ALBERT

Description: Author(s): Bohm-Jung Yang, Mohammad Saeed Bahramy, Ryotaro Arita, Hiroki Isobe, Eun-Gook Moon, and Naoto Nagaosa We construct a general theory describing the topological quantum phase transitions in 3D systems with broken inversion symmetry. While the consideration of the system’s codimension generally predicts the appearance of a stable metallic phase between the normal and topological insulators, it is shown... [Phys. Rev. Lett. 110, 086402] Published Tue Feb 19, 2013

Description: Author(s): Bohm-Jung Yang and Naoto Nagaosa [Phys. Rev. B 84, 245123] Published Mon Dec 19, 2011

Description: Author(s): Bohm-Jung Yang and Naoto Nagaosa Because of the recent development of thin film and artificial superstructure growth techniques, it is possible to control the dimensionality of the system, smoothly between two and three dimensions. In this Letter we unveil the dimensional crossover of emergent topological phenomena in correlated to... [Phys. Rev. Lett. 112, 246402] Published Wed Jun 18, 2014

Description: Abstract 5 Wiskott Aldrich Syndrome is a life-threatening immune-disorder characterized by bleeding secondary to microthrombocytopenia, immunodeficiency, autoimmunity, and susceptibility to lymphoma. A clinical gene therapy protocol using a GALV pseudotyped MLV-derived retroviral vector was developed at Hannover Medical School. We here present an analysis of ten patients treated in this trial between 2006 and 2009. All patients had evidence of engraftment of WASP-positive hematopoietic progenitor cells except for one patient in whom an insufficient number of CD34+ cells could be harvested. WASP expression was determined in myeloid and lymphoid cells as well as in CD34+ hematopoietic progenitor cells using Western Blot and FACS analysis, respectively. While the percentage of WASP-positive myeloid cells was relatively stable over time (range 10 to 60%), a marked increase over time in the percentage of WASP-positive T lymphocytes and NK cells was observed, resulting in more than 80% of WASP-positive lymphoid cells 12 months after gene therapy. Early after gene therapy, an increase in thrombocyte counts was observed in all patients. Furthermore, the majority of peripheral thrombocytes showed evidence of WASP expression, detectable as early as 3 months after gene therapy. Functional immune reconstitution was documented in dendritic cells (podosome formation), T cells (proliferation in response to CD3-signaling), and NK cells (formation of immunological synapse and NK cell killing activity). TCR Vb spectratyping analyses showed in improvement of receptor skewing upon gene therapy in some patients. A clinical benefit was notable in all patients with the exception of the patients with insufficient engraftment of genetically corrected progenitor cells: eczema, bleeding diathesis and immunodeficiency resolved. Strikingly, the various autoimmune phenomena which the patients in this trial had shown prior to gene therapy resolved when the majority of T lymphocytes were positive for WASP expression, and a particular advantage of WASP-positive regulatory T lymphocytes (Tregs) could be observed at this point, suggesting a crucial role in WASP reconstitution in Tregs for autoimmnity resolution. Repetitive bone marrow examinations did not reveal morphological or cytogenetic alterations. Comprehensive insertion site analysis using 454 pyrosequencing demonstrated vector integration that targeted multiple genes controlling growth, development and immunological responses in a persistently polyclonal hematopoiesis. In sum, hematopoietic stem cell gene therapy for Wiskott-Aldrich Syndrome is feasible and effective at correcting the various cellular defects implicated in this disease. Our trial provides the first proof-of-principle for gene therapy in Wiskott-Aldrich syndrome and provides evidence that gene therapy may be effective at correcting disorders involving autoimmunity and/or platelets. Prospective monitoring is used in this trial to determine the long-term efficacy and safety profile of this experimental therapeutic approach in Wiskott-Aldrich syndrome. Disclosures: No relevant conflicts of interest to declare.

