Spinocerebellar ataxia type 1 (SCA1) is a neurodegenerative disease caused by the expansion of a polyglutamine repeat within the disease protein, ataxin 1. To elucidate cellular pathways involved in SCA1, we used DNA microarrays to determine the pattern of gene expression in SCA1 transgenic mice at two specific times in the disease process; 5 weeks, a timepoint prior to onset of pathology, and 12 weeks, at the midpoint of the disease progression. Taking advantage of the availability of three SCA1 transgenic mouse lines, each expressing a different form of ataxin-1, we utilized a strategy that resulted in the identification of a limited number of genes with an altered pattern of expression specific to the development of disease. By comparing the pattern of gene expression in the SCA1 ataxic B05-ataxin-1[82Q] transgenic mouse line with those seen in two non-ataxic lines, A02-ataxin-1[30Q] and K772T-[82Q], nine genes were identified whose expression was consistently altered in the cerebellum of B05[82Q] mice at 5 and 12 weeks of age. Interestingly, five of the genes in this group form a biological cohort centered on glutamate signaling pathways in Purkinje cells.
Use of unrelated donor cord blood (CB) as an alternative stem cell source is increasing, and yet there is little information to guide transplant centers in the unique aspects of the search and selection of CB grafts. There is no mechanism to easily access the global inventory of CB units, nor is the product information provided by all banks standardized. To address these challenges, this manuscript reviews the logistics of the search, selection process, and acquisition of CB grafts as practiced by our center. Topics include who should be considered for a CB search, how to access the global CB inventory, and how to balance total nucleated cell dose and human leukocyte antigen match in unit selection. We discuss aspects of unit quality and other graft characteristics (processing methods, unit age, availability of attached segments, infectious disease, and hemoglobinopathy screening) to be considered. We incorporate these considerations into a unit selection algorithm, including how to select double-unit grafts. We also describe how we plan for unit shipment and the role of backup grafts. This review aims to provide a framework for CB unit selection and help transplantation centers perform efficient CB searches. (Blood. 2011;117(8):2332-2339) IntroductionUnrelated donor cord blood transplantation (CBT) has become a widely accepted treatment for lethal hematologic diseases. Both the number of CB transplantations 1 and the global inventory of CB units (estimated at 400 000) 2 are growing rapidly. Therefore, it is critically important that transplantation centers (TCs) have a thorough understanding of how to perform a CB search as well as the challenges encountered in the selection and acquisition of CB grafts. This article is a practical guide for the TCs, especially those new to the field of CBT, and is based on our daily experience of searching the global CB inventory, our knowledge of CB banking and CB testing standards, and evaluation of recently published data. Thus, we outline our search practices at Memorial SloanKettering Cancer Center (MSKCC). Who should get a formal CB search with confirmatory HLA typing of CB unitsThere is a progressive decrease in post-transplantation survival with each human leukocyte antigen (HLA) or allele mismatch at HLA-A, -B, -C, -DRB1 loci of adult unrelated donor (URD) grafts, with donor-recipient HLA-DQ disparity being detrimental when present with other mismatches. 3 Therefore, TCs must decide what level of HLA disparity will be tolerated with a URD before alternative hematopoietic stem cell sources such as CB are sought. In addition, as CB grafts are available faster than URD, 4 transplantation urgency may be an additional reason to use CB. Prolonged URD searches are unlikely to result in acquisition of a suitably matched URD if one is not identified early in the search. 5,6 Knowledge of the patient's ancestry is critical given that patients from racial and ethnic minorities (including all those with nonEuropean ancestry) frequently do not have suitably matched URDs, 7 a result...
