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Stevens Point, TX, United States

Qi L.,Soochow University of China | Qi L.,Texas Childrens Cancer Center | Zhang X.-D.,Soochow University of China | Zhang X.-D.,University of Texas M. D. Anderson Cancer Center
Acta Biochimica et Biophysica Sinica | Year: 2014

Mutant N-terminal huntingtin (Htt) protein resulting from Huntington's disease (HD) with expanded polyglutamine accumulates and forms aggregates in vulnerable neurons. Both ubiquitin proteasomal and autophagic pathways contribute to the degradation of mutant Htt. Here, we focus on the involvement of chaperone-mediated autophagy (CMA), a selective form of autophagy in the clearance of Htt. Selective catabolism in CMA is conferred by the presence of a KFERQ-like targeting motif in the substrates, by which molecular chaperones recognize the hydrophobic surfaces of the misfolded substrates, and transfer them to the lysosomal membrane protein type-2A, LAMP-2A. The substrates are taken into the lysosomes through LAMP-2A and are rapidly degraded by the lysosomal enzymes. Taken together, we summarize the recent evidence to elucidate that Htt is also a potential substrate of CMA. We propose that the manipulation of CMA could be a therapeutic strategy for HD.©The Author 2013. Source

Kamdar K.Y.,Methodist Hospital | Kamdar K.Y.,Texas Childrens Cancer Center | Rooney C.M.,Methodist Hospital | Rooney C.M.,Center for Cell and Gene Therapy | And 2 more authors.
Current Opinion in Organ Transplantation | Year: 2011

Purpose of review: Despite contemporary immunosuppressive regimens, posttransplant lymphoproliferative disease (PTLD) remains a major complication after liver transplantation. This review highlights advances in the understanding of the pathophysiology, diagnosis, and management of PTLD in liver transplant recipients. Recent findings: The spectrum of PTLD after liver transplant ranges from polymorphic lymphoproliferation to high-grade monoclonal lymphoma and is usually related to outgrowth of lymphocytes infected with Epstein-Barr virus (EBV). Risk factors for PTLD include EBV-seronegativity of the recipient, young age, intensity of immunosuppression, and the first year posttransplant. Measurement of EBV load by quantitative polymerase chain reaction assays is an important aid in the surveillance and diagnosis of PTLD although the specificity for PTLD is only about 50% (specificity for EBV is ∼100%). In patients diagnosed with PTLD, management options include reduction of immunosuppression, rituximab, combination chemotherapy, and adoptive immunotherapy. Outcomes have improved because rituximab has been incorporated into treatment regimens, and immunotherapy approaches show promise. Summary: PTLD is a significant complication after liver transplantation, particularly in children. Advances in early detection approaches have aided in the diagnosis and management of PTLD, but further research to identify better predictive biomarkers is needed to improve risk-based treatment strategies. © 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins. Source

Smith A.R.,University of Minnesota | Majhail N.S.,University of Minnesota | MacMillan M.L.,University of Minnesota | DeFor T.E.,University of Minnesota | And 4 more authors.
Blood | Year: 2011

Quantifying the risk of hematopoietic cell transplantation (HCT)-related mortality for pediatric patients is challenging. The HCT-specific comorbidity index (HCT-CI) has been confirmed as a useful tool in adults, but has not yet been validated in children. We conducted a retrospective cohort study of 252 pediatric patients undergoing their first allogeneic HCT between January 2008 and May 2009. Pretransplantation comorbidities were scored prospectively using the HCT-CI. Median age at transplantation was 6 years (range, 0.1-20) and median follow-up was 343 days (range, 110-624). HCT-CI scores were distributed as follows: 0, n = 139; 1-2, n = 52; and 3+, n = 61. The 1-year cumulative incidence of nonrelapse mortality (NRM) increased (10%, 14%, and 28%, respectively; P < .01) and overall survival (OS) decreased (88%, 67%, and 62%, respectively; P < .01) with increasing HCT-CI score. Multivariate analysis showed that compared with score 0, those with scores of 1-2 and 3+ had relative risks of NRM of 1.5 (95% confidence interval, 0.5-4.3, P = .48) and 4.5 (95% confidence interval, 1.7-12.1, P < .01), respectively. These results indicate that the HCT-CI score predicts NRM and OS in pediatric patients undergoing HCT and is a useful tool to assess risk, guide counseling in the pretransplantation setting, and devise innovative therapies for the highest risk groups. © 2011 by The American Society of Hematology. Source

Berres M.-L.,Mount Sinai School of Medicine | Berres M.-L.,Tisch Cancer Institute | Berres M.-L.,Immunology Institute | Allen C.E.,Texas Childrens Cancer Center | And 4 more authors.
Advances in Immunology | Year: 2013

Histiocytic disorders represent a group of complex pathologies characterized by the accumulation of histiocytes, an old term for tissue-resident macrophages and dendritic cells. Langerhans cell histiocytosis is the most frequent of histiocytosis in humans and has been thought to arise from the abnormal accumulation of epidermal dendritic cells called Langerhans cells. In this chapter, we discuss the origin and differentiation of Langerhans cells and dendritic cells and present accumulated evidence that suggests that Langerhans cell histiocytosis does not result from abnormal Langerhans cell homeostasis but rather is a consequence of misguided differentiation programs of myeloid dendritic cell precursors. We propose reclassification of Langerhans cell histiocytosis, juvenile xanthogranuloma, and Erdheim-Chester disease as inflammatory myeloid neoplasias. © 2013 Elsevier Inc. Source

Berres M.-L.,Mount Sinai School of Medicine | Berres M.-L.,RWTH Aachen | Merad M.,Mount Sinai School of Medicine | Allen C.E.,Texas Childrens Cancer Center | Allen C.E.,Baylor College of Medicine
British Journal of Haematology | Year: 2015

Langerhans cell histiocytosis (LCH), the most common histiocytic disorder, is characterized by the accumulation of CD1A+/CD207+ mononuclear phagocytes within granulomatous lesions that can affect nearly all organ systems. Historically, LCH has been presumed to arise from transformed or pathologically activated epidermal dendritic cells called Langerhans cells. However, new evidence supports a model in which LCH occurs as a consequence of a misguided differentiation programme of myeloid dendritic cell precursors. Genetic, molecular and functional data implicate activation of the ERK signalling pathway at critical stages in myeloid differentiation as an essential and universal driver of LCH pathology. Based on these findings, we propose that LCH should be re-defined as an inflammatory myeloid neoplasia. Increased understanding of LCH pathogenesis will provide opportunities to optimize and personalize therapy through improved risk-stratification, targeted therapy and assessment of therapy response based on specific molecular features and origin of the pathological myeloid cells. © 2014 John Wiley & Sons Ltd. Source

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