The Gobioninae are a group of morphologically and ecologically diverse Eurasian freshwater cyprinid fishes. The intergeneric relationships of this group are unresolved and the possible monophyly of this subfamily remains to be established. We used complete mitochondrial cytochrome b gene sequences from most genera within the gobionine group, in addition to a selection of cyprinid outgroups, to investigate the possible monophyly of this group and resolve the interrelationships within the group. Our results support the monophyly of the Gobioninae and identify four monophyletic groups within the subfamily; the Hemibarbus group, the Sarcocheilichthys group, the Gobio group, and the Pseudogobio group. The morphologically aberrant genera Gobiobotia, Xenophysogobio and Gobiocypris are included in the Gobioninae, with the latter a sister group of Gnathopogon.
Although immortalized cell lines have been extensively used to optimize treatment strategies in cancer, the usefulness of such in vitro systems to recapitulate primary disease is limited. Therefore, the design of in vivo models ideally utilizing patientderived material is of critical importance. In this regard, NOD.Cg-Prkdc scid IL2rg tmWjl /Sz (NSG) mice have been reported to provide superior engraftment rates. However, limited data exist on the validity of such a model to constitute a surrogate marker for clinical parameters. We studied primary and serial engraftment on more than 200 NSG mice with 54 primary pediatric B cell precursor acute lymphatic leukemia (B-ALL), myeloid leukemia (AML) and T cell leukemia (T-ALL) samples, characterized the leukemogenic profile and correlated engraftment kinetics with clinical outcome. Median time to engraftment was 7-10 weeks and 90% of the mice engrafted. Male recipients conferred significantly higher engraftment levels than female recipients (p 0.004). PCR-based minimal residual disease marker expression and fluorescence in situ hybridization confirmed the presence of patient-specific genetic aberrations in mice. Transcriptome cluster analysis of genes known to be important in the leukemogenesis of all three diseases revealed that well-known tumor-regulating genes were expressed to a comparable extent in mice and men. The extent of engraftment and overall survival of NSG mice highly correlated with the individual prognosis of B-ALL, AML and T-ALL patients. Thus, we propose an in vivo model that provides a valuable preclinical tool to explore the heterogeneity of leukemic disease and exploit patient-tailored leukemia-targeting strategies within multivariate analyses.Over the last decades, remarkable progress has been made in curing childhood acute leukaemia. 1,2 However, the current protocols using intensive poly-chemotherapy induce longterm remission in only 80% of the children and are often associated with significant treatment-related toxicity. Therefore, ongoing research aims to improve therapy for children who are at risk for relapse, while reducing adverse effects in patients with a more favorable prognosis. 3,4 To this end, cultured immortalized cell lines have been widely used to study the characteristics of various malignant stem cell clones or blasts and to evaluate or optimize new treatment strategies. However, the usefulness of such in vitro systems to
To evaluate the human herpes virus 6 (HHV-6) -specific immune response in individuals with chromosomally integrated HHV-6 (ciHHV-6), we measured HHV-6-antigen-specific cytokine responses (interferon-γ, interleukin-2, tumour necrosis factor-α) in T cells by flow cytometry in 12 and 16 individuals with and without ciHHV-6, respectively. All individuals with ciHHV-6 showed HHV-6-specific T cells with higher frequencies of HHV-6-specific CD8(+) cells (0.03-14.93, median 2.15% of CD8(+) cells) compared with non-ciHHV-6 (0.0-10.67, median 0.36%, p 0.026). The observed increased HHV-6-specific functionally active responses in individuals with ciHHV-6 clearly disprove speculations on immune tolerance in ciHHV-6 and indicate clinical and immunological implications of ciHHV-6.
581 Primary refractory or relapsed B-lineage acute lymphoblastic leukemia can be successfully treated by allogeneic stem cell transplantation (SCT). However, relapse remains still a major risk and will be significantly influenced by residual disease prior to or after SCT. In addition to standard chemotherapy, immunotherapeutic approaches are assumed to be able to reduce or clear persistent minimal disease. Here we investigated an Fc-optimized chimerized CD19 antibody on a compassionate use basis in pediatric patients at very high risk prior to and after allogeneic, HLA matched (n=2) or mismatched (n=9) first or subsequent SCT. Through its improved capability to recruit FcγRIIIA bearing effector cells, this mAb mediates enhanced ADCC by NK cells but no complement lysis. 11 patients with B-lineage ALL (CR2 with MRD>10−4, n=3; ≥CR3, n=4; active disease, n=4; 8/11 had previous SCTs) received a mean number of 10 (range 1–30) infusions with an anti-CD19 mAb (4G7SDIE) over 6 hours weekly or every second week posttransplant. In 7 patients, additional infusions were given prior to transplant. Dosages ranged from 5 to 50 mg/m2. The infusions were well tolerated without any severe side effects; only fever or headache was observed in a few patients (n=4). Minimal residual disease (MRD) or overt relapse (>50% blasts) was detectable in bone marrow aspirates prior to therapeutic mAb administration in 5/11 and 2/11 patients, respectively. Prophylactic CD19mAb infusions were given posttransplant without measurable MRD levels in 4/11 patients and in another 2 patients (who did not respond to pretransplant CD19mAb because of overt relapse but reached MRD negativity after SCT) due to an extremely high relapse risk. In 4 out of 5 patients with detectable MRD, leukemic load was reduced for at least 1 log or eradicated by the mAb. 2 out of those patients relapsed, 2 other patients are in molecular remission since 270 and 350 days. Both patients with overt relapse did not respond. 2/6 patients with prophylactic mAb infusions relapsed after 121 and 186 days, 4 other patients remain in molecular remission since 52–180 days. Taken together, a response could be documented in 4/7 patients; a total of 6/11 patients are in molecular remission (median follow up 157 days). Concomitant in vitro investigations showed that NK cells of the patients exerted insufficient lysis of primary B-lineage ALL blasts (mean specific lysis: 4,00%). However, lysis could be significantly increased by adding autologous patient serum taken after antibody treatment (mean specific lysis: 20,33 %, p = 0.0001, student's t-test) or by adding 1 μg/ml 4G7SDIE (mean specific lysis: 34.84 %, p < 0.0001). Activity of patient NK cells was similar to NK cells of healthy donors. ADCC relevant serum titers of biologically active CD19mAb were detectable up to 7 days after antibody infusion. In conclusion, promising antileukemic effects have been observed in vitro and in vivo in this pilot study and a further clinical trial has to address the question whether this approach will be able to reduce relapse rates. Disclosures: No relevant conflicts of interest to declare.
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