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Diffuse pediatric high-grade glioma of methylation-based RTK2A and RTK2B subclasses present distinct radiological and histomolecular features including Gliomatosis cerebri phenotype. 基于甲基化的RTK2A和RTK2B亚类的弥漫性小儿高级别胶质瘤呈现出不同的放射学和组织分子特征,包括脑胶质瘤病表型。
IF 6.2 2区 医学 Q1 NEUROSCIENCES Pub Date : 2024-11-18 DOI: 10.1186/s40478-024-01881-1
Arnault Tauziède-Espariat, Lea L Friker, Gunther Nussbaumer, Brigitte Bison, Volodia Dangouloff-Ros, Alice Métais, David Sumerauer, Josef Zamecnik, Martin Benesch, Thomas Perwein, Dannis van Vuurden, Pieter Wesseling, Andrés Morales La Madrid, Maria Luisa Garrè, Manila Antonelli, Felice Giangaspero, Torsten Pietsch, Dominik Sturm, David T W Jones, Stefan M Pfister, Yura Grabovska, Alan Mackay, Chris Jones, Jacques Grill, Yassine Ajlil, André O von Bueren, Michael Karremann, Marion Hoffmann, Christof M Kramm, Robert Kwiecien, David Castel, Gerrit H Gielen, Pascale Varlet

Diffuse pediatric-type high-grade gliomas (pedHGG), H3- and IDH-wildtype, encompass three main DNA-methylation-based subtypes: pedHGG-MYCN, pedHGG-RTK1A/B/C, and pedHGG-RTK2A/B. Since their first description in 2017 tumors of pedHGG-RTK2A/B have not been comprehensively characterized and clinical correlates remain elusive. In a recent series of pedHGG with a Gliomatosis cerebri (GC) growth pattern, an increased incidence of pedHGG-RTK2A/B (n = 18) was observed. We added 14 epigenetically defined pedHGG-RTK2A/B tumors to this GC series and provided centrally reviewed radiological, histological, and molecular characterization. The final cohort of 32 pedHGG-RTK2A/B tumors consisted of 25 pedHGG-RTK2A (78%) and seven pedHGG-RTK2B (22%) cases. The median age was 11.6 years (range, 4-17) with a median overall survival of 16.0 months (range 10.9-28.2). Seven of 11 of the newly added cases with imaging available showed a GC phenotype at diagnosis or follow-up. PedHGG-RTK2B tumors exhibited frequent bithalamic involvement (6/7, 86%). Central neuropathology review confirmed a diffuse glial neoplasm in all tumors with prominent angiocentric features in both subclasses. Most tumors (24/27 with available data, 89%) diffusely expressed EGFR with focal angiocentric enhancement. PedHGG-RTK2A tumors lacked OLIG2 expression, whereas 43% (3/7) of pedHGG-RTK2B expressed this glial transcription factor. ATRX loss occurred in 3/6 pedHGG-RTK2B samples with available data (50%). DNA sequencing (pedHGG-RTK2A: n = 18, pedHGG-RTK2B: n = 5) found EGFR alterations (15/23, 65%; predominantly point mutations) in both subclasses. Mutations in BCOR (14/18, 78%), SETD2 (7/18, 39%), and the hTERT promoter (7/19, 37%) occurred exclusively in pedHGG-RTK2A tumors, while pedHGG-RTK2B tumors were enriched for TP53 alterations (4/5, 80%). In conclusion, pedHGG-RTK2A/B tumors are characterized by highly diffuse-infiltrating growth patterns and specific radiological and histo-molecular features. By comprehensively characterizing methylation-based tumors, the chance to develop specific and effective therapy concepts for these detrimental tumors increases.

