Activation of the phosphatidylinositol-3-kinase (PI3K) pathway via PIK3CA mutations occurs in 28%-46% of hormone receptor-positive (HR+), human epidermal growth factor receptor-2-negative (HER2−) ...advanced breast cancers (ABCs) and is associated with poor prognosis. The SOLAR-1 trial showed that the addition of alpelisib to fulvestrant treatment provided statistically significant and clinically meaningful progression-free survival (PFS) benefit in PIK3CA-mutated, HR+, HER2− ABC.
Men and postmenopausal women with HR+, HER2− ABC whose disease progressed on or after aromatase inhibitor (AI) were randomized 1 : 1 to receive alpelisib (300 mg/day) plus fulvestrant (500 mg every 28 days and once on day 15) or placebo plus fulvestrant. Overall survival (OS) in the PIK3CA-mutant cohort was evaluated by Kaplan–Meier methodology and a one-sided stratified log-rank test was carried out with an O'Brien–Fleming efficacy boundary of P ≤ 0.0161.
In the PIK3CA-mutated cohort (n = 341), median OS 95% confidence interval (CI) was 39.3 months (34.1-44.9) for alpelisib-fulvestrant and 31.4 months (26.8-41.3) for placebo-fulvestrant hazard ratio (HR) = 0.86 (95% CI, 0.64-1.15; P = 0.15). OS results did not cross the prespecified efficacy boundary. Median OS (95% CI) in patients with lung and/or liver metastases was 37.2 months (28.7-43.6) and 22.8 months (19.0-26.8) in the alpelisib-fulvestrant and placebo-fulvestrant arms, respectively HR = 0.68 (0.46-1.00). Median times to chemotherapy (95% CI) for the alpelisib-fulvestrant and placebo-fulvestrant arms were 23.3 months (15.2-28.4) and 14.8 months (10.5-22.6), respectively HR = 0.72 (0.54-0.95). No new safety signals were observed with longer follow-up.
Although the analysis did not cross the prespecified boundary for statistical significance, there was a 7.9-month numeric improvement in median OS when alpelisib was added to fulvestrant treatment of patients with PIK3CA-mutated, HR+, HER2− ABC. Overall, these results further support the statistically significant prolongation of PFS observed with alpelisib plus fulvestrant in this population, which has a poor prognosis due to a PIK3CA mutation.
NCT02437318.
•In SOLAR-1, the key secondary endpoint of OS was evaluated in patients with HR+, HER2−, PIK3CA-mutated ABC.•Adding alpelisib to fulvestrant numerically improved mOS by 7.9 months, though the result was not statistically significant.•OS was numerically improved in hard-to-treat disease, including a 14-month median improvement in those with lung/liver metastases.•Median time to first chemotherapy was delayed by 8.5 months with the addition of alpelisib to fulvestrant.•With longer follow-up the alpelisib plus fulvestrant safety profile was similar to prior reports with no new safety signals.
Science communication is commonly framed as a battle with ignorance and the field of radiological protection is not exempt from this tendency. By correcting deficits in the public’s understanding of ...science, the expert is often imagined to be able to convince the public of its objective safety (‘anzen’), thereby inspiring a sense of calm (‘anshin’). In the wake of the 2011 Fukushima Daiichi disaster, however, the International Commission on Radiological Protection has sought to break with this tradition by organising a series of participatory seminars in which experts engage those affected by the disaster as equals. Drawing on ethnographic fieldwork, this article suggests that the Dialogue seminars can be best understood using the metaphor of therapy; using it to describe the premise, form, and objectives of the Dialogues with a view to identifying good practice for future radiological protection scenarios.
