Design, synthesis, and antitumor activity evaluation of potent fourth-generation EGFR inhibitors for treatment of Osimertinib resistant non-small cell lung cancer (NSCLC).

Epidermal growth factor receptor (EGFR) is one of the most studied drug targets for treating non-small-cell lung cancer (NSCLC). However, there are no approved inhibitors for the C797S resistance mutation caused by the third-generation EGFR inhibitor (Osimertinib). Therefore, the development of fourth-generation EGFR inhibitors is urgent. In this study, we clarified the structure-activity relationship of several synthesized compounds as fourth-generation inhibitors against human triple (Del19/T790M/C797S) mutation. Representative compound 52 showed potent inhibitory activity against EGFRL858R/T790M/C797S with an IC50 of 0.55 nM and significantly inhibited the proliferation of the Ba/F3 cell line harboring EGFRL858R/T790M/C797S with an IC50 of 43.28 nM. Moreover, 52 demonstrated good pharmacokinetic properties and excellent in vivo efficacy. Overall, the compound 52 can be considered a promising candidate for overcoming EGFR C797S-mediated mutations.

Efficacy and immunogenicity of AS04-HPV-16/18 vaccine in females with existing cervical HR-HPV infection at first vaccination: A pooled analysis of four large clinical trials worldwide.

Females with existing high-risk HPV (HR-HPV) infections remain at risk of subsequent multiple or recurrent infections, on which benefit from HPV vaccines was under-reported. We pooled individual-level data from four large-scale, RCTs of AS04-HPV-16/18 vaccine to evaluate efficacy and immunogenicity in females DNA-positive to any HR-HPV types at first vaccination. Females receiving the AS04-HPV-16/18 vaccine in the original RCTs constituted the vaccine group in the present study, while those unvaccinated served as the control group. Vaccine efficacy (VE) against new infections and associated cervical intraepithelial neoplasia (CIN) 2+ in females DNA-negative to the considered HR-HPV type but positive to any other HR-HPV types, VE against reinfections in females DNA-positive to the considered HR-HPV type but cleared naturally during later follow-up, and levels of anti-HPV-16/18 IgG were assessed. Our final analyses included 5137 females (vaccine group = 2532, control group = 2605). The median follow-up time was 47.88 months (IQR: 45.72-50.04). For the prevention of precancerous lesions related to the non-infected HR-HPV types at baseline, VE against HPV-16/18 related CIN 2+ was 82.70% (95% CI: 63.70-93.00%). For the prevention of reinfections related to the infected HR-HPV types following natural clearance, VE against HPV-16/18 12MPI was non-significant (p > .05), albeit robust immunity persisted for at least 48 months. Females with existing HR-HPV infections at first vaccination still benefit from vaccination in preventing precancers related to the non-infected types at baseline. VE against reinfections related to the infected types following natural clearance remains to be further investigated.

Species sensitivities to artificial light at night: A phylogenetically controlled multilevel meta-analysis on melatonin suppression.

The rapid urbanization of our world has led to a surge in artificial lighting at night (ALAN), with profound effects on wildlife. Previous research on wildlife's melatonin, a crucial mechanistic indicator and mediator, has yielded inconclusive evidence due to a lack of comparative analysis. We compiled and analysed an evidence base including 127 experiments with 437 observations across 31 wild vertebrates using phylogenetically controlled multilevel meta-analytic models. The evidence comes mainly from the effects of white light on melatonin suppression in birds and mammals. We show a 36% average decrease in melatonin secretion in response to ALAN across a diverse range of species. This effect was observed for central and peripheral melatonin, diurnal and nocturnal species, and captive and free-living populations. We also reveal intensity-, wavelength-, and timing-dependent patterns of ALAN effects. Exposure to ALAN led to a 23% rise in inter-individual variability in melatonin suppression, with important implications for natural selection in wild vertebrates, as some individuals may display higher tolerance to ALAN. The cross-species evidence has strong implications for conservation of wild populations that are subject to natural selection of ALAN. We recommend measures to mitigate harmful impacts of ALAN, such as using 'smart' lighting systems to tune the spectra to less harmful compositions.

Magnetic resonance radiographic features which might lead to misdiagnosis of muscle-invasive bladder cancer based on vesical imaging reporting and data system: the application experience of a single center.