Allogeneic transplant access can be severely limited for patients of racial and ethnic minorities without suitable sibling donors. Whether cord blood (CB) transplantation can extend transplant access due to the reduced stringency of required HLA-match is not proven. We prospectively evaluated availability of unrelated donors (URD) and CB according to patient ancestry in 553 patients without suitable sibling donors. URDs had priority if adequate donors were available. Otherwise ≥ 4/6 HLA-matched CB grafts were chosen utilizing double units to augment graft dose. Patients had highly diverse ancestries including 35% non-Europeans. In 525 patients undergoing combined searches, 10/10 HLA-matched URDs were identified in 53% of those with European ancestry, but only 21% of patients with non-European origins (p < 0.001). However, the majority of both groups had 5–6/6 CB units. The 269 URD transplant recipients were predominantly European, with non-European patients accounting for only 23%. By contrast, 56% of CB transplant recipients had non-European ancestries (p < 0.001). Of 26 patients without any suitable stem cell source, 73% had non-European ancestries (p < 0.001). Their median weight was significantly higher than CB transplant recipients (p < 0.001), partially accounting for their lack of a CB graft. Availability of CB significantly extends allo-transplant access, especially in non-European patients, and has the greatest potential to provide a suitable stem cell source regardless of race or ethnicity. Minority patients in need of allografts, but without suitable matched sibling donors, should be referred for combined URD and CB searches to optimize transplant access.
Spinocerebellar ataxia type 1 (SCA1) is one of nine inherited neurodegenerative disorders caused by a mutant protein with an expanded polyglutamine tract. Phosphorylation of ataxin‐1 (ATXN1) at serine 776 is implicated in SCA1 pathogenesis. Previous studies, utilizing transfected cell lines and a Drosophila photoreceptor model of SCA1, suggest that phosphorylating ATXN1 at S776 renders it less susceptible to degradation. This work also indicated that oncogene from AKR mouse thymoma (Akt) promotes the phosphorylation of ATXN1 at S776 and severity of neurodegeneration. Here, we examined the phosphorylation of ATXN1 at S776 in cerebellar Purkinje cells, a prominent site of pathology in SCA1. We found that while phosphorylation of S776 is associated with a stabilization of ATXN1 in Purkinje cells, inhibition of Akt either in vivo or in a cerebellar extract‐based phosphorylation assay did not decrease the phosphorylation of ATXN1‐S776. In contrast, immunodepletion and inhibition of cyclic AMP‐dependent protein kinase decreased phosphorylation of ATXN1‐S776. These results argue against Akt as the in vivo kinase that phosphorylates S776 of ATXN1 and suggest that cyclic AMP‐dependent protein kinase is the active ATXN1‐S776 kinase in the cerebellum.
The availability of cord blood (CB) and haploidentical (haplo) donors in all patient populations is not established. We have investigated the addition of haplo-CD34 cells to CB grafts (haplo-CBT) to speed myeloid engraftment. Thus, we have prospectively assessed CB and haplo donor availability in adult patients without 8/8 HLA-allele matched unrelated donors (URDs). Analysis of 89 patients eligible for haplo-CBT revealed 4 distinct patient groups. First, 6 patients (7% of total, 33% non-European) underwent CBT only as they had no suitable family members to type. In group 2, 49 patients (45% non-European) received haplo-CBT using the first haplo donor chosen. Group 3 (n = 21, 76% non-European) underwent CBT with/without haplo. In this group, the first haplo donor chosen failed clearance in 20 patients and transplantation was too urgent to permit donor evaluation in 1. Fifty-three haplo donors were evaluated (2 to 6 per patient) for 21 group 3 patients, and 43 of 53 (81%) haplos failed clearance for predominantly medical and/or psychosocial reasons. Group 4, (n = 13, 85% non-European with a high median weight of 96 kilograms) had no CB grafts with/without no haplo donors. Overall, African patients had the worst donor availability with only 65% having a suitable CB graft and only 44% having a suitable haplo donor. Additionally, in non-European patients, a greater number of haplos required evaluation/patient to secure a suitable haplo graft. Although these data should be confirmed in a larger study, it suggests that there are barriers to the availability of both CB and haplo grafts in adult patients without 8/8 URDs, especially in those with African ancestry, and has multiple practical implications for patient management.
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