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ALK-positive histiocytosis: Report of a rare case with exclusive involvement of the central nervous system in an adult woman. ALK阳性组织细胞增生症:报告一例成年女性中枢神经系统完全受累的罕见病例。
IF 1.3 4区 医学 Q4 CLINICAL NEUROLOGY Pub Date : 2024-09-03 DOI: 10.1111/neup.13002
Yuting Luo, Pingling Wang, Qinru Zhan, Jiao Luo, Baohong Luo

ALK-positive histiocytosis is a rare histiocytic disease characterized by ALK positivity. It was first described in 2008 as a systemic disease in infants. The disease often shows positivity for CD68 and CD163 on immunohistochemistry, and genomic analysis frequently reveals KIF5B::ALK fusions. ALK-positive histiocytosis typically follows an indolent course and has a promising prognosis, with conventional treatments usually being effective. Here, we report a rare case of ALK-positive histiocytosis with exclusive involvement of the central nervous system in a 33-year-old Asian adult woman. Although cranial MRI suggested a meningioma, immunohistochemical workup showed that the ALK-positive tumor cells expressed macrophage/histiocyte markers such as CD163 and CD68. Additionally, second-generation sequencing revealed a KIF5B::ALK fusion. Our case highlights the importance of the differential diagnosis in adult central nervous system tumors, emphasizing the combination of morphology, immunophenotype, and molecular approach with ALK status evaluation to confirm a diagnosis of ALK-positive histiocytosis. This case also expands the clinicopathologic spectrum of ALK-positive histiocytosis.

ALK阳性组织细胞增生症是一种以ALK阳性为特征的罕见组织细胞疾病。该病于 2008 年首次被描述为婴儿的一种全身性疾病。该病的免疫组化结果常显示 CD68 和 CD163 阳性,基因组分析常显示 KIF5B::ALK 融合。ALK阳性组织细胞增生症通常病程不长,预后良好,常规治疗通常有效。在此,我们报告了一例罕见的ALK阳性组织细胞增生症病例,患者是一名33岁的亚洲成年女性,中枢神经系统完全受累。虽然头颅磁共振成像提示为脑膜瘤,但免疫组化检查显示,ALK阳性肿瘤细胞表达巨噬细胞/组织细胞标记物,如CD163和CD68。此外,第二代测序发现了KIF5B::ALK融合。我们的病例凸显了成人中枢神经系统肿瘤鉴别诊断的重要性,强调了结合形态学、免疫表型、分子方法和 ALK 状态评估来确诊 ALK 阳性组织细胞增生症的重要性。该病例还扩展了ALK阳性组织细胞增多症的临床病理范围。
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引用次数: 0
An autopsy case of progressive supranuclear palsy with severe corticospinal tract degeneration. 一例伴有严重皮质脊髓束变性的进行性核上性麻痹尸检病例。
IF 1.3 4区 医学 Q4 CLINICAL NEUROLOGY Pub Date : 2024-08-24 DOI: 10.1111/neup.13001
Satoshi Kuru, Motoko Sakai, Hideyuki Moriyoshi, Hiroaki Miyahara, Yasushi Iwasaki

We report an autopsy case of a 70-year-old man who was clinically diagnosed with atypical progressive supranuclear palsy (PSP). He initially presented with gait ataxia and then showed vertical gaze palsy, rigidity, akinesia, dysphagia, and mild cognitive impairment, followed by prominent upper motor signs later in the course of the disease. Cranial magnetic resonance imaging revealed tegmental atrophy of the midbrain. Autopsy revealed severe neuronal loss and gliosis in the motor cortex and corticospinal degeneration and mild to moderate neuronal loss and gliosis in the basal ganglia, substantia nigra, midbrain, and pons. Tufted astrocytes were primarily found in the motor cortex and basal ganglia. Globose-type neurofibrillary tangles were observed in the locus coeruleus and nucleus olivaris inferior. In the cerebellar cortex, mild Purkinje cell loss and scattered axonal torpedoes were observed with tau-positive Purkinje cells. The dentate nucleus displayed severe neuronal loss and gliosis. The present case showed characteristics of both PSP with prominent cerebellar ataxia (PSP-C) and PSP-primary lateral sclerosis (PSP-PLS).

