ENWEndNote BIBJabRef, Mendeley RISPapers, Reference Manager, RefWorks, Zotero AMA Pronicki M, Piekutowska-Abramczuk D, Jurkiewicz E, et al. Neuropathological characteristics of the brain in two patients with SLC19A3 mutations related to the biotin-thiamine-responsive basal ganglia disease. Folia Neuropathologica. 2017;55(2):146-153. doi:10.5114/fn.2017.68581. APA Pronicki, M., Piekutowska-Abramczuk, D., Jurkiewicz, E., Rokicki, D., Ciara, E., & Trubicka, J. et al. (2017). Neuropathological characteristics of the brain in two patients with SLC19A3 mutations related to the biotin-thiamine-responsive basal ganglia disease. Folia Neuropathologica, 55(2), 146-153. https://doi.org/10.5114/fn.2017.68581 Chicago Pronicki, Maciej, Dorota Piekutowska-Abramczuk, Elżbieta Jurkiewicz, Dariusz Rokicki, Elżbieta Ciara, Joanna Trubicka, and Katarzyna Iwanicka-Pronicka et al. 2017. "Neuropathological characteristics of the brain in two patients with SLC19A3 mutations related to the biotin-thiamine-responsive basal ganglia disease". Folia Neuropathologica 55 (2): 146-153. doi:10.5114/fn.2017.68581. Harvard Pronicki, M., Piekutowska-Abramczuk, D., Jurkiewicz, E., Rokicki, D., Ciara, E., Trubicka, J., Iwanicka-Pronicka, K., Pajdowska, M., Migdał, M., and Grajkowska, W. (2017). Neuropathological characteristics of the brain in two patients with SLC19A3 mutations related to the biotin-thiamine-responsive basal ganglia disease. Folia Neuropathologica, 55(2), pp.146-153. https://doi.org/10.5114/fn.2017.68581 MLA Pronicki, Maciej et al. "Neuropathological characteristics of the brain in two patients with SLC19A3 mutations related to the biotin-thiamine-responsive basal ganglia disease." Folia Neuropathologica, vol. 55, no. 2, 2017, pp. 146-153. doi:10.5114/fn.2017.68581. Vancouver Pronicki M, Piekutowska-Abramczuk D, Jurkiewicz E, Rokicki D, Ciara E, Trubicka J et al. Neuropathological characteristics of the brain in two patients with SLC19A3 mutations related to the biotin-thiamine-responsive basal ganglia disease. Folia Neuropathologica. 2017;55(2):146-153. doi:10.5114/fn.2017.68581.
Abstract The majority of supratentorial ependymomas in children contain oncogenic fusions, such as ZFTA–RELA or YAP1‐MAMLD1 . In contrast, posterior fossa (PF) ependymomas lack recurrent somatic mutations and are classified based on gene expression or methylation profiling into group A (PFA) and group B (PFB). We have applied a novel method, NanoString nCounter Technology, to identify four molecular groups among 16 supratentorial and 50 PF paediatric ependymomas, using 4–5 group‐specific signature genes. Clustering analysis of 16 supratentorial ependymomas revealed 9 tumours with a RELA fusion‐positive signature (RELA+), 1 tumour with a YAP1 fusion‐positive signature (YAP1+), and 6 not‐classified tumours. Additionally, we identified one RELA+ tumour among historically diagnosed CNS primitive neuroectodermal tumour samples. Overall, 9 of 10 tumours with the RELA+ signature possessed the ZFTA‐RELA fusion as detected by next‐generation sequencing ( p = 0.005). Similarly, the only tumour with a YAP1+ signature exhibited the YAP1‐MAMLD1 fusion. Among the remaining unclassified ependymomas, which did not exhibit the ZFTA‐RELA fusion, the ZFTA‐MAML2 fusion was detected in one case. Notably, among nine ependymoma patients with the RELA+ signature, eight survived at least 5 years after diagnosis. Clustering analysis of PF tumours revealed 42 samples with PFA signatures and 7 samples with PFB signatures. Clinical characteristics of patients with PFA and PFB ependymomas corroborated the previous findings. In conclusion, we confirm here that the NanoString method is a useful single tool for the diagnosis of all four main molecular groups of ependymoma. The differences in reported survival rates warrant further clinical investigation of patients with the ZFTA‐RELA fusion.
