Association of the triglyceride-glucose index with early-onset atherosclerotic cardiovascular disease events and all-cause mortality: a prospective cohort study.

BACKGROUND: The association between the triglyceride glucose (TyG) index and the risk of early-onset atherosclerotic cardiovascular disease (ASCVD) events or all-cause mortality in young and middle-aged people is not fully elucidated. METHODS: The present study included 64,489 young and middle-aged people who participated in the 2006 Kailuan Study physical examination. Multivariate Cox proportional hazards models and restricted cubic spline curves were used to assess the association of TyG index with early-onset ASCVD events and all-cause mortality. RESULTS: During a median of 11-year follow-up, 1984 (3.08%) participants experienced at least one ASCVD event and 1,392 (2.16%) participants experienced all-cause death. A higher TyG index was significantly associated with a higher risk of early-onset ASCVD events (HR: 1.61, 95% CI 1.38-1.89) and all-cause mortality (HR: 1.39, 95% CI 1.17-1.65), respectively. For each unit increase in TyG index, the risk of early-onset ASCVD events increased by 20%. In addition, there was a non-linear association between the TyG index and early-onset ASCVD events (P for non-linear < 0.01), and a linear association between TyG index and all-cause mortality (P for non-linear = 0.476). CONCLUSIONS: A higher TyG index is significantly associated with an increased incidence of early-onset ASCVD events and all-cause mortality in a young and middle-aged population from North China.

The transcriptional regulator EtrA mediates ompW contributing to the pathogenicity of avian pathogenic Escherichia coli.

Avian pathogenic Escherichia coli (APEC) causes avian colibacillosis and leads to high mortality in poultry and huge economic losses. Therefore, it is important to investigate the pathogenic mechanisms of APEC. Outer membrane protein OmpW is involved in the environmental adaptation and pathogenesis of Gram-negative bacteria. OmpW is regulated by many proteins, including FNR, ArcA, and NarL. In previous studies, regulator EtrA is involved in the pathogenicity of APEC and affects the transcript levels of ompW. However, the function of OmpW in APEC and its regulation remain unclear. In this study, we constructed mutant strains with altered etrA and/or ompW genes to evaluate the roles of EtrA and OmpW in the biological characteristics and pathogenicity of APEC. Compared with wild-type strain AE40, mutant strains ∆etrA, ∆ompW, and ∆etrA∆ompW showed significantly lower motility, lower survival under external environmental stress, and lower resistance to serum. Biofilm formation by ∆etrA and ∆etrA∆ompW was significantly enhanced relative to that of AE40. The transcript levels of TNF-α, IL1ß, and IL6 were also significantly enhanced in DF-1 cells infected with these mutant strains. Animal infection assays showed that deletion of etrA and ompW genes attenuated the virulence of APEC in chick models, and damage to the trachea, heart, and liver caused by these mutant strains was attenuated relative to that caused by the wild-type strain. RT-qPCR and ß-galactosidase assay showed that EtrA positively regulates the expression of the ompW gene. These findings demonstrate that regulator EtrA positively regulates the expression of OmpW, and that they both contribute to APEC motility, biofilm formation, serum resistance, and pathogenicity.

Atrial fibrillation is an independent risk factor for new-onset myocardial infarction: a prospective study.

BACKGROUND: Atrial fibrillation (AF) and myocardial infarction (MI) share common cardiovascular risk factors, therefore coexistence of AF and MI is very common, in addition, both AF and MI aggravate and exacerbate each other through multiple pathological processes. The aim of this study is to investigate whether AF increases the risk of new-onset MI. METHODS: In total 171,086 participants from an industrial city in North China were selected and enrolled in this prospective cohort study, participants were divided into the AF group or the non-AF group according to their medical history. 1542 participants from the AF group were propensity-matched with 4626 participants from the non-AF group. All the participants were followed up every 2 years from June 2006 to December 2020, the median follow-up was 14.25 years and the endpoint of this study was new-onset MI. The association between AF and new-onset MI was analysed by using both univariate and multivariate Cox proportional hazards regression analysis. RESULTS: New-onset MI was documented in 56 cases from the AF group and 98 cases from the non-AF group, respectively, the cumulative incidence of new-onset MI in the AF group (3.73%) was significantly higher than that in the non-AF group (2.23%) (p < 0.01). In a univariate analysis, AF was associated with an increased risk of new-onset MI (hazard ratio: 1.73, 95% confidence interval: 1.24-2.40), in two multivariable-adjusted analyses, AF was still associated with an increased risk of new-onset MI (hazard ratio: 1.78, 95% confidence interval, 1.28-2.47). CONCLUSIONS: AF is an independent risk factor for new-onset MI in an industrial population of North China.

