In Vivo Disruption of TGF-β Signaling by Smad7 in Airway Epithelium Alleviates Allergic Asthma but Aggravates Lung Carcinogenesis in Mouse

BACKGROUND: TGF-beta has been postulated to play an important role in the maintenance of epithelial homeostasis and the development of epithelium-derived cancers. However, most of previous studies are mainly focused on the function of TGF-beta in immune cells to the development of allergic asthma and how TGF-beta signaling in airway epithelium itself in allergic inflammation is largely unknown. Furthermore, the in vivo TGF-beta function specifically in the airway epithelium during lung cancer development has been largely elusive. METHODOLOGY/PRINCIPAL FINDINGS: To evaluate the in vivo contribution of TGF-beta signaling in lung epithelium to the development of allergic disease and lung cancer, we generated a transgenic mouse model with Smad7, an intracellular inhibitor of TGF-beta signaling, constitutively expressed in mouse airway Clara cells using a mouse CC10 promoter. The mice were subjected to the development of OVA-induced allergic asthma and urethane-induced lung cancer. The Smad7 transgenic animals significantly protected from OVA-induced asthma, with reduced airway inflammation, airway mucus production, extracellular matrix deposition, and production of OVA-specific IgE. Further analysis of cytokine profiles in lung homogenates revealed that the Th2 cytokines including IL-4, IL-5 and IL-13, as well as other cytokines including IL-17, IL-1, IL-6, IP10, G-CSF, and GM-CSF were significantly reduced in the transgenic mice upon OVA induction. In contrast, the Smad7 transgenic animals had an increased incidence of lung carcinogenesis when subjected to urethane treatment. CONCLUSION/SIGNIFICANCE: These studies, therefore, demonstrate for the first time the in vivo function of TGF-beta signaling specifically in airway epithelium during the development of allergic asthma and lung cancer

Hyperpolarization-activated cyclic nucleotide-gated cation channel 3 promotes HCC development in a female-biased manner

Sex differences in hepatocellular carcinoma (HCC) development are regulated by sex and non-sex chromosomes, sex hormones, and environmental factors. We previously reported that Ncoa5(+/-) mice develop HCC in a male-biased manner. Here we show that NCOA5 expression is reduced in male patient HCCs while the expression of an NCOA5-interacting tumor suppressor, TIP30, is lower in female HCCs. Tip30 heterozygous deletion does not change HCC incidence in Ncoa5(+/-) male mice but dramatically increases HCC incidence in Ncoa5(+/-) female mice, accompanied by hepatic hyperpolarization-activated cyclic nucleotide-gated cation channel 3 (HCN3) overexpression. HCN3 overexpression cooperates with MYC to promote mouse HCC development, whereas Hcn3 knockout preferentially hinders HCC development in female mice. Furthermore, HCN3 amplification and overexpression occur in human HCCs and correlate with a poorer prognosis of patients in a female-biased manner. Our results suggest that TIP30 and NCOA5 protect against female liver oncogenesis and that HCN3 is a female-biased HCC driver

New model-based bioequivalence statistical approaches for pharmacokinetic studies with sparse sampling

In traditional pharmacokinetic (PK) bioequivalence analysis, two one-sided tests (TOST) are conducted on the area under the concentration-time curve and the maximal concentration derived using a non-compartmental approach. When rich sampling is unfeasible, a model-based (MB) approach, using nonlinear mixed effect models (NLMEM) is possible. However, MB-TOST using asymptotic standard errors (SE) presents increased type I error when asymptotic conditions do not hold. Methods : In this work, we propose three alternative calculations of the SE based on i) an adaptation to NLMEM of the correction proposed by Gallant, ii) the a posteriori distribution of the treatment coefficient using the Hamiltonian Monte Carlo algorithm, and iii) parametric random effects and residual errors bootstrap. We evaluate these approaches by simulations, for two-arms parallel and two-periods two-sequences cross-over design with rich (n=10) and sparse (n=3) sampling under the null and the alternative hypotheses, with MB-TOST. Results: All new approaches correct for the in ation of MB-TOST type I error in PK studies with sparse designs. The approach based on the a posteriori distribution appears to be the best compromise between controlled type I errors and computing times. Conclusion: MB-TOST using non-asymptotic SE controls type I error rate better than when using asymptotic SE estimates for bioequivalence on PK studies with sparse sampling

