Discovery of KT-413, a Targeted Protein Degrader of IRAK4 and IMiD Substrates Targeting MYD88 Mutant Diffuse Large B-Cell Lymphoma.

Developing therapies for the activated B-cell like (ABC) subtype of diffuse large B-cell lymphomas (DLBCL) remains an area of unmet medical need. A subset of ABC DLBCL tumors is driven by activating mutations in myeloid differentiation primary response protein 88 (MYD88), which lead to constitutive activation of interleukin-1 receptor associated kinase 4 (IRAK4) and cellular proliferation. IRAK4 signaling is driven by its catalytic and scaffolding functions, necessitating complete removal of this protein and its escape mechanisms for complete therapeutic suppression. Herein, we describe the identification and characterization of a dual-functioning molecule, KT-413 and show it efficiently degrades IRAK4 and the transcription factors Ikaros and Aiolos. KT-413 achieves concurrent degradation of these proteins by functioning as both a heterobifunctional degrader and a molecular glue. Based on the demonstrated activity and safety of KT-413 in preclinical studies, a phase 1 clinical trial in B-cell lymphomas, including MYD88 mutant ABC DLBCL, is currently underway.

2D single crystal Bragg-dip mapping by time-of-flight energy-resolved neutron imaging on IMAT@ISIS.

The cold neutron imaging and diffraction instrument IMAT, at the second target station of the pulsed neutron and muon source ISIS, is used to investigate bulk mosaicity within as-cast single crystal CMSX-4 and CMSX-10 Ni-base superalloys. Within this study, neutron transmission spectrum is recorded by each pixel within the microchannel plate image detector. The movement of the lowest transmission wavelength within a specified Bragg-dip for each pixel is tracked. The resultant Bragg-dip shifting has enabled crystallographic orientation mapping of bulk single crystal specimens with good spatial resolution. The total acquisition time required to collect sufficient statistics for each test is ~ 3 h. In this work, the influence of a change in bulk solidification conditions on the variation in single crystal mosaicity was investigated. Misorientation of the (001) crystallographic plane has been visualised and a new spiral twisting solidification phenomena observed. This proof of concept work establishes time-of-flight energy-resolved neutron imaging as a fundamental characterisation tool for understanding and visualising mosaicity within metallic single crystals and provides the foundation for post-mortem deduction of the shape of the solid/liquid isotherm.

Egyptian Grave Goods of Kha and Merit Studied by Neutron and Gamma Techniques.

Artifacts from the Egyptian grave goods of Kha and Merit preserved at the Museo Egizio in Turin were studied through a combination of non-destructive and non-invasive neutron and gamma techniques (namely neutron imaging, neutron diffraction and prompt gamma activation analysis). The results provide unprecedented morphological reconstructions of the inner parts of the two alabaster and metallic vases and their isotopic and phase composition, thereby extending our knowledge of the hitherto unknown content of the vases and their functions.

Characterisation of nanovoiding in dental porcelain using small angle neutron scattering and transmission electron microscopy.

OBJECTIVES: Recent studies of the yttria partially stabilised zirconia-porcelain interface have revealed the presence of near-interface porcelain nanovoiding which reduces toughness and leads to component failure. One potential explanation for these nanoscale features is thermal creep which is induced by the combination of the residual stresses at the interface and sintering temperatures applied during manufacture. The present study provides improved understanding of this important phenomenon. METHODS: Transmission electron microscopy and small angle neutron scattering were applied to a sample which was crept at 750°C and 100MPa (sample C), a second which was exposed to an identical heat treatment schedule in the absence of applied stress (sample H), and a reference sample in the as-machined state (sample A). RESULTS: The complementary insights provided by the two techniques were in good agreement and log-normal void size distributions were found in all samples. The void number density was found to be 1.61µm-2, 25.4µm-2 and 98.6µm-2 in samples A, H and C respectively. The average void diameter in sample A (27.1nm) was found to be more than twice as large as in samples H (10.2nm) and C (11.6nm). The crept data showed the highest skewness parameter (2.35), indicating stress-induced growth of larger voids and void coalescence that has not been previously observed. SIGNIFICANCE: The improved insight presented in this study can be integrated into existing models of dental prostheses in order to optimise manufacturing routes and thereby reduce the significant detrimental impact of this nanostructural phenomenon.

Determination and mitigation of the uncertainty of neutron diffraction measurements of residual strain in large-grained polycrystalline material.

For large-grained samples it is advantageous to perform pairs of neutron diffraction measurements at the same spatial location but rotated 180° around the geometric centre of the gauge volume as a means of minimizing the scatter coming from the random positioning of grains within the gauge volume.