Carbon nanotubes (CNTs)/aluminum (Al) composites with various interfacial reaction degrees were fabricated by powder metallurgy at sintering temperature range of 700–900 K (75–96% melting point of ...Al). Interfacial reaction product, aluminum carbide (Al4C3), was formed in Al matrix composites (AMCs) reinforced by homogeneously-dispersed CNTs. Microscopy observations revealed three types of temperature-dependent interfaces, i) clean CNT-Al interfaces without interfacial carbide, ii) CNT-Al4C3-Al interfaces for partially reacted CNTs with Al4C3 nanoparticles, and iii) Al4C3-Al interface for in-situ Al4C3 nanorods evolved from completely reacted CNTs. Interfacial Al4C3 on partially reacted CNTs led to significant improvement of interfacial strength and consequent enhancement of load transfer efficiency in AMCs, compared to those composites without carbide. The load transfer mechanism of CNTs in composites was confirmed by the pull-out phenomena during in-situ tensile tests. The role of interfacial carbide played in determining the load transfer efficiency of CNTs was discussed. This study may provide new insights into the interfacial phenomena and load transfer mechanism in CNT-reinforced metal matrix composites.
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The limited ductility of high-strength aluminum (Al) matrix composites (AMCs) reinforced with carbon nanotubes (CNTs) is a critical issue, which hinders their engineering applications. Here, we ...report a significantly improved ductility of CNT/Al composites with a simultaneously increased tensile strength using elevated sintering temperatures. The traditional trade-off tendency between strength and ductility is evaded in CNT/Al composites owing to concurrent improvement of Al–Al grain and CNT–Al interface bonding. The interfacial characteristics are investigated through microstructural examination and quantitative estimation using strengthening models. The study provides a strategy for fabricating CNT-reinforced metal matrix composites with high strength and good ductility.
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In the hole-doped cuprates, a small number of carriers suppresses antiferromagnetism and induces superconductivity. In the electron-doped cuprates, on the other hand, superconductivity appears only ...in a narrow window of high-doped Ce concentration after reduction annealing, and strong antiferromagnetic correlation persists in the superconducting phase. Recently, Pr(1.3-x)La0.7Ce(x)CuO4 (PLCCO) bulk single crystals annealed by a protect annealing method showed a high critical temperature of around 27 K for small Ce content down to 0.05. Here, by angle-resolved photoemission spectroscopy measurements of PLCCO crystals, we observed a sharp quasi-particle peak on the entire Fermi surface without signature of an antiferromagnetic pseudogap unlike all the previous work, indicating a dramatic reduction of antiferromagnetic correlation length and/or of magnetic moments. The superconducting state was found to extend over a wide electron concentration range. The present results fundamentally challenge the long-standing picture on the electronic structure in the electron-doped regime.
Previous trials showed promising antitumor activity and an acceptable safety profile associated with pembrolizumab in patients with early triple-negative breast cancer. Whether the addition of ...pembrolizumab to neoadjuvant chemotherapy would significantly increase the percentage of patients with early triple-negative breast cancer who have a pathological complete response (defined as no invasive cancer in the breast and negative nodes) at definitive surgery is unclear.
In this phase 3 trial, we randomly assigned (in a 2:1 ratio) patients with previously untreated stage II or stage III triple-negative breast cancer to receive neoadjuvant therapy with four cycles of pembrolizumab (at a dose of 200 mg) every 3 weeks plus paclitaxel and carboplatin (784 patients; the pembrolizumab-chemotherapy group) or placebo every 3 weeks plus paclitaxel and carboplatin (390 patients; the placebo-chemotherapy group); the two groups then received an additional four cycles of pembrolizumab or placebo, and both groups received doxorubicin-cyclophosphamide or epirubicin-cyclophosphamide. After definitive surgery, the patients received adjuvant pembrolizumab or placebo every 3 weeks for up to nine cycles. The primary end points were a pathological complete response at the time of definitive surgery and event-free survival in the intention-to-treat population.