弥漫性儿科型高级别胶质瘤(pedHGG),H3-和IDH-野生型,包括三个主要的基于DNA甲基化的亚型:pedHGG-MYCN、pedHGG-RTK1A/B/C和pedHGG-RTK2A/B。自2017年首次描述以来,pedHGG-RTK2A/B肿瘤尚未得到全面描述,临床相关性仍难以捉摸。在最近一系列具有脑胶质瘤病(GC)生长模式的pedHGG中,观察到pedHGG-RTK2A/B(n = 18)的发生率增加。我们将 14 例经表观遗传学定义的 pedHGG-RTK2A/B 肿瘤加入到这一 GC 系列中,并提供了集中审查的放射学、组织学和分子特征。最终32例pedHGG-RTK2A/B肿瘤包括25例pedHGG-RTK2A(78%)和7例pedHGG-RTK2B(22%)。中位年龄为11.6岁(4-17岁),中位总生存期为16.0个月(10.9-28.2个月)。在新增的 11 例有影像学资料的病例中,有 7 例在诊断或随访时显示出 GC 表型。PedHGG-RTK2B肿瘤经常累及双侧丘脑(6/7,86%)。中央神经病理学检查证实,所有肿瘤均为弥漫性胶质肿瘤,两个亚类的肿瘤均具有显著的血管中心特征。大多数肿瘤(24/27,89%)弥漫表达表皮生长因子受体(EGFR),并伴有局灶性血管中心强化。PedHGG-RTK2A肿瘤缺乏OLIG2表达,而43%(3/7)的pedHGG-RTK2B肿瘤表达这种神经胶质转录因子。3/6的pedHGG-RTK2B样本(50%)出现了ATRX缺失。DNA测序(pedHGG-RTK2A:n = 18,pedHGG-RTK2B:n = 5)在两个亚类中都发现了表皮生长因子受体的改变(15/23,65%;主要是点突变)。BCOR突变(14/18,78%)、SETD2突变(7/18,39%)和hTERT启动子突变(7/19,37%)只发生在pedHGG-RTK2A肿瘤中,而pedHGG-RTK2B肿瘤则富含TP53突变(4/5,80%)。总之,pedHGG-RTK2A/B肿瘤具有高度弥漫浸润的生长模式以及特殊的放射学和组织分子特征。通过对基于甲基化的肿瘤进行全面的特征描述,为这些有害肿瘤开发特异性和有效治疗概念的机会增加了。
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引用次数: 0
A primary intracranial neuroepithelial neoplasm with novel TCF3::BEND2 fusion: a case report. 伴有新型 TCF3::BEND2 融合的原发性颅内神经上皮肿瘤:病例报告。
IF 6.2 2区 医学 Q1 NEUROSCIENCES Pub Date : 2024-11-11 DOI: 10.1186/s40478-024-01884-y
Linmao Zheng, Tao Luo, Jie Xian, Mengxin Zhang, Xiuyi Pan, Xiang Wang, Qiang Yue, Qiao Zhou, Ni Chen

Astroblastoma, MN1-altered, is a rare circumscribed glial neoplasm that is composed of round, cuboidal, orcolumnar cells with astroblastic perivascular pseudorosettes, often associated with MN1::BEND2 and MN1::CXXC5 fusions. Atroblastoma-like gliomas harbouring EWSR1::BEND2 have been reported that they defined an epigenetically distinct subtype of astroblastoma. We report a case of a 19-year-old female with an intracranial neuroepithelial tumor featuring a novel TCF3::BEND2 fusion. This tumor, while classified as EWSR1::BEND2 gliomas based on DNA methylation, did not exhibit the MN1 alteration or typical astroblastoma morphology. The patient, initially diagnosed as ependymoma WHO grade 2 following surgery for an intracranial tumor four years prior, presented with a suspected recurrence. Magnetic resonance imaging identified a mixed solid-cystic lesion in the temporal area of the left lateral ventricle. For the recurrent tumor, the histological examination revealed the tumor cells predominantly exhibited a solid arrangement, with the solid areas primarily consisting of oval and short-spindle cells. In certain regions, loosely arranged short-spindle cells was observed. The tumor exhibited high cellular density, nuclear atypia, and frequent mitoses, but lacked the hallmark features typically associated with astroblastoma. Immunohistochemistry revealed patchy positivity for GFAP and OLIG2, diffuse positivity for EMA, and a high MIB-1 labeling index. Genome-wide DNA methylation profiling confirmed the tumor's classification as EWSR1::BEND2 gliomas with a high-confidence match and revealed focal deletion of chromosome 9q. Targeted next-generation sequencing identified a TCF3::BEND2 fusion, validated by reverse transcription polymerase chain reaction and Sanger sequencing. This case broadens the genetic spectrum of high-grade neuroepithelial tumor and suggests that BEND2 alterations may serve as critical determinants for this EWSR1::BEND2 glioma subgroup within the methylation classifier.

