Synthesis and characterization of microencapsulated paraffin with melamine-urea-formaldehyde shell modified with lignin.

The study aims to fabricate MUF/paraffin microcapsules with lignin nanoparticles (LNPs)/ melamine-urea-formaldehyde (MUF) resin as hybrid shell material with different LNPs addition were synthesized in oil-in-water emulsion stabilized synergistically by styrene/maleic anhydride (SMA) and LNPs. The morphological characterization of LNPs was observed by transmission electron microscopy (TEM). The particle size of LNPs, the mean particle size and ξ potentials of SMA/LNPs mixture at pH =4.5 were investigated by zeta potential measurement. Field emission scanning electron microscopy (FE-SEM), Fourier-transform infrared spectroscopy (FT-IR), X-ray diffraction (XRD), thermogravimetric analyzer (TGA), and differential scanning calorimetry (DSC) were characterized the morphologies, crystallography, chemical component, thermal stability and phase change properties of MUF/paraffin microcapsules with different LNPs addition. The results showed that MUF/paraffin microcapsules were spherical. The LNPs did not influence the chemical structure or crystal type of MUF/paraffin microcapsules. When the LNPs addition was 0.15 g, the melting enthalpy and crystallization enthalpy is respectively 130.03 and 121.92 J/g and the encapsulation efficiency of MicroC-15 is 61.04 %.

Relationship Between Serum Uric Acid and Carotid Plaque in Patients With Coronary Artery Disease by Sex and Blood Pressure Status.

The purpose of this study was to explore the sex difference and effects of blood pressure (BP) on the relationship between serum uric acid (SUA) and carotid plaque in patients with coronary heart disease (CHD). This large multicenter retrospective study included 12099 patients with CHD (aged 35-75 years) between January 1, 2014 and September 30, 2020. Patients were divided into three groups according to systolic BP (SBP) and diastolic BP (DBP), and the SUA levels in males and females were converted into three groups. Logistic regression was used to analyze the influence of sex and BP on the relationship between SUA levels and carotid plaque in patients with CHD. In the model of male BP subgroups, using the BP of group A (normal with SBP <120 mmHg and DBP <80 mmHg) as a reference, SUA levels were significantly correlated with the occurrence of carotid plaque under different BP states (P < .001). In contrast, in the model of female BP subgroups, most of these correlations were not statistically significant. Our study showed that SUA levels were significantly associated with carotid plaque occurrence in males with CHD, which remained significant across different BP states.

Association of thyroid hormone sensitivity index with stroke in patients with coronary artery disease.

BACKGROUND AND AIMS: Thyroid hormones (THs) will affect the occurrence and prognosis of stroke, and the research on THs sensitivity index and stroke in patients with coronary heart disease (CHD) is scarce. The goal of this study is to look into the relationship between central and peripheral THs sensitivity index and stroke in patients with CHD. METHODS: Between January 1, 2014, and September 30, 2020, 30,160 patients with CHD were enrolled in this study. By computing the thyroid feedback quantile index (TFQI), thyroid stimulating hormone index (TSHI), and thyrotropin thyroxine resistance index (TT4RI), the central sensitivity indexes to THs was assessed, and the ratio of serum free triiodothyronine (FT3) to serum free thyroxine (FT4) was used to assess peripheral THs sensitivity. The relationship between central and peripheral THs sensitivity index and stroke was investigated using logistic regression, especially in different types of stroke, ages, sexes, and blood glucose levels. RESULTS: Stroke risk is positive associated with TSHI, TFQI, and PTFQI. In subgroup analysis, the OR values of these relationships are higher in people younger than 65 years old, male, and diagnosed with diabetes. In addition, stroke risk was negatively associated with FT3/FT4, and the OR values of these relationships were lower in people older than 65 years, female, and diagnosed with prediabetes. CONCLUSIONS: This study demonstrates that the increase in the central THs sensitivity index and the decrease in the peripheral THs sensitivity index are associated with a higher risk of stroke in CHD patients, and provides new ideas for the assessment of stroke in patients with CHD.

Associations Between Atherosclerosis and Elevated Serum Alkaline Phosphatase in Patients With Coronary Artery Disease in an Inflammatory State.

