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Patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) often develop resistance to current standard third-generation EGFR tyrosine kinase inhibitors (TKIs); no targeted treatments are approved in the osimertinib-relapsed setting. In this open-label, dose-escalation and dose-expansion phase 1 trial, the potential for improved anti-tumor activity by combining amivantamab, an EGFR-MET bispecific antibody, with lazertinib, a third-generation EGFR TKI, was evaluated in patients with EGFR-mutant NSCLC whose disease progressed on third-generation TKI monotherapy but were chemotherapy naive (CHRYSALIS cohort E). In the dose-escalation phase, the recommended phase 2 combination dose was established; in the dose-expansion phase, the primary endpoints were safety and overall response rate, and key secondary endpoints included progression-free survival and overall survival. The safety profile of amivantamab and lazertinib was generally consistent with previous experience of each agent alone, with 4% experiencing grade ≥3 events; no new safety signals were identified. In an exploratory cohort of 45 patients who were enrolled without biomarker selection, the primary endpoint of investigator-assessed overall response rate was 36% (95% confidence interval, 22-51). The median duration of response was 9.6 months, and the median progression-free survival was 4.9 months. Next-generation sequencing and immunohistochemistry analyses identified high EGFR and/or MET expression as potential predictive biomarkers of response, which will need to be validated with prospective assessment. ClinicalTrials.gov identifier: NCT02609776 .

BackgroundSeminal oxidative stress has been shown to be a key factor in the development of male infertility. However, the benefits of infertility treatments with antioxidants such as coenzyme Q10 (CoQ10) remains controversial.ObjectivesThe aim of the present study was to assess the effects of CoQ10 supplementation on semen quality, i.e., semen volume, total sperm number, sperm concentration, total sperm motility, percentage of progressive sperm motility and sperm morphology. In addition, the effects of CoQ10 supplementation on circulating testosterone, luteinizing hormone (LH), follicle-stimulating hormone (FSH), and inhibin B levels were evaluated.DesignA systematic review and a meta-analysis of randomized controlled trials (RCTs) were performed to assess the effects of CoQ10 supplementation on semen quality and serum levels of male reproductive hormones.MethodsWe conducted a strategic literature search in the Cochrane, EMBASE, PubMed/MEDLINE, Scopus, and Web of Science databases and collected only RCTs. The data in the collected RCTs were then meta-analyzed according to PRISMA guidelines.ResultsOut of 2,144 collected studies, only eight were classified eligible. The studies included a total of 877 male subjects; 462 CoQ10-treated and 415 untreated/placebo-treated. We found significantly higher total sperm counts (SMD -13.38 [95% CI: −16.33, −10.43] P< 0.0001), total (SMD -7.26 [95% CI: −10.15, −4.36] P< 0.00001) and progressive motility (SMD -6.386 [95% CI: −10.04, −2.73] P= 0.0006), and normally formed sperm (SMD -1.96 [95% CI: −3.29, −0.62] P= 0.004) in CoQ10-treated male subjects compared with untreated/placebo-treated male subjects. Nonetheless, there was a significant inter-study heterogeneity in these studies. Moreover, significantly higher serum testosterone (SMD -0.59 [95% CI: −0.79, −0.40] P< 0.00001) and inhibin B levels (SMD -0.92 [95% CI: −1.47, −0.37] P= 0.001) were recorded in CoQ10-treated subjects compared to untreated/placebo-treated subjects. In addition, CoQ10 supplementation significantly lowered serum LH (SMD 1.77 [95% CI: 1.26, 2.28] P< 0.00001) and FSH concentrations (SMD 1.60 [95% CI: 1.38, 1.81] P< 0.00001). Interestingly, there was no significant inter-study heterogeneity in the hormonal studies. However, CoQ10 supplementation had no significant effect on semen volume (SMD 0.12 [95% CI: −0.13, 0.37] P= 0.34) and sperm concentration (SMD -6.69 [95% CI: −16.28, 2.90] P= 0.17).ConclusionOur study shows that CoQ10 supplementation increases total sperm count, total and progressive sperm motility, and the proportion of normally formed sperm in association with higher serum testosterone and inhibin B levels. Our study therefore supports the view in the literature of a beneficial use of CoQ10 in male infertility treatment. However, further well-designed RCTs with sufficiently large numbers of subjects are required to reach a final conclusion.

The production of high stiffness Ti-based Metal Matrix Composites (Ti-MMCs) displaying significant ductility is extremely challenging due to the high reinforcement content required. This study outlines the production process of stiffness-driven Ti-TiC MMCs displaying a remarkable ductility. The process consists in powder Mechanical Blending, Laser Powder Bed Fusion (LPBF), and a heat treatment. A TiC fraction of more than 20 vol% was formed in-situ through the reaction of titanium with carbon during the LPBF process. The as-built sub-stoichiometric TiC dendrites are converted in equiaxed TiC grains during the heat treatment. The TiC C/Ti ratio was found to be close to 0.5 in as-built conditions, and 0.7 in heat treated conditions, resulting in an effective reinforcement content nearly twice the one expected for stoichiometric TiC, leading to stronger reinforcement. The mechanical analysis revealed a Young’s modulus of up to 149 GPa and total elongations of up to 2.8 %. The former represents a 27 % improvement compared to commercially pure Titanium and the latter exceeds by 115 % reported values for LPBF Ti-MMCs with similar Young’s modulus. It is enabled by the in-situ formation of defect-free TiC reinforcements during the LPBF process combined with their globularisation through heat treatment.

Layer-wise laser-based additive manufacturing techniques offer immense versatility and flexibility in fabricating metallic composites with complex shapes. Interest in producing new multi-materials with advanced characteristics outpaces the available methods that provide insights into the bulk material formation, which in turn enables process and material optimisation. While some advanced operando studies enable highly local observations in the established metallic layers, the effect of intrinsic heat treatment inherent in the process in the bulk of the material is generally beyond reach of operando characterisation. Here, we approach the regime through advanced operando neutron imaging utilising a custom-designed laser powder bed fusion device on a neutron beamline. Operando polarisation contrast neutron imaging experiments were carried out during building centimetre-sized specimens with different powder premixture compositions of 316L and CuCrZr. The results of these full-field spatially resolved measurements reveal the quantitative evolution of ferromagnetic phases and temperature throughout the specimens and processing time.

Laser powder bed fusion of metals (PBF-LB/M) is a pivotal additive manufacturing technique that enables the production of intricate components. In addition to enabling the production of complex shapes, it allows for a high degree of freedom in manipulating the microstructure. The present investigation explores the manipulation of the crystallographic texture in AISI 304L stainless steels via PBF-LB/M, due to the possibility of tailoring the secondary hardening phenomena. Neutron diffraction provides efficient texture assessment, while decision tree regression reveals the complex interplay between processing parameters and the resulting crystallographic textures. Our investigation identifies the optimal PBF-LB/M processing parameters for obtaining strong texture along the build and laser scan directions. Additionally, microstructural characterisation of selected samples reveals the complex solidification structures. By employing advanced characterisation techniques and machine learning, this work provides insights into achieving or avoiding specific crystallographic textures during PBF-LB/M processing of stainless steels or other materials.