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Moratto D.,University of Brescia | Giliani S.,University of Brescia | Bonfim C.,Federal University of Paraná | Mazzolari E.,Spedali Civili | And 30 more authors.
Blood | Year: 2011

In this retrospective collaborative study, we have analyzed long-term outcome and donor cell engraftment in 194 patients with Wiskott-Aldrich syndrome (WAS) who have been treated by hematopoietic cell transplantation (HCT) in the period 1980-2009. Overall survival was 84.0% and was even higher (89.1% 5-year survival) for those who received HCT since the year 2000, reflecting recent improvement of outcome after transplantation from mismatched family donors and for patients who received HCT from an unrelated donor at older than 5 years. Patients who went to transplantation in better clinical conditions had a lower rate of post-HCT complications. Retrospective analysis of lineage-specific donor cell engraftment showed that stable full donor chimerism was attained by 72.3% of the patients who survived for at least 1 year after HCT. Mixed chimerism was associated with an increased risk of incomplete reconstitution of lymphocyte count and post-HCT autoimmunity, and myeloid donor cell chimerism < 50% was associated with persistent thrombocytopenia. These observations indicate continuous improvement of outcome after HCT for WAS and may have important implications for the development of novel protocols aiming to obtain full correction of the disease and reduce post-HCT complications. © 2011 by The American Society of Hematology.


Booth C.,Institute of Child Health | Gilmour K.C.,Institute of Child Health | Veys P.,Institute of Child Health | Gennery A.R.,Northumbria University | And 43 more authors.
Blood | Year: 2011

X-linked lymphoproliferative disease (XLP1) is a rare immunodeficiency characterized by severe immune dysregulation and caused by mutations in the SH2D1A/SAP gene. Clinical manifestations are varied and include hemophagocytic lymphohistiocytosis (HLH), lymphoma and dysgammaglobulinemia, often triggered by Epstein-Barr virus infection. Historical data published before improved treatment regimens shows very poor outcome. We describe a large cohort of 91 genetically defined XLP1 patients collected from centers worldwide and report characteristics and outcome data for 43 patients receiving hematopoietic stem cell transplant (HSCT) and 48 untransplanted patients. The advent of better treatment strategies for HLH and malignancy has greatly reduced mortality for these patients, but HLH still remains the most severe feature of XLP1. Survival after allogeneic HSCT is 81.4% with good immune reconstitution in the large majority of patients and little evidence of posttransplant lymphoproliferative disease. However, survival falls to 50% in patients with HLH as a feature of disease. Untransplanted patients have an overall survival of 62.5% with the majority on immunoglobulin replacement therapy, but the outcome for those untransplanted after HLH is extremely poor (18.8%). HSCT should be undertaken in all patients with HLH, because outcome without transplant is extremely poor. The outcome of HSCT for other manifestations of XLP1 is very good, and if HSCT is not undertaken immediately, patients must be monitored closely for evidence of disease progression. © 2011 by The American Society of Hematology.


Speckmann C.,Albert Ludwigs University of Freiburg | Lehmberg K.,University of Hamburg | Albert M.H.,Dr. von Haunersches Kinderspital | Damgaard R.B.,Novo Nordisk AS | And 28 more authors.
Clinical Immunology | Year: 2013

X-linked inhibitor of apoptosis (XIAP) deficiency caused by mutations in BIRC4 was initially described in patients with X-linked lymphoproliferative syndrome (XLP) who had no mutations in SH2D1A. In the initial reports, EBV-associated hemophagocytic lymphohistiocytosis (HLH) was the predominant clinical phenotype. Among 25 symptomatic patients diagnosed with XIAP deficiency, we identified 17 patients who initially presented with manifestations other than HLH. These included Crohn-like bowel disease (n. =. 6), severe infectious mononucleosis (n. =. 4), isolated splenomegaly (n. =. 3), uveitis (n. =. 1), periodic fever (n. =. 1), fistulating skin abscesses (n. =. 1) and severe Giardia enteritis (n. =. 1). Subsequent manifestations included celiac-like disease, antibody deficiency, splenomegaly and partial HLH. Screening by flow cytometry identified 14 of 17 patients in our cohort. However, neither genotype nor protein expression nor results from cell death studies were clearly associated with the clinical phenotype. Only mutation analysis can reliably identify affected patients. XIAP deficiency must be considered in a wide range of clinical presentations. © 2013 Elsevier Inc.