我们报告了一例 70 岁男性的尸检病例,他被临床诊断为非典型进行性核上性麻痹(PSP)。他最初表现为步态共济失调,随后出现垂直凝视麻痹、僵直、运动障碍、吞咽困难和轻度认知障碍,病程后期出现明显的上肢运动症状。头颅磁共振成像显示中脑被盖区萎缩。尸检显示,运动皮质和皮质脊髓变性存在严重的神经元缺失和胶质增生,基底节、黑质、中脑和脑桥存在轻度至中度神经元缺失和胶质增生。簇状星形胶质细胞主要出现在运动皮层和基底节。在脑室和橄榄核下部观察到球状神经纤维缠结。在小脑皮层,观察到轻度的浦肯野细胞缺失和散在的轴突鱼雷,浦肯野细胞tau阳性。齿状核显示出严重的神经元缺失和胶质增生。本病例同时表现出小脑共济失调综合征(PSP-C)和小脑原发性侧索硬化症(PSP-PLS)的特征。
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引用次数: 0
Unveiling primary intracranial eosinophilic angiocentric fibrosis: A rare case report and diagnostic dilemmas. 揭开原发性颅内嗜酸性粒细胞血管中心纤维化的神秘面纱:罕见病例报告与诊断难题。
IF 1.3 4区 医学 Q4 CLINICAL NEUROLOGY Pub Date : 2024-08-06 DOI: 10.1111/neup.12997
Rumela Nayak, Bevinahalli N Nandeesh

Eosinophilic angiocentric fibrosis (EAF) is a rare, benign fibroinflammatory condition primarily affecting the sinonasal and upper respiratory tract, with a few cases reported beyond these regions. Primary intracranial EAF is rare. To date, only one case of intracranial EAF has been reported; ours is the second. This case report presents a case of EAF in a 55-year-old man, initially misdiagnosed as meningioma based on clinical and radiological features. The patient complained of a persistent dull headache for six months without associated neurological symptoms. Brain magnetic resonance imaging revealed a dural-based lesion with characteristics suggestive of meningioma. However, histopathological examination post-surgical resection revealed a nodular vascular lesion with concentric angiocentric fibrosis, a distinctive onion skin pattern, and an inflammatory infiltrate rich in eosinophils, plasma cells, and histiocytes. Immunohistochemistry ruled out IgG4-related disease, and other systemic disorders were ruled out based on combined clinical and histological features. This case underscores the need for considering EAF in the differential diagnosis of dural-based lesions. Awareness of its potential mimicking of meningioma is crucial for accurate diagnosis and appropriate management, emphasizing the importance of histopathological examination in challenging cases.

嗜酸性粒细胞血管中心纤维化(EAF)是一种罕见的良性纤维炎症,主要累及鼻窦和上呼吸道,少数病例报告超出了这些区域。原发性颅内 EAF 很少见。迄今为止,仅有一例颅内 EAF 的报道,我们是第二例。本病例报告介绍了一例颅内 EAF 病例,患者是一名 55 岁的男性,最初根据临床和放射学特征被误诊为脑膜瘤。患者主诉持续钝性头痛 6 个月,无相关神经症状。脑磁共振成像显示,硬脑膜病变具有脑膜瘤的特征。然而,手术切除后的组织病理学检查显示,病变为结节状血管病变,伴有同心圆状血管中心纤维化、独特的洋葱皮形态以及富含嗜酸性粒细胞、浆细胞和组织细胞的炎性浸润。免疫组化检查排除了 IgG4 相关疾病,根据临床和组织学综合特征排除了其他系统性疾病。该病例强调了在硬脑膜病变的鉴别诊断中考虑 EAF 的必要性。认识到EAF可能与脑膜瘤相似是准确诊断和适当处理的关键,强调了组织病理学检查在疑难病例中的重要性。
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引用次数: 0
Ipsilateral simultaneous multiple hypertensive intracerebral hemorrhages: Analysis of hematoma formation and comparison with distribution of hypertensive mixed-type hematoma. 同侧同时多发性高血压脑内出血:血肿形成分析及与高血压混合型血肿分布的比较。
IF 1.3 4区 医学 Q4 CLINICAL NEUROLOGY Pub Date : 2024-08-06 DOI: 10.1111/neup.12998
Shigeki Takeda, Hitoshi Takahashi, Teruo Miyakawa, Kazunori Yamazaki, Kiyoshi Onda

