Anaplastic lymphoma kinase (ALK) rearrangements are present in about 5–6% of non-small cell lung cancer (NSCLC) cases and associated with increased risks of central nervous system (CNS) involvement. Envonalkib, a novel ALK inhibitor, demonstrated promising anti-tumor activity and safety in advanced ALK-positive NSCLC in the first-in-human phase I study. This phase III trial (ClinicalTrials.gov NCT04009317) investigated the efficacy and safety of first-line envonalkib in advanced ALK-positive NSCLC cases. Totally 264 participants were randomized 1:1 to receive envonalkib (n = 131) or crizotinib (n = 133). Median independent review committee (IRC)-assessed progression-free survival (PFS) times were 24.87 (95% confidence interval [CI]: 15.64–30.36) and 11.60 (95% CI: 8.28–13.73) months in the envonalkib and crizotinib groups, respectively (hazard ratio [HR] = 0.47, 95% CI: 0.34–0.64, p < 0.0001). IRC-assessed confirmed objective response rate (ORR) was higher (81.68% vs. 70.68%, p = 0.056) and duration of response was longer (median, 25.79 [95% CI, 16.53–29.47] vs. 11.14 [95% CI, 9.23–16.59] months, p = 0.0003) in the envonalkib group compared with the crizotinib group. In participants with baseline brain target lesions, IRC-assessed CNS-ORR was improved with envonalkib compared with crizotinib (78.95% vs. 23.81%). Overall survival (OS) data were immature, and median OS was not reached in either group (HR = 0.84, 95% CI: 0.48–1.47, p = 0.5741). The 12-month OS rates were 90.6% (95% CI, 84.0%–94.5%) and 89.4% (95% CI, 82.8%–93.6%) in the envonalkib and crizotinib groups, respectively. Grade ≥3 treatment-related adverse events were observed in 55.73% and 42.86% of participants in the envonalkib and crizotinib groups, respectively. Envonalkib significantly improved PFS and delayed brain metastasis progression in advanced ALK-positive NSCLC.

PurposeTo predict the International Neuroblastoma Pathology Classification (INPC) in neuroblastoma using a computed tomography (CT)-based radiomics approach.MethodsWe enrolled 297 patients with neuroblastoma retrospectively and divided them into a training group (n = 208) and a testing group (n = 89). To balance the classes in the training group, a Synthetic Minority Over-sampling Technique was applied. A logistic regression radiomics model based on the radiomics features after dimensionality reduction was then constructed and validated in both the training and testing groups. To evaluate the diagnostic performance of the radiomics model, the receiver operating characteristic curve and calibration curve were utilized. Moreover, the decision curve analysis to assess the net benefits of the radiomics model at different high-risk thresholds was employed.ResultsSeventeen radiomics features were used to construct radiomics model. In the training group, radiomics model achieved an area under the curve (AUC), accuracy, sensitivity, and specificity of 0.851 (95% confidence interval (CI) 0.805–0.897), 0.770, 0.694, and 0.847, respectively. In the testing group, radiomics model achieved an AUC, accuracy, sensitivity, and specificity of 0.816 (95% CI 0.725–0.906), 0.787, 0.793, and 0.778, respectively. The calibration curve indicated that the radiomics model was well fitted in both the training and testing groups (p > 0.05). Decision curve analysis further confirmed that the radiomics model performed well at different high-risk thresholds.ConclusionRadiomics analysis of contrast-enhanced CT demonstrates favorable diagnostic capabilities in distinguishing the INPC subgroups of neuroblastoma.Graphical AbstractCritical relevance statementRadiomics features of contrast-enhanced CT images correlate with the International Neuroblastoma Pathology Classification (INPC) of neuroblastoma.

Aerobic exercise effectively ameliorates mental disorders including anxiety and depression. Current findings mainly attribute its neural mechanism to the improvement of adult neurogenesis, while leaving the possible circuitry mechanism unclear. In the current study, we identify the overexcitation of the medial prefrontal cortex (mPFC) to basolateral amygdala (BLA) pathway under chronic restraint stress (CRS), and 14-day treadmill exercise selectively reverses such abnormalities. Using chemogenetic approaches, we find that the mPFC-BLA circuit is necessary for preventing anxiety-like behaviors in CRS mice. These results collectively suggest a neural circuitry mechanism by which exercise training improves the resilience against environmental stress.