星形母细胞瘤(MN1-altered)是一种罕见的环形胶质肿瘤,由圆形、立方体或柱状细胞组成,具有星形母细胞周围血管假膜,通常与 MN1::BEND2 和 MN1::CXXC5 融合有关。有报道称,携带 EWSR1::BEND2 的成胶质细胞瘤是星形母细胞瘤的一种表观遗传学独特亚型。我们报告了一例 19 岁女性颅内神经上皮肿瘤病例,该肿瘤具有新型 TCF3::BEND2 融合。该肿瘤虽然根据DNA甲基化被归类为EWSR1::BEND2胶质瘤,但并未表现出MN1改变或典型的星形母细胞瘤形态。该患者四年前曾因颅内肿瘤接受手术治疗,最初被诊断为上皮瘤,WHO 分级为 2 级。磁共振成像检查发现,左侧外脑室颞区有一个实性囊性混合病灶。复发肿瘤的组织学检查显示,肿瘤细胞主要呈实性排列,实性区域主要由卵圆形和短纺锤形细胞组成。在某些区域观察到排列松散的短纺锤形细胞。肿瘤细胞密度高、核不典型、有丝分裂频繁,但缺乏星形母细胞瘤的典型特征。免疫组化显示 GFAP 和 OLIG2 呈斑片状阳性,EMA 呈弥漫阳性,MIB-1 标记指数较高。全基因组DNA甲基化分析证实该肿瘤属于EWSR1::BEND2胶质瘤,匹配可信度高,并发现9q染色体局灶性缺失。靶向新一代测序发现了TCF3::BEND2融合,并通过反转录聚合酶链反应和桑格测序进行了验证。该病例拓宽了高级别神经上皮肿瘤的基因谱,并提示BEND2改变可能是甲基化分类中EWSR1::BEND2胶质瘤亚组的关键决定因素。
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引用次数: 0
Correction: Revisiting gliomatosis cerebri in adult-type diffuse gliomas: a comprehensive imaging, genomic and clinical analysis. 更正:重新审视成人型弥漫性胶质瘤中的脑胶质瘤病:成像、基因组和临床综合分析。
IF 6.2 2区 医学 Q1 NEUROSCIENCES Pub Date : 2024-11-06 DOI: 10.1186/s40478-024-01869-x
Ilah Shin, Yae Won Park, Yongsik Sim, Seo Hee Choi, Sung Soo Ahn, Jong Hee Chang, Se Hoon Kim, Seung-Koo Lee, Rajan Jain
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引用次数: 0
Host genetics and gut microbiota influence lipid metabolism and inflammation: potential implications for ALS pathophysiology in SOD1G93A mice. 宿主遗传学和肠道微生物群影响脂质代谢和炎症:对 SOD1G93A 小鼠 ALS 病理生理学的潜在影响。
IF 6.2 2区 医学 Q1 NEUROSCIENCES Pub Date : 2024-11-06 DOI: 10.1186/s40478-024-01877-x
Elena Niccolai, Leandro Di Gloria, Maria Chiara Trolese, Paola Fabbrizio, Simone Baldi, Giulia Nannini, Cassandra Margotta, Claudia Nastasi, Matteo Ramazzotti, Gianluca Bartolucci, Caterina Bendotti, Giovanni Nardo, Amedeo Amdei

Amyotrophic Lateral Sclerosis (ALS) is a devastating neurodegenerative disorder characterized by the progressive loss of motor neurons, with genetic and environmental factors contributing to its complex pathogenesis. Dysregulated immune responses and altered energetic metabolism are key features, with emerging evidence implicating the gut microbiota (GM) in disease progression. We investigated the interplay among genetic background, GM composition, metabolism, and immune response in two distinct ALS mouse models: 129Sv_G93A and C57Ola_G93A, representing rapid and slow disease progression, respectively.Using 16 S rRNA sequencing and fecal metabolite analysis, we characterized the GM composition and metabolite profiles in non-transgenic (Ntg) and SOD1G93A mutant mice of both strains. Our results revealed strain-specific differences in GM composition and functions, particularly in the abundance of taxa belonging to Erysipelotrichaceae and the levels of short and medium-chain fatty acids in fecal samples. The SOD1 mutation induces significant shifts in GM colonization in both strains, with C57Ola_G93A mice showing changes resembling those in 129 Sv mice, potentially affecting disease pathogenesis. ALS symptom progression does not significantly alter microbiota composition, suggesting stability.Additionally, we assessed systemic immunity and inflammatory responses revealing strain-specific differences in immune cell populations and cytokine levels.Our findings underscore the substantial influence of genetic background on GM composition, metabolism, and immune response in ALS mouse models. These strain-specific variations may contribute to differences in disease susceptibility and progression rates. Further elucidating the mechanisms underlying these interactions could offer novel insights into ALS pathogenesis and potential therapeutic targets.