A 55-year-old Japanese woman with a history of hypertension and right putaminal hemorrhage developed simultaneous hemorrhages in the left thalamus and putamen and died 24 h later. There were no vascular anomalies in the brain. Synaptophysin immunostaining combined with eosin azure 50 (EA50) staining clearly identified the hematoma and the surrounding brain structures. In the right cerebral hemisphere, a cystic lesion as a sequela of the usual type of hypertensive putaminal hematoma was evident. In the left cerebral hemisphere, two fresh hematomas were evident. One was a thalamic hematoma, which had destroyed the dorsal and medial structures of the thalamus, and the other was an unusual putaminal hematoma, which had destroyed the entire putamen and crossed the internal capsule and caudate nucleus. α-Smooth muscle actin immunostaining combined with EA50 and Victoria bleu staining demonstrated three ruptured arteries associated with fibrin aggregates in the anterior thalamic nucleus and anterior putamen. Some circular structures composed of fibrin, suggesting the presence of ruptured arteries in the neighborhood, were evident in the thalamus and putamen. In the putamen, ruptured arteries and circular structures were present in the lateral to medial areas. Fibrin aggregates in the anterior thalamic nucleus were more numerous than those in the putamen. On the basis of these findings, we concluded that: (i) the artery with numerous fibrin aggregates in the anterior thalamic nucleus had ruptured first, followed by the arteries distributed in other parts of the thalamus and putamen; (ii) the unusual putaminal hematoma was attributable to rupture of the arteries around the center of the putamen, which are not responsible for the usual type of hypertensive putaminal hematoma; and (iii) it is suggested that even if hypertensive hemorrhage occurs simultaneously in the ipsilateral putamen and thalamus, the usual type of hypertensive mixed-type hematoma does not form.

一名 55 岁的日本妇女有高血压和右侧普坦门出血病史,左侧丘脑和普坦门同时出血,24 小时后死亡。患者脑部无血管异常。突触素免疫染色联合天青素 50(EA50)染色可清楚地识别血肿和周围的脑结构。在右侧大脑半球,明显可见囊性病变,这是常见的高血压性椎管内血肿的后遗症。左侧大脑半球有两个明显的新鲜血肿。α-平滑肌肌动蛋白免疫染色法结合 EA50 和 Victoria bleu 染色法显示,丘脑前核和大脑前部有三条破裂的动脉,并伴有纤维蛋白聚集。丘脑和丘脑前部明显可见一些由纤维蛋白组成的圆形结构,表明附近存在破裂的动脉。在大脑丘脑,从外侧到内侧区域都有破裂的动脉和圆形结构。丘脑前核中的纤维蛋白聚集物数量多于普方肌中的纤维蛋白聚集物。根据这些发现,我们得出以下结论(i) 丘脑前核中有大量纤维蛋白聚集的动脉首先破裂,其次是分布在丘脑其他部位和普特间脑的动脉;(ii) 不寻常的普特间脑血肿是由于普特间脑中心周围的动脉破裂造成的,而这种动脉破裂并不是常见的高血压性普特间脑血肿的原因;(iii) 研究表明,即使同侧的普脑和丘脑同时发生高血压出血,也不会形成常见的高血压混合型血肿。
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引用次数: 0
Elevated expression of N-myc downstream regulated gene 1 protein in glioblastomas reflects tumor angiogenesis and poor patient prognosis. 胶质母细胞瘤中N-myc下游调控基因1蛋白的高表达反映了肿瘤血管生成和患者预后不良。
IF 1.3 4区 医学 Q4 CLINICAL NEUROLOGY Pub Date : 2024-08-06 DOI: 10.1111/neup.12999
Yasuo Sugita, Takuya Furuta, Kenji Takahashi, Koichi Higaki, Yuichi Murakami, Michihiko Kuwano, Mayumi Ono, Hideyuki Abe, Jun Akiba, Motohiro Morioka

