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Although comprehensive biomarker testing is recommended for all patients with advanced/metastatic non-small cell lung cancer (NSCLC) before initiation of first-line treatment, tissue availability can limit testing. Genomic testing in liquid biopsies can be utilized to overcome the inherent limitations of tissue sampling and identify the most appropriate biomarker-informed treatment option for patients. The Blood First Assay Screening Trial is a global, open-label, multicohort trial that evaluates the efficacy and safety of multiple therapies in patients with advanced/metastatic NSCLC and targetable alterations identified by liquid biopsy. We present data from Cohort D ( ROS1 -positive). Patients ≥18 years of age with stage IIIB/IV, ROS1 -positive NSCLC detected by liquid biopsies received entrectinib 600 mg daily. At data cutoff (November 2021), 55 patients were enrolled and 54 had measurable disease. Cohort D met its primary endpoint: the confirmed objective response rate (ORR) by investigator was 81.5%, which was consistent with the ORR from the integrated analysis of entrectinib (investigator-assessed ORR, 73.4%; data cutoff May 2019, ≥12 months of follow-up). The safety profile of entrectinib was consistent with previous reports. These results demonstrate consistency with those from the integrated analysis of entrectinib in patients with ROS1 -positive NSCLC identified by tissue-based testing, and support the clinical value of liquid biopsies to inform clinical decision-making. The integration of liquid biopsies into clinical practice provides patients with a less invasive diagnostic method than tissue-based testing and has faster turnaround times that may expedite the reaching of clinical decisions in the advanced/metastatic NSCLC setting. ClinicalTrials.gov registration: NCT03178552 . Results from this single-arm cohort of the BFAST trial showed that the clinical efficacy of entrectinib in patients with ROS1 -positive NSCLC, selected using liquid biopsies, is consistent with that seen in previous reports where patients were selected using tissue-based testing methods.

Tryptase, the most abundant mast cell granule protein, is elevated in severe asthma patients independent of type 2 inflammation status. Higher active β tryptase allele counts are associated with higher levels of peripheral tryptase and lower clinical benefit from anti-IgE therapies. Tryptase is a therapeutic target of interest in severe asthma and chronic spontaneous urticaria. Active and inactive allele counts may enable stratification to assess response to therapies in asthmatic patient subpopulations. Tryptase gene loci TPSAB1 and TPSB2 have high levels of sequence identity, which makes genotyping a challenging task. Here, we report a targeted next-generation sequencing (NGS) assay and downstream bioinformatics analysis for determining polymorphisms at tryptase TPSAB1 and TPSB2 loci. Machine learning modeling using multiple polymorphisms in the tryptase loci was used to improve the accuracy of genotyping calls. The assay was tested and qualified on DNA extracted from whole blood of healthy donors and asthma patients, achieving accuracy of 96%, 96% and 94% for estimation of inactive α and βΙΙΙ FS tryptase alleles and α duplication on TPSAB1 , respectively. The reported NGS assay is a cost-effective method that is more efficient than Sanger sequencing and provides coverage to evaluate known as well as unreported tryptase polymorphisms.

BackgroundCD8+ tissue-resident memory T (TRM) cells, marked by CD103 (ITGAE) expression, are thought to actively suppress cancer progression, leading to the hypothesis that their presence in tumors may predict response to immunotherapy.MethodsHere, we test this by combining high-dimensional single-cell modalities with bulk tumor transcriptomics from 1868 patients enrolled in lung and bladder cancer clinical trials of atezolizumab (anti-programmed cell death ligand 1 (PD-L1)).ResultsITGAE was identified as the most significantly upregulated gene in inflamed tumors. Tumor CD103+ CD8+ TRM cells exhibited a complex phenotype defined by the expression of checkpoint regulators, cytotoxic proteins, and increased clonal expansion.ConclusionsOur analyses indeed demonstrate that the presence of CD103+ CD8+ TRM cells, quantified by tracking intratumoral CD103 expression, can predict treatment outcome, suggesting that patients who respond to PD-1/PD-L1 blockade are those who exhibit an ongoing antitumor T-cell response.

We present the first study of spatially integrated higher-order stellar kinematics over cosmic time. We use deep rest-frame optical spectroscopy of quiescent galaxies at redshifts z=0.05, 0.3 and 0.8 from the SAMI, MAGPI and LEGA-C surveys to measure the excess kurtosis \\(h_4\\) of the stellar velocity distribution, the latter parametrised as a Gauss-Hermite series. Conservatively using a redshift-independent cut in stellar mass (\\(M_\\star = 10^{11}\\,{\\rm M}_\\odot\\)), and matching the stellar-mass distributions of our samples, we find 7 \\(\\sigma\\) evidence of \\(h_4\\) increasing with cosmic time, from a median value of 0.019\\(\\pm\\)0.002 at z=0.8 to 0.059\\(\\pm\\)0.004 at z=0.06. Alternatively, we use a physically motivated sample selection, based on the mass distribution of the progenitors of local quiescent galaxies as inferred from numerical simulations; in this case, we find 10 \\(\\sigma\\) evidence. This evolution suggests that, over the last 7 Gyr, there has been a gradual decrease in the rotation-to-dispersion ratio and an increase in the radial anisotropy of the stellar velocity distribution, qualitatively consistent with accretion of gas-poor satellites. These findings demonstrate that massive galaxies continue to accrete mass and increase their dispersion support after becoming quiescent.

We present the first statistical study of spatially integrated non-Gaussian stellar kinematics spanning 7 Gyr in cosmic time. We use deep, rest-frame optical spectroscopy of massive galaxies (stellar mass \\(M_\\star > 10^{10.5} {\\rm M}_\\odot\\)) at redshifts z = 0.05, 0.3 and 0.8 from the SAMI, MAGPI and LEGA-C surveys, to measure the excess kurtosis \\(h_4\\) of the stellar velocity distribution, the latter parametrised as a Gauss-Hermite series. We find that at all redshifts where we have large enough samples, \\(h_4\\) anti-correlates with the ratio between rotation and dispersion, highlighting the physical connection between these two kinematic observables. In addition, and independently from the anti-correlation with rotation-to-dispersion ratio, we also find a correlation between \\(h_4\\) and \\(M_\\star\\), potentially connected to the assembly history of galaxies. In contrast, after controlling for mass, we find no evidence of independent correlation between \\(h_4\\) and aperture velocity dispersion or galaxy size. These results hold for both star-forming and quiescent galaxies. For quiescent galaxies, \\(h_4\\) also correlates with projected shape, even after controlling for the rotation-to-dispersion ratio. At any given redshift, star-forming galaxies have lower \\(h_4\\) compared to quiescent galaxies, highlighting the link between kinematic structure and star-forming activity.