BACKGROUND AND AIM: Serum alkaline phosphatase (ALP) has been shown to be associated with cardiovascular disease (CVD) risk. Inflammation is the initiator of atherosclerosis, throughout the life of atherosclerosis. This study investigated the relationship between serum ALP and atherosclerosis in patients with coronary artery disease (CAD) in an inflammatory state. METHODS: This was a multicentre retrospective study including 22,989 patients with CAD. Serum alkaline phosphatase was converted into the quartiles. C-reactive protein (CRP) was assayed as a marker of systemic inflammation. The atherosclerosis index (AI) was used to assess the degree of atherosclerosis. Binary logistic regression was used to analyse the relationship between ALP and AI. Stratified analysis was performed according to sex and age. RESULTS: Elevated serum ALP was associated with the risk of atherosclerosis in patients with CAD, and after quartiling ALP, the OR for Q4 was 1.17 (95% CI 1.08-1.26; p<0.001) when using Q1 as reference. The odds ratio (OR) for ALP and risk of atherosclerosis was higher in patients aged ≤60 years (OR 1.33, 95% CI 1.15-1.53; p<0.001) than in patients aged >60 years (OR 1.11, 95% CI 1.01-1.23; p<0.05), and higher in males (OR 1.21, 95% CI 1.09-1.35; p<0.001) than in females (OR 1.16, 95% CI 1.03-1.31; p<0.05). Q4 (ALP >83.00 U/L) was significantly associated with increased risk of atherosclerosis in the inflammatory state (OR 1.48, 95% CI 1.18-1.86; p<0.001), and it remained after stratified analysis according to sex and age. CONCLUSIONS: The risk of atherosclerosis tended to increase with increasing ALP levels and the correlation between ALP and the degree of atherosclerosis was significantly stronger when ALP was >83.00 U/L. This relationship was more pronounced in inflammatory states, and there were sex and age differences. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT04026724.

The impact of SWI/SNF and NuRD inactivation on gene expression is tightly coupled with levels of RNA polymerase II occupancy at promoters.

SWI/SNF and NuRD are protein complexes that antagonistically regulate DNA accessibility. However, repression of their activities often leads to unanticipated changes in target gene expression (paradoxical), highlighting our incomplete understanding of their activities. Here we show that SWI/SNF and NuRD are in a tug-of-war to regulate PRC2 occupancy at lowly expressed and bivalent genes in mouse embryonic stem cells (mESCs). In contrast, at promoters of average or highly expressed genes, SWI/SNF and NuRD antagonistically modulate RNA polymerase II (Pol II) release kinetics, arguably owing to accompanying alterations in H3.3 and H2A.Z levels at promoter-flanking nucleosomes, leading to paradoxical changes in gene expression. Owing to this mechanism, the relative activities of the two remodelers potentiate gene promoters toward Pol II-dependent open or PRC2-dependent closed chromatin states. Our results highlight RNA Pol II occupancy as the key parameter in determining the direction of gene expression changes in response to SWI/SNF and NuRD inactivation at gene promoters in mESCs.

Relationship between red cell distribution width/albumin ratio and carotid plaque in different glucose metabolic states in patients with coronary heart disease: a RCSCD-TCM study in China.

BACKGROUND: Red cell distribution width/albumin ratio (RAR) is thought to be associated with the prognosis of a variety of diseases, including diabetes and heart failure. To date, no studies have focused on the relationship between RAR and carotid plaque in patients with coronary heart disease (CHD). METHODS: A total of 10,267 patients with CHD were divided according to RAR quartiles (Q1: RAR ≤ 2.960; Q2: 2.960 < RAR ≤ 3.185; Q3: 3.185 < RAR < 3.441; Q4: RAR ≥ 3.441). Logistic regression was used to analyze the relationship between RAR and carotid plaques in CHD patients. The relationship between RAR and carotid plaques in according to sex, age and glucose regulation state groups were also assessed. RESULTS: Among the 10,267 participants, 75.43% had carotid plaques. After adjusting for confounding factors, RAR was found to be associated with carotid plaque formation (OR: 1.23; 95% CI 1.08-1.39). The risk of carotid plaque formation in the Q4 group was 1.24 times higher than that in the Q1 group. After multivariate adjustment, RAR was associated with the risk of carotid plaque in female (OR: 1.29; 95% CI 1.09-1.52). And the relationship between RAR and carotid plaques in patients younger than 60 years old (OR: 1.43; 95% CI 1.16-1.75) was stronger than that in those older than 60 years old (OR: 1.29; 95% CI 1.10-1.51). Under different glucose metabolism states, RAR had the highest correlation with the risk of carotid plaques in diabetes patients (OR: 1.28; 95% CI 1.04-1.58). CONCLUSIONS: RAR was significantly related to carotid plaques in patients with CHD. In addition, the correlation between RAR and the incidence of carotid plaque in patients with CHD was higher in women and middle-aged and elderly patients. In patients with CHD and diabetes, the correlation between RAR and carotid plaque was higher.

