Explore the vast range of titles available.

The identification of novel and effective therapeutic targets for oral squamous cell carcinoma (OSCC) is of paramount importance. This study investigates the expression, potential functions, and mechanistic insights of G protein inhibitory subunit 3 (Gαi3) in OSCC. Gαi3 is found to be upregulated in human OSCC tissues as well as in various primary and established OSCC cells. In different OSCC cells, silencing of Gαi3 through shRNA resulted in inhibited cell proliferation and migration, while also inducing apoptosis. Knockout (KO) of Gαi3 via the CRISPR/Cas9 method produced significant anti-cancer effects in OSCC cells. Conversely, ectopic overexpression of Gαi3 enhanced OSCC cell growth, promoting cell proliferation and migration. Gαi3 plays a crucial role in activating the Akt-mTOR signaling pathway in OSCC cells. Silencing or KO of Gαi3 led to decreased phosphorylation levels of Akt and S6K, whereas overexpression of Gαi3 increased their phosphorylation. Restoration of Akt-mTOR activation through a constitutively active mutant Akt1 mitigated the anti-OSCC effects induced by Gαi3 shRNA. In vivo, Gαi3 silencing significantly suppressed the growth of subcutaneous OSCC xenografts in nude mice, concomitant with inactivation of the Akt-mTOR pathway and induction of apoptosis. Collectively, these findings underscore the critical role of Gαi3 in OSCC cell growth both in vitro and in vivo.

Serum tumor markers carcinoembryonic antigen (CEA), cancer antigen 125 (CA125), cytokeratin 19 fragment (CYFRA21-1) and squamous-cell carcinoma-related antigen (SCC-Ag) are routinely used for monitoring the response to chemotherapy or targeted therapy in advanced-stage non-small cell lung cancer (NSCLC), however their role in immunotherapy remains unclear. The aim of this study was to investigate whether dynamics of these serum markers were associated with the efficacy and prognosis of Chinese late-stage NSCLC patients treated with programmed cell death-1/programmed cell death ligand-1 (PD-1/PD-L1) inhibitors. We initiated a longitudinal prospective study on advanced NSCLC patients treated with PD-1/PD-L1 inhibitors in Chinese PLA general hospital (Beijing, China). Blood samples of baseline and after 6 weeks' treatment were collected. CT scan were used by all patients to evaluate treatment efficacy according to RECIST 1.1. Serum tumor markers levels were measured with an electrochemical luminescence for SCC-Ag and with a chemiluminescent microparticle immunoassay for serum CEA, CA125, and CYFRA21-1. At least 20% decreases of the biomarkers from baseline were considered as meaningful improvements after 6 weeks of treatment with immune checkpoint inhibitors (ICIs). Optimization-based method was used to balance baseline covariates between different groups. Associations between serum tumor biomarker improvements and objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) were analyzed. A total of 308 Chinese patients with advanced NSCLC were enrolled in the study. After balancing baseline covariates, patients with meaningful improvements in <2 out of 4 biomarkers (CEA, CA125, CYFRA21-1, and SCC-Ag) was ended up with lower ORR (0.08 vs. 0.35, < 0.001), shorten PFS (median: 5.4 vs. 12.5 months, < 0.001), and OS (median: 11.7 vs. 25.6 months, < 0.001) in the total population. Subgroup analysis of patients with adenocarcinoma revealed that patients with meaningful improvements in <2 out of 4 biomarkers had significant lower ORR (0.06 vs. 0.36, < 0.001), shorten PFS (median: 4.1 vs. 11.9 months, < 0.001), and OS (median: 11.9 vs. 24.2 months, < 0.001). So as in patients with squamous cell carcinoma, meaningful improvements in at least 2 out of 4 biomarkers were linked to better ORR (0.42 vs. 0.08, = 0.014), longer PFS (median: 13.1 vs. 5.6 months, = 0.001), and OS (median: 25.6 vs. 10.9 months, = 0.06). The dynamic change of CEA, CA125, CYFRA21-1, and SCC-Ag from baseline have prognostic value for late-stage NSCLC patients treated with PD-1/PD-L1 inhibitors. Decrease of associated biomarkers serum levels were associated with favorable clinical outcomes.

Mantle cell lymphoma (MCL) is a mature B-cell neoplasm with a high initial response rate followed almost invariably by relapse. Here we report the pooled data from 2 studies, BGB-3111-AU-003 and BGB-3111-206, to explore the efficacy of zanubrutinib monotherapy in relapsed/refractory (R/R) MCL. A total of 112 patients were included. Median follow-up durations were 24.7 and 24.9 months for BGB-3111-AU-003 and BGB-3111-206, respectively. Overall response rate (ORR) and complete response (CR) rate were 84.8% and 62.5%, and median duration of response, progression-free survival (PFS) and overall survival (OS) were 24.9, 25.8 and 38.2 months, respectively. After weighting, the PFS (median: NE vs. 21.1 months, P  = 0.235) and OS (median: NE vs. 38.2 months, P  = 0.057) were similar but numerically better in the second-line than later-line group. Zanubrutinib was well-tolerated with treatment discontinuation and dose reduction for adverse events in 12.5% and 2.7% of patients, respectively. Hypertension, major hemorrhage and atrial fibrillation/flutter rates were 11.6%, 5.4% and 1.8%, respectively. Zanubrutinib is efficacious in R/R MCL, with a favorable safety profile.

The mutation of K‐RAS represents one of the most frequent genetic alterations in cancer. Targeting of downstream effectors of RAS, including of MEK and ERK, has limited clinical success in cancer patients with K‐RAS mutations. The reduced sensitivity of K‐RAS‐mutated cells to certain MEK inhibitors (MEKi) is associated with the feedback phosphorylation of MEK by C‐RAF and with the reactivation of mitogen‐activated protein kinase (MAPK) signaling. Here, we report that the RAF dimer inhibitors lifirafenib (BGB‐283) and compound C show a strong synergistic effect with MEKi, including mirdametinib (PD‐0325901) and selumetinib, in suppressing the proliferation of K‐RAS‐mutated non‐small‐cell lung cancer and colorectal cancer (CRC) cell lines. This synergistic effect was not observed with the B‐RAFV600E selective inhibitor vemurafenib. Our mechanistic analysis revealed that RAF dimer inhibition suppresses RAF‐dependent MEK reactivation and leads to the sustained inhibition of MAPK signaling in K‐RAS‐mutated cells. This synergistic effect was also observed in several K‐RAS mutant mouse xenograft models. A pharmacodynamic analysis supported a role for the synergistic phospho‐ERK blockade in enhancing the antitumor activity observed in the K‐RAS mutant models. These findings support a vertical inhibition strategy in which RAF dimer and MEKi are combined to target K‐RAS‐mutated cancers, and have led to a Phase 1b/2 combination therapy study of lifirafenib and mirdametinib in solid tumor patients with K‐RAS mutations and other MAPK pathway aberrations. The reduced sensitivity of K‐RAS‐mutated cancer cells to MEK inhibitors (MEKi), such as selumetinib and mirdametinib, is associated with feedback phosphorylation of MEK by upstream RAF reactivation. RAF dimer inhibitors, such as lifirafenib and compound C, in combination with MEKi potently suppress RAF‐dependent MEK phosphorylation and lead to sustained inhibition of MAPK signaling and tumor growth.

With the gradual popularization of consumer-grade drones, the abuse of drones by people has led to an increasing potential hazard of drones in daily life. The demand for the prevention and control of drones in key areas and important activities has become more and more urgent. Due to the serious dependence of drones on satellite navigation systems, as well as the characteristics of the satellite navigation signals themselves, such as weak signal strength and publicly available format, this paper analyzes the countermeasure methods against drones by means of suppressing interference and spoofing interference targeting navigation signals, conducts field measurement experiments, and achieves the goal of countering drones through the application of satellite navigation spoofing interference and suppressing interference.

In the current work, the effects of biochar, vermicompost, as well as their combined application on ammonia-oxidizing archaea (AOA) and ammonia-oxidizing bacteria (AOB) in soils contaminated with potentially toxic elements (PTEs) were investigated. In this regard, four treatments were performed; among them, treatment A served as a control without additive, treatment B with vermicompost (2%), treatment C with biochar (2%), and treatment D with biochar (2%) plus vermicompost (2%). In addition, the abundance and structure of the AOA and AOB amoA gene were measured using quantitative PCR and high-throughput sequencing. The relationships between the microbial community, physicochemical parameters, and CaCl2-extractable PTEs were analyzed using the Pearson correlation method. We found that adding biochar and vermicompost promoted the immobilization of PTEs and nitrogen biotransformation. The rational use of biochar and vermicompost is beneficial for the growth of bacterial and fungal communities in soils polluted by PTEs. AOA and AOB amoA genes were stimulated by biochar, vermicompost, and their combination, but their structure was hardly affected.

This paper considers a new way of parameterizing mixture models where parameters are interpreted as the generalized moments of the mixing distribution. Following a dimensionality reduction approach, approximate models have a finite-dimensional parameter with a corresponding parameter space: a moment space. The geometry of the moment space is studied and we derive the properties of the reconstructed mixing distributions. Links between the reparameterization and estimation methods for mixture models are also briefly discussed.

Abstract Introduction Assessing cognitive and functional changes at the early stage of Alzheimer's disease (AD) and detecting treatment effects in clinical trials for early AD are challenging. Methods Under the assumption that transformed versions of the Mini–Mental State Examination, the Clinical Dementia Rating Scale–Sum of Boxes, and the Alzheimer's Disease Assessment Scale–Cognitive Subscale tests'/components' scores are from a multivariate linear mixed-effects model, we calculated the sample sizes required to detect treatment effects on the annual rates of change in these three components in clinical trials for participants with mild cognitive impairment. Results Our results suggest that a large number of participants would be required to detect a clinically meaningful treatment effect in a population with preclinical or prodromal Alzheimer's disease. We found that the transformed Mini–Mental State Examination is more sensitive for detecting treatment effects in early AD than the transformed Clinical Dementia Rating Scale–Sum of Boxes and Alzheimer's Disease Assessment Scale–Cognitive Subscale. The use of optimal weights to construct powerful test statistics or sensitive composite scores/endpoints can reduce the required sample sizes needed for clinical trials. Conclusion Consideration of the multivariate/joint distribution of components' scores rather than the distribution of a single composite score when designing clinical trials can lead to an increase in power and reduced sample sizes for detecting treatment effects in clinical trials for early AD.

Let B p n = { x ∈ ℝ n | ‖ x ‖ p ≤ 1 } be the unit ball in ℓ p n . We prove the inequalities for the volume of the B p n : V B p n + 1 1 n + 1 < V B p n 1 n 2 Γ ( 1 p + 1 ) p n + p p V B p n ≤ V B p n + 1 for all 𝑛 ≥ 1 and 𝑝 ≥ 1, where V B p n denotes the volumes of B p n . Furthermore, we obtain the upper and lower bounds of V B p n + 1 n n + 1 / V B p n and V B p n + 1 / V B p n . Our results are generalizations for inequalities in R𝑛proved and refined by G.D. Anderson et al., K.H. Borgwardt, D.A.Klain and G.-C. Rota and H. Alzer.