Barth syndrome (BTHS) is an X-linked mitochondrial defect characterised by dilated cardiomyopathy, neutropaenia and 3-methylglutaconic aciduria (3-MGCA). We report on two affected brothers with c.646G > A (p.G216R) TAZ gene mutations. The pathogenicity of the mutation, as indicated by the structure-based functional analyses, was further confirmed by abnormal monolysocardiolipin/cardiolipin ratio in dry blood spots of the patients as well as the occurrence of this mutation in another reported BTHS proband. In both brothers, 2D-echocardiography revealed some features of left ventricular noncompaction (LVNC) despite marked differences in the course of the disease; the eldest child presented with isolated cardiomyopathy from late infancy, whereas the youngest showed severe lactic acidosis without 3-MGCA during the neonatal period. An examination of the patients' fibroblast cultures revealed that extremely low mitochondrial membrane potentials (mtΔΨ about 50 % of the control value) dominated other unspecific mitochondrial changes detected (respiratory chain dysfunction, abnormal ROS production and depressed antioxidant defense). 1) Our studies confirm generalised mitochondrial dysfunction in the skeletal muscle and the fibroblasts of BTHS patients, especially a severe impairment in the mtΔΨ and the inhibition of complex V activity. It can be hypothesised that impaired mtΔΨ and mitochondrial ATP synthase activity may contribute to episodes of cardiac arrhythmia that occurred unexpectedly in BTHS patients. 2) Severe lactic acidosis without 3-methylglutaconic aciduria in male neonates as well as an asymptomatic mild left ventricular noncompaction may characterise the ranges of natural history of Barth syndrome.
Genome-wide association studies (GWAS) have been successful in identifying common genetic variation involved in susceptibility to etiologically complex disease.We conducted a GWAS to identify common genetic variation involved in susceptibility to upper aero-digestive tract (UADT) cancers.Genome-wide genotyping was carried out using the Illumina HumanHap300 beadchips in 2,091 UADT cancer cases and 3,513 controls from two large European multi-centre UADT cancer studies, as well as 4,821 generic controls.The 19 top-ranked variants were investigated further in an additional 6,514 UADT cancer cases and 7,892 controls of European descent from an additional 13 UADT cancer studies participating in the INHANCE consortium.Five common variants presented evidence for significant association in the combined analysis (p#5610 27 ).Two novel variants were identified, a 4q21 variant (rs1494961, p = 1610 28 ) located near DNA repair related genes HEL308 and FAM175A (or Abraxas) and a 12q24 variant (rs4767364, p = 2610 28 ) located in an extended linkage disequilibrium region that contains multiple genes including the aldehyde dehydrogenase 2 (ALDH2) gene.Three remaining variants are located in the ADH gene cluster and were identified previously in a candidate gene study involving some of these samples.The association between these three variants and UADT cancers was independently replicated in 5,092 UADT cancer cases and 6,794 controls nonoverlapping samples presented here (rs1573496-ADH7, p = 5610 28 ; rs1229984-ADH1B, p = 7610 29 ; and rs698-ADH1C, p = 0.02).These results implicate two variants at 4q21 and 12q24 and further highlight three ADH variants in UADT cancer susceptibility.