Description: Abstract 2141 Acute myeloid leukemia (AML), one of the most common leukemia in adults, is characterized by the accumulation of abnormal white blood cells in the bone marrow. Even with modern advances in therapeutics and molecular diagnostics, the majority of AML patients die from their disease. Angiogenesis contributes to the development of hematologic malignancies, although its role has not been as clearly defined in hematologic malignancies as in solid tumors. In the present study we have determined antitumoral activity of two well-known inhibitors of angiogenesis. Sorafenib, a small molecule inhibitor affecting inter alia the VEGF pathway (100mg/kg/day (d); applied 12 consecutive days) and Cetuximab, a chimeric antibody against human EGFR (30 mg/kg/d; applied once weekly for 3 weeks) were evaluated in comparison to Etoposide, a topoisomerase II inhibitor (24mg/kg/day; applied 3 consecutive days) as a well established compound in AML treatment regimens in comparison with a control group. Equal parts of HL-60 cells were injected intravenously and into the peritoneal cavity of NOD/SCID mice and respective therapies were started 14 days after implantation. Tumor growth was monitored by a) daily monitoring of AML symptoms, and b) weekly fluorescence-based in vivo imaging (FI) using a Alexa750-labeled anti-human CD45 antibody and c) verification of the FI data by histological examination of bone marrow and spleen at the end of the study. Tumor inhibition was calculated as the proportional reduction of mean AML cell infiltration at the respective compartment of the test- compared to the control-group (in %). HL-60 cells engrafted predominantly in bone marrow (BM; take rate = 100%), but were as well detectable in the spleen (30%). At the respective doses and schedules the examined compounds were well tolerated in tumor-bearing mice. No acute toxicity could be observed and maximal body weight loss was below 15%. Tumor development was clearly reduced by Cetuximab (reduction of 53% vs control), albeit to a lesser extend then Sorafenib (reduction of 99% vs control), which induced a complete remission within the treatment period. Treatment of Etoposide induced no markable tumor growth inhibition (reduction of 10% vs control). Thus, HL-60 cells engrafted in NOD/SCID mice representing a valuable in vivo model for AML which exhibits high reproducibility and take-rates in relevant compartments closely mimicking the clinical situation. Collection of whole-body FI data proved to be a time- and animal-saving analysis that allows to closely monitor AML growth. With regard to the demographic development, AML will be more and more a disease of the elderly. Thus, development of new therapeutic options compared to high-dose chemotherapy will be highly required. As the VEGF and EGFR pathways are closely related, further investigations will include the evaluation of potentially synergistic effects in combination of Sorafenib with Cetuximab in human disseminated AML xenograft models. Disclosures: No relevant conflicts of interest to declare.

Description: Abstract 1418 Introduction: Presence of minimal residual disease (MRD) after induction therapy predicts risk of relapse in AML (San Miguel JF et al 2001). Furthermore, achievement of complete remission (CR) rather than CR with incomplete platelet recovery (CRp) (defined using standard morphologic criteria) after induction therapy is independently associated with shorter relapse-free survival (Walter RB et al 2010). These results suggest a correlation between peripheral blood count recovery at the time of morphologic remission and MRD; however, this has not been documented. Here we address this question and examine whether response and MRD have independent effects on relapse. Patients and methods: We retrospectively analyzed data from 340 adults with AML who achieved CR, CRp or CRi (CR with incomplete peripheral count recovery; cellular marrow with 0 (hazard ratio [HR] 1.85; 95% CI 1.25–2.72; p=0.002) or as a numerical variable (HR 1.15 for each 1% increase; 95% CI 1.06–1.25; p

Description: Abstract 1495 Severe congenital neutropenia (SCN) is a heterogenous group of disorders characterized by an increased susceptibility to bacterial infections. Recently, our discovery of G6PC3 deficiency in 12 patients with SCN and various developmental features highlighted the role of glucose metabolism in the viability of neutrophil granulocytes. To further delineate the molecular and clinical phenotype of this complex syndrome, we analyzed a second cohort of 23 SCN patients referred to us for molecular analysis of G6PC3 mutations. All patients had at least one syndromic feature in addition to congenital neutropenia such as such as congenital heart defects, urogenital malformations or increased venous marking. Among these 23 patients, we identified 14 patients with biallelic mutations in G6PC3. 10 patients had novel mutations in G6PC3. A comprehensive review of the clinical characteristics of these patients underlined the phenotypic variability of G6PC3 deficiency. In addition to known manifestations including cardiac (14/14) and urogenital malformations such as cryptorchidism (3/14), novel features such as facial dysmorphy (11/14) or malformation of the outer genitalia (4/14) were found. No obvious genotype-phenotype correlations could be established. All patients except one had a good response to treatment with G-CSF characterized by increased peripheral neutrophil counts and decreased frequency and severity of infections. To assess the risk of leukemogenesis, we performed a meta-analysis comparing the 14 G6PC3-deficient SCN patients combined with the 12 patients in the original publication with a cohort of 374 patients SCN patients bearing mutations in ELANE or HAX1, in which 61 developed MDS or AML. The rate of MDS/AML was found to be significantly lower in G6PC3-deficient patients (p=0.02). Our analysis suggests that the risk of transition to MDS/AML may be lower in G6PC3-deficient SCN compared with other genetically defined SCN subgroups. Disclosures: No relevant conflicts of interest to declare.