The histone demethylase KDM5C functions as a tumor suppressor in AML by repression of bivalently marked immature genes.

Epigenetic regulators are frequently mutated in hematological malignancies including acute myeloid leukemia (AML). Thus, the identification and characterization of novel epigenetic drivers affecting AML biology holds potential to improve our basic understanding of AML and to uncover novel options for therapeutic intervention. To identify novel tumor suppressive epigenetic regulators in AML, we performed an in vivo short hairpin RNA (shRNA) screen in the context of CEBPA mutant AML. This identified the Histone 3 Lysine 4 (H3K4) demethylase KDM5C as a tumor suppressor, and we show that reduced Kdm5c/KDM5C expression results in accelerated growth both in human and murine AML cell lines, as well as in vivo in Cebpa mutant and inv(16) AML mouse models. Mechanistically, we show that KDM5C act as a transcriptional repressor through its demethylase activity at promoters. Specifically, KDM5C knockdown results in globally increased H3K4me3 levels associated with up-regulation of bivalently marked immature genes. This is accompanied by a de-differentiation phenotype that could be reversed by modulating levels of several direct and indirect downstream mediators. Finally, the association of KDM5C levels with long-term disease-free survival of female AML patients emphasizes the clinical relevance of our findings and identifies KDM5C as a novel female-biased tumor suppressor in AML.

Collagen VI antibody reduces atherosclerosis by activating monocyte/macrophage polarization in ApoE-/- mice.

Atherosclerosis (AS) has been regarded as an autoimmune disease. However, studies on immunotherapy against AS are limited. We previously found that IgG in AS patients serum binding to alpha 5 and 6 chain of collagen VI (COL6A5 or COL6A6) was significantly higher than that in healthy subjects, here we tried to identify whether they are AS-protective, and tried to develop human antibodies against them. ApoE-/- mice were immunized with COL6A5 or COL6A6 and COL6A6 was found a protective antigen against atherosclerosis. A phage display human single-chain antibody (scFv) library was constructed and COL6A6-specific scFv was obtained, and cloned into a modified pcDNA3 vector to express full-length human antibodies. ApoE-/- mice were fed a high-fat diet (HFD) for 20 weeks and administered three weekly injections of CVI monoclonal antibody (mAb) or isotype control antibody, CVI mAb was found to be able to reduce plaque area by 45 % via aorta oil red O staining. Flowcytometry method predicted that CVI mAb induced monocyte/macrophage polarization from M1 to M2. Furthermore, CVI mAb induced decreases of pro-inflammatory cytokines of MCP-1and IL-1ß, and increases of IL-4 and IL-10 levels in animal serum by using theLuminexassay. Overall, we found a novel atherosclero-related antigen - Collagen VI, and its protective fragment - Collagen VI alpha 6 chain (COL6A6) and proved that humanized antibody against COL6A6 therapy regresses atherosclerosis and induces monocyte/macrophage polarization from M1 to M2 in ApoE-/- mice animal model.

Impaired Sensitivity to Thyroid Hormones Is Associated With Elevated Blood Glucose in Coronary Heart Disease.

