EBV-negative Hodgkin's disease
Authors: H. E. Kohrt, R. Advani, R. Hoppe, S. Rosenberg, S. Horning, P. P. Lee
Journal: Journal of Clinical Oncology (2009)

8573 Background: Multiple translational efforts in HD are actively investigating augmentation of the anti-tumor immune response by stimulating cytotoxic T lymphocytes (CTL) against tumor-associated EBV antigens. It has previously been believed that this therapeutic strategy and presence of EBV-specific CTLs are limited to EBV-positive HD. Here, we challenge this belief by characterizing EBV-specific CTL responses in EBV-negative HD. Methods: Among 52 consecutive patients with EBV-negative HD, CTL responses to latent antigens (LMP2, LMP2a) and lytic antigens (BMLF, BRLF) were serially assessed at diagnosis, during chemotherapy, and throughout followup for 2 years by IFN-γ Elispot and flow cytometric tetramer analysis. Results: We detected weak EBV-specific responses to both lytic and latent antigens by IFN-γ Elispot among patients with EBV-negative HD. Response to lytic antigen, BMLF1, was more robust in function and size among healthy donors compared to patients as determined by IFN-γ Elispot and flow cytometry of BMLF1-tetramer positive, CD8 T cells. Chemoradiotherapy was associated temporally with an initial decrease in LMP2A- and BMLF1-specific responses during the first 5–15 weeks of treatment, which subsequently became more robust 20–50 weeks after diagnosis, 2 to 4-fold greater compared to response at diagnosis. At final follow-up (24 months), increases in both lytic (2.6-fold) and latent (2.5-fold) CTL responses were observed with robustness of lytic-specific response equivalent to healthy controls. No significant change in control peptide response was observed. Conclusions: We confirm evidence of EBV-specific CTLs in patients with EBV-negative HD and provide the first report of dynamic variance in this population during treatment, challenging prior belief that patients with HD remain immunodeficient following therapy and arguing that the clinical significance of EBV-specific immune responses in EBV-negative HD should be further investigated. [Table: see text] No significant financial relationships to disclose.
Progression of Skin Fibrosis Is Associated with Decline in Lung Function in Patients with Diffuse Cutaneous Systemic Sclerosis: A European Scleroderma Trials and Research (EUSTAR) Analysis
Authors: W Wu, S Jordan, N Graf, J Pena, J Curram, Y Allanore, M Matucci-Cerinic, JE Pope, C Denton, D Khanna, O Distler
Journal: Annals of the Rheumatic Diseases (2019)

Objectives To determine whether progressive skin fibrosis is associated with visceral organ progression and mortality during follow-up in patients with diffuse cutaneous systemic sclerosis (dcSSc).

Methods We evaluated patients from the European Scleroderma Trials and Research database with dcSSc, baseline modified Rodnan skin score (mRSS) ≥7, valid mRSS at 12±3 months after baseline and ≥1 annual follow-up visit. Progressive skin fibrosis was defined as an increase in mRSS >5 and ≥25% from baseline to 12±3 months. Outcomes were pulmonary, cardiovascular and renal progression, and all-cause death. Associations between skin progression and outcomes were evaluated by Kaplan-Meier survival analysis and multivariable Cox regression.

Results Of 1021 included patients, 78 (7.6%) had progressive skin fibrosis (skin progressors). Median follow-up was 3.4 years. Survival analyses indicated that skin progressors had a significantly higher probability of FVC decline ≥10% (53.6% vs 34.4%; p<0.001) and all-cause death (15.4% vs 7.3%; p=0.003) than non-progressors. These significant associations were also found in subgroup analyses of patients with either low baseline mRSS (≤22/51) or short disease duration (≤15 months). In multivariable analyses, skin progression within 1 year was independently associated with FVC decline ≥10% (HR 1.79, 95% CI 1.20 to 2.65) and all-cause death (HR 2.58, 95% CI 1.31 to 5.09).

Conclusions Progressive skin fibrosis within 1 year is associated with decline in lung function and worse survival in dcSSc during follow-up. These results confirm mRSS as a surrogate marker in dcSSc, which will be helpful for cohort enrichment in future trials and risk stratification in clinical practice.