While epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have changed the treatment landscape for EGFR mutant (L858R and ex19del)-driven non-small-cell lung cancer (NSCLC), ...most patients will eventually develop resistance to TKIs. In the case of first- and second-generation TKIs, up to 60% of patients will develop an EGFR T790M mutation, while third-generation irreversible TKIs, like osimertinib, lead to C797S as the primary on-target resistance mutation. The development of reversible inhibitors of these resistance mutants is often hampered by poor selectivity against wild-type EGFR, resulting in potentially dose-limiting toxicities and a sub-optimal profile for use in combinations. BLU-945 (compound 30) is a potent, reversible, wild-type-sparing inhibitor of EGFR+/T790M and EGFR+/T790M/C797S resistance mutants that maintains activity against the sensitizing mutations, especially L858R. Pre-clinical efficacy and safety studies supported progression of BLU-945 into clinical studies, and it is currently in phase 1/2 clinical trials for treatment-resistant EGFR-driven NSCLC.
Nickel-catalyzed enantioselective cross-couplings between symmetric cyclic sulfates and aromatic Grignard reagents are described. These reactions are effective with a broad range of substituted ...cyclic sulfates and deliver products with asymmetric tertiary carbon centers. Mechanistic experiments point to a stereoinvertive SN2-like oxidative addition of a nickel complex to the electrophilic substrate.
Kinetic resolution during the catalytic allyl‐propargyl cross‐coupling with chiral starting materials can be accomplished with a chiral palladium catalyst. These reactions offer ready access to ...enantiomerically enriched enyne products from simple, readily available starting materials.
A rhodium complex, in conjunction with commercially available Ph-BPE ligand, catalyzes the branch-selective asymmetric hydroformylation of 1-alkenes and rapidly generates α-chiral aldehydes. A wide ...range of terminal olefins including 1-dodecene were examined, and all delivered high enantioselectivity (up to 98:2 er) as well as good branch:linear ratios (up to 15:1).
The advent of the silicon photomultiplier has allowed the development of highly segmented calorimeters using plastic scintillator as the active media, with photodetectors embedded in the calorimeter, ...in dimples in the plastic. To reduce the photodetector’s dark current and radiation damage, the high granularity calorimeter designed for the high luminosity upgrade of the CMS detector at CERN’s Large Hadron Collider will be operated at a temperature of about –30 °C. Due to flammability considerations, a low oxygen environment is being considered. However, the radiation damage to the plastic scintillator during irradiation in this operating environment needs to be considered. In this paper, we present measurements of the relative decrease of light output during irradiation of small plastic scintillator tiles read out by silicon photomultipliers. The irradiations were performed using a source both to produce the tiles’ light and as a source of ionizing irradiation at dose rates of 0.3, 1.3, and 1.6 Gy/h, temperatures of –30, –15, –5, and 0 °C, and with several different oxygen concentrations in the surrounding atmosphere. The effect of the material used to wrap the tile was also studied. Substantial temporary damage, which annealed when the sample was warmed, was seen during the low-temperature irradiations, regardless of the oxygen concentration and wrapping material. The relative light loss was largest with 3MTM Enhanced Specular Reflector Film wrapping and smallest with no wrapping, although due to the substantially higher light yield with wrapping, the final light output is largest with wrapping. The light loss was less at warmer temperatures. Damage with 3% oxygen was similar to that in standard atmosphere. Evidence of a plateau in the radical density was seen for the 0 °C data.
Plastic scintillators are a versatile and inexpensive option for particle detection, which is why the largest particle physics experiments, CMS and ATLAS, use them extensively in their calorimeters. ...One of their challenging aspects, however, is their relatively low radiation hardness, which might be inadequate for very high luminosity future projects like the FCC-hh. In this study, results on the effects of ionizing radiation on the optical properties of plastic scintillator samples are presented. The samples are made from two different matrix materials, polystyrene and polyvinyltoluene, and have been irradiated at dose rates ranging from \(2.2\,\)Gy/h up to \(3.4\,\)kGy/h at room temperature. An internal boundary that separates two regions of different indices of refraction is visible in the samples depending on the dose rate, and it is compatible with the expected oxygen penetration depth during irradiation. The dose rate dependence of the oxygen penetration depth for the two matrix materials suggests that the oxygen penetration coefficient differs for PS and PVT. The values of the refractive index for the internal regions are elevated compared to those of the outer regions, which are compatible with the indices of unirradiated samples.
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