Abstract Four molecular types of rare central nervous system (CNS) tumors have been recently identified by gene methylation profiling: CNS Neuroblastoma with FOXR2 activation (CNS NB-FOXR2), CNS Ewing Sarcoma Family Tumor with CIC alteration (CNS EFT-CIC), CNS high grade neuroepithelial tumor with MN1 alteration (CNS HGNET-MN1) and CNS high grade neuroepithelial tumor with BCOR alteration (CNS HGNET-BCOR). Although they are not represented in 2016 updated WHO classification of CNS tumors, their diagnostic recognition is important because of clinical consequences. We have introduced a diagnostic method based on transcription profiling of tumor specific signature genes from formalin-fixed, paraffin-embedded tumor blocks using NanoString nCounter Technology. Altogether, 14 out of 187 (7.4%) high grade pediatric brain tumors were diagnosed with either of four new CNS categories. Histopathological examination of the tumors confirmed, that they demonstrate a spectrum of morphology mimicking other CNS high grade tumors. However, they also exhibit some suggestive histopathological and immunohistochemical features that allow for a presumptive diagnosis prior to molecular assessment. Clinical characteristics of patients corroborated with the previous findings for CNS EFT-CIC, CNS NB-FOXR2 and CNS HGNET-MN1 patients, with a favorable survival rate for the latter two groups. Among six CNS HGNET-BCOR patients, three patients are long term survivors, suggesting possible heterogeneity within this molecular category of tumors. In summary, we confirmed the effectiveness of NanoString method using a single, multi-gene tumor specific signature and recommend this novel approach for identification of either one of the four newly described CNS tumor entities.
Background . Analysis of candidate genes in individual studies has had only limited success in identifying particular gene variants that are conclusively associated with lung cancer risk. In the International Lung Cancer Consortium (ILCCO), we conducted a coordinated genotyping study of 10 common variants selected because of their prior evidence of an association with lung cancer. These variants belonged to candidate genes from different cancer-related pathways including inflammation ( IL1B ), folate metabolism ( MTHFR ), regulatory function ( AKAP9 and CAMKK1 ), cell adhesion ( SEZL6 ) and apoptosis ( FAS , FASL , TP53 , TP53BP1 and BAT3 ). Methods. Genotype data from 15 ILCCO case–control studies were available for a total of 8431 lung cancer cases and 11 072 controls of European descent and Asian ethnic groups. Unconditional logistic regression was used to model the association between each variant and lung cancer risk. Results . Only the association between a non-synonymous variant of TP53BP1 (rs560191) and lung cancer risk was significant (OR = 0.91, P = 0.002). This association was more striking for squamous cell carcinoma (OR = 0.86, P = 6 × 10 −4 ). No heterogeneity by center, ethnicity, smoking status, age group or sex was observed. In order to confirm this association, we included results for this variant from a set of independent studies (9966 cases/11 722 controls) and we reported similar results. When combining all these studies together, we reported an overall OR = 0.93 (0.89–0.97) ( P = 0.001). This association was significant only for squamous cell carcinoma [OR = 0.89 (0.85–0.95), P = 1 × 10 −4 ]. Conclusion. This study suggests that rs560191 is associated to lung cancer risk and further highlights the value of consortia in replicating or refuting published genetic associations.
Wingless-activated (WNT) medulloblastoma have been identified over the past decade as being a candidate for therapy de-escalation based on their excellent survival, however a paucity of relapses in any single cohort have precluded any additional analysis of markers of relapse. To address this gap in knowledge, an international cohort of 91 WNT-MB was assembled where we identified 14 relapsed cases where five-year progression free survival was 0.84 (95% 0.763-0.925). Maintenance chemotherapy was identified as a strong predictor of relapse, where no relapses were observed in cases receiving high doses of cyclophosphamide or ifosphamide (p=0.0026). The location of relapse was metastatic in 10/14 of relapses, with 7/10 metastatic relapses presenting along the ependymal lining in the lateral ventricles. Maintenance chemotherapy, specifically cumulative cyclophosphamide dose is a significant predictor of relapse across WNT-MB. Future efforts to de-escalate therapy need to carefully consider not only the radiation dose but also the chemotherapy regimen, and the propensity to metastatic relapses.
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