The two-component system histidine kinase EnvZ contributes to Avian pathogenic Escherichia coli pathogenicity by regulating biofilm formation and stress responses.

EnvZ, the histidine kinase (HK) of OmpR/EnvZ, transduces osmotic signals in Escherichia coli K12 and affects the pathogenicity of Shigella flexneri and Vibrio cholera. Avian pathogenic E. coli (APEC) is an extra-intestinal pathogenic E. coli (ExPEC), causing acute and sudden death in poultry and leading to severe economic losses to the global poultry industry. How the functions of EnvZ correlate with APEC pathogenicity was still unknown. In this study, we successfully constructed the envZ mutant strain AE17ΔenvZ and the inactivation of envZ significantly reduced biofilms and altered red, dry, and rough (rdar) morphology. In addition, AE17ΔenvZ was significantly less resistant to acid, alkali, osmotic, and oxidative stress conditions. Deletion of envZ significantly enhanced sensitivity to specific pathogen-free (SPF) chicken serum and increased adhesion to chicken embryonic fibroblast DF-1 cells and elevated inflammatory cytokine IL-1ß, IL6, and IL8 expression levels. Also, when compared with the WT strain, AE17ΔenvZ attenuated APEC pathogenicity in chickens. To explore the molecular mechanisms underpinning envZ in APEC17, we compared the WT and envZ-deletion strains using transcriptome analyses. RNA-Seq results identified 711 differentially expressed genes (DEGs) in the envZ mutant strain and DEGs were mainly enriched in outer membrane proteins, stress response systems, and TCSs. Quantitative real-time reverse transcription PCR (RT-qPCR) showed that EnvZ influenced the expression of biofilms and stress responses genes, including ompC, ompT, mlrA, basR, hdeA, hdeB, adiY, and uspB. We provided compelling evidence showing EnvZ contributed to APEC pathogenicity by regulating biofilms and stress response expression.

Acetoacetyl-CoA transferase ydiF regulates the biofilm formation of avian pathogenic Escherichia coli.

Avian pathogenic Escherichia coli (APEC) causes persistent infection of poultry and multi-system diseases, which seriously endanger the development of the poultry industry. Biofilm allows bacteria to adapt to the natural environment and plays an important role in resistance to the external environment and the pathogenicity of APEC, but the mechanism of its formation and regulatory network have not been clarified. In this study, we used a Tn5 transposon random mutation library constructed with APEC and identified ydiF, a gene that has not previously been recognized in E. coli biofilm formation. To confirm that the ydiF gene really can regulate the formation of APEC biofilm, the ydiF gene deletion strain was constructed using APEC81. Protein association networks prediction results show that ydiF is mainly associated with genes related to the metabolism of sugars and fatty acids. Deletion of the ydiF gene significantly reduces the formation of APEC biofilm and scanning electron microscopy indicated that the degree of adhesion between the bacteria was also reduced. The deletion of the ydiF gene also significantly reduced the motility of APEC81 and through transmission electron microscopy APEC81 was observed to have significantly fewer flagella. However, the colony morphology of APEC81 on Congo red and Coomassie brilliant blue media was unaffected. The results of fluorescence quantification showed that the deletion of the ydiF gene caused a down-regulation in the transcription of genes related to the second messenger, sugar metabolism, and quorum sensing. These results indicate that ydiF plays an important role in biofilm formation and the movement of APEC. In addition, it may be possible to regulate the formation of APEC biofilms by different methods such as by regulating the second messenger and metabolic system.

Geometric characterization of dynamical structure for neural firing activities induced by inhibitory pulse.

In general, inhibitory stimuli are thought to inhibit neuronal firing, but they may actually enhance firing sometimes, such as post-inhibitory rebound spike (PIR spike) and post-inhibitory facilitation (PIF) phenomena, which play an important role in human neuronal activities. We study responses to inhibitory pulse in a classical neuron model (Quartic adaptive Integrate-and-fire model) well known to reproduce a number of biologically realistic behaviors. The three phenomena that we study are PIR, in which a neuron fires after an inhibitory pulse, and PIF, in which a subthreshold excitatory input can induce a spike if it is applied with proper timing after an inhibitory pulse, as well as period firing after inhibitory pulse. When the system features focus and saddle two equilibriums, the three phenomena will be occurred under the inhibitory pulse, while all three phenomena will not be induced when the system features node and saddle two equilibriums. Using dynamical systems theory, we explain the threshold mechanism of enhancement of neural firing response induced by inhibitory pulse and analyze the origin of these phenomena from several factors. We also describe the geometric characterization of dynamical structures of these three phenomena. This study therefore enrich the paradoxical phenomena that induced by inhibitory input and advance our understanding of its role.

Meta-analysis of the efficacy and safety of sintilimab for treating advanced non-small cell lung cancer.

Lung cancer is the leading cause of death from malignant tumors in China, and non-small cell lung cancer (NSCLC) accounts for >80% of all types of lung cancer. Novel immunotherapeutic agents targeting programmed death protein-1 (PD-1) and its ligands [programmed death ligands (PD-L)1 and 2] have emerged as important therapeutic measures and trends in the treatment of advanced NSCLC. Sintilimab (trade name, Daboshu) is a humanized IgG4 monoclonal antibody targeting PD-1 that was developed by Innovent Biologics and Eli Lilly and Company. Studies have shown that sintilimab has the characteristics of high affinity, long-lasting stability and an increased target occupancy rate, and that it is a broad-spectrum drug. The present study uses a meta-analysis to evaluate the safety and efficacy of sintilimab in treating advanced NSCLC. The PubMed, Cochrane Library, Embase, Chinese Biomedical Literature, China National Knowledge Infrastructure, VIP Chinese Science and Technology Journal and Wanfang Medical databases were searched from their establishment until October 2021. Randomized controlled trials of patients with NSCLC who were treated with conventional chemotherapy (chemotherapy) plus sintilimab treatment or sintilimab alone, compared with a chemotherapy group, were included, and a meta-analysis was performed using RevMan 5.3 software. The findings revealed that there was no significant difference between the conventional chemotherapy group and the sintilimab group in terms of the overall incidence of adverse drug reactions (ADR) or grade 3-5 ADRs (risk ratio, 1.04; 95% confidence interval, 0.96-1.14; P=0.33), respectively. Sintilimab coupled with chemotherapy outperformed standard chemotherapy in treating advanced NSCLC. The ADRs did not differ considerably from those of conventional chemotherapy, which will help in the assessment of the clinical efficacy of sintilimab combined with chemotherapy and conventional chemotherapy in treating advanced NSCLC.

A tailored bioactive 3D porous poly(lactic-acid)-exosome scaffold with osteo-immunomodulatory and osteogenic differentiation properties.

Polylactic acid (PLA) is a versatile and biodegradable scaffold widely used in biomedical fields to repair tissue defects. Exosomes derived from mesenchymal stem cells (MSCs) are nano-sized extracellular vesicles, which play an important role in tissue engineering in recent years. The primary focus of this study was to develop a bioactive 3D PLA scaffold using exosome-based strategy to improve its osteogenic and immunoregulatory potential. We firstly successfully isolated MSC-derived exosomes (MSC-Exo). Morphological analysis revealed that MSC-Exo exhibits a typical cup-shaped morphology with high expression of exosomal marker CD63. MSC-Exo internalization into recipient cells were also investigated using flow cytometry and confocal laser scanning microscopy. Porous 3D PLA scaffold coated MSC-Exo were used for immunoregulatory and osteogenic testing. Exosomes released from 3D PLA scaffold were validated in RAW264.7 and hBMSCs. The cell proliferation and live/dead assay indicated high biocompatibility for PLA-Exo scaffold. Additionally, PLA-Exo scaffold could reduce the pro-inflammatory marker expression and reactive oxygen species (ROS) production, indicating potential immunoregulatory potential. It is also confirmed that PLA-Exo scaffold could potentiate osteogenic differentiation in the osteogenesis assay. In conclusion, our results demonstrate this bioactive 3D-printed PLA scaffolds with MSC-Exo modification holds immunoregulatory potential and favor osteogenic differentiation, thus having potential applications in bone tissue regeneration.

LuxR family transcriptional repressor YjjQ modulates the biofilm formation and motility of avian pathogenic Escherichia coli.

Avian pathogenic Escherichia coli (APEC) can cause the acute and sudden death of poultry, which leads to serious economic losses in the poultry industry. Biofilm formation contributes to the persistence of bacterial infection, drug resistance, and resistance to diverse environmental stress. Many transcription regulators in APEC play an essential role in the formation of biofilm and could provide further insights into APEC pathogenesis. YjjQ has an important role in the pathogenicity of bacteria by regulating the expression of virulence factors, such as flagellar and iron uptake. However, YjjQ regulates other virulence factors, and their role in the overall regulatory network is unclear. Here, we further evaluate the function of YjjQ on APEC biofilm formation and motility. In this study, we successfully constructed mutant (AE27∆yjjQ) and complement (AE27ΔyjjQ-comp) strains of the wild-type strain AE27. Inactivation of the yjjQ gene significantly increased biofilm-forming ability in APEC. Scanning electron microscopy showed that the biofilm formation of the AE27 was single-layered and flat, whereas that of the AE27∆yjjQ had a porous three-dimensional structure. Moreover, the deletion of the yjjQ gene inhibited the motility of APEC. RNA-sequencing was used to further investigate the regulatory mechanism of YjjQ in APEC. The results indicate that YjjQ regulates biofilm formation and flagellar genes in AE27∆yjjQ. RT-qPCR shows that YjjQ affects the transcriptional levels of genes, including flagella genes (flhD, flhC and flgE), and biofilm formation genes (pstA, uhpC, nikD, and ygcS). These results confirm that the transcription regulator YjjQ is involved in APEC biofilm formation and motility, and provide new evidence for the prevention and control of APEC.

The differences in cocoon and silk qualities among sex-related mulberry and silkworm feeding groups.

Sexual dimorphism is seen in many dioecious plant and animal species, which may influence their trophic interactions. The differences in trophic interactions derived from sexual dimorphism in plants may influence herbivorous performance and population dynamics. Both silkworm (Bombyx mori L.) and mulberry (Morus alba L.) usually exhibit sexual dimorphism. However, few studies have been conducted on the effect of sex-related silkworm and mulberry pairings on cocoon and silk qualities, which are crucial in sericulture. Here, we compared the differences in cocoon and silk qualities under four feeding combinations (FS-FL: female silkworm fed with leaves from female mulberry trees; MS-FL: male silkworm fed with leaves from female mulberry trees; FS-ML: female silkworm fed with leaves from male mulberry trees; MS-ML: male silkworm fed with leaves from male mulberry trees). The results showed that silkworms exhibited male-biased herbivory with more male mulberry leaves digested. The FS-ML group had higher silk weight and silk ratio of fresh cocoons than the FS-FL group, and the MS-ML group had lower coarse points than the MS-FL group. Compared with groups FS-ML and FS-FL, both MS-FL and MS-ML had smaller cocoons with longer silk lengths and a higher silk ratio of the fresh cocoons. In addition, the Entropy Weight-TOPSIS method showed the cocoon quality rank as FS-ML > FS-FL > MS-FL > MS-ML, whereas silk quality rank was MS-ML > FS-FL > FS-ML > MS-FL. These results indicate that the quality of cocoon and silk is related to the interaction of silkworm and mulberry at the sex level. Furthermore, female silkworms fed with female and male tree leaves have a higher total yield in cocoon production, while male silkworms fed with male tree leaves produced higher silk quality.