N-myc downstream regulated gene 1 (NDRG1) is a member of the NDRG family, of which four members (NDRG1, NDRG2, NDRG3, and NDRG4) have been identified. NDRG1 is repressed by c-MYC and N-MYC proto-oncogenes. NDRG1 is translated into a 43 kDa protein that is associated with the regulation of cellular stress responses, proliferation, and differentiation. In this study, we aimed to clarify the relationship between progression of glioblastoma (GB) IDH-wildtype and NDRG1 expression in tumor cells. We assessed the expression of NDRG1 in 41 GBs using immunostaining and evaluated its prognostic significance. NDRG1 expression by GBs was evaluated using Histoscore, which showed high and low scores in 23 and 18 cases, respectively. NDRG1-positive cells were strongly expressed in Ki-67 labeled proliferating tumor cells and CD105 positive proliferating microvessels around the area of palisading necrosis. Statistical analyses showed lower survival rates in the high-score group than the low-score group (P < 0.01). This study indicated that overexpression of NDRG1 by GB reflects tumor angiogenesis and poor patient prognosis.

N-myc 下游调控基因 1(NDRG1)是 NDRG 家族的一个成员,目前已发现其四个成员(NDRG1、NDRG2、NDRG3 和 NDRG4)。NDRG1 受 c-MYC 和 N-MYC 原癌基因的抑制。NDRG1 翻译成 43 kDa 蛋白,与细胞应激反应、增殖和分化的调控有关。本研究旨在阐明胶质母细胞瘤(GB)IDH-野生型的进展与肿瘤细胞中 NDRG1 表达之间的关系。我们使用免疫染色法评估了 41 例 GB 中 NDRG1 的表达,并评估了其预后意义。用Histoscore评估了GB的NDRG1表达情况,结果显示高分和低分的病例分别为23例和18例。NDRG1阳性细胞在Ki-67标记的增殖肿瘤细胞和悸动坏死区周围CD105阳性的增殖微血管中强表达。统计分析显示,高分辨率组的生存率低于低分辨率组(P
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引用次数: 0
A case of disseminated spinal astroblastoma harboring a MAMLD1::BEND2 fusion. 一例携带 MAMLD1::BEND2 融合基因的播散性脊柱星形母细胞瘤。
IF 1.3 4区 医学 Q4 CLINICAL NEUROLOGY Pub Date : 2024-08-01 Epub Date: 2023-12-21 DOI: 10.1111/neup.12960
Erin N Walker, Maxwell T Laws, Francesca Cozzi, Martha Quezado, Desmond A Brown, Eric C Burton

Astroblastoma, MN1-altered, is a rare neoplasm of the central nervous system (CNS). This malignancy shares similar histopathological features with other CNS tumors, including ependymomas, making it challenging to diagnose. DNA methylation profiling is a new and robust technique that may be used to overcome this diagnostic hurdle. We report the case of a now 25-year-old female diagnosed with what was initially called an ependymoma located in the cervical spine at the age of 2 years old. After initial resection, the tumor recurred multiple times and within 2 years of diagnosis had disseminated disease throughout the brain and spinal cord. She has now undergone over two decades of treatment, including multiple surgical resections, radiation therapy, and administration of numerous chemotherapeutic agents. In 2021, the patient presented to our institution with lumbosacral radicular symptoms due to enlarging lesions within the lumbosacral spine. Reexamination of formalin-fixed, paraffin-embedded material from the patient's tumor using genomic DNA methylation profiling resulted in a diagnostic change from grade III anaplastic ependymoma to astroblastoma, MN1-altered. This work describes another confirmed case of astroblastoma, MN1-altered, to the growing body of literature.

