BionoiNet: ligand-binding site classification with off-the-shelf deep neural network.

MOTIVATION: Fast and accurate classification of ligand-binding sites in proteins with respect to the class of binding molecules is invaluable not only to the automatic functional annotation of large datasets of protein structures but also to projects in protein evolution, protein engineering and drug development. Deep learning techniques, which have already been successfully applied to address challenging problems across various fields, are inherently suitable to classify ligand-binding pockets. Our goal is to demonstrate that off-the-shelf deep learning models can be employed with minimum development effort to recognize nucleotide- and heme-binding sites with a comparable accuracy to highly specialized, voxel-based methods. RESULTS: We developed BionoiNet, a new deep learning-based framework implementing a popular ResNet model for image classification. BionoiNet first transforms the molecular structