Search

Abgesehen von histopathologischen, allerdings eingeschrankt reproduzierbaren Merkmalen sind keine Kriterien bekannt, die die Entwicklung einer Myelofibrose (MF) als typische Komplikation myeloproliferativer Neoplasien (MPN; chronische myeloproliferative Erkrankungen nach alter Nomenklatur) in fruhen noch unverfaserten Stadien vorhersagen. Altersassoziierte klonale Hamatopoese („age-related clonal hematopoiesis“, ARCH, oder „clonal hematopoiesis of indetermined potential“, CHIP) wird ab dem 65. Lebensjahr in bis zu 10 % dieser Alterskohorte angetroffen. ARCH wurde kombiniert mit typischen Treibermutationen (JAK2, MPL und CALR) bei MPN beschrieben. Um die Auswirkung von ARCH auf das Fibroserisiko von primarer Myelofibrose (PMF) im unverfaserten Fruhstadium (MF 0) zu ermitteln, wurden in dieser Studie 77 Falle von fruher PMF mit spaterer Entwicklung einer Myelofibrose (MF 2 und 3) im Verlauf (Median 6,2 Jahre) hinsichtlich ihres Mutationsstatus untersucht. Als Vergleichskollektiv dienten PMF-Falle (n = 27) ohne Entwicklung einer Myelofibrose mit einer medianen Beobachtungszeit von 7,2 Jahren. Die haufigsten ARCH-Mutationen, die Gene TET2, ASXL1 und DNMT3A betreffend, zeigten dabei keine Korrelation mit dem fibrotischen Progress, wenn sie bereits in der initialen Biopsie bestanden. Andere, eher beim myelodysplastischen Syndrom (MDS) und nicht bei ARCH anzutreffende Mutationen der Hamatopoese wie SRSF2, U2AF1, SF3B1, IDH1/2 und EZH2 fanden sich bei 24,7 % der prafibrotischen PMF-Falle mit spaterem fibrotischen Progress, aber in keinem der prafibrotischen PMF-Falle ohne Fibroseentwicklung (p = 0,0028). Aus diesen Befunden ergibt sich, dass die haufigen ARCH/CHIP-Mutationen TET2, ASXL1 und DNMT3A kein gesteigertes Fibroserisiko bei PMF im unverfaserten Fruhstadium bewirken, wahrend die MDS- und Nicht-ARCH-assoziierten Mutationen SRSF2, U2AF1, SF3B1, IDH1/2 und EZH2 einen signifikanten Risikofaktor fur den schnellen Progress in eine MF (Median 2 Jahre) darstellen.

Chromosomal translocations resulting in fusion genes represent important oncogenic drivers and potential therapeutic targets in rare leukemia subtypes. Formalin-fixed, paraffin-embedded trephines are frequently used in hematologic diagnostic tests and provide relevant access to leukemic cells for further studies, for example, phenotyping in bone marrow fibrosis. However, high-throughput molecular analysis of nucleic acids obtained from this material is challenging, especially the reliable detection of RNA transcripts. Sixty-three formalin-fixed, paraffin-embedded bone marrow trephines of patients with chronic eosinophilic leukemia, chronic myeloid leukemia, acute myeloid leukemia, and myeloproliferative neoplasms were analyzed for gene mutations and the presence of fusion transcripts with a commercial amplicon-based next-generation sequencing approach. Fusion transcripts relevant for diagnosis and therapy could be detected and validated (by RT-PCR) in 25 patients (39.7%). Retrospectively selected material, up to 10 years old, was used for this purpose, and only one sample failed in the RNA analysis (1.6%). This study concludes that amplicon-based fusion transcript detection in bone marrow trephines is feasible and that bone marrow trephines taken for histologic assessment can also be applied for high-throughput molecular analysis.

Active hybrid composites represent a novel class of smart materials used to design morphing surfaces, opening up new applications in the aircraft and automotive industries. The bending of the active hybrid composite is induced by the contraction of electrically activated shape memory alloy (SMA) wires, which are placed with an offset to the neutral axis of the composite. Therefore, the adhesion strength between the SMA wire and the surrounding polymer matrix is crucial to the load transfer and the functionality of the composite. Thus, the interface adhesion strength is of great importance for the performance and the actuation potential of active hybrid composites. In this work, the surface of a commercially available one-way effect NiTi SMA wire with a diameter of 1 mm was structured by selective electrochemical etching that preferably starts at defect sites, leaving the most thermodynamically stable surfaces of the wire intact. The created etch pits lead to an increase in the surface area of the wire and a mechanical interlocking with the polymer, resulting in a combination of adhesive and cohesive failure modes after a pull-out test. Consequently, the force of the first failure determined by an optical stress measurement was increased by more than 3 times when compared to the as-delivered SMA wire. The actuation characterization test showed that approximately the same work capacity could be retrieved from structured SMA wires. Moreover, structured SMA wires exhibited the same shape of the stress-strain curve as the as-delivered SMA wire, and the mechanical performance was not influenced by the structuring process. The austenite start As and austenite finish Af transformation temperatures were also not found to be affected by the structuring process. The formation of etching pits with different geometries and densities was discussed with regard to the kinetics of oxide formation and dissolution.