At the first interim analysis, among the first 602 patients who underwent randomization, the percentage of patients with a pathological complete response was 64.8% (95% confidence interval CI, 59.9 to 69.5) in the pembrolizumab-chemotherapy group and 51.2% (95% CI, 44.1 to 58.3) in the placebo-chemotherapy group (estimated treatment difference, 13.6 percentage points; 95% CI, 5.4 to 21.8; P<0.001). After a median follow-up of 15.5 months (range, 2.7 to 25.0), 58 of 784 patients (7.4%) in the pembrolizumab-chemotherapy group and 46 of 390 patients (11.8%) in the placebo-chemotherapy group had disease progression that precluded definitive surgery, had local or distant recurrence or a second primary tumor, or died from any cause (hazard ratio, 0.63; 95% CI, 0.43 to 0.93). Across all treatment phases, the incidence of treatment-related adverse events of grade 3 or higher was 78.0% in the pembrolizumab-chemotherapy group and 73.0% in the placebo-chemotherapy group, including death in 0.4% (3 patients) and 0.3% (1 patient), respectively.
Among patients with early triple-negative breast cancer, the percentage with a pathological complete response was significantly higher among those who received pembrolizumab plus neoadjuvant chemotherapy than among those who received placebo plus neoadjuvant chemotherapy. (Funded by Merck Sharp & Dohme a subsidiary of Merck; KEYNOTE-522 ClinicalTrials.gov number, NCT03036488.).
In the present work, we studied the effect of the aspect ratio of carbon nanotubes (CNTs) on strengthening aluminum metal matrix composites (Al MMCs). To this end, Al samples reinforced with CNTs of ...various aspect ratios were produced via three different powder metallurgy methods. Microstructural examination revealed that the CNTs were uniformly dispersed in the materials with a range of aspect ratios from 6.5 to 55. The tensile results showed that the CNTs exhibited a strong strengthening effect in the composites regardless of their aspect ratios. However, the post-loading examination and quantitative analysis indicated that there was a strengthening mechanism transition for CNTs, which was closely associated with the aspect ratio or length of CNTs. The origin of such transition was explored from the viewpoint of dislocation-CNTs interaction under loading. The findings may provide a new insight in understanding the strengthening behaviors of CNT-reinforced MMCs.
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► We performed laser direct joining of CFRP to zinc-coated steel. ► Strong lap joint with 3300N was obtained by laser beam irradiation. ► The joint was tightly bonded on atomic or molecular sized ...level. ► The lap joint was accomplished by mechanical, chemical and physical bonding.
This study was performed to investigate the feasibilities, characteristics and mechanisms of dissimilar joints between carbon fiber reinforced plastics (CFRPs) and zinc-coated steel using a continuous wave (CW) diode laser. Tensile shear tests show that the high strength joint with about 3300N could be produced. Many bubbles of sub-millimeter size inside the melted zone of CFRP at the cross sections of the joints were widely formed, and thin zinc-coated layer at the joint interface was partially fractured. Then, the melted plastic was filled closely to flow in the fractured zinc-coated layer, suggesting strong mechanical bonding. Furthermore, the joint was tightly bonded on atomic or molecular sized level between the melted plastic containing most carbon and nanometer thick zinc oxide film on the surface of zinc-coated layer, inducing strong possibility of physical and chemical bonding. It is consequently confirmed that a strong joint of CFRP to zinc-coated steel could be obtained by laser direct joining process.
Searching for space-time variations of the constants of Nature is a promising way to search for new physics beyond general relativity and the standard model motivated by unification theories and ...models of dark matter and dark energy. We propose a new way to search for a variation of the fine-structure constant using measurements of late-type evolved giant stars from the S star cluster orbiting the supermassive black hole in our Galactic Center. A measurement of the difference between distinct absorption lines (with different sensitivity to the fine structure constant) from a star leads to a direct estimate of a variation of the fine structure constant between the star's location and Earth. Using spectroscopic measurements of five stars, we obtain a constraint on the relative variation of the fine structure constant below 10^{-5}. This is the first time a varying constant of nature is searched for around a black hole and in a high gravitational potential. This analysis shows new ways the monitoring of stars in the Galactic Center can be used to probe fundamental physics.
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