星形母细胞瘤(MN1-altered)是一种罕见的中枢神经系统(CNS)肿瘤。这种恶性肿瘤与其他中枢神经系统肿瘤(包括上皮瘤)具有相似的组织病理学特征,因此诊断难度很大。DNA甲基化分析是一种新的、强大的技术,可用于克服这一诊断障碍。我们报告了一例现年 25 岁的女性病例,她在两岁时被诊断为颈椎上皮瘤。在最初的切除术后,肿瘤多次复发,并在确诊后的两年内扩散到整个大脑和脊髓。目前,她已接受了二十多年的治疗,包括多次手术切除、放射治疗和多种化疗药物的应用。2021 年,患者因腰骶部病变扩大而出现腰骶神经根症状来我院就诊。通过基因组 DNA 甲基化分析对患者肿瘤的福尔马林固定石蜡包埋材料进行复查后,诊断结果从 III 级无弹性上皮瘤转变为星形母细胞瘤,MN1 改变。这项研究为日益增多的文献提供了又一例星形母细胞瘤(MN1-altered)确诊病例。
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引用次数: 0
Corticobasal degeneration with visual hallucination as an initial symptom: A case report. 以视幻觉为首发症状的皮质基底层变性:病例报告。
IF 1.3 4区 医学 Q4 CLINICAL NEUROLOGY Pub Date : 2024-08-01 Epub Date: 2024-01-30 DOI: 10.1111/neup.12963
Kentaro Yoshida, Tadashi Adachi, Yuki Suzuki, Mayuko Sakuwa, Hiroki Fukuda, Masato Hasegawa, Yoshiki Adachi, Hiroshi Miura, Ritsuko Hanajima

Although the initial symptoms of corticobasal degeneration (CBD) are varied, psychiatric symptoms are uncommon. Here, we report the autopsy findings of a patient with early CBD who presented with hallucinations. A 68-year-old man developed memory loss and visions of bears and insects. Because of slow vertical eye movement, postural instability, and levodopa-unresponsive parkinsonism, the patient initially was clinically diagnosed with progressive supranuclear palsy. He died of a urinary tract infection 11 months after the onset of the disease. Histopathological examination revealed neuronal loss and gliosis, which were severe in the substantia nigra and moderate in the globus pallidus and subthalamic nucleus. Astrocytic plaques were scattered throughout the amygdala and premotor cortex. The superficial cortical layers lacked ballooned neurons and spongiosis, and tau deposition was greater in glia than in neurons. The amygdala contained a moderate number of argyrophilic grains and pretangles. Western blot analysis showed a 37-kDa band among the low-molecular-weight tau fragments. Because the CBD pathology was mild, we attributed the patient's visual hallucinations to the marked argyrophilic grain pathology. CBD can occur with psychiatric symptoms, including visual hallucinations, and argyrophilic grain pathology may be associated with psychiatric symptoms.

虽然皮质基底层变性(CBD)的初期症状多种多样,但精神症状并不常见。在此,我们报告了一名出现幻觉的早期CBD患者的尸检结果。一名 68 岁的男子出现记忆力减退,并幻觉到熊和昆虫。由于患者的眼球垂直运动缓慢、姿势不稳和左旋多巴无反应性帕金森病,临床上最初诊断为进行性核上性麻痹。发病 11 个月后,他死于尿路感染。组织病理学检查显示,黑质神经元缺失和胶质增生严重,球状苍白球和丘脑下核中度缺失和胶质增生。星形胶质细胞斑块散布在杏仁核和前运动皮层。皮质浅层缺乏气球状神经元和海绵状血管增生,胶质细胞中的tau沉积多于神经元。杏仁核中含有一定数量的嗜杏仁颗粒和前角质层。Western 印迹分析显示,低分子量 tau 片段中有一条 37 kDa 的条带。由于CBD病变较轻,我们将患者的视幻觉归因于明显的霰粒细胞病变。CBD可伴有包括视幻觉在内的精神症状,而嗜碱性颗粒病理可能与精神症状有关。
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引用次数: 0
An autopsy case of MV 2K + C subtype of Creutzfeldt-Jakob disease. 一例克雅氏病 MV 2K + C 亚型尸检病例。
IF 1.3 4区 医学 Q4 CLINICAL NEUROLOGY Pub Date : 2024-08-01 Epub Date: 2024-02-14 DOI: 10.1111/neup.12964
Akiko Uchino, Yuko Saito, Sho Tokuda, Yagishita Saburo, Shigeo Murayama, Kazuko Hasegawa

Methionine/valine (MV) 2 type of sporadic Creutzfeldt-Jakob (sCJD) is divided into three subtypes based on neuropathological criteria: MV2-kuru (MV2K), MV2-cortical (MV2C), and MV2K + C, exhibiting the co-occurrence of these two pathological features. We report an autopsy case of MV2K + C subtype of sCJD. A 46-year-old Japanese man began to make mistakes at work. Two months later, he gradually developed gait instability. The initial neurological examination revealed limb ataxia and myoclonus. Diffusion-weighted images (DWI) showed a hyperintensity in the right frontal cortex, basal ganglia, and thalamus. Ten months after the onset of disease, he fell into akinetic mutism. He died at 47 years of age, 12 months after the initial presentation. Pathological investigation revealed microvacuolation and confluent vacuoles in the cerebral cortex. In the basal ganglia and thalamus, there was severe neuronal loss and gliosis with mild spongiform change. Kuru plaques were found within the cerebellum. Prion protein (PrP) immunostaining revealed synaptic, perivacuolar, perineuronal, and plaque-like deposits in the cerebral cortex. There were synaptic and plaque-like PrP deposits in the basal ganglia, thalamus, and granular cell layer of the cerebellum. In these areas, plaque-like deposits mainly consisted of small deposits, whereas plaque-like deposits in the cerebral cortex consisted both of coarse granular and small deposits. Analysis of the PrP gene showed no pathogenic mutations, and Western blot examination revealed a mixture of type 2 and intermediate-type PrP. The progressive cognitive decline and ataxia in addition to the hyperintensity in the basal ganglia and/or thalamus on DWI are the basis for clinical diagnosis of MV2. The severe gliosis in the basal ganglia and various morphologies of plaque-like deposits that differ by the region may be characteristic of MV2K + C. Detailed neuropathological examination together with Western blot analysis is important to collect more cases for elucidating the pathogenesis of MV2K + C.

