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Inhibiting tau-induced elevated nSMase2 activity and ceramides is therapeutic in an Alzheimer’s disease mouse model

Translational Neurodegeneration 2023年第1期12卷 70-89页

作者： Carolyn Tallon Benjamin j.Bell Medhinee M.Malvankar Pragney Deme Carlos Nogueras-Ortiz Erden eren Ajit G.Thomas Kristen R.Hollinger Arindom Pal Maja Mustapic Meixiang Huang Kaleem Coleman Tawnjerae R.joe Rana Rais Norman j.Haughey Dimitrios Kapogiannis Barbara S.Slusher johns Hopkins Drug Discovery Johns Hopkins University School of MedicineBaltimoreMD 21205USA Neurology Johns Hopkins University School of MedicineBaltimoreMD 21205USA Cell Biology Johns Hopkins University School of MedicineBaltimoreMD 21205USA Oncology Johns Hopkins University School of MedicineBaltimoreMD 21205USA Medicine Johns Hopkins University School of MedicineBaltimoreMD 21205USA Pharmacology and Molecular Sciences Johns Hopkins University School of MedicineBaltimoreMD 21205USA Psychiatry and Behavioral Science Johns Hopkins University School of Medicine855 N.Wolfe StreetRangos 278BaltimoreMD 21205USA Intramural Research Program Laboratory of Clinical InvestigationNational Institute on AgingNational Institutes of Health251 Bayview BlvdSte 8C228BaltimoreMD 21224USA johns Hopkins University School of Medicine 600 N.Wolfe StreetPathology 517BaltimoreMD 21287USA

Background Cognitive decline in Alzheimer’s disease(AD)is associated with hyperphosphorylated tau(pTau)propagation between neurons along synaptically connected networks,in part via extracellular vesicles(EVs).EV biogenesis is triggered by ceramide enrichment at the plasma membrane from neutral sphingomyelinase2(nSMase2)-mediated cleavage of *** report,for the first time,that human tau expression elevates brain ceramides and nSMase2 *** To determine the therapeutic benefit of inhibiting this elevation,we evaluated PDDC,the first potent,selective,orally bioavailable,and brain-penetrable nSMase2 inhibitor in the transgenic PS19 AD mouse ***,we directly evaluated the effect of PDDC on tau propagation in a mouse model where an adeno-associated virus(AAV)encoding P301L/S320F double mutant human tau was stereotaxically-injected unilaterally into the *** contralateral transfer of the double mutant human tau to the dentate gyrus was *** examined ceramide levels,histopathological changes,and pTau content within EVs isolated from the mouse *** Similar to human AD,the PS19 mice exhibited increased brain ceramide levels and nSMase2 activity;both were completely normalized by PDDC *** PS19 mice also exhibited elevated tau immunostaining,thinning of hippocampal neuronal cell layers,increased mossy fiber synaptophysin immunostaining,and glial activation,all of which were pathologic features of human *** treatment reduced these *** plasma of PDDC-treated PS19 mice had reduced levels of neuronal-and microglial-derived EVs,the former carrying lower pTau levels,compared to untreated *** the tau propagation model,PDDC normalized the tau-induced increase in brain ceramides and significantly reduced the amount of tau propagation to the contralateral *** PDDC is a first-in-class therapeutic candidate that normalizes elevated brain ceramides and nSMase2 activity,leading to the slo

关键词： Alzheimer’s disease Extracellular vesicles Neutral sphingomyelinase 2 Tau Ceramide

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肝脏肿瘤的腹腔镜超声检查和活检术:310例经验

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中国微创外科杂志 2005年第2期5卷 127-128页

作者： eren Berber Adella M.Garland Kristen L.Engle Stanley j.Rogers Allan E.Siperstern 陈大伟美国加利福尼亚州旧金山大学外科上海第二医科大学附属新华医院外科上海200092

目的　探讨腹腔镜超声肝脏检查及在其引导下肝脏肿瘤穿刺活检术的价值。　方法　10mm 7 5MHz线性超声探头检查肝脏。18G穿刺针进行穿刺。在腹腔镜和超声波共同引导下,穿刺针经皮刺入肿瘤组织。穿刺时,穿刺针要与超声波的平面平行。　结... 详细信息

目的　探讨腹腔镜超声肝脏检查及在其引导下肝脏肿瘤穿刺活检术的价值。　方法　10mm 7 5MHz线性超声探头检查肝脏。18G穿刺针进行穿刺。在腹腔镜和超声波共同引导下,穿刺针经皮刺入肿瘤组织。穿刺时,穿刺针要与超声波的平面平行。　结果　310例发现肝脏原发或转移性肿瘤 1 080个。穿刺无一例假阴性,无出血性并发症及其他脏器损伤。310例随访 6年,穿刺点无肿瘤种植。　结论　腹腔镜超声波检查能较准确对肝脏进行全面评估。

关键词：腹腔镜超声肝脏肿瘤

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化疗药物抵抗性胎盘滋养层细胞瘤伴肺门淋巴结转移:罕见的转移部位

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世界核心医学期刊文摘（妇产科学分册） 2005年第6期1卷 54-54页

作者： Metindir j. Pak I. Ozdilekcan C. eren E. 王伟华 Dept. of Obstetrics and Gynecology Ankara Oncology Hospital Mithatpas.a Caddesi No:48/12 06420 Kizilay/Ankara Turkey

Placental site trophoblastic tumor (PSTT) is an uncommon variant of gestational trophoblastic diseases. In most cases, disease is confined to the uterus and treated with a simple hysterectomy. However, 30% of these patients will present with metastatic disease. Patients with metastases frequently have progression of disease and die despite aggressive multiagent chemotherapy. We present a case of 33- year- old female with PSTT and metastases to the hilar lymph nodes of the right lung. Primary surgical treatment consisting of abdominal hysterectomy and unilateral salpingo- oophorectomy was followed by six cycles of EMA/CO (etoposide, methotrexate, actinomycin D, cyclophosphamide, and vincristine) chemotherapy. After the completion of chemotherapy, β hCG titers stayed within normal range, but a repeated CT scan of chest revealed enlargement of the hilar lymph nodes. The patient underwent right thoracotomy with hilar lymph nodes resection. The resected nodules were pathologically consistent with primary PSTT. In this case report, we have determined a PSTT with hilar region metastasis other than parenchyma of lung and confirmed the chemoresistant nature of tumor with the guidance of the previous reports.

关键词：肺门淋巴结转移部位胎盘滋养层化疗药物抵抗性足叶乙甙妊娠性肺门区子宫切除术甲氨蝶呤

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