Ependymal tumors across age groups are currently classified and graded solely by histopathology. It is, however, commonly accepted that this classification scheme has limited clinical utility based ...on its lack of reproducibility in predicting patients’ outcome. We aimed at establishing a uniform molecular classification using DNA methylation profiling. Nine molecular subgroups were identified in a large cohort of 500 tumors, 3 in each anatomical compartment of the CNS, spine, posterior fossa, supratentorial. Two supratentorial subgroups are characterized by prototypic fusion genes involving RELA and YAP1, respectively. Regarding clinical associations, the molecular classification proposed herein outperforms the current histopathological classification and thus might serve as a basis for the next World Health Organization classification of CNS tumors.
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•DNA methylation profiling of ependymomas identifies nine molecular subgroups•YAP1 and RELA fusions characterize two distinct groups of supratentorial ependymoma•Patients with PFA or supratentorial RELA-positive ependymoma show dismal prognosis•Risk stratification by molecular subgrouping is superior to histological grading
Pajtler et al. classify 500 ependymal tumors using DNA methylation profiling into nine molecular subgroups. This molecular classification outperforms the current histopathological grading in the risk stratification of patients.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
•Reward layouts can lead an ideal reward searcher to fixate clustered low value cues.•Humans can implement search eye movements to low value cues to increase decision rewards.•Multiplicity of near ...optimal saccade plans related to fixation variability across observers.•Suboptimal eye movements likely more common for non-ecologically valid lab tasks.
Rewards have important influences on the motor planning of primates and the firing of neurons coding visual information and action. When eye movements to a target are differentially rewarded across locations, primates execute saccades towards the possible target location with the highest expected value, a product of sensory evidence and potentially earned reward (saccade to maximum expected value model, sMEV). Yet, in the natural world eye movements are not directly rewarded. Their role is to gather information to support subsequent rewarded search decisions and actions. Less is known about the effects of decision rewards on saccades. We show that when varying the decision rewards across cued locations following visual search, humans can plan their eye movements to increase decision rewards. Critically, we report a scenario for which five of seven tested humans do not preferentially deploy saccades to the possible target location with the highest reward, a strategy which is optimal when rewarding eye movements. Instead, these humans make saccades towards lower value but clustered locations when this strategy optimizes decision rewards consistent with the preferences of an ideal Bayesian reward searcher that takes into account the visibility of the target across eccentricities. The ideal reward searcher can be approximated with a sMEV model with pooling of rewards from spatially clustered locations. We also find observers with systematic departures from the optimal strategy and inter-observer variability of eye movement plans. These deviations often reflect multiplicity of fixation strategies that lead to near optimal decision rewards but, for some observers, it relates to suboptimal choices in eye movement planning.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract
Ependymomas are the third most common childhood brain tumor. These tumors arise throughout the nervous system, but in children, are most common within posterior fossa (PF). Treatment ...consists of surgery and radiation, as chemotherapy has demonstrated little to no survival benefit. We have shown previously that PF ependymomas are divided into two clinically and molecularly distinct subtypes, termed Group A and Group B. While Group B tumors, which have a favorable outcome (5 year survival ∼95%) and are characterized by increased copy number alterations (CNAs), Group A tumours have a poor prognosis (5 year survival ∼20%) and have few somatic CNAs.
To discover somatic SNVs of PF ependymomas, we performed whole genome-, and whole exome-sequencing of 47 PF ependymomas including matched germline DNA (27 PFA, and 20 PFB). In addition, we analysed DNA methylation patterns in a discovery cohort of 79 ependymomas using methyl-binding domain-2 (MBD2) protein recovery followed by hybridization to Nimblegen 385K CpG Island Promoter Plus microarrays (MBD2-chip). Unsupervised consensus clustering of CpG methylation profiles yielded in principle two distinct subtypes of posterior fossa ependymomas (Group A and B) respectively, in a pattern highly similar to that yielded by unsupervised clustering of gene expression profiles. We validated our findings in a non-overlapping cohort of 48 PF ependymomas using an orthogonal technology (Illumina Infinium450k methylation arrays). To uncover additional epigenetic alteration we performed whole genome bisulphite-sequencing in 6 tumors and H3K27me3 ChIP-seq in 11 primary PF ependymomas.
Unlike some other childhood malignancies, the rate of somatic SNVs was extremely low in PF ependymomas, with an average of 5.0 somatic non-synonymous SNVs per exome across the entire cohort. While devoid of recurrent SNVs and focal copy number aberrations, poor prognosis Group A ependymomas exhibit a CpG island methylator phenotype (CIMP+). Further, transcriptional silencing driven by CpG methylation converges exclusively on targets of the polycomb repressor complex 2 (PRC2) that represses expression of differentiation genes through tri-methylation of H3K27. CIMP positive PF ependymomas (Group A) are responsive to clinical drugs that target either DNA or H3K27 methylation both in vitro and in vivo.