The response regulator OmpR contributes to the pathogenicity of avian pathogenic Escherichia coli.

Avian colibacillosis is a serious systemic infectious disease in poultry and caused by avian pathogenic Escherichia coli (APEC). Previous studies have shown that 2-component systems (TCSs) are involved in the pathogenicity of APEC. OmpR, a response regulator of OmpR/EnvZ TCS, plays an important role in E. coli K-12. However, whether OmpR correlates with APEC pathogenesis has not been established. In this study, we constructed an ompR gene mutant and complement strains by using the CRISPR-Cas9 system and found that the inactivation of the ompR gene attenuated bacterial motility, biofilm formation, and the production of curli. The resistance to environmental stress, serum sensitivity, adhesion, and invasion of DF-1 cells, and pathogenicity in chicks were all significantly reduced in the mutant strain AE17ΔompR. These phenotypes were restored in the complement strain AE17C-ompR. The qRT-PCR results showed that OmpR influences the expression of genes associated with the flagellum, biofilm formation, and virulence. These findings indicate that the regulator OmpR contributes to APEC pathogenicity by affecting the expression and function of virulence factors.

Effects and Mechanism of Action of Panax notoginseng Saponins on the Pharmacokinetics of Warfarin.

BACKGROUD: The interactions between Chinese herbs and drugs pose a great challenge to the combined clinical application of Chinese herbs and drugs. Chinese medicinal products contain complex pharmacologically active components that may influence the in vivo processes of drugs in a variety of ways. In China, drugs based on Panax ginseng total saponins (PNS) are often combined with warfarin for the treatment of cardiovascular diseases. OBJECTIVES: To assess the effects of Panax notoginseng saponins (PNS) on the pharmacokinetics of warfarin and its mechanism. METHOD: Blood was collected for the determination of the prothrombin time (PT) and international normalized ratio (INR) from rats treated with warfarin alone or with warfarin + PNS. The plasma concentration of warfarin was determined by high-performance liquid chromatography. Western blot was used to detect the expression of cytochrome P450 (CYP) enzymes. RESULTS: When warfarin and PNS were co-administered, the PT and INR increased compared to when warfarin was given alone. 72 hours after administration, compared to the warfarin alone group, the warfarin + low-dose PNS, warfarin + medium-dose PNS, and warfarin + high-dose PNS groups showed 110%, 122%, and 126% increases in PT, respectively (all P < 0.05), as well as 111%, 124%, and 128% increases in INR (all P < 0.05). Compared with the warfarin alone group, the clearance rate (CL/F) of warfarin in the warfarin + low-dose PNS, warfarin + medium-dose PNS, and warfarin + high-dose PNS groups was 10% (P > 0.05), 23% (P < 0.05), and 33% (P < 0.05) lower, respectively, while the systemic exposure (area under the concentration-time curve, AUC0-t) increased by 106% (P > 0.05), 119% (P < 0.05), and 134% (P < 0.05), respectively, and the blood concentration of warfarin incresed by 112%, 113%, and 114%, respectively (all P > 0.05). After combined treatment of HepG2 cells with warfarin + PNS, CYP1A2 expression was upregulated (P < 0.05) and CYP3A4 was downregulated (P < 0.05) but there was no effect on CYP2C9. In animal experiments, PNS had different effect on the expression of CYP1A2 in different doses. While a low dose of PNS resulted in downregulated CYP1A2 expression (P < 0.05), a medium dose resulted in upregulation (P < 0.05), and CYP1A2 expression was not significantly affected by a high dose of PNS (P > 0.05). Meanwhile, PNS at all doses downregulated the expression of CYP3A4 (P < 0.05) but had no effect on the expression of CYP2C9 (P > 0.05). CONCLUSION: PNS can increase the blood concentration of warfarin, as well as the exposure time, and it can enhance the anticoagulant effect of warfarin by inhibiting the expression of the liver enzyme CYP3A4.