Context: Thyroid hormones influence glucose homeostasis through central and peripheral regulation. To date, the association between thyroid hormone sensitivity and elevated blood glucose (EBG) in patients with coronary heart disease (CHD) remains unknown. The purpose of this study was to investigate the association between thyroid hormone sensitivity and risk of EBG in patients with CHD, and to further explore their association in different sexes and ages. Methods: This large multicenter retrospective study included 30,244 patients with CHD (aged 30-80 years) between 1 January 2014 and 30 September 2020. Parameters representing central and peripheral sensitivity to thyroid hormones were calculated. Central sensitivity to thyroid hormones was assessed by calculating the Thyroid Feedback Quantile-based Index (TFQI), Thyroid-stimulating Hormone Index (TSHI), and Thyrotropin Thyroxine Resistance Index (TT4RI), and Parametric Thyroid Feedback Quantile-based Index (PTFQI); peripheral sensitivity to thyroid hormones was evaluated using the ratio of free triiodothyronine (FT3) /free thyroxine (FT4). Taking normal glucose tolerance (NGT) as a reference, logistic regression was used to analyse the relationship between central and peripheral thyroid hormone sensitivity and EBG in patients with CHD. Results: Among the 30,244 participants, 15,493 (51.23%) had EBG. The risk of EBG was negatively correlated with TSHI (OR: 0.91; 95%CI: 0.91 to 0.92; P < 0.001), TT4RI (OR: 0.99; 95% CI: 0.99 to 0.99; P<0.001), TFQI (OR: 0.82; 95%CI: 0.80 to 0.84; P <0.001) and PTFQI (OR: 0.76; 95%CI: 0.74 to 0.78; P<0.001). Compared to males and patients aged 60 and below, the OR value for EBG was lower in females and in patients aged over 60 years old. Conversely, EBG risk was positively associated with FT3/FT4 (OR: 1.08; 95% CI: 1.07 to 1.09; P <0.001) and in the sex-categorized subgroups, males had higher OR values than females. Conclusions: This study showed that thyroid hormone sensitivity is significantly associated with EBG in patients with CHD. This association is higher in females than in males, and the association in those aged over 60 years old is higher than that in patients aged 60 years and below.

Remnant cholesterol for the detection of glucose metabolic states in patients with coronary heart disease angina pectoris.

BACKGROUND: This study aimed to evaluate the relationship between remnant cholesterol (RC) and glucose metabolic states in coronary heart disease (CHD) patients with angina pectoris. METHODS: This study collected data from 11,557 CHD patients with angina pectoris aged 35-75 years in Tianjin, China. Participants were divided into normal glucose regulation (NGR), prediabetes (Pre-DM) and diabetes mellitus (DM) groups according to glucose metabolic states. Linear regression analysis was used to explore the relationship between glucose metabolism [fasting blood glucose (FBG) and glycated hemoglobin (HbA1c)] and RC levels. Logistic regression was performed to analyze the relationship between RC levels and glucose metabolic states. RESULTS: Among all participants, 5883 (50.9%) had a DM state and 4034 (34.9%) had a Pre-DM state. FBG levels and HbA1c levels were positively related with RC in all patients (P < 0.001). NGR was used as a reference, multi-adjusted model showing that RC level was significantly associated with Pre-DM [Odds ratio (OR): 1.37; 95% confidence interval (CI) 1.19-1.56; P < 0.001] and DM state (OR:1.47; 95% CI 1.29-1.67; P < 0.001). When considering RC as categorical variables (tertiles), using T1 as a reference, T3 had the strongest relationship between RC levels and Pre-DM and DM state in univariate model and multivariate model. In the stratified analyses, the association between RC levels and pre-DM and DM in women was higher than that in men, and the elderly patients was higher than in the middle-aged patients. CONCLUSION: The study demonstrated a significant association between RC levels and pre-DM and DM state among CHD patients with angina pectoris, and the relationship was stronger in women and elderly patients.

Triglyceride glucose index for the detection of the severity of coronary artery disease in different glucose metabolic states in patients with coronary heart disease: a RCSCD-TCM study in China.

BACKGROUND: Triglyceride glucose (TyG) index is a new marker associated with atherosclerosis. This study aimed to assess the association between TyG index and the severity of coronary artery disease (CAD) in patients with coronary heart disease (CHD) and further explore the association between TyG index and CAD severity in different glucose metabolic states. METHODS: This multi-centre retrospective study included 731 patients with CHD between January 1, 2014 and September 30, 2020 in China. All patients were stratified into groups based on the tertiles of TyG index (T1: 5.48 ≤ TyG index ≤ 7.17; T2: 7.18 ≤ TyG index ≤ 7.76; T3: 7.77 ≤ TyG index ≤ 10.82). The number of diseased vessels [single-vessel and multi-vessel CAD (≥ 50% stenosis in ≥ 2 large vessels)] represented the severity of CAD, which was measured using coronary angiography (CAG). Glucose metabolic states were defined by the American Diabetes Association as normal glucose regulation (NGR), prediabetes mellitus (Pre-DM), and diabetes mellitus (DM). RESULTS: The baseline analysis results showed significant differences in the clinical and biological characteristics of CHD patients according to TyG index tertiles (P < 0.05 to < 0.001). Logistic regression analysis showed that the TyG index was significantly related to the risk of multi-vessel CAD (odds ratio [OR]: 1.715; 95% confidence interval [CI] 1.339-2.197; P < 0.001). The OR for multi-vessel CAD in TyG index T3 compared to that of T1 was 2.280 (95% CI 1.530-3.398; P < 0.001). Receiver operating characteristic (ROC) curve was generated to evaluate the accuracy of the TyG index in detecting the CAD severity, and the area under the curve (AUC) of the ROC plots was 0.601 (95% CI 0.559-0.643). The association between TyG index and multi-vessel CAD was significant in patients with DM, achieving the highest OR among the different glucose metabolic states (OR: 1.717; 95% CI 1.161-2.539; P < 0.05). CONCLUSION: TyG index was associated with CAD severity in patients with CHD, and an increased TyG index could identify patients with a high risk of multi-vessel CAD. There was an association between TyG index and CAD severity for the condition of DM.

Correlation between the triglyceride-to-high-density lipoprotein cholesterol ratio and other unconventional lipid parameters with the risk of prediabetes and Type 2 diabetes in patients with coronary heart disease: a RCSCD-TCM study in China.

OBJECTIVE: Type 2 diabetes mellitus (T2DM) is often accompanied by undiagnosed dyslipidemia. Research on the association of unconventional lipid markers with prediabetes (pre-DM) and T2DM simultaneously is limited in coronary heart disease (CHD) patients. METHODS: This study included 28,476 patients diagnosed with CHD. Their lipid levels, including triglycerides (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C), were measured, and non-traditional lipid parameters were calculated. The patients were divided into three groups based on the diabetic status including normoglycemic (NG), pre-DM, and T2DM. Multiple logistic regression was used to compare the association of TG/HDL-C and other non-traditional lipid parameters with pre-DM and T2DM. The tertiles of TG/HDL-C included T1 (TG/HDL-C < 1.10), T2 (1.10 ≤ TG/HDL-C ≤ 1.89) and T3 (TG/HDL-C > 1.89). Low and high TG/HDL-C was defined with sex-specific cutoff points. RESULTS: Multiple logistic regression results showed that the non-traditional lipid parameters, including non-HDL-C, LDL-C/HDL-C, TC/HDL-C, non-HDL-C/HDL-C and TG/HDL-C, were all correlated with the risk of pre-DM and T2DM. Meanwhile TG/HDL-C showed the strongest correlation (odds ratio [OR]: 1.19; 95% confidence interval [CI] 1.16-1.23), (OR: 1.36; 95% CI 1.33-1.39). When dividing TG/HDL-C into tertiles, using T1 as a reference, T3 was observed to have the highest association with both pre-DM and T2DM (OR: 1.60; 95% CI 1.48-1.74), (OR: 2.79; 95% CI 2.60-3.00). High TG/HDL-C was significantly associated with pre-DM and T2DM (OR: 1.69; 95% CI 1.52-1.88), (OR: 2.85; 95% CI 2.60-3.12). The association of TG/HDL-C with T2DM and pre-DM existed across different sex, age, smoking, and drinking statuses. CONCLUSION: Elevated non-traditional lipid parameters were significantly associated with pre-DM and T2DM in CHD patients, especially TG/HDL-C. High TG/HDL-C was the risk factor with a strong correlation with the risk of pre-DM and T2DM.

Transcription factor-driven coordination of cell cycle exit and lineage-specification in vivo during granulocytic differentiation : In memoriam Professor Niels Borregaard.

Differentiation of multipotent stem cells into mature cells is fundamental for development and homeostasis of mammalian tissues, and requires the coordinated induction of lineage-specific transcriptional programs and cell cycle withdrawal. To understand the underlying regulatory mechanisms of this fundamental process, we investigated how the tissue-specific transcription factors, CEBPA and CEBPE, coordinate cell cycle exit and lineage-specification in vivo during granulocytic differentiation. We demonstrate that CEBPA promotes lineage-specification by launching an enhancer-primed differentiation program and direct activation of CEBPE expression. Subsequently, CEBPE confers promoter-driven cell cycle exit by sequential repression of MYC target gene expression at the G1/S transition and E2F-meditated G2/M gene expression, as well as by the up-regulation of Cdk1/2/4 inhibitors. Following cell cycle exit, CEBPE unleashes the CEBPA-primed differentiation program to generate mature granulocytes. These findings highlight how tissue-specific transcription factors coordinate cell cycle exit with differentiation through the use of distinct gene regulatory elements.