蛋氨酸/缬氨酸(MV)2 型散发性克雅氏病(sCJD)根据神经病理学标准分为三个亚型:MV2-库鲁型(MV2K)、MV2-皮层型(MV2C)和MV2K + C型这两种病理特征同时存在。我们报告了一例尸检发现的 MV2K + C 亚型 sCJD 病例。一名 46 岁的日本男子开始在工作中犯错。两个月后,他逐渐出现步态不稳。最初的神经系统检查显示他有肢体共济失调和肌阵挛。弥散加权成像(DWI)显示右侧额叶皮层、基底节和丘脑出现高密度。发病 10 个月后,他陷入了运动性缄默症。初次发病 12 个月后,他在 47 岁时去世。病理检查发现,大脑皮层有微小空泡和汇合空泡。基底节和丘脑出现严重的神经元缺失和胶质增生,并伴有轻微的海绵样变。小脑中发现了库鲁斑。朊病毒蛋白(PrP)免疫染色显示,大脑皮层出现突触、小脑周围、神经元周围和斑块样沉积。基底节、丘脑和小脑颗粒细胞层有突触和斑块样PrP沉积。在这些区域,斑块样沉积物主要由小沉积物组成,而大脑皮层的斑块样沉积物则由粗颗粒状沉积物和小沉积物组成。PrP基因分析表明没有致病突变,Western印迹检查显示混合了2型和中间型PrP。除了基底节和/或丘脑在 DWI 上的高密度外,进行性认知能力下降和共济失调也是 MV2 临床诊断的依据。基底节严重胶质增生和不同区域不同形态的斑块样沉积物可能是 MV2K + C 的特征。详细的神经病理学检查和 Western 印迹分析对于收集更多病例以阐明 MV2K + C 的发病机制非常重要。
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引用次数: 0
Neuropilin-1 enhances temozolomide resistance in glioblastoma via the STAT1/p53/p21 axis. 神经蛋白-1通过STAT1/p53/p21轴增强胶质母细胞瘤对替莫唑胺的耐药性
IF 1.3 4区 医学 Q4 CLINICAL NEUROLOGY Pub Date : 2024-08-01 Epub Date: 2024-03-06 DOI: 10.1111/neup.12966
Ping Huang, Lixia Zhang, Hongwei Wang, Changwu Dou, Haitao Ju, Peng Yue, Jiaxing Ren

Glioblastoma (GBM) is the most prevalent primary intracranial tumor. Temozolomide (TMZ) is the first-line chemotherapy for GBM. Nonetheless, the development of TMZ resistance has become a main cause of treatment failure in GBM patients. Evidence suggests that neuropilin-1 (NRP-1) silencing can attenuate GBM cell resistance to TMZ. This study aims to determine potential mechanisms by which NRP-1 affects TMZ resistance in GBM. The parental U251 and LN229 GBM cells were exposed to increasing concentrations of TMZ to construct TMZ-resistant GBM cells (U251/TMZ, LN229/TMZ). BALB/c nude mice were injected with U251/TMZ cells to establish the xenograft mouse model. Functional experiments were carried out to examine NRP-1 functions. Western blotting and real-time quantitative polymerase chain reaction were used to evaluate molecular protein and mRNA expression, respectively. Immunohistochemical staining showed NRP-1 and STAT1 expression in mouse tumors. The results showed that NRP-1 was highly expressed in TMZ-resistant cells. Moreover, knocking down NRP-1 attenuated the TMZ resistance of U251/TMZ cells, while upregulating NRP-1 enhanced TMZ resistance of the parental cells. NRP-1 silencing elevated GBM cell sensitivity to TMZ in tumor-bearing mice. Depleting NRP-1 reduced STAT1, p53, and p21 expression in U251/TMZ cells. STAT1 depletion offset NRP-1 silencing evoked attenuation of GBM cell resistance to TMZ. Collectively, our study reveals that NRP-1 enhances TMZ resistance in GBM possibly by regulating the STAT1/p53/p21 axis.