The ETT2 transcriptional regulator EivF affects the serum resistance and pathogenicity of avian pathogenic Escherichia coli.

Avian pathogenic Escherichia coli (APEC), a pathotype of extraintestinal pathogenic Escherichia coli (ExPEC), can cause serious systemic infectious diseases in poultry. Escherichia coli type III secretion system 2 (ETT2) is widely distributed in E. coli strains, including ExPEC and Enterohemorrhagic Escherichia coli (EHEC). The transcriptional regulator EivF, which is located at the ETT2 cluster, affects the secretion of LEE-encoded proteins and increases bacterial adhesion to human intestinal epithelial cells in EHEC O157:H7. In a previous study, we demonstrated the transcriptional regulator can affect APEC's motility and biofilm formation. Here, we evaluated whether EivF is involved in the pathogenicity of APEC, and we found that inactivation of eivF significantly enhanced resistance to the serum, adherence to chicken embryo fibroblast (DF-1) cells, and the colonization ability of APEC in chicks. To further clarify the regulation mechanism of transcriptional regulator EivF, we performed transcriptome sequencing to analyze the differentially expressed genes and pathways, showing that EivF regulates membrane, adhesion, environmental stress, and secretion protein genes, and EivF is involved in the localization, biological adhesion, biological regulation, membrane, and toxin activity. These findings indicated that the ETT2 transcriptional regulator EivF plays a crucial role in the pathogenicity of APEC as a negative repressor.

Identification and Characterization of Glycine Decarboxylase as a Direct Target of Snail in the Epithelial-Mesenchymal Transition of Cancer Cells.

CONTEXT/AIMS: Metabolic reprogramming and cellular plasticity drive tumorigenesis. However, how these cellular events collectively contribute to the oncogenic process is poorly understood. Epithelial-mesenchymal transition (EMT), a fundamental mechanism of cellular plasticity, is governed by the EMT transcription repressors such as Snail. In the present study, through establishment and characterization of inducible overexpression of Snail in A549 lung cancer cells, we aim to define the metabolic reprogramming in response to Snail in the EMT of lung cancer cells. METHODS/RESULTS: Our metabolomic analysis suggests that forced expression of Snail accompanied reduced diversion of glycolytic metabolites to the serine/glycine metabolic shunt, a critical metabolic branch that distributes glucose catabolic intermediates to the major anabolic pathways. Our gene expression profiling and molecular characterization revealed that Snail actively suppressed the expression of glycine decarboxylase (GLDC), a key enzyme on the serine/glycine metabolic shunt, through binding to an evolutionarily conserved E-box motif and thereby inhibiting the promoter of the GLDC gene. Besides, knockdown of GLDC led to a cellular function shift from proliferation to migration. CONCLUSION: This study has revealed a novel molecular link that integrates the serine/glycine metabolism with the Snail-mediated EMT program in cancer cells.

Quantitative protein expression of blood-brain barrier transporters in the vasculature of brain metastases of patients with lung and breast cancer.

This study determined absolute transporter protein abundances in isolated microvessels of human noncancerous cerebral cortex as well as brain metastases of patients with lung and breast cancer, using a validated targeted proteomics approach. As compared with those in microvessels of noncancerous cerebral cortex, the median protein abundances of glucose transporter 1 (a brain endothelial marker) and sodium-potassium pump (Na/K ATPase, a plasma membrane marker) were decreased by ~ 80% in brain metastasis microvessels. The major efflux transporters (ABCB1 and ABCG2) fell to undetectable in microvessels of more than 80% of brain metastasis specimens. Monocarboxylate transporter 1 was undetectable in microvessels of more than 80% of brain metastases, whereas large neutral amino acid transporter 1 levels remained unchanged. In conclusion, the integrity of the physical and biochemical barrier with respect to transporter protein expression is largely disrupted in brain metastasis tumor vasculatures. Differential transporter protein abundances at the blood-brain barrier and blood-brain tumor barrier provided mechanistic and quantitative basis for prediction of heterogeneous drug penetration into human brain and brain tumors, which is critical not only to the understanding of the success or failure of systemic chemotherapy in the treatment of brain tumors but also to the development of more effective therapeutic strategies.