Synergistic inhibitory effect of berberine and icotinib on non-small cell lung cancer cells via inducing autophagic cell death and apoptosis.

Resistance to epidermal growth factor receptor-tyrosin kinase inhibitors (TKIs, e.g. icotinib) remains a major clinical challenge. Non-small cell lung cancer patients with wild-type EGFR and/or K-RAS mutation are primary resistance to EGFR-TKIs. Berberine has been found to have potent anticancer activities via distinct molecular mechanism. In this study, we sought to investigate the therapeutic utility of BBR in combination with icotinib to overcome icotinib resistance in NSCLC cells, and explore the molecular mechanism of synergism of icotinib and BBR to EGFR-resistant NSCLC cells. We used the two EGFR-resistant NSCLC cell lines H460 and H1299 for testing the inhibitory effect of icotinib and/or BBR on them. Moreover, xenograft mouse model was applied for assessing the anti-tumor activities of BBR and icotinib in combination. Results showed that BBR and icotinib have a synergistic inhibitory effect on H460 and H1299 cells through induction of autophagic cell death and apoptosis. Accordingly, the anti-cancer effect of BBR plus icotinib was further confirmed in the NSCLC xenograft mouse models. Combination of BBR and icotinib significantly inhibited the protein expression and the activity of EGFR by inducing autophagic EGFR degradation. BBR plus icotinib resulted in intracellular ROS accumulation, which could mediated autophagy and apoptosis and involved in the suppression of cell migration and invasion. In conclusions, combination application of BBR and icotinib could be an effective strategy to overcome icotinib resistance in the treatment of NSCLC.

The role of lymphocyte-monocyte ratio on axial spondyloarthritis diagnosis and sacroiliitis staging.

BACKGROUND: Axial spondyloarthritis (axial SpA) is a chronic inflammatory disorder could lead to disability due to the failure of timely treatment. The role of lymphocyte-to-monocyte ratio (LMR) in axial SpA remains unclear. The aim of this study was to investigate the role of LMR in axial SpA diagnosis, disease activity classification and sacroiliitis staging. METHODS: Seventy-eight axial SpA patients [51males and 27 females; mean age 41.0 (29-52) years] and 78 healthy controls (HCs) [55males and 23 females; mean age 40 (30-53) years] were enrolled in this study. The diagnosis of axial SpA was performed according to the New York criteria or the Assessment of Spondyloarthritis international Society (ASAS) classification criteria, whereas the staging of sacroiliitis in axial SpA patients was determined by X-ray examination. Comparisons of LMR levels between groups were performed using t test. Pearson or Spearman correlation analysis were used to assess correlations between LMR and other indicators. Receiver operating characteristic (ROC) curves were used to determine the role of LMR in the diagnosis of axial SpA. RESULTS: Higher neutrophil-to-lymphocyte ratio(NLR), red blood cell distribution width(RDW), platelet-to-lymphocyte ratio(PLR), mean platelet volume(MPV), erythrocyte sedimentation rate (ESR), and C-reactive protein(CRP) levels and lower red blood cell (RBC), hemoglobin (Hb), Hematocrit (Hct), LMR, alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBIL) and albumin/globulin (A/G) levels were noted in axial SpA patients compared to HCs. Positive correlations were observed between LMR and RBC, Hb, Hct and A/G, whereas negative correlations were found between LMR and NLR, PLR, AST, and TBIL (P < 0.05). ROC curves showed that the area under the curve (AUC) for LMR in the diagnosis of ankylosing spondylitis was 0.803 (95% CI = 0.734-0.872) with a sensitivity and specificity of 62.8 and 87.2%, respectively, and the AUC (95% CI) for the combination of ESR, CRP and LMR was 0.975 (0.948-1.000) with a sensitivity and specificity of 94.9 and 97.4%, respectively. LMR levels were lower (P < 0.05) and significant differences in LMR values were observed among different stages (P < 0.05). CONCLUSIONS: Our study suggested that LMR might be an important inflammatory marker to identify axial SpA and assess disease activity and X-ray stage of sacroiliitis.