肌萎缩侧索硬化症(ALS)是一种以运动神经元进行性丧失为特征的破坏性神经退行性疾病,其复杂的发病机制与遗传和环境因素有关。免疫反应失调和能量代谢改变是其主要特征,有新的证据表明肠道微生物群(GM)与疾病进展有关。我们在两种不同的 ALS 小鼠模型中研究了遗传背景、GM 组成、新陈代谢和免疫反应之间的相互作用:利用 16 S rRNA 测序和粪便代谢物分析,我们描述了这两个品系的非转基因(Ntg)和 SOD1G93A 突变小鼠的肠道微生物群组成和代谢物特征。我们的研究结果表明,转基因小鼠的转基因组成和功能存在品系特异性差异,尤其是在粪便样本中属于Erysipelotrichaceae的类群丰度以及短链和中链脂肪酸水平方面。SOD1突变会导致两个品系的基因组定植发生显著变化,C57Ola_G93A小鼠的变化与129 Sv小鼠相似,可能会影响疾病的发病机制。我们的发现强调了遗传背景对 ALS 小鼠模型中基因组的组成、代谢和免疫反应的重大影响。这些品系特异性差异可能会导致疾病易感性和进展率的不同。进一步阐明这些相互作用的内在机制可为了解 ALS 发病机制和潜在治疗靶点提供新的视角。
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引用次数: 0
NF1 expression profiling in IDH-wildtype glioblastoma: genomic associations and survival outcomes. IDH 野生型胶质母细胞瘤中 NF1 的表达谱分析:基因组关联与生存结果。
IF 6.2 2区 医学 Q1 NEUROSCIENCES Pub Date : 2024-10-29 DOI: 10.1186/s40478-024-01875-z
Michael Chang, Mohamed Sherief, Maria Ioannou, Viveka Chinnasamy, Lucy Chen, Michael Frost, Michelle Mattson-Hoss, Herb Sarnoff, David O Kamson, Matthias Holdhoff, Debraj Mukherjee, Chetan Bettegowda, Jordina Rincon-Torroella, Victoria Croog, Peng Huang, Fausto J Rodriguez, Calixto-Hope G Lucas, Karisa C Schreck

Background: NF1 inactivation is associated with sensitivity to MEK inhibitor targeted therapy in low-grade and some high-grade gliomas. NF1 loss may also be a harbinger of exploitable vulnerabilities in IDH-wildtype glioblastoma (GBM). Accurate and consistent detection of NF1 loss, however, is fraught given the large gene size, challenges with complete coverage and variant calling upon sequencing, and mechanisms of mRNA and protein regulation that result in early degradation in the absence of genomic alterations. Here, we seek to perform a composite analysis for NF1 loss accounting for genomic alterations and protein expression via immunohistochemistry. We also characterize the landscape of NF1 alterations in GBM.

Methods: We assembled a single-institution, retrospective cohort of 542 IDH-wildtype GBM with somatic next generation sequencing to investigate the frequency and nature of detected NF1 alterations. We selected 69 GBMs from which to build a tissue microarray (TMA) of 44 NF1-wildtype and 25 NF1-mutant cases. We performed NF1 immunohistochemistry using two different NF1 antibodies (NFC, Sigma-Aldrich; and iNF-07E, iNFixion Bioscience) and correlated results with clinical, genomic, and other immunohistochemical features.

Results: In our retrospective cohort, we identified 88 IDH-wildtype GBM with NF1 alterations (16%). NF1 alterations were mutually exclusive with EGFR and MDM2 alterations (p-adj < 0.001, 0.05, respectively), but co-occurred with PIK3R1 alterations (Log2(OR) = - 1.6, p-adj = 0.03). Of the 63 scorable sporadic GBMs in the TMA, 14 harbored NF1 inactivating alterations and of those, 12 (86%) demonstrated minimal NF1 immunoreactivity by NFC antibody, compared to 8 (57%) by iNF-07E antibody. Among the 42 scorable NF1-wildtype GBM in the TMA, NF1 immunostaining was minimal in 18 (43%) by NFC antibody compared to 4 (10%) by iNF-07E antibody, potentially reflecting false positives or differential protein regulation. Minimal immunoreactivity by NFC antibody was associated with decreased median overall survival (8.5 vs. 16.4 months, p = 0.011). Cox proportional hazards model correcting for prognostic variables in this subset revealed HR 3.23 (95% CI 1.29-8.06, p = 0.01) associated with decreased NF1 expression by IHC.

Conclusion: NF1 immunostaining may serve as a sensitive surrogate marker of NF1 genomic inactivation and a valuable extension to next-generation sequencing for defining NF1 status. Minimal NF1 immunoreactivity is a poor prognostic marker, even in IDH-wildtype glioblastoma without apparent NF1 genomic alterations, but the underlying molecular mechanism requires further investigation.

背景:NF1 失活与低级别和某些高级别胶质瘤对 MEK 抑制剂靶向治疗的敏感性有关。NF1 缺失也可能预示着 IDH 野生型胶质母细胞瘤(GBM)中存在可利用的漏洞。然而,由于 NF1 基因体积庞大、测序时的完全覆盖和变异调用面临挑战,以及 mRNA 和蛋白质调控机制导致基因组未发生改变时的早期降解,因此准确一致地检测 NF1 缺失充满了困难。在此,我们试图对 NF1 基因缺失进行综合分析,考虑基因组改变和免疫组化的蛋白表达。我们还描述了 NF1 在 GBM 中的改变情况:我们对 542 例 IDH 野生型 GBM 进行了体细胞新一代测序,建立了一个单一机构的回顾性队列,以研究检测到的 NF1 改变的频率和性质。我们选择了 69 例 GBM,并从中建立了一个组织芯片(TMA),其中包括 44 例 NF1 野生型病例和 25 例 NF1 突变病例。我们使用两种不同的 NF1 抗体(NFC,Sigma-Aldrich;iNF-07E,iNFixion Bioscience)进行了 NF1 免疫组化,并将结果与临床、基因组和其他免疫组化特征相关联:在我们的回顾性队列中,我们发现了 88 例伴有 NF1 改变的 IDH 野生型 GBM(16%)。NF1改变与表皮生长因子受体(EGFR)和MDM2改变相互排斥(p-adj 2(OR) = - 1.6,p-adj = 0.03)。在TMA中的63个可扫描散发性GBM中,14个存在NF1失活改变,其中12个(86%)通过NFC抗体显示出最小的NF1免疫反应,而8个(57%)通过iNF-07E抗体显示出最小的NF1免疫反应。在 TMA 中 42 个可扫描的 NF1 野生型 GBM 中,NFC 抗体显示 18 个(43%)的 NF1 免疫反应极低,而 iNF-07E 抗体显示 4 个(10%),这可能反映了假阳性或蛋白调控的差异。NFC 抗体的最小免疫反应与中位总生存期的降低有关(8.5 个月 vs. 16.4 个月,p = 0.011)。校正该子集预后变量的 Cox 比例危险模型显示,HR 3.23(95% CI 1.29-8.06,p = 0.01)与 IHC 表达的 NF1 减少有关:NF1免疫染色可作为NF1基因组失活的灵敏替代标记物,是下一代测序的重要延伸,可用于确定NF1状态。即使在没有明显NF1基因组改变的IDH-野生型胶质母细胞瘤中,NF1的最低免疫反应也是预后不良的标志物,但其潜在的分子机制还需要进一步研究。
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引用次数: 0
Genotype‒phenotype correlation in recessive DNAJB4 myopathy. 隐性DNAJB4肌病基因型与表型的相关性
IF 6.2 2区 医学 Q1 NEUROSCIENCES Pub Date : 2024-10-28 DOI: 10.1186/s40478-024-01878-w
Michio Inoue, Divya Jayaraman, Rocio Bengoechea, Ankan Bhadra, Casie A Genetti, Abdulrahman A Aldeeri, Betül Turan, Rafael Adrian Pacheco-Orozco, Almundher Al-Maawali, Nadia Al Hashmi, Ayşe Gül Zamani, Emine Göktaş, Sevgi Pekcan, Hanife Tuğçe Çağlar, Heather True, Alan H Beggs, Conrad C Weihl

Protein aggregate myopathies can result from pathogenic variants in genes encoding protein chaperones. DNAJB4 is a cochaperone belonging to the heat shock protein-40 (HSP40) family and plays a vital role in cellular proteostasis. Recessive loss-of-function variants in DNAJB4 cause myopathy with early respiratory failure and spinal rigidity, presenting from infancy to adulthood. This study investigated the broader clinical and genetic spectrum of DNAJB4 myopathy. In this study, we performed whole-exome sequencing on seven patients with early respiratory failure of unknown genetic etiology. We identified five distinct pathogenic variants in DNAJB4 in five unrelated families of diverse ethnic backgrounds: three loss-of-function variants (c.547 C > T, p.R183*; c.775 C > T, p.R259*; an exon 2 deletion) and two missense variants (c.105G > C, p.K35N; c.181 A > G, p.R61G). All patients were homozygous. Most affected individuals exhibited early respiratory failure, and patients from three families had rigid spine syndrome with axial weakness in proportion to appendicular weakness. Additional symptoms included dysphagia, ankle contractures, scoliosis, neck stiffness, and cardiac dysfunction. Notably, J-domain missense variants were associated with a more severe phenotype, including an earlier age of onset and a higher mortality rate, suggesting a strong genotype‒phenotype correlation. Consistent with a loss of function, the nonsense variants presented decreased stability. In contrast, the missense variants exhibited normal or increased stability but behaved as loss-of-function variants in yeast complementation and TDP-43 disaggregation assays. Our findings suggest that DNAJB4 is an emerging cause of myopathy with rigid spine syndrome of variable age of onset and severity. This diagnosis should be considered in individuals presenting with suggestive symptoms, particularly if they exhibit neck stiffness during infancy or experience respiratory failure in adults without significant limb muscle weakness. Missense variants in the J domain may predict a more severe phenotype.

编码蛋白伴侣的基因中的致病变异可导致蛋白聚集性肌病。DNAJB4 是一种属于热休克蛋白-40(HSP40)家族的伴侣蛋白,在细胞蛋白稳态中发挥着重要作用。DNAJB4 的隐性功能缺失变体会导致肌病,并伴有早期呼吸衰竭和脊柱僵硬,从婴儿期一直持续到成年期。本研究调查了DNAJB4肌病更广泛的临床和遗传谱。在这项研究中,我们对七名遗传病因不明的早期呼吸衰竭患者进行了全外显子组测序。我们在五个不同种族背景的无亲属关系家庭中发现了 DNAJB4 的五个不同致病变异:三个功能缺失变异(c.547 C > T,p.R183*;c.775 C > T,p.R259*;一个外显子 2 缺失)和两个错义变异(c.105G > C,p.K35N;c.181 A > G,p.R61G)。所有患者均为同型变异。大多数患者表现出早期呼吸衰竭,三个家族的患者患有脊柱僵硬综合征,轴向无力与阑尾无力成正比。其他症状包括吞咽困难、踝关节挛缩、脊柱侧弯、颈部僵硬和心脏功能障碍。值得注意的是,J-domain 错义变异与更严重的表型有关,包括更早的发病年龄和更高的死亡率,这表明基因型与表型之间存在很强的相关性。与功能缺失相一致的是,无义变体的稳定性降低。相反,错义变体表现出正常或更高的稳定性,但在酵母互补和TDP-43分解试验中表现为功能缺失变体。我们的研究结果表明,DNAJB4 是导致发病年龄和严重程度不一的脊柱僵直综合征肌病的一个新病因。如果患者出现提示性症状,尤其是在婴儿期表现出颈部僵硬或在成年后出现呼吸衰竭而无明显四肢肌无力时,应考虑这一诊断。J 结构域的错义变异可能预示着更严重的表型。
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引用次数: 0
Glioma immune microenvironment composition calculator (GIMiCC): a method of estimating the proportions of eighteen cell types from DNA methylation microarray data. 胶质瘤免疫微环境组成计算器(GIMiCC):一种从 DNA 甲基化芯片数据估算十八种细胞类型比例的方法。
IF 6.2 2区 医学 Q1 NEUROSCIENCES Pub Date : 2024-10-28 DOI: 10.1186/s40478-024-01874-0
Steven C Pike, John K Wiencke, Ze Zhang, Annette M Molinaro, Helen M Hansen, Devin C Koestler, Brock C Christensen, Karl T Kelsey, Lucas A Salas

A scalable platform for cell typing in the glioma microenvironment can improve tumor subtyping and immune landscape detection as successful immunotherapy strategies continue to be sought and evaluated. DNA methylation (DNAm) biomarkers for molecular classification of tumor subtypes have been developed for clinical use. However, tools that predict the cellular landscape of the tumor are not well-defined or readily available. We developed the Glioma Immune Microenvironment Composition Calculator (GIMiCC), an approach for deconvolution of cell types in gliomas using DNAm data. Using data from 17 isolated cell types, we describe the derivation of the deconvolution libraries in the biological context of selected genomic regions and validate deconvolution results using independent datasets. We utilize GIMiCC to illustrate that DNAm-based estimates of immune composition are clinically relevant and scalable for potential clinical implementation. In addition, we utilize GIMiCC to identify composition-independent DNAm alterations that are associated with high immune infiltration. Our future work aims to optimize GIMiCC and advance the clinical evaluation of glioma.

随着人们不断寻找和评估成功的免疫疗法策略,一个可扩展的胶质瘤微环境细胞分型平台可以改善肿瘤亚型和免疫格局检测。用于肿瘤亚型分子分类的 DNA 甲基化(DNAm)生物标记物已开发出供临床使用。然而,预测肿瘤细胞景观的工具还没有明确定义,也不容易获得。我们开发了胶质瘤免疫微环境组成计算器(GIMiCC),这是一种利用DNAm数据解构胶质瘤细胞类型的方法。我们利用来自 17 种分离细胞类型的数据,描述了在选定基因组区域的生物学背景下衍生出的解卷积库,并利用独立数据集验证了解卷积结果。我们利用 GIMiCC 说明了基于 DNAm 的免疫组成估计值与临床相关,并可扩展到潜在的临床应用中。此外,我们还利用 GIMiCC 确定了与高免疫浸润相关的不依赖于组成的 DNAm 改变。我们未来的工作旨在优化 GIMiCC 并推进胶质瘤的临床评估。
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引用次数: 0
Dual phenotypes in recurrent astrocytoma, IDH-mutant; coexistence of IDH-mutant and IDH-wildtype components: a case report with genetic and epigenetic analysis. IDH突变型复发性星形细胞瘤的双重表型;IDH突变型和IDH野生型成分共存:一份病例报告及遗传学和表观遗传学分析。
IF 6.2 2区 医学 Q1 NEUROSCIENCES Pub Date : 2024-10-26 DOI: 10.1186/s40478-024-01879-9
Junya Yamaguchi, Fumiharu Ohka, Masafumi Seki, Kazuya Motomura, Shoichi Deguchi, Yoshiki Shiba, Yuka Okumura, Yuji Kibe, Hiroki Shimizu, Sachi Maeda, Yuhei Takido, Ryo Yamamoto, Akihiro Nakamura, Kennosuke Karube, Ryuta Saito