WNT3 promotes chemoresistance to 5-Fluorouracil in oral squamous cell carcinoma via activating the canonical β-catenin pathway

Abstract Background 5-Fluorouracil (5FU) is a primary chemotherapeutic agent used to treat oral squamous cell carcinoma (OSCC). However, the development of drug resistance has significantly limited its clinical application. Therefore, there is an urgent need to determine the mechanisms underlying drug resistance and identify effective targets. In recent years, the Wingless and Int-1 (WNT) signaling pathway has been increasingly studied in cancer drug resistance; however, the role of WNT3, a ligand of the canonical WNT signaling pathway, in OSCC 5FU-resistance is not clear. This study delved into this potential connection. Methods 5FU-resistant cell lines were established by gradually elevating the drug concentration in the culture medium. Differential gene expressions between parental and resistant cells underwent RNA sequencing analysis, which was then substantiated via Real-time quantitative PCR (RT-qPCR) and western blot tests. The influence of the WNT signaling on OSCC chemoresistance was ascertained through WNT3 knockdown or overexpression. The WNT inhibitor methyl 3-benzoate (MSAB) was probed for its capacity to boost 5FU efficacy. Results In this study, the WNT/β-catenin signaling pathway was notably activated in 5FU-resistant OSCC cell lines, which was confirmed through transcriptome sequencing analysis, RT-qPCR, and western blot verification. Additionally, the key ligand responsible for pathway activation, WNT3, was identified. By knocking down WNT3 in resistant cells or overexpressing WNT3 in parental cells, we found that WNT3 promoted 5FU-resistance in OSCC. In addition, the WNT inhibitor MSAB reversed 5FU-resistance in OSCC cells. Conclusions These data underscored the activation of the WNT/β-catenin signaling pathway in resistant cells and identified the promoting effect of WNT3 upregulation on 5FU-resistance in oral squamous carcinoma. This may provide a new therapeutic strategy for reversing 5FU-resistance in OSCC cells

Pool Boiling Performance of Multilayer Micromeshes for Commercial High-Power Cooling

With the rapid development of electronics, thermal management has become one of the most crucial issues. Intense research has focused on surface modifications used to enhance heat transfer. In this study, multilayer copper micromeshes (MCMs) are developed for commercial compact electronic cooling. Boiling heat transfer performance, including critical heat flux (CHF), heat transfer coefficients (HTCs), and the onset of nucleate boiling (ONB), are investigated. The effect of micromesh layers on the boiling performance is studied, and the bubbling characteristics are analyzed. In the study, MCM-5 shows the highest critical heat flux (CHF) of 207.5 W/cm2 and an HTC of 16.5 W(cm2·K) because of its abundant micropores serving as nucleate sites, and outstanding capillary wicking capability. In addition, MCMs are compared with other surface structures in the literature and perform with high competitiveness and potential in commercial applications for high-power cooling

FinChain-BERT: A High-Accuracy Automatic Fraud Detection Model Based on NLP Methods for Financial Scenarios

This research primarily explores the application of Natural Language Processing (NLP) technology in precision financial fraud detection, with a particular focus on the implementation and optimization of the FinChain-BERT model. Firstly, the FinChain-BERT model has been successfully employed for financial fraud detection tasks, improving the capability of handling complex financial text information through deep learning techniques. Secondly, novel attempts have been made in the selection of loss functions, with a comparison conducted between negative log-likelihood function and Keywords Loss Function. The results indicated that the Keywords Loss Function outperforms the negative log-likelihood function when applied to the FinChain-BERT model. Experimental results validated the efficacy of the FinChain-BERT model and its optimization measures. Whether in the selection of loss functions or the application of lightweight technology, the FinChain-BERT model demonstrated superior performance. The utilization of Keywords Loss Function resulted in a model achieving 0.97 in terms of accuracy, recall, and precision. Simultaneously, the model size was successfully reduced to 43 MB through the application of integer distillation technology, which holds significant importance for environments with limited computational resources. In conclusion, this research makes a crucial contribution to the application of NLP in financial fraud detection and provides a useful reference for future studies

