Expression of pSTAT5 predicts FLT3 internal tandem duplications in acute myeloid leukemia

Mutations of the Fms-like tyrosine kinase 3 (FLT3) can be detected in a significant number of acute myeloid leukemias (AML). Seventy-five cases of acute myeloid leukemia were evaluated for FLT3-internal tandem duplications (ITD) by polymerase chain reaction. Paraffin-embedded formalin-fixed trephine biopsies of these cases were evaluated for expression of phosphorylated signal transducer and activator of transcription 1 (pSTAT1), pSTAT3, and pSTAT5. Specific expression of pSTAT5 was proven in leukemic blasts in situ by double staining with a blast-specific marker. Expression of pSTAT5 in ≥1% of blasts was highly predictive of FLT3-ITD. Neither expression of pSTAT1 nor pSTAT3 were associated with FLT3 mutations. Altogether we conclude that pSTAT5 expression can precisely be assessed by immunohistochemistry in routinely processed bone marrow trephines, STAT5 is highly likely the preferred second messenger of FLT3-mediated signaling in AML, and expression of pSTAT5 is predictive of FLT3-IT

In situ RHAMM protein expression in acute myeloid leukemia blasts suggests poor overall survival

Treatment options for patients with high-risk acute myeloid leukemia (AML) include high-dose chemotherapy regimens in combination with allogeneic hematopoietic stem cell transplantation, which takes advantage of the donor T-cell-mediated graft-versus-leukemia effect. Together with beneficial responses observed in assays targeted at leukemia-associated antigens (LAA), this encouraged research on cancer vaccines and adoptive cellular therapies in AML. The receptor for hyaluronic acid-mediated motility (RHAMM, CD168) was identified as one of the most promising LAA in AML. Thus far, little is known about in situ expression in leukemic bone marrow blasts or the prognostic role of RHAMM and its interaction partners in AML. We immunohistochemically analyzed the expression and prognostic significance of RHAMM on trephine bone marrow biopsies from 71 AML cases that had been evaluated for cytogenetics and presence of FLT3-internal tandem duplications and NPM1 mutations. Fifty-five patients (77%) were treated with curative intent, while 16 (23%) received the most appropriate supportive care. Twenty of 71 (28%) AML cases were considered RHAMM+. Receiver operating characteristic curves showed significant discriminatory power considering overall survival (OS) in AML patients treated curatively for RHAMM (p = 0.015). Multivariable analysis revealed that expression of RHAMM in >5% of leukemic blasts identifies a subgroup of curatively treated cases with adverse OS independent of failures to achieve complete remission. RHAMM not only represents a promising LAA with specific T-cell responses in AML but, if assessed in situ on blasts, also a probable prognostic facto

Aplastic anemia and concomitant autoimmune diseases

The association of aplastic anemia (AA) with other autoimmune diseases (AID) has been described but so far not systematically evaluated. We assessed the incidence and the outcome of concomitant AID in a retrospective, single-center study of 243 patients with severe AA treated between 1974 and 2006 with either immunosuppression (186) or hematopoietic stem cell transplantation (57) and a median follow-up time of 9.3years (0-33). Clinically manifest AID were observed in 24 out of 243 (10 ± 3.7%) patients. Age at diagnosis of AA was significantly younger in patients without AID compared to patients with AID (median, 20 versus 52years; P < 0.001). In 12 patients where the diagnosis of AID was done before AA therapy, response to antithymocyte globulin was good for AA (ten out of 12) but not for AID (2 out of 12). In 13 patients in which AID occurred after first-line therapy, the median time to the AID was 7years (range 3months-27.5years

CD123-Engager T Cells as a Novel Immunotherapeutic for Acute Myeloid Leukemia

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Combining geographic information systems and ethnography to better understand and plan ocean space use

Agencies in the US with oversight for marine renewable energy development have idealistically sought space where this new use might proceed unhindered by other uses. Despite experiential evidence of spatial overlap among existing ocean uses, a lack of documentation makes the identification of potential space-use conflicts, communication among existing and potential ocean users, and the design of mitigation exceedingly challenging. We conducted a study in select communities along the US Atlantic and Pacific coasts to gather and document available spatial information on existing use through a compilation and organization of geographic information system (GIS) data. Stakeholder group meetings were used to vet the collected spatial data and ethnographic interviews were conducted to gather additional knowledge and cultural perspectives. Results show extensive overlap of existing ocean space uses and provide a visualization of the social and cultural landscape of the ocean that managers can use to determine which stakeholders to engage when considering the development of alternative uses. Marine space use is dynamic and multi-dimensional and there are important linkages within and across fisheries and other uses, communities and interests, as well as across the land-sea interface. The research reported here demonstrates the feasibility and necessity of (1) integrating ethnographic and geospatial data collection and analysis; (2) engaging stakeholders throughout the process; and (3) recognizing the unique qualities of each geographic location and user group to support sound decision-making.Keywords: Ethnography, Marine Spatial Planning, GIS, Participatory Mapping, P-GIS, Ocean Space Us

Doing diversity: intercultural understanding in primary and secondary schools

Doing Diversity: Intercultural understanding in primary and secondary schools1 was a three year, multi-method programme of research involving intensive work in 12 diverse profile schools in Melbourne, Victoria, that examined the facilitators and impediments to the intercultural capabilities described in the Victorian and Australian curricula for students and schools

Disruption of AP1S1, Causing a Novel Neurocutaneous Syndrome, Perturbs Development of the Skin and Spinal Cord

Adaptor protein (AP) complexes regulate clathrin-coated vesicle assembly, protein cargo sorting, and vesicular trafficking between organelles in eukaryotic cells. Because disruption of the various subunits of the AP complexes is embryonic lethal in the majority of cases, characterization of their function in vivo is still lacking. Here, we describe the first mutation in the human AP1S1 gene, encoding the small subunit σ1A of the AP-1 complex. This founder splice mutation, which leads to a premature stop codon, was found in four families with a unique syndrome characterized by mental retardation, enteropathy, deafness, peripheral neuropathy, ichthyosis, and keratodermia (MEDNIK). To validate the pathogenic effect of the mutation, we knocked down Ap1s1 expression in zebrafish using selective antisens morpholino oligonucleotides (AMO). The knockdown phenotype consisted of perturbation in skin formation, reduced pigmentation, and severe motility deficits due to impaired neural network development. Both neural and skin defects were rescued by co-injection of AMO with wild-type (WT) human AP1S1 mRNA, but not by co-injecting the truncated form of AP1S1, consistent with a loss-of-function effect of this mutation. Together, these results confirm AP1S1 as the gene responsible for MEDNIK syndrome and demonstrate a critical role of AP1S1 in development of the skin and spinal cord

Significant Progress in CAR T-Cell Therapy for Difficult-to-Treat Hematologic Malignancies

The latest clinical and real-world evidence of chimeric antigen receptor (CAR) T-cell therapy continues to challenge standard treatment paradigms for many hematologic malignancies with limited treatment options. In particular, recently approved CAR T-cell therapies are forging a path towards improving patient outcomes and health-related quality of life (HRQoL) in difficult-to-treat relapsed/refractory (R/R) blood cancers such as diffuse large B-cell lymphoma (DLBCL), multiple myeloma (MM), mantle cell lymphoma (MCL) and B-cell acute lymphoblastic leukemia (B-ALL). Here the latest data on commercially available CAR T-cell therapies are summarized and discussed