Mutations in the isocitrate dehydrogenase (IDH) gene are recognized as the key drivers in the oncogenesis of astrocytoma and oligodendroglioma. However, the significance of IDH mutation in tumor maintenance and malignant transformation has not been elucidated. We encountered a unique case of IDH-mutant astrocytoma that, upon malignant transformation, presented two distinct intratumoral components: one IDH-wildtype and one IDH-mutant. The IDH-wild-type component exhibited histological findings similar to those of small cell-type glioblastoma with a higher Ki-67 index than the IDH-mutant component. Despite their genetic divergence, both components exhibited similar comprehensive methylation profiles within the CpG island and were classified into methylation class of "Astrocytoma, IDH-mutant; High Grade" by the German Cancer Center (DKFZ) classifier v11.4. Phylogenetic analysis demonstrated that the IDH-wildtype component emerged as a subclonal component of the primary tumor. Detailed molecular analyses revealed that the loss of the IDH mutation was induced by the hemizygous loss of the entire arm of chromosome 2, on which IDH1 gene is located. Notably, the IDH-wild-type subclones uniquely acquired CDKN2A/B homozygous deletion and PDGFRA amplification, which is a marker of the aggressive phenotype of astrocytoma, IDH-mutant. Because these genetic abnormalities can drive oncogenic pathways, such as the PI3K/AKT/mTOR and RB signaling pathway, IDH-mutant gliomas that acquired these mutations were no longer dependent on the initial driver mutation, the IDH mutation. Molecular analysis of this unique case provides insight that in a subset of astrocytoma, IDH-mutant that acquired these genetic abnormalities, IDH mutation may not play a pivotal role in tumor growth and acquisition of these genetic abnormalities may contribute to the acquisition of resistance to IDH inhibitors.

异柠檬酸脱氢酶(IDH)基因突变被认为是星形细胞瘤和少突胶质细胞瘤肿瘤发生的关键驱动因素。然而,IDH 基因突变在肿瘤维持和恶性转化中的意义尚未得到阐明。我们遇到了一例独特的IDH突变星形细胞瘤,该瘤在恶性转化后出现了两种不同的瘤内成分:一种是IDH野生型,一种是IDH突变型。IDH野生型成分的组织学表现与小细胞型胶质母细胞瘤相似,Ki-67指数高于IDH突变型成分。尽管在基因上存在差异,但这两种成分在 CpG 岛内都表现出类似的全面甲基化特征,并被德国癌症中心(DKFZ)分类器 v11.4 归入 "星形细胞瘤,IDH 突变;高级别 "甲基化类别。系统发育分析表明,IDH-野生型成分是原发肿瘤的亚克隆成分。详细的分子分析表明,IDH突变的缺失是由IDH1基因所在的2号染色体整个臂的半等位缺失引起的。值得注意的是,IDH-wild 型亚克隆独特地获得了 CDKN2A/B 同源缺失和 PDGFRA 扩增,这是 IDH 突变型星形细胞瘤侵袭性表型的标志。由于这些基因异常可以驱动致癌通路,如PI3K/AKT/mTOR和RB信号通路,因此获得这些突变的IDH突变胶质瘤不再依赖于最初的驱动突变,即IDH突变。对这一独特病例的分子分析表明,在获得这些基因异常的IDH突变型星形细胞瘤亚群中,IDH突变可能在肿瘤生长中不再起关键作用,而获得这些基因异常可能有助于获得对IDH抑制剂的耐药性。
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引用次数: 0
Correction to: ADNP dysregulates methylation and mitochondrial gene expression in the cerebellum of a Helsmoortel-Van Der Aa syndrome autopsy case. 更正:ADNP对Helsmoortel-Van Der Aa综合征尸检病例小脑甲基化和线粒体基因表达的失调。
IF 6.2 2区 医学 Q1 NEUROSCIENCES Pub Date : 2024-10-24 DOI: 10.1186/s40478-024-01787-y
Claudio D'Incal, Anke Van Dijck, Joe Ibrahim, Kevin De Man, Lina Bastini, Anthony Konings, Ellen Elinck, Claudia Theys, Illana Gozes, Zlatko Marusic, Mirna Anicic, Jurica Vukovic, Nathalie Van der Aa, Ligia Mateiu, Wim Vanden Berghe, R Frank Kooy
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引用次数: 0
A minimally invasive biomarker for sensitive and accurate diagnosis of Parkinson's disease. 用于敏感、准确诊断帕金森病的微创生物标记。
IF 6.2 2区 医学 Q1 NEUROSCIENCES Pub Date : 2024-10-22 DOI: 10.1186/s40478-024-01873-1
Zerui Wang, Tricia Gilliland, Hyun Jo Kim, Maria Gerasimenko, Kailey Sajewski, Manuel V Camacho, Gurkan Bebek, Shu G Chen, Steven A Gunzler, Qingzhong Kong