Rudnik-Schoneborn S.,RWTH Aachen | Senderek J.,RWTH Aachen | Senderek J.,Ludwig Maximilians University of Munich | Jen J.C.,University of California at Los Angeles | And 24 more authors.
Neurology | Year: 2013

Objectives: Pontocerebellar hypoplasia with spinal muscular atrophy, also known as PCH1, is a group of autosomal recessive disorders characterized by generalized muscle weakness and global developmental delay commonly resulting in early death. Gene defects had been discovered only in single patients until the recent identification of EXOSC3 mutations in several families with relatively mild course of PCH1.We aim to genetically stratify subjects in a large and well-defined cohort to define the clinical spectrum and genotypephenotype correlation. Methods: We documented clinical, neuroimaging, and morphologic data of 37 subjects from 27 families with PCH1. EXOSC3 gene sequencing was performed in 27 unrelated index patients of mixed ethnicity. Results: Biallelic mutations in EXOSC3 were detected in 10 of 27 families (37%). The most common mutation among all ethnic groups was c.395A>C, p.D132A, responsible for 11 (55%) of the 20 mutated alleles and ancestral in origin. The mutation-positive subjects typically presented with normal pregnancy, normal birth measurements, and relative preservation of brainstemand cortical structures. Psychomotor retardation was profound in all patients but lifespan was variable, with 3 subjects surviving beyond the late teens. Abnormal oculomotor function was commonly observed in patients surviving beyond the first year. Major clinical features previously reported in PCH1, including intrauterine abnormalities, postnatal hypoventilation and feeding difficulties, joint contractures, and neonatal death,were rarely observed inmutation-positive infants but were typical among themutation-negative subjects. Conclusion: EXOSC3 mutations account for 30%-40% of patients with PCH1 with variability in survival and clinical severity that is correlated with the genotype. © 2013 American Academy of Neurology.


Strauss A.,Dr. von Haunersches Kinderspital | Herbert B.,Dr. von Haunersches Kinderspital | Mitschek C.,Bayerisches Landesamt fur Gesundheit und Lebensmittelsicherheit | Duvinage K.,Dr. von Haunersches Kinderspital | Koletzko B.,Dr. von Haunersches Kinderspital
Bundesgesundheitsblatt - Gesundheitsforschung - Gesundheitsschutz | Year: 2011

The high prevalence of childhood obesity necessitates broadly effective prevention measures. A behavioral program for children in daycare settings was developed, and its effects were assessed in a 2-year cluster randomized controlled trial. A total of 64 daycare settings were cluster randomized in a 2:1 ratio to intervention and control in order to assess the effects of the program. Samples of 1318 and 1340 children were assessed after 5.7±2.6 and 17.6±2.3 months. Main outcome measures were prevalence of high fruit and vegetable consumption and of low consumption of high caloric drinks at home assessed by parental questionnaires. TigerKids achieved a significantly higher prevalence of high home consumption of fruits (66.6 vs. 55.7%, p<0.0001) and vegetables (42.7 vs. 33.6%, p=0.001) as well as a lower frequency of high consumption of energy rich beverages (47.7 vs. 60.4%, p<0.0001). The TigerKids group tended to show a lower prevalence of overweight (13.9 vs. 18.0%, p=0.05) and obesity (3.4 vs. 5.4%, p=0.07) in the first year. TigerKids is a low cost program applied in daycare settings which achieves significant behavioral changes in the home environment. © 2011 Springer Medizin Verlag.