We conclude that epigenetic modifiers are the first rational therapeutic candidates for this deadly malignancy, which is epigenetically deregulated but genetically bland. Since epigenetic modulators are already approved drugs, this therapeutic strategy could be rapidly repurposed to treat children with ependymoma.
Citation Format: Hendrik Witt, Steve C. Mack, Stefan M. Pfister, Andrey Korshunov, Michael D. Taylor, Ependymoma Collaborative Consortium. Epigenomic alterations define lethal CIMP-positive ependymomas of infancy. abstract. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-198. doi:10.1158/1538-7445.AM2014-LB-198
BACKGROUND: Ependymomas are common childhood brain tumors that occur throughout the nervous system, but are most common in the pediatric hindbrain. Current standard therapy comprises surgery and ...radiation, but not cytotoxic chemotherapy as it does not further increase survival. METHODS: We undertook genetic, and epigenetic studies of a series of childhood posterior fossa ependymomas. RESULTS: Whole-genome and whole-exome sequencing of 47 hindbrain ependymomas reveals an extremely low mutation rate, and zero significant recurrent somatic SNVs. While devoid of recurrent SNVs and focal copy number aberrations, poor prognosis hindbrain ependymomas exhibit a CpG island methylator phenotype (CIMP). Transcriptional silencing driven by CpG methylation converges exclusively on targets of the polycomb repressor complex 2 (PRC2) that represses expression of differentiation genes through tri-methylation of H3K27. CIMP-positive (CIMP+) hindbrain ependymomas are responsive to clinical drugs that target either DNA or H3K27 methylation both in vitro and in vivo. CONCLUSIONS: We conclude that epigenetic modifiers are the first rational therapeutic candidates for this deadly malignancy, which is epigenetically de-regulated but genetically bland. SECONDARY CATEGORY: n/a.
Abstract
Since it has become evident that histopathological grading of ependymoma according to the WHO classification of CNS tumors is not capable of accurately classifying patients into meaningful ...strata, a broadly accepted molecular classification scheme with prognostic significance is desperately needed. In recent years, ependymomas were classified into molecular subgroups based on transcriptomic alterations. In tumors localized within the posterior fossa, two distinct biological entities of ependymoma were delineated by several studies (designated posterior fossa A and posterior fossa B), which show striking differences in genetic characteristics and clinical outcome. A similar consensus for supratentorial and spinal ependymoma is lacking.
We studied genome-wide DNA methylation (Illumina HumanMethylation450 (450k) array) in 180 primary ependymal tumors (80 with corresponding gene expression profiling data generated by Affymetrix 133plus2.0 arrays), including ependymomas (posterior fossa, supratentorial, spinal), subependymomas (SE), myxopapillary ependymoma (MPE), pineal parenchymal tumors of intermediate differentiation (PPTID), and papillary tumors of the pineal region (PTPR). We performed hierarchical clustering to identify robust molecular subgroups. Independent gene expression profiling datasets from previously published ependymoma studies (Johnson et al.; Wani et al.; Witt et al.) were used as validation cohorts.
DNA methylation data showed that ependymal brain tumors can be classified into eight molecular subgroups. Notably, MPE, SE, PPTID and PTPR tumors formed robust distinct clusters, as did posterior fossa Group A and Group B ependymomas. Supratentorial ependymomas can be classified into two principle molecular subgroups, one of which displays a dismal prognosis, and comprises predominantly children and infants, and is associated with highly recurrent gene fusion. Notably, a significant number of ependymomas previously classified by histology as WHO Grade II/III look like SE by methylation, and also have extremely good survival.
In summary, using genome-wide DNA methylation and transcriptome analysis we could decipher robust molecular subgroups of ependymal brain tumors including supratentorial ependymoma. Diagnoses of tumors with challenging histopathological features can now be supported by this technology. Hence, this approach offers the possibility to replace the unambiguous histological grading system that is currently in use with a robust molecular classification that readily distinguishes biologically, genetically, and clinically meaningful subgroups of ependymal brain tumors.
Citation Format: Hendrik Witt, Martin Sill, Khalida Wani, Steve Mack, David Capper, Stephanie Heim, Pascal Johann, Sally Lambert, Marina Rhyzova, Volker Hovestadt, Theophilos Tzaridis, Kristian Pajtler, Sebastian Bender, Till Milde, Paul A. Northcott, Andreas E. Kulozik, Olaf Witt, Peter Lichter, V Peter Collins, Andreas von Deimling, Marcel Kool, Michael D. Taylor, Martin Hasselblatt, David TW Jones, Andrey Korshunov, Ken Aldape, Stefan Pfister. Epigenetic classification of ependymal brain tumors across age groups. abstract. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3094. doi:10.1158/1538-7445.AM2014-3094
Tuberculosis and diabetes in Guyana Alladin, Bibi; Mack, Steve; Singh, Aruna ...
