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Alpelisib is a selective inhibitor of PI3Kα, shown to improve outcomes for PIK3CA mutant, hormone receptor positive (HR+) metastatic breast cancers (MBC) when combined with antiestrogen therapy. To uncover mechanisms of resistance, we conducted a detailed, longitudinal analysis of tumor and plasma circulating tumor DNA among such patients from a phase I/II trial combining alpelisib with an aromatase inhibitor (AI) (NCT01870505). The trial's primary objective was to establish safety with maculopapular rash emerging as the most common grade 3 adverse event (33%). Among 44 evaluable patients, the observed clinical benefit rate was 52%. Correlating genetic alterations with outcome, we identified loss-of-function PTEN mutations in 25% of patients with resistance. ESR1 activating mutations also expanded in number and allele fraction during treatment and were associated with resistance. These data indicate that genomic alterations that mediate resistance to alpelisib or antiestrogen may promote disease progression and highlight PTEN loss as a recurrent mechanism of resistance to PI3Kα inhibition.

Pathogenic germline mutations in the RAD51 paralog genes RAD51C and RAD51D, are known to confer susceptibility to ovarian and triple-negative breast cancer. Here, we investigated whether germline loss-of-function variants affecting another RAD51 paralog gene, RAD51B, are also associated with breast and ovarian cancer. Among 3422 consecutively accrued breast and ovarian cancer patients consented to tumor/germline sequencing, the observed carrier frequency of loss-of-function germline RAD51B variants was significantly higher than control cases from the gnomAD population database (0.26% vs 0.09%), with an odds ratio of 2.69 (95% CI: 1.4–5.3). Furthermore, we demonstrate that tumors harboring biallelic RAD51B alteration are deficient in homologous recombination DNA repair deficiency (HRD), as evidenced by analysis of sequencing data and in vitro functional assays. Our findings suggest that RAD51B should be considered as an addition to clinical germline testing panels for breast and ovarian cancer susceptibility.

Bonded and fully-dense magnets prepared from melt-spun RE 2 Fe 14 B-type powders continue to find new applications in consumer electronics, automotive and industrial motors. The unique nanostructure of these materials promotes high magnetic performance, environmental stability and near-net shape formability. This article reviews the various types of melt spun powder from a compositional and microstructural standpoint. The powder with best overall performance and stability for bonded magnets appears to be the RE 2 Fe 14 B single phase type. Additional corrosion resistance can be achieved by coating the powder with an organic micro-dispersion prior to molding. Regarding higher performance fully dense magnets, multi-phase RE 2 Fe 14 B/RE melt spun powder offers a highly flexible precursor for hot forming near-net shape isotropic and anisotropic magnets. The composition of the melt spun powder along with the degree of hot deformation can be tailored to provide a range of magnetic properties from these types of magnet.

The microstructure and magnetic properties of rapidly quenched nanocomposites Pr9Fe91-xBx (x=4, 5, 6, 7, 8, 8.5, 9, 10.5 and 12) have been studied in this work. The results showed that the phases present in the Pr9Fe91–xBx nanocomposites were strongly dependent on the B content. The samples consist of Pr2Fe14B and α-Fe phases when the B content was low (4–8 at%), and Pr2Fe14B, α-Fe and Fe3B when the B content was sufficiently high (>11 at%). The metastable Pr2Fe23B3 phase appears in the intermediate B content (8–10.5 at%) and is associated with poor magnetic performance. It was further found that this metastable phase can be transformed into Pr2Fe14B, α-Fe and Fe3B by annealing the sample at temperatures above 750 °C, leading to a more square demagnetization curve. However, the Br of such nanocomposites decreases slightly due to the excessive grain growth during high-temperature annealing. A comparison of microstructure and magnetic properties between Pr2Fe14B/α-Fe and Pr2Fe14B/Fe3B was also made in this work. It was found that the Pr2Fe14B/α-Fe exhibited a finer and more uniform microstructure with an average grain size of ∼10 nm, whereas a relatively coarse microstructure (grain size up to 100 nm) was observed in the Pr2Fe14B/Fe3B. It was also found that the Pr2Fe14B/α-Fe yielded higher Br, (BH)max and a more square demagnetization loop, although the Hci was slightly lower. The superior magnetic properties observed in the Pr2Fe14B/α-Fe can be attributed to the more favorable intrinsic magnetic properties of α-Fe (higher Ms and lower K) and the much finer microstructure which produces stronger inter-grain exchange coupling between the Pr2Fe14B and α-Fe phases. The results indicate that RE2Fe14B/α-Fe nanocomposites are more desirable than RE2Fe14B/Fe3B for future development of RE-Fe-B nanocomposite magnets.