Ehrhardt H.,Helmholtz Center Munich | Ehrhardt H.,Ludwig Maximilians University of Munich | Schrembs D.,Helmholtz Center Munich | Moritz C.,Helmholtz Center Munich | And 5 more authors.
Blood | Year: 2011

Application of anthracyclines and Vinca alkaloids on the same day represents a hallmark of polychemotherapy protocols for hematopoietic malignancies. Here we show, for the first time, that both drugs might act most efficiently if they are applied on different days. Proof-of-concept studies in 18 cell lines revealed that anthracyclines inhibited cell death by Vinca alkaloids in 83% of cell lines. Importantly, in a preclinical mouse model, doxorubicin reduced the anti-tumor effect of vincristine. Both drugs acted in a sequencedependent manner and the strongest anti-tumor effect was obtained if both drugs were applied on different days. Most notably for clinical relevance, in 34% of 35 fresh primary childhood leukemia cells tested in vitro, doxorubicin reduced the anti-tumor effect of vincristine. As underlying mechanism, doxorubicin activated p53, p53 induced cell-cycle arrest, and cell-cycle arrest disabled inactivation of antiapoptotic Bcl-2 family members by vincristine; therefore, vincristine was unable to activate downstream apoptosis signaling. As molecular proof, antagonism was rescued by knockdown of p53, whereas knockdown of cyclin A inhibited vincristine-induced apoptosis. Our data suggest evaluating anthracyclines and Vinca alkaloids on different days in future trials. Selecting drug combinations based on mechanistic understanding represents a novel conceptional strategy for potent polychemotherapy protocols. © 2011 by The American Society of Hematology.


Magg T.,Dr. von Haunersches Kinderspital | Mannert J.,Dr. von Haunersches Kinderspital | Ellwart J.W.,Helmholtz Center for Environmental Research | Schmid I.,Dr. von Haunersches Kinderspital | Albert M.H.,Dr. von Haunersches Kinderspital
European Journal of Immunology | Year: 2012

The transcriptional regulator FOXP3 is an important determinant of regulatory T (Treg) cell development and function and is frequently used to quantitate Treg cells. However, FOXP3 is also expressed in recently activated conventional human T cells. Here, we investigated the FOXP3 expression patterns in Treg and activated T cells at a cellular level. Upon activation, human CD4 +CD25 - T cells expressed FOXP3 mainly in the cytoplasm, in sharp contrast to human CD4 +CD25 + Treg cells, where we found FOXP3 to be predominantly expressed in the nucleus. A GFP-FOXP3-fusion protein shuttled from the nucleus to the cytoplasm in transfected primary human T cells. We identified two novel leucine-rich nuclear export signals in FOXP3. Site-directed mutagenesis of both sequences completely abolished nuclear export of FOXP3 in human T cells. Both export sequences localized to exons affected by alternative splicing. The three isoforms FOXP3Δ2, FOXP3Δ7, and FOXP3Δ2Δ7 localized preferentially to the nucleus. Additionally, forced expression of nucleus-directed FOXP3 induced a Treg-cell-associated gene expression pattern and induced regulatory capacity. These findings should aid in the interpretation of future studies utilizing FOXP3 expression as a Treg-cell marker and shed some light on the molecular mechanisms controlling subcellular FOXP3 localization in human T cells. © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


PubMed | Humboldtallee, Dr. von Haunersches Kinderspital and University of Gottingen
Type: | Journal: Scientific reports | Year: 2015

The targeting signals and mechanisms of soluble peroxisomal proteins are well understood, whereas less is known about the signals and targeting routes of peroxisomal membrane proteins (PMP). Pex15 and PEX26, tail-anchored proteins in yeast and mammals, respectively, exert a similar cellular function in the recruitment of AAA peroxins at the peroxisomal membrane. But despite their common role, Pex15 and PEX26 are neither homologs nor they are known to follow similar targeting principles. Here we show that Pex15 targets to peroxisomes in mammalian cells, and PEX26 reaches peroxisomes when expressed in yeast cells. In both proteins C-terminal targeting information is sufficient for correct sorting to the peroxisomal membrane. In yeast, PEX26 follows the pathway that also ensures correct targeting of Pex15: PEX26 enters the endoplasmic reticulum (ER) in a GET-dependent and Pex19-independent manner. Like in yeast, PEX26 enters the ER in mammalian cells, however, independently of GET/TRC40. These data show that conserved targeting information is employed in yeast and higher eukaryotes during the biogenesis of peroxisomal tail-anchored proteins.

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