Synergistic killing effect of paclitaxel and honokiol in non-small cell lung cancer cells through paraptosis induction.

PURPOSE: Paclitaxel is an anticancer drug for the treatment of non-small cell lung cancer (NSCLC). However, drug-resistance remains a major problem. Honokiol is a natural component which has been found to exhibit anti-tumor activity. Paclitaxel and honokiol have been reported to be able to induce paraptosis. The aim of this study was to investigate whether honokiol can reverse paclitaxel resistance by inducing paraptosis in NSCLC cells. METHODS: NSCLC cell lines H1650 (paclitaxel-sensitive), H1299 and H1650/PTX (intrinsic and acquired paclitaxel-resistant, respectively) were used to assess the cytotoxic effects of paclitaxel and honokiol. Light and transmission electron microscopy were performed to detect cytoplasmic vacuolation. In vitro cell viability and clonogenic survival assays, as well as in vivo xenograft assays were conducted to test synergistic killing effects of paclitaxel and honokiol on NSCLC cells. Western blotting, flow cytometry and immunofluorescence were performed to evaluate paraptosis-regulating mechanisms. RESULTS: We found that combination treatment with paclitaxel and honokiol synergistically killed H1650, H1299 and H1650/PTX cells by inducing paraptosis, which is characterized by cytoplasmic vacuolation. Moreover, paclitaxel/honokiol treatment resulted in a significant growth delay in H1299 xenograft tumors that showed extensive cytoplasmic vacuolation. Mechanistically, proteasomal inhibition-mediated endoplasmic reticulum (ER) stress and unfolded protein responses leading to ER dilation, and the disruption of intracellular Ca2+ homeostasis and mitochondrial Ca2+ overload resulting in mitochondrial disfunction, were found to be involved in paclitaxel/honokiol-induced paraptosis. Cellular protein light chain 3 (LC3) may play an important role in paclitaxel/honokiol induced cytoplasmic vacuolation and NSCLC cell death. CONCLUSIONS: Combination of honokiol and paclitaxel may represent a novel strategy for the treatment of paclitaxel-resistant NSCLC.

An artificial intelligence model for the simulation of visual effects in patients with visual field defects.

BACKGROUND: This study aimed to simulate the visual field (VF) effects of patients with VF defects using deep learning and computer vision technology. METHODS: We collected 3,660 Humphrey visual fields (HVFs) as data samples, including 3,263 reliable 24-2 HVFs. The convolutional neural network (CNN) analyzed and converted the grayscale map of reliable samples into structured data. The artificial intelligence (AI) simulations were developed using computer vision technology. In statistical analyses, the pilot study determined 687 reliable samples to conduct clinical trials, and the two independent sample t-tests were used to calculate the difference of the cumulative gray values. Three volunteers evaluated the matching degree of shape and position between the grayscale map and the AI simulation, which was graded from 0 to100 scores. Based on the average ranking, the proportion of good and excellent grades was determined, and thus the reliability of the AI simulations was assessed. RESULTS: The reliable samples in the experimental data consisted of 1,334 normal samples and 1,929 abnormal samples. Based on the existing mature CNN model, the fully connected layer was integrated to analyze the VF damage parameters of the input images, and the prediction accuracy of the damage type of the VF defects was up to 89%. By mapping the area and damage information in the VF damage parameter quintuple data set into the real scene image and adjusting the darkening effect according to the damage parameter, the visual effects in patients were simulated in the real scene image. In the clinical validation, there was no statistically significant difference in the cumulative gray value (P>0.05). The good and excellent proportion of the average scores reached 96.0%, thus confirming the accuracy of the AI model. CONCLUSIONS: An AI model with high accuracy was established to simulate the visual effects in patients with VF defects.

The important role of apolipoprotein A-II in ezetimibe driven reduction of high cholesterol diet-induced atherosclerosis.

