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Niemann-Pick Type C disease (NPC) is a cholesterol storage disease with defects in the intracellular trafficking of exogenous cholesterol derived from low density lipoproteins. In NPC cases with a chronic progressive course, neurofibrillary tangles (NFTs) that consist of paired helical filaments (PHFs) have been reported. To determine if NPC tangles contain abnormal tau proteins (known as PHFtau) similar to those found in Alzheimer's disease (AD) tangles, we examined the brains of five NPC cases by immunohistochemical and Western blot methods using a library of antibodies to defined epitopes of PHFtau. We show here that PHFtau in tangle-rich NPC brains is indistinguishable from PHFtau in AD brains. We speculate, that the generation of PHFtau in NPC may induce a cascade of pathological events that contribute to the widespread degeneration of neurons, and that these events may be similar in NPC and AD.

Hematologic stem cell rescue after highdose cytotoxic therapy is extensively used for the treatment of many hematopoietic and solid cancers. Gene marking studies suggest that occult tumor cells within the autograft may contribute to clinical relapse. To date purging of autografts contaminated with cancer cells has been unsuccessful. The selective oncolytic property of reovirus against myriad malignant histologies in in vitro, in vivo, and ex vivo systems has been previously demonstrated. In the present study we have shown that reovirus can successfully purge cancer cells within autografts. IntroductionAutologous hematopoietic progenitor stem cell (ASC) transplantations following high-dose chemotherapy has gained extensive application as a therapeutic modality in several malignancies. [1][2][3][4][5][6][7] Globally, the number of autologous blood and marrow transplantations now surpasses the number of allotransplantations. [6][7][8] Despite the significant increase in ASC transplantations, controversy still exists as to the contribution of minimal residual disease to the development of relapse after high-dose chemotherapy. Evidence supported by gene marking studies indicates relapse following high-dose ablative therapy followed by ASC transplantation may be due to contaminating cancer cells within the autograft. [9][10][11] It has been estimated that more than 30% of all autografts are contaminated with tumor cells, and this number likely will increase with better detection methodology and increasing use of ASC transplantations in patients with advanced disease.To minimize the number of contaminating tumor cells, a variety of purging techniques to rid the graft of residual tumor cells have been used. The ideal purging technique should preferentially destroy contaminating tumor cells while preserving the number and function of the collected stem cells. Widely cited purging methods of autografts include the use of ex vivo chemotherapy, tumor targeting monoclonal antibodies linked with toxins or selected on immunocolumns, and positive (CD34 ϩ ) selection. 12,13 More recently, photodynamic purging processes, [14][15][16] virus-directed enzyme prodrug therapy, 17 receptor-targeted ligand toxins, 18,19 and attenuated replication-competent virus-based purging techniques 20 have been reported. Yet, to date no method has proved 100% successful in depleting autografts of tumor cells in the clinical setting. Although several studies have suggested that graft manipulation is of clinical benefit, 21-24 until purging techniques lead to a complete eradication of contaminating tumor cells, it will be unclear whether the recurrence of the disease is the result of the contaminating tumor cells or a reflection of a resistant in vivo malignancy or both. In the present study we investigated the use of an unattenuated oncolytic virus, reovirus, as the basis for a novel purging strategy for ASC transplantation.Reovirus is an ubiquitous double-stranded RNA virus that can be isolated from the upper respiratory and gastrointestinal tract...

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