Seeding activities of disease-associated α-synuclein aggregates (αSynD), a hallmark of Parkinson's disease (PD), are detectable by seed amplification assay (αSyn-SAA) and being developed as a diagnostic biomarker for PD. Sensitive and accurate αSyn-SAA for blood or saliva would greatly facilitate PD diagnosis. This prospective diagnostic study conducted αSyn-SAA analyses on serum and saliva samples collected from patients clinically diagnosed with PD or healthy controls (HC). 124 subjects (82 PD, 42 HC) donated blood and had extensive clinical assessments, of whom 74 subjects (48 PD, 26 HC) also donated saliva at the same visits. An additional 57 subjects (35 PD, 22 HC) donated saliva and had more limited clinical assessments. The mean ages were 69.21, 66.55, 69.58, and 64.71 years for PD serum donors, HC serum donors, PD saliva donors, and HC saliva donors, respectively. αSynD seeding activities in either sample type alone or both sample types together were evaluated for PD diagnosis. Serum αSyn-SAA data from 124 subjects showed 80.49% sensitivity, 90.48% specificity, and 0.9006 accuracy (AUC of ROC); saliva αSyn-SAA data from 131 subjects attained 74.70% sensitivity, 97.92% specificity, and 0.8966 accuracy. Remarkably, the combined serum and saliva αSyn-SAA from 74 subjects with both sample types achieved better diagnostic performance: 95.83% sensitivity, 96.15% specificity, and 0.98 accuracy. In addition, serum αSynD seeding activities correlated inversely with Montreal Cognitive Assessment in males and positively with Hamilton Depression Rating Scale in females and in the < 70 age group, whereas saliva αSynD seeding activities correlated inversely with age at diagnosis in males and in the < 70 age group. Our data indicate that serum and saliva αSyn-SAA together can achieve high diagnostic accuracy for PD comparable to that of CSF αSyn-SAA, suggesting their potential utility for highly sensitive, accurate, and minimally invasive diagnosis of PD in routine clinical practice and clinical studies.

与疾病相关的α-突触核蛋白聚集体(αSynD)的种子活性是帕金森病(PD)的标志,可通过种子扩增分析法(αSyn-SAA)检测到,目前正被开发为帕金森病的诊断生物标志物。对血液或唾液进行敏感而准确的αSyn-SAA检测将大大有助于帕金森病的诊断。这项前瞻性诊断研究对临床诊断为帕金森病患者或健康对照组(HC)的血清和唾液样本进行了αSyn-SAA分析。124 名受试者(82 名帕金森病患者,42 名健康对照组患者)捐献了血液并接受了广泛的临床评估,其中 74 名受试者(48 名帕金森病患者,26 名健康对照组患者)还在相同的访问中捐献了唾液。另有 57 名受试者(35 名白内障患者,22 名白内障患者)捐献了唾液,并接受了较为有限的临床评估。白内障患者血清捐献者、白内障患者血清捐献者、白内障患者唾液捐献者和白内障患者唾液捐献者的平均年龄分别为 69.21 岁、66.55 岁、69.58 岁和 64.71 岁。在诊断脊髓灰质炎时,评估了两种样本中任何一种的αSynD播散活性。124名受试者的血清αSyn-SAA数据显示灵敏度为80.49%,特异度为90.48%,准确度为0.9006(ROC的AUC);131名受试者的唾液αSyn-SAA数据显示灵敏度为74.70%,特异度为97.92%,准确度为0.8966。值得注意的是,74 名受试者的血清和唾液αSyn-SAA 两种样本的联合诊断效果更好:灵敏度为 95.83%,特异度为 96.15%,准确度为 0.98。此外,男性血清 αSynD 播种活性与蒙特利尔认知评估呈反向相关,女性与汉密尔顿抑郁量表呈正向相关;男性 D 播种活性与诊断时的年龄呈反向相关,女性与诊断时的年龄呈正向相关。
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引用次数: 0
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Acta Neuropathologica Communications
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