Background: The Vesical Imaging Reporting and Data System (VI-RADS) has been widely used for diagnosing muscle-invasive bladder cancer (MIBC), yet instances of misdiagnosis persist. However, limited research discusses the factors affecting its accuracy. This study aimed to evaluate the diagnostic efficacy of the VI-RADS in our center and to preliminarily identify possible magnetic resonance imaging (MRI) characteristics of misdiagnosis. Methods: From January 2018 to February 2023, a consecutive series of 211 participants pathologically diagnosed with bladder cancer (BC) who underwent an MRI exam were retrospectively enrolled. MRI was interpreted by 2 radiologists with different levels of experience, the diagnostic performance was validated using the receiver operating characteristic (ROC) curve, and VI-RADS ≥4 was considered to indicate MIBC-positive status. The clinical and radiographic characteristics of the true-positive (TP), true-negative (TN), false-positive (FP), and false-negative (FN) groups were analyzed using Kruskal-Wallis test or Fisher exact test. Results: With VI-RADS ≥4 as the cutoff value, the area under the ROC curves (AUCs) were 0.951 (0.912-0.976) and 0.847 (0.791-0.893) for the more-experienced reader and less-experienced reader, respectively, with good interobserver agreement (κ=0.74105). The median tumor size in the TP (more experienced: 57 cases; less experienced: 44 cases) and FP (more experienced: 8 cases; less experienced: 9 cases) groups was larger than that in the TN (more experienced: 141 cases; less experienced: 139 cases) group for the more-experienced reader (TP: 28 mm; FP: 31 mm; TN: 19 mm; P<0.001 and P=0.031, respectively) and the less-experienced reader (TP: 31 mm; FP: 28 mm; TN: 19 mm; P<0.001 and P=0.042, respectively). The tumor base in the TP and FP groups was larger than that in the TN group for the more-experienced reader (TP: 37 mm; FP: 48 mm; TN: 15 mm; both P<0.001) and for the less-experienced reader (FP: 42 mm; FP: 36 mm; TN: 15 mm; P<0.001 and P=0.022, respectively). The median tumor base in the TP group was larger than that in the FN group for the less-experienced reader (TP: 42 mm; FN: 17 mm; P=0.004). Conclusions: We observed good to excellent AUCs with good interobserver agreement among radiologists with different levels of expertise using VI-RADS. Large tumor size and wide tumor base affected the accuracy of VI-RADS in MIBC diagnosis.

Performance of deep learning algorithms to distinguish high-grade glioma from low-grade glioma: A systematic review and meta-analysis.

This study aims to evaluate deep learning (DL) performance in differentiating low- and high-grade glioma. Search online database for studies continuously published from 1st January 2015 until 16th August 2022. The random-effects model was used for synthesis, based on pooled sensitivity (SE), specificity (SP), and area under the curve (AUC). Heterogeneity was estimated using the Higgins inconsistency index (I2). 33 were ultimately included in the meta-analysis. The overall pooled SE and SP were 94% and 93%, with an AUC of 0.98. There was great heterogeneity in this field. Our evidence-based study shows DL achieves high accuracy in glioma grading. Subgroup analysis reveals several limitations in this field: 1) Diagnostic trials require standard method for data merging for AI; 2) small sample size; 3) poor-quality image preprocessing; 4) not standard algorithm development; 5) not standard data report; 6) different definition of HGG and LGG; and 7) poor extrapolation.

In vivo prediction of abdominal fat and breast muscle in broiler chicken using live body measurements based on machine learning.

The purpose of this study was to predict the carcass characteristics of broilers using support vector regression (SVR) and artificial neural network (ANN) model methods. Data were obtained from 176 yellow feather broilers aged 100-day-old (90 males and 86 females). The input variables were live body measurements, including external measurements and B-ultrasound measurements. The predictors of the model were the weight of abdominal fat and breast muscle in male and female broilers, respectively. After descriptive statistics and correlation analysis, the datasets were randomly divided into train set and test set according to the ratio of 7:3 to establish the model. The results of this study demonstrated that it is feasible to use machine learning methods to predict carcass characteristics of broilers based on live body measurements. Compared with the ANN method, the SVR method achieved better prediction results, for predicting breast muscle (male: R2 = 0.950; female: R2 = 0.955) and abdominal fat (male: R2 = 0.802; female: R2 = 0.944) in the test set. Consequently, the SVR method can be considered to predict breast muscle and abdominal fat of broiler chickens, except for abdominal fat in male broilers. However, further revaluation of the SVR method is suggested.

Effects of light color and intensity on discrimination of red objects in broilers.

Poultry are sensitive to red objects, such as comb and blood on the body surface, likely inducing injurious pecking in flocks. Light is an important factor that affects the pecking behavior of poultry. A wooden box was built to investigate the effects of Light Emitting Diode (LED) light color (warm white and cold white) and intensity (5 and 50 lux) of background light on the discrimination of red objects in broilers. A piece of red photographic paper (Paper 1) was used to simulate a red object and paired with another piece of paper (Paper 2 to 8) with a different color. Bigger number of the paired paper indicated greater color difference. The experiment consisted of three phases: adaptation, training, and test. In the adaptation phase, birds were selected for the adaptation to reduce the stress from the box. In the training phase, birds were trained to discriminate and peck at Paper 1 when paired with Paper 8 under one type of background light. Twenty-three birds were tested when the paired paper was changed from Paper 7 to 2. Each pair of paper included 12 trials for every bird, and response time to peck and proportion of choices of Paper 1 in the last 10 trials were collected. The results showed that broilers tested under 5 lux light had longer response times than broilers tested under 50 lux light (P < 0.05). When Paper 1 was paired with paper 7, broilers tested under warm white light had lower proportion of choices of Paper 1 than those tested under cold white light (P < 0.05). Color difference had a significant effect on response time of broilers (P < 0.05). Moreover, the proportion of choices of Paper 1 decreased to 50% (chance-level performance) when color of the paired paper was gradually similar to Paper 1. Conclusively, rearing broilers in warm white rather than cold white light with appropriate light intensity should be recommended to reduce damaging pecking behavior in broiler production.

Poultry are sensitive to red objects, such as comb and blood on the body surface, likely inducing injurious pecking in flocks. We built a wooden box to investigate the effects of light color (reddish and bluish) and intensity (5 and 50 lux) of background light on the discrimination of red objects in broilers. A piece of red photographic paper (Paper 1) was used and paired with another piece of paper (Paper 2 to 8) with a different color. Every bird was trained to discriminate and peck at Paper 1 when paired with Paper 8 under one type of background light. Then, Paper 8 was changed from Paper 7 to 2. Response time to peck and proportion of choices of Paper 1 were collected. We found that broilers under 5 lux light had longer response times than under 50 lux light. Broilers under reddish light had lower proportion of choices than under bluish light. Moreover, color difference had a significant effect on the response time and the proportion of choices. Conclusively, rearing broilers under reddish rather than bluish light with appropriate intensity should be recommended to reduce damaging pecking behavior in broiler production.

Promoting anti-tumor immunity by targeting TMUB1 to modulate PD-L1 polyubiquitination and glycosylation.

Immune checkpoint blockade therapies targeting the PD-L1/PD-1 axis have demonstrated clear clinical benefits. Improved understanding of the underlying regulatory mechanisms might contribute new insights into immunotherapy. Here, we identify transmembrane and ubiquitin-like domain-containing protein 1 (TMUB1) as a modulator of PD-L1 post-translational modifications in tumor cells. Mechanistically, TMUB1 competes with HECT, UBA and WWE domain-containing protein 1 (HUWE1), a E3 ubiquitin ligase, to interact with PD-L1 and inhibit its polyubiquitination at K281 in the endoplasmic reticulum. Moreover, TMUB1 enhances PD-L1 N-glycosylation and stability by recruiting STT3A, thereby promoting PD-L1 maturation and tumor immune evasion. TMUB1 protein levels correlate with PD-L1 expression in human tumor tissue, with high expression being associated with poor patient survival rates. A synthetic peptide engineered to compete with TMUB1 significantly promotes antitumor immunity and suppresses tumor growth in mice. These findings identify TMUB1 as a promising immunotherapeutic target.

Log P analyzation-based discovery of GSH activated biotin-tagged fluorescence probe for selective colorectal cancer imaging.

Targeted activatable fluorescent probes could provide an effective approach for colorectal cancer imaging. In this study, F1 was found as an effective targeted activatable fluorescent probe based on log P analysis. In vitro experiments demonstrated that the initial fluorescence of the developed probe F1 was initially well quenched, and the fluorescence increased after the probe interacted with glutathione. Cell imaging results showed that the probe had good cell permeability and selectivity. Remarkably, F1 displayed enhanced tumor tissue fluorescence in MC-38 tumor-bearing mice. Notably, it showed selectivity in imaging clinical specimens of human colorectal cancer tissues. Accordingly, this study shows that log P analysis can facilitate the developing efficient of biotin-tagged activatable probes, and the identified F1 has a good potential in clinical colorectal cancer diagnosis.

Design, synthesis and biological evaluation of new dihydropyridine derivatives as PD-L1 degraders for enhancing antitumor immunity.

Immune checkpoint blockade (ICB) by targeting programmed cell death-1/programmed cell death ligand 1 (PD-1/PD-L1) signaling pathway is a promising strategy for tumor immunotherapy. Developing small-molecules inducing PD-L1 protein degradation has been proven as an alternative and useful approach for targeting the immunotherapy pathway. Our previous study showed that Lercanidipine could down-regulate the expression of PD-L1 protein, but its calcium influx antagonistic activity hampers further development. For attenuating the unexpected calcium channel blockade effect, a series of compounds were synthesized and evaluated through structure-activity relationship (SAR) exploration. Amongst, compound F4 exhibited a loss of calcium antagonistic activity, while the PD-L1 degradation activity can still retain. Further studies indicated that F4 degraded PD-L1 dose- and time-dependently, and may function through a lysosomal-dependent manner. Furthermore, compound F4 showed a good bioavailability value of 24.9% in mice. Moreover, the F4-induced PD-L1 degradation strengthened the T cell-mediated killing of tumor cells. Our findings show the discovery of a new PD-L1 degrader, providing a potential strategy for immunotherapy.

Identification of Potential WSB1 Inhibitors by AlphaFold Modeling, Virtual Screening, and Molecular Dynamics Simulation Studies.

WD40 repeat and SOCS box containing 1 (WSB1) consists of seven WD40 repeat structural domains at the N-terminal end and one SOCS box structural domain at the C-terminal end. WSB1 promotes cancer progression by affecting the Von Hippel-Lindau tumor suppressor protein (pVHL) and upregulating hypoxia inducible factor-1α (HIF-1α) target gene expression. However, the crystal structure of WSB1 has not been reported, which is not beneficial to the research on WSB1 inhibitors. Therefore, we focused on specific small molecule inhibitors of WSB1. This study applied virtual screening and molecular dynamics simulations; finally, 20 compounds were obtained. Among them, compound G490-0341 showed the best stable structure and was a promising composite for further development of WSB1 inhibitors.

Design, synthesis, and biological evaluation of quinazoline derivatives with covalent reversible warheads as potential FGFR4 inhibitors.

Fibroblast growth factor receptor 4 (FGFR4) together with co-receptors modulate the activation of downstream proteins that regulate fundamental processes, and elevated FGFR4 activity is associated with Hepatocellular Carcinoma (HCC). Hence, FGFR4 is a promising therapeutic target for HCC. Based on BLU9931, we designed and synthesized a series of phenylquinazoline derivatives as novel inhibitors of FGFR4 through the covalent reversible strategy. Among them, a novel compound (C3) showed FGFR4 and cell proliferation inhibitory activity. Cellular mechanism studies demonstrated that compound C3 induced apoptosis via the FGFR4 signaling pathway blockage. Further mechanism study showed that C3 has the reversible covalent binding capacity, could be used as a reference for the development of novel FGFR4 covalent reversible inhibitors.

Design, synthesis and biological evaluation of quinazoline derivatives as potent and selective FGFR4 inhibitors.

Aberrant activation of the fibroblast growth factor 19-fibroblast growth factor receptor 4 (FGF19-FGFR4) signaling pathway has been proved to promote hepatocellular carcinoma (HCC) proliferation. It is assumed that the first FGFR4 inhibitor BLU9931 did not enter clinical studies, presumably due to its rapid metabolism in liver microsomes. Here, we report the development of series of quinazoline derivatives based on FGFR4 inhibitor BLU9931 through structural modification of its solvent region pocket to minimize its potential metabolic liability. Among them, compound 35a exhibited comparable or superior kinase inhibitory activity (IC50 = 8.5 nM) and selectivity in cells. More importantly, compound 35a improved liver microsomes stability compared to BLU9931. Cellular mechanistic studies demonstrated that 35a induced apoptosis via the FGFR4 signaling pathway blockage. In addition, the computational simulation revealed the possible binding mode to FGFR4 protein, which provides a plausible explanation of high potent and metabolic stability.

Recent advance of peptide-based molecules and nonpeptidic small-molecules modulating PD-1/PD-L1 protein-protein interaction or targeting PD-L1 protein degradation.

