Ductility Anisotropy Induced by Ferrite in Direct Laser Deposited 17-4 PH Steel: Combined Microstructure and Dislocation Density Simulation

The anisotropic ductility of a direct laser deposited 17-4 PH cubic part was investigated.Anisotropic elongations in the specimens from varied surfaces of the part were obtained:~6.2%,~1.5%,and~4.5%in XY,YZ,and XZ samples,respectively.Furthermore,various orientations of ferrite were found in different specimens,taking the loading direction as reference.A finite element analysis depending on actual microstructures and dislocation density revealed that the orientation of ferrite caused the ductility anisotropy.The orientation of ferrite affected its plastic deformability and the deformation compatibility between phases during the uniaxial loading.The ferrite parallel to the tensile direction in the YZ sample had the worst deformability and induced severe strain localization and stress triaxiality,which resulted in inferior ductility.The ferrite perpendicular to the tensile direction showed the best deformability,whereas strain localization remained intense in the XZ sample owing to the unmatched deformability of martensite.The inclined ferrite in the XY sample exhibited moderate deformability and was found to enhance the plastic flow of martensite,leading to the best deformation compatibility and ductility.

Stem cell gene therapy:the risks of insertional mutagenesis and approaches to minimize genotoxicity

Virus-based vectors are widely used in hematopoietic stem cell(HSC)gene therapy,and have the ability to integrate permanently into genomic DNA,thus driving long-term expression of corrective genes in all hematopoietic lineages.To date,HSC gene therapy has been successfully employed in the clinic for improving clinical outcomes in small numbers of patients with X-linked severe combined immunodeficiency(SCID-X1),adenosine deaminase deficiency(ADA-SCID),adrenoleukodystrophy(ALD),thalassemia,chronic granulomatous disease(CGD),and Wiskott-Aldrich syndrome(WAS).However,adverse events were observed during some of these HSC gene therapy clinical trials,linked to insertional activation of proto-oncogenes by integrated proviral vectors leading to clonal expansion and eventual development of leukemia.Numerous studies have been performed to understand the molecular basis of vector-mediated genotoxicity,with the aim of developing safer vectors and lower-risk gene therapy protocols.This review will summarize current information on the mechanisms of insertional mutagenesis in hematopoietic stem and progenitor cells due to integrating gene transfer vectors,discuss the available assays for predicting genotoxicity and mapping vector integration sites,and introduce newlydeveloped approaches for minimizing genotoxicity as a way to further move HSC gene therapy forward into broader clinical application.