BACKGROUND AND AIMS: It has been well established that ezetimibe blocks cholesterol absorption to prevent the negative effects of a high-fat diet in atherosclerosis. However, the exact mechanism is unknown. Here we use a transgenic zebrafish, which expresses different fluorescent proteins on either endothelial cells or granulocytes and macrophages, to explore the specific mechanism of ezetimibe and its role in reducing atherosclerosis-related hypercholesteremia. METHODS: Zebrafish larvae were exposed to a control diet, high cholesterol diet (HCD) or a HCD with ezetimibe treatment. Both the control diet and high cholesterol diet were mixed with red or green fluorophore labeled cholesteryl ester to trace lipid distribution. Isobaric tags were used for relative and absolute quantification to examine protein expression profiles of zebrafish larvae in the different treatment groups. To knock down Apo A-II and investigate the role of Apo A-II in the anti-atherosclerotic function of ezetimibe, we used morpholinos to target zebrafish Apoa2 mRNA. To confirm ezetimibe regulatory role on Apo A-II expression, siRNA against HNF4, PPARα, and SREBP1 were transfected into HepG2 cells. RESULTS: The results show that ezetimibe increased the expression of Apo A-II but failed to reduce vascular lipid accumulation and macrophage recruitment induced by the HCD diet when Apo A-II was knocked down. Finally, we found that ezetimibe increased the expression of Apo A-II through HNF4 and PPARα transcriptional factors. CONCLUSIONS: Our data indicates that ezetimibe may not only prevents atherosclerosis by inhibiting cholesterol absorption in the intestine, but also by increasing the expression of Apo A-II in hepatocytes, thereby enhancing reverse cholesterol transport and removing excess cholesterol from the periphery.

Pulsed electromagnetic fields inhibit osteoclast differentiation in RAW264.7 macrophages via suppression of the protein kinase B/mammalian target of rapamycin signaling pathway.

When bone resorption, aided by the activity of osteoclasts, exceeds bone formation induced by osteoblasts, bone metabolism loses equilibration, which results in the development of bone diseases, including osteoporosis. Pulsed electromagnetic fields (PEMFs) are known to be involved in various biological processes, including cell proliferation, differentiation and apoptosis. However, the exact mechanism of action of osteoclasts remains poorly understood. In the present study, the effects of PEMFs on osteoclast differentiation and associated signaling pathways were systematically investigated in RAW264.7 macrophages. RAW264.7 cells were induced by receptor activator of nuclear factor­κB ligand (RANKL) to obtain osteoclasts in vitro. The results of the present study demonstrated that PEMF exposure decreased osteoclast formation, limited tartrate­resistant acid phosphatase activity, contracted bone resorption area and inhibited osteoclastic specific gene and protein expression. Furthermore, western blot analysis indicated that PEMFs distinctly abolished the upregulation of phosphorylated­protein kinase B (Akt), ­mammalian target of rapamycin (mTOR) and ­ribosome S6 protein kinase (p70S6K) induced by RANKL, which was consistent with the effects of pharmacological inhibitor perifosine and rapamycin. Therefore, the present study suggested that PEMFs reduced osteoclast formation from RAW264.7 macrophages via inhibition of the Akt/mTOR signaling pathway. These findings provided novel insight into the mechanisms through which PEMFs suppress osteoclast differentiation.

Suppression of the FA pathway combined with CHK1 inhibitor hypersensitize lung cancer cells to gemcitabine.

The combination of platinum and gemcitabine is one of the standard regimens in the treatment of advanced lung squamous carcinoma (LSC). Resistance to gemcitabine is main barrier to the successful treatment of LSC. In this study, we showed that suppression of the Fanconi anemia (FA) pathway increased the sensitivity of two LSC cell lines SK-MES-1 and KLN205 to gemcitabine. Moreover, we found that the CHK1 pathway and the FA pathway are functionally compensatory in the repair of DNA damage in the LSC cell lines. Inactivation of one of the two pathways led to DNA damage, triggering compensatory activation of other pathway. Furthermore, we demonstrated that FANCD2 depletion combined with CHK1 inhibitor MK-8776 significantly potentiated the cytotoxicity of gemcitabine to the two LSC cell lines, compared to individual FANCD2 depletion or MK-8776 treatment. The enhanced effect of gemcitabine-chemosensitization was accompanied by loss of DNA repair function and accumulation of DNA single strand breaks and double strand breaks, in parallel with obvious increase of caspase-3 dependent apoptosis. Our results indicate that the enhancement effect of FANCD2 depletion combined with CHK1 inhibitor in sensitizing the LCS cells to gemcitabine supports the FA pathway and CHK1 as two therapeutic targets for improvement of anti-tumor regimens in treatment of LSC.