胶质母细胞瘤(GBM)是最常见的原发性颅内肿瘤。替莫唑胺(TMZ)是治疗 GBM 的一线化疗药物。然而,TMZ 耐药性的产生已成为 GBM 患者治疗失败的主要原因。有证据表明,沉默神经蛋白1(NRP-1)可减轻GBM细胞对TMZ的耐药性。本研究旨在确定 NRP-1 影响 GBM 细胞 TMZ 耐药性的潜在机制。将亲本 U251 和 LN229 GBM 细胞暴露于浓度不断增加的 TMZ,以构建 TMZ 抗性 GBM 细胞(U251/TMZ、LN229/TMZ)。给 BALB/c 裸鼠注射 U251/TMZ 细胞,建立异种移植小鼠模型。进行了功能实验以检测 NRP-1 的功能。分别使用 Western 印迹和实时定量聚合酶链反应评估分子蛋白和 mRNA 的表达。免疫组化染色显示了小鼠肿瘤中 NRP-1 和 STAT1 的表达。结果显示,NRP-1在TMZ耐药细胞中高表达。此外,敲除NRP-1可减轻U251/TMZ细胞对TMZ的耐药性,而上调NRP-1可增强亲代细胞对TMZ的耐药性。在肿瘤小鼠体内,沉默NRP-1可提高GBM细胞对TMZ的敏感性。消耗 NRP-1 可减少 U251/TMZ 细胞中 STAT1、p53 和 p21 的表达。STAT1 的消耗抵消了 NRP-1 的沉默,从而削弱了 GBM 细胞对 TMZ 的耐药性。总之,我们的研究揭示了NRP-1可能通过调节STAT1/p53/p21轴增强了GBM对TMZ的耐药性。
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引用次数: 0
From pathological mechanisms in Krabbe disease to cutting-edge therapy: A comprehensive review. 从克拉伯病的病理机制到前沿疗法:全面回顾。
IF 1.3 4区 医学 Q4 CLINICAL NEUROLOGY Pub Date : 2024-08-01 Epub Date: 2024-03-06 DOI: 10.1111/neup.12967
Imen Ketata, Emna Ellouz

Since its initial documentation by Knud Krabbe in 1916, numerous studies have scrutinized the characteristics of Krabbe disease (KD) until the identification of the mutation in the GALC gene. In alignment with that, we investigated the natural history of KD spanning eight decades to gain a deeper understanding of the evolutionary trajectory of its mechanisms. Through our comprehensive analysis, we unearthed additional novel elements in molecular biology involving the micropathological mechanism of the disease. This review offers an updated perspective on the metabolic disorder that defines KD. Recently, extracellular vesicles (EVs), autophagy impairment, and α-synuclein have emerged as pivotal players in the neuropathological processes. EVs might serve as a cellular mechanism to avoid or alleviate the detrimental impacts of excessive toxic psychosine levels, and extracting EVs could contribute to synapse dysfunction. Autophagy impairment was found to be independent of psychosine and reliant on AKT and B-cell lymphoma 2. Additionally, α-synuclein has been recognized for inducing cellular death and dysfunction in common biological pathways. Our objective is to assess the effectiveness of advanced therapies in addressing this particular condition. While hematopoietic stem cells have been a primary treatment, its administration proves challenging, particularly in the presymptomatic phase. In this review, we have compiled information from over 10 therapy trials, comparing them based on their benefits and disadvantage.

自从克努德-克拉伯(Knud Krabbe)于 1916 年首次记录克拉伯病(KD)以来,直到 GALC 基因突变被确认之前,已有大量研究对克拉伯病(KD)的特征进行了仔细研究。为此,我们研究了 KD 长达八十年的自然史,以深入了解其机制的演变轨迹。通过全面分析,我们发现了涉及该病微观病理机制的分子生物学新元素。这篇综述从一个最新的角度阐述了 KD 的代谢紊乱。最近,细胞外囊泡(EVs)、自噬功能障碍和α-突触核蛋白已成为神经病理过程中的关键因素。EVs可能是一种细胞机制,可避免或减轻过量有毒精神氨酸的有害影响,而提取EVs可能会导致突触功能障碍。研究发现,自噬损伤与精神卫生碱无关,而依赖于 AKT 和 B 细胞淋巴瘤 2。此外,α-突触核蛋白已被认为可诱导细胞死亡和常见生物通路的功能障碍。我们的目标是评估先进疗法在治疗这一特殊疾病方面的有效性。虽然造血干细胞一直是一种主要的治疗方法,但事实证明,特别是在无症状阶段,使用造血干细胞具有挑战性。在这篇综述中,我们汇编了10多项治疗试验的信息,并根据其利弊进行了比较。
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Neuropathology
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