Objectives Myeloproliferative neoplasms (MPN) comprising Poycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF) follow a bi-phasic course of disease with fibrotic and/or blastic progression. At presentation in the chronic phase, currently there are only insufficient tools to predict the risk of progression in individual cases. Methods In this study chronic phase MPN (16 PMF, 11 PV, and 11 MPN unclassified) with blastic transformation during course of disease (n = 38, median follow-up 5.3 years) were analyzed by high-throughput sequencing. MPN cases with a comparable follow-up period and without evidence of blast increase served as control (n = 63, median follow-up 5.8 years). Results Frequent ARCH/CHIP-associated mutations (TET2, ASXL1, DNMT3A) found at presentation were not significantly associated with blastic transformation. By contrast, mutations of SRSF2, U2AF1, and IDH1/2 at first presentation were exclusively observed in the progression cohort (13/38, 34.2%) and were completely missing in the control group without blast transformation during follow-up (P = 0.0007 for SRSF2; P = 0.0063 for U2AF1 and IDH1/2). Conclusion Unlike frequent ARCH/CHIP alterations (TET2, ASXL1, DNMT3A) mutations in SRSF2, IDH1/2, and U2AF1 when manifest already at first presentation provide an independent risk factor for blast transformation of MPN.

Besides histopathological findings there are no indicators of increased risk for fibrotic progression in myeloproliferative neoplasms (MPN). Age-related clonal hematopoiesis (ARCH/CHIP) is a frequent finding in the elderly and combinations with MPN driver mutations (JAK2, MPL, and CALR) have been described. To determine the impact of ARCH/CHIP-related mutations for development of fibrosis in primary myelofibrosis (PMF), the mutational status of cases with fibrotic progression from grade 0 to grade 2/3 (n = 77) as evidenced by follow-up bone marrow biopsies (median 6.2 years) was compared with prefibrotic PMF samples without development of fibrosis (n = 27; median follow-up 7.3 years). Frequent ARCH/CHIP-associated mutations (TET2, ASXL1, and DNMT3A) demonstrable at presentation were not connected with fibrotic progression. However, mutations which are rarely found in ARCH/CHIP (SRSF2, U2AF1, SF3B1, IDH1/2, and EZH2) were present in 24.7% of cases with later development of fibrosis and not detectable in cases staying free from fibrosis (P = 0.0028). Determination of the tumor mutational burden (TMB) in a subgroup of cases (n = 32) did not show significant differences (7.68 mutations/MB vs. 6.85 mutations/MB). We conclude that mutations rarely found in ARCH/CHIP provide an independent risk factor for rapid fibrotic progression (median 2.0 years) when manifest already at first presentation.

The benefit of fiber-reinforced composites originates from the interaction between the fiber reinforcement and the matrix. This interplay controls many of its mechanical properties and is of utmost importance to enable its unique performance as a lightweight material. However, measuring the fiber−matrix interphase strength with micromechanical tests, like the Broutman test, is challenging, due to the many, often unknown boundary conditions. Therefore, this study uses state-of-the-art, high-resolution X-ray computed microtomography (XRM) as a tool to investigate post mortem the failure mechanisms of single carbon fibers within an epoxy matrix. This was conducted at the example of single carbon fiber Broutman test specimens. The capabilities of today’s XRM analysis were shown in comparison to classically obtained light microscopy. A simple finite element model was used to enhance the understanding of the observed fracture patterns. In total, this research reveals the possibilities and limitations of XRM to visualize and assess compression-induced single fiber fracture patterns. Furthermore, comparing two different matrix systems with each other illustrates that the failure mechanisms originate from differences in the fiber−matrix interphases. The carbon fiber seems to fail due to brittleness under compression stress. Observation of the fiber slippage and deformed small fracture pieces between the fragments suggests a nonzero stress state at the fragment ends after fiber failure. Even more, these results demonstrate the usefulness of XRM as an additional tool for the characterization of the fiber−matrix interphase.