International journal of infectious diseases,
12/2011, Volume:
15, Issue:
12
Journal Article
Peer reviewed
Open access
Summary Objectives This study was conducted to determine the prevalence of diabetes mellitus among tuberculosis (TB) patients attending three TB clinics in Guyana. Methods A cross-sectional study was ...conducted among TB patients attending TB clinics in three regions in Guyana. A structured questionnaire was used to collect demographic, clinical, and risk factor data. Random blood sugar testing was done using the OneTouch UltraSmart glucometer (LifeScan, Inc., 2002). Results One hundred TB patients were recruited; 90 had pulmonary TB and 10 had extrapulmonary disease. Fourteen patients were classified as diabetic: 12 had been previously diagnosed as diabetic by a physician and two had abnormally high random blood sugar at the time of enrolment. Of the 12 known diabetics, seven had been diagnosed before TB was discovered, three were identified at the time TB was diagnosed, and two after TB was diagnosed. All 14 diabetic patients presented with pulmonary TB. Thirty-one patients were HIV-positive and 28 of these had pulmonary TB, whereas three had extrapulmonary TB. None of the diabetics were infected with HIV. TB-diabetic patients tended to be older than non-diabetics (median age 44 vs. 36.5 years), were more likely to have been incarcerated at the time of TB diagnosis than non-diabetics ( p = 0.06), and were more likely to have an elevated (random) blood sugar level ( p = 0.02). Clinically, diabetes did not influence the presentation of TB. Conclusions This study clearly highlights that diabetes and HIV are frequent in Guyanese TB patients. Routine screening of TB patients for diabetes and diabetic patients for TB should be speedily implemented. The National TB Programme should work closely with the diabetes clinics so that TB patients who are diabetics are optimally managed.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Summary Objectives The objective of this study was to describe the sociodemographic and clinical characteristics of patients dually infected with HIV and tuberculosis (TB) in Guyana. Methods The data ...for this study were obtained as part of a related project conducted to determine the prevalence of diabetes mellitus among TB patients in Guyana. From April to June 2006, a convenience sample of 100 patients was selected from those attending three TB clinics in Guyana and a structured questionnaire was used to collect relevant sociodemographic and risk factor data. The sociodemographic and clinical data of HIV-negative and HIV-positive patients with pulmonary TB were compared. Logistic regression was conducted to determine independent relationships between sociodemographic and clinical features. Results One hundred TB patients were considered for enrolment in the study, but since the HIV status was known for only 77 persons, these were included in the analysis. Thirty-one of the 77 (40.3%) were HIV-positive. Seventy-two of the 77 (93.5%) patients had pulmonary TB, 28 of whom were HIV-positive; the other five had extrapulmonary TB, three of whom were dually infected. Several social factors and clinical manifestations including incarceration at the time of TB diagnosis ( p = 0.01), cigarette smoking ( p = 0.05), homelessness ( p = 0.07), chest pain ( p = 0.001), hemoptysis ( p = 0.02), cough ( p = 0.08), and being acid-fast bacillus (AFB) sputum smear-positive ( p = 0.06) were associated with HIV-negative pulmonary TB. In the logistic regression model, HIV-negative TB patients demonstrated higher frequencies of complaints of chest pain (odds ratio (OR) 34.48, 95% confidence interval (CI) 4.35–250) and were more likely to be AFB sputum smear-positive (OR 11.97, 95% CI 1.91–74.76) than HIV-positive TB patients. Conclusions Guyana is faced with a particularly high burden of HIV infection among TB patients. Given the impact of HIV on the clinical presentation of TB, physicians managing HIV patients should demonstrate a high level of suspicion for TB among these patients. Incarceration is a strong correlate of TB, overall.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Surface water samples from marinas, commercial ports and open bay areas collected from Biscayne Bay and the Miami River, Florida, USA, were analyzed for the occurrence of IRGAROL1051 by GC/MS. The ...anifouling boosting herbicide was found in 80% (46/57) of the samples collected between March 1999 and September 2000. Concentrations within the bay range between non-detected (<1 ppt) and 61 ppt (ng/L) and were generally low compared with levels reported in European or Japanese waters. Aside from the elevated concentrations observed along the Miami River South Fork (61 ppt), the highest concentrations observed in the bay corresponded to marinas with high density of pleasure craft and restricted water circulation. In contrast, occurrence of IRGAROL 1051 along the commercial port or the cruise line terminal was generally lower (<1–2.2 ppt). Concentrations around Coconut Grove Marina were consistently higher (5–12 ppt) than the rest of the bay waters during the whole period of time surveyed.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
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