Prognostic Value of Cardiac Magnetic Resonance in Assessing Right Ventricular Strain in Cardiovascular Disease: A Systematic Review and Meta-Analysis

Objective: To evaluate the prognostic value of cardiac magnetic resonance (CMR) imaging in assessing right ventricular strain via meta-analysis of current literature. Background: Right ventricular strain recorded with CMR serves as a novel indicator to quantify myocardial deformation. Although several studies have reported the predictive value of right ventricular strain determined using CMR, their validity is limited by small sample size and low event number. Methods: Embase, Medline and Web of Science were searched for studies assessing the prognostic value of myocardial strain. The primary endpoint was a composite of all-cause mortality, cardiovascular death, aborted sudden cardiac death, heart transplantation and heart failure admissions. Results: A total of 14 studies met the selection criteria and were included in the analysis (n = 3239 adults). The random-effects model showed the association of parameters of right ventricular strain with major adverse cardiac events. Absolute value of right ventricular global longitudinal strain was negatively correlated with right ventricular ejection fraction (hazard ratio: 1.07, 95% confidence interval: 1.05–1.08; p = 0.013). Despite the small number of studies, right ventricular radial strain, right ventricular circumferential strain and right ventricular long-axis strain displayed potential prognostic value. Conclusions: Right ventricular strain measured with CMR is an effective prognostic indicator for cardiovascular disease

Model-based bioequivalence approach for sparse pharmacokinetic bioequivalence studies: Model selection or model averaging?

International audienceConventional pharmacokinetic (PK) bioequivalence (BE) studies aim to compare the rate and extent of drug absorption from a test (T) and reference (R) product using non‐compartmental analysis (NCA) and the two one‐sided test (TOST). Recently published regulatory guidance recommends alternative model‐based (MB) approaches for BE assessment when NCA is challenging, as for long‐acting injectables and products which require sparse PK sampling. However, our previous research on MB‐TOST approaches showed that model misspecification can lead to inflated type I error. The objective of this research was to compare the performance of model selection (MS) on R product arm data and model averaging (MA) from a pool of candidate structural PK models in MBBE studies with sparse sampling. Our simulation study was inspired by a real case BE study using a two‐way crossover design. PK data were simulated using three structural models under the null hypothesis and one model under the alternative hypothesis. MB‐TOST was applied either using each of the five candidate models or following MS and MA with or without the simulated model in the pool. Assuming T and R have the same PK model, our simulation shows that following MS and MA, MB‐TOST controls type I error rates at or below 0.05 and attains similar or even higher power than when using the simulated model. Thus, we propose to use MS prior to MB‐TOST for BE studies with sparse PK sampling and to consider MA when candidate models have similar Akaike information criterion

Evaluation of model‐based bioequivalence approach for single sample pharmacokinetic studies

International audienceAbstract In a traditional pharmacokinetic (PK) bioequivalence (BE) study, a two‐way crossover study is conducted, PK parameters (namely the area under the time‐concentration curve [AUC] and the maximal concentration []) are obtained by noncompartmental analysis (NCA), and the BE analysis is performed using the two one‐sided test (TOST) method. For ophthalmic drugs, however, only one sample of aqueous humor, in one eye, per eye can be obtained in each patient, which precludes the traditional BE analysis. To circumvent this issue, the U.S. Food and Drug Administration (FDA) has proposed an approach coupling NCA with either parametric or nonparametric bootstrap (NCA bootstrap). The model‐based TOST (MB‐TOST) has previously been proposed and evaluated successfully for various settings of sparse PK BE studies. In this paper, we evaluate, via simulations, MB‐TOST in the specific setting of single sample PK BE study and compare its performance to NCA bootstrap. We performed BE study simulations using a published PK model and parameter values and evaluated multiple scenarios, including study design (parallel or crossover), sampling times (5 or 10 spread across the dosing interval), and geometric mean ratio (of 0.8, 0.9, 1, and 1.25). Using the simulated structural PK model, MB‐TOST performed similarly to NCA bootstrap for AUC. For , the latter tended to be conservative and less powerful. Our research suggests that MB‐TOST may be considered as an alternative BE approach for single sample PK studies, provided that the PK model is correctly specified and the test drug has the same structural model as the reference drug