BackgroundDespite epidemiological evidence associating gallstone disease (GSD) with cardiovascular disease (CVD), a dilemma remains on the role of cholecystectomy in modifying the risk of CVD. We aimed to characterize the phenotypic and genetic relationships between GSD and two CVD events – stroke and coronary artery disease (CAD).MethodsWe first performed a meta-analysis of cohort studies to quantify an overall phenotypic association between GSD and CVD. We then investigated the genetic relationship leveraging the largest genome-wide genetic summary statistics. We finally examined the phenotypic association using the comprehensive data from UK Biobank (UKB).ResultsAn overall significant effect of GSD on CVD was found in meta-analysis (relative risk [RR] = 1.26, 95% confidence interval [CI] = 1.19–1.34). Genetically, a positive shared genetic basis was observed for GSD with stroke (rg\documentclass[12pt]{minimal}\usepackage{amsmath}\usepackage{wasysym}\usepackage{amsfonts}\usepackage{amssymb}\usepackage{amsbsy}\usepackage{mathrsfs}\usepackage{upgreek}\setlength{\oddsidemargin}{-69pt}\begin{document}$${r}_{g}$$\end{document}=0.16, P = 6.00 × 10–4) and CAD (rg\documentclass[12pt]{minimal}\usepackage{amsmath}\usepackage{wasysym}\usepackage{amsfonts}\usepackage{amssymb}\usepackage{amsbsy}\usepackage{mathrsfs}\usepackage{upgreek}\setlength{\oddsidemargin}{-69pt}\begin{document}$${r}_{g}$$\end{document}=0.27, P = 2.27 × 10–15), corroborated by local signals. The shared genetic architecture was largely explained by the multiple pleiotropic loci identified in cross-phenotype association study and the shared gene-tissue pairs detected by transcriptome-wide association study, but not a causal relationship (GSD to CVD) examined through Mendelian randomization (MR) (GSD-stroke: odds ratio [OR] = 1.00, 95%CI = 0.97–1.03; GSD-CAD: OR = 1.01, 95%CI = 0.98–1.04). After a careful adjustment of confounders or considering lag time using UKB data, no significant phenotypic effect of GSD on CVD was detected (GSD-stroke: hazard ratio [HR] = 0.95, 95%CI = 0.83–1.09; GSD-CAD: HR = 0.98, 95%CI = 0.91–1.06), further supporting MR findings.ConclusionsOur work demonstrates a phenotypic and genetic relationship between GSD and CVD, highlighting a shared biological mechanism rather than a direct causal effect. These findings may provide insight into clinical and public health applications.

BackgroundCancer immunotherapy has demonstrated significant clinical activity in different cancers. T cells represent a crucial component of the adaptive immune system and are thought to mediate anti-tumoral immunity. Antigen-specific recognition by T cells is via the T cell receptor (TCR) which is unique for each T cell. Next generation sequencing (NGS) of the TCRs can be used as a platform to profile the T cell repertoire. Though there are a number of software tools available for processing repertoire data by mapping antigen receptor segments to sequencing reads and assembling the clonotypes, most of them are not designed to track and examine the dynamic nature of the TCR repertoire across multiple time points or between different biologic compartments (e.g., blood and tissue samples) in a clinical context.ResultsWe integrated different diversity measures to assess the T cell repertoire diversity and examined the robustness of the diversity indices. Among those tested, Clonality was identified for its robustness as a key metric for study design and the first choice to measure TCR repertoire diversity. To evaluate the dynamic nature of T cell clonotypes across time, we utilized several binary similarity measures (such as Baroni-Urbani and Buser overlap index), relative clonality and Morisita’s overlap index, as well as the intraclass correlation coefficient, and performed fold change analysis, which was further extended to investigate the transition of clonotypes among different biological compartments. Furthermore, the application of differential testing enabled the detection of clonotypes which were significantly changed across time. By applying the proposed “3D” analysis pipeline to the real example of prostate cancer subjects who received sipuleucel-T, an FDA-approved immunotherapy, we were able to detect changes in TCR sequence frequency and diversity thus demonstrating that sipuleucel-T treatment affected TCR repertoire in blood and in prostate tissue. We also found that the increase in common TCR sequences between tissue and blood after sipuleucel-T treatment supported the hypothesis that treatment-induced T cell migrated into the prostate tissue. In addition, a second example of prostate cancer subjects treated with Ipilimumab and granulocyte macrophage colony stimulating factor (GM-CSF) was presented in the supplementary documents to further illustrate assessing the treatment-associated change in a clinical context by the proposed workflow.ConclusionsOur paper provides guidance to study the diversity and dynamics of NGS-based TCR repertoire profiling in a clinical context to ensure consistency and reproducibility of post-analysis. This analysis pipeline will provide an initial workflow for TCR sequencing data with serial time points and for comparing T cells in multiple compartments for a clinical study.