Physiologically Based Pharmacokinetic Modeling of Central Nervous System Pharmacokinetics of CDK4/6 Inhibitors to Guide Selection of Drug and Dosing Regimen for Brain Cancer Treatment.

A better understanding of the human central nervous system (CNS) pharmacokinetics is critical to the selection of the right drug and refinement of dosing regimen for more effective treatment of primary and metastatic brain cancer. Using the physiologically-based pharmacokinetic (PBPK) modeling approach, we systematically compared the CNS pharmacokinetics of three cyclin D-cyclin dependent kinase 4 and 6 (CDK4/6) inhibitors (ribociclib, palbociclib, and abemaciclib) in patients with cancer. A PBPK model platform was developed and verified for predicting plasma and CNS pharmacokinetics. Target engagement ratio (TER), defined as the ratio of the average steady-state unbound drug brain concentration to the in vitro half-maximal inhibitory concentration (IC50 ) for CDK4/6 inhibition, was used as a crude predictor of efficacy. As compared with ribociclib and palbociclib, abemaciclib penetrated into the human brain to a larger extent, but at a slower rate, and was retained in the brain longer. Following the standard dosing regimens, the predicted CDK4/6 TERs were 26/5.2 for abemaciclib, 2.4/0.62 for ribociclib, and 0.36/0.27 for palbociclib. Simulations suggested that abemaciclib achieved comparable TERs following twice daily or daily dosing; ribociclib may sufficiently inhibit both CDK4 and CDK6 at the maximum tolerated dose; whereas, palbociclib achieved TERs < 0.5 even at a dose 50% higher than the standard dose. In conclusion, the PBPK modeling, supported by available preclinical and clinical evidence, suggests that abemaciclib is the best CDK4/6 inhibitor for brain cancer treatment, whereas palbociclib is not recommended. The model refined dosing regimen is 300 mg daily on a 4-weeks-on schedule for abemaciclib, and 900 mg daily on a 3-weeks-on/1-week-off schedule for ribociclib.

Staphylococcus aureus induces mammary gland fibrosis through activating the TLR/NF-κB and TLR/AP-1 signaling pathways in mice.

To investigate the TLR-NF-κB/AP-1 pathways in S. aureus infection-induced mammary gland fibrosis, mice were infected with S. aureus isolated from the mammary glands of cows with mastitis. Lactating mice were divided into three groups: control group (CON); PBS control group (PBS) and the S. aureus-treated group (S. aureus). Pathological observations revealed that neutrophil infiltration into mammary gland tissue was obviously induced by S. aureus at the early stage of infection (1-7 d). With persistent S. aureus infection, mammary gland fibrosis developed and was characterized by infiltration and proliferation of macrophage, lymphocyte and fibroblast and ECM hyperplasia (7-21 d). Immunohistochemistry staining showed upregulation of fibrosis associated cytokines viz bFGF and PDGF-BB. Real-time qPCR and Western blot analysis revealed that transcription and translation of TLR2, TLR4, bFGF, PDGF-BB, α-SMA and COL Ⅰ α1 was significantly upregulated by S. aureus. NF-κB p65 and AP-I c-jun were translocated into the nucleus after S. aureus infection. There was no remarkable difference between the CON and PBS groups. The datas indicate that mammary gland fibrosis in mice is induced by S. aureus, which promotes cytokine release and the expression of ECM though activating the TLR/NF-κB p65 and TLR/AP-1 c-jun signaling pathways.