Tumor immunotherapy has made great progress in recent years. In the tumor microenvironment, the binding of PD-1 and its ligand PD-L1 can promote tumor immune escape and tumor survival. Clinical studies have indicated that antibodies blocking PD-1 and PD-L1 have reliable effects on many advanced malignant tumors. However, no small-molecule inhibitors have been approved so far, indicating that the development of marketable small-molecules PD-1/PD-L1 targeted therapy drugs is a challenging process. Small-molecule inhibitors can overcome the limitations of monoclonal antibodies, including poor oral bioavailability, high cost, poor tissue and tumor penetration and long half-life, which prompt researchers to turn their attention to the development of peptide molecules and small-molecule inhibitors modulating PD-1/PD-L1 to overcome some disadvantages of monoclonal antibodies or targeting PD-L1 protein degradation as potential alternatives or supplements. In this review, we will focus on the peptide-based and nonpeptidic molecules against PD-1/PD-L1 base on the structural classification. More importantly, we also focus on the latest research progress of small-molecules mediated PD-L1 degradation mechanism.

Working conditions and health status of 6,317 front line public health workers across five provinces in China during the COVID-19 epidemic: a cross-sectional study.

BACKGROUND: Public health workers at the Chinese Centre for Disease Control and Prevention (China CDC) and primary health care institutes (PHIs) were among the main workers who implemented prevention, control, and containment measures. However, their efforts and health status have not been well documented. We aimed to investigate the working conditions and health status of front line public health workers in China during the COVID-19 epidemic. METHODS: Between 18 February and 1 March 2020, we conducted an online cross-sectional survey of 2,313 CDC workers and 4,004 PHI workers in five provinces across China experiencing different scales of COVID-19 epidemic. We surveyed all participants about their work conditions, roles, burdens, perceptions, mental health, and self-rated health using a self-constructed questionnaire and standardised measurements (i.e., Patient Health Questionnaire and General Anxiety Disorder scale). To examine the independent associations between working conditions and health outcomes, we used multivariate regression models controlling for potential confounders. RESULTS: The prevalence of depression, anxiety, and poor self-rated health was 21.3, 19.0, and 9.8%, respectively, among public health workers (27.1, 20.6, and 15.0% among CDC workers and 17.5, 17.9, and 6.8% among PHI workers). The majority (71.6%) made immense efforts in both field and non-field work. Nearly 20.0% have worked all night for more than 3 days, and 45.3% had worked throughout the Chinese New Year holiday. Three risk factors and two protective factors were found to be independently associated with all three health outcomes in our final multivariate models: working all night for >3 days (multivariate odds ratio [ORm]=1.67~1.75, p<0.001), concerns about infection at work (ORm=1.46~1.89, p<0.001), perceived troubles at work (ORm=1.10~1.28, p<0.001), initiating COVID-19 prevention work after January 23 (ORm=0.78~0.82, p=0.002~0.008), and ability to persist for > 1 month at the current work intensity (ORm=0.44~0.55, p<0.001). CONCLUSIONS: Chinese public health workers made immense efforts and personal sacrifices to control the COVID-19 epidemic and faced the risk of mental health problems. Efforts are needed to improve the working conditions and health status of public health workers and thus maintain their morale and effectiveness during the fight against COVID-19.

Artificial light and biological responses of broiler chickens: dose-response.

Light intensity is an important aspect for broiler production. However, previous results do not provide a solid scientific basis for quantifying the response of broilers to light intensity. This study performed a meta-analysis to model the response of broilers to 0.1-200 lux of light intensity. Meta-analysis was used to integrate smaller studies and increase the statistical power over that of any single study and explore new hypotheses. The results indicated that light intensity <5 lux caused welfare concern (P < 0.05) and light intensity <1 lux induced productivity loss of broiler (P < 0.05), whereas greater level of light intensity >10 lux led to increased mortality (P < 0.01) and decreased uniformity (P < 0.05). Meta-regression showed that 30-200 lux light intensity was negatively related to BW (P = 0.047) and feed intake change (P = 0.054), whereas a quadratic relationship was observed between feed conversion ratio change and 50-180 lux light intensity (R2 = 0.95). In addition, the majority of carcass characteristics (abdominal fat weight and wing weight) and metabolic indicators (K+, Ca2+, and T3) were affected by light intensity >5 lux. To conclude, this meta-analysis based on published data quantitatively identified that 5 lux of light intensity during grow-out period should be the minimum level to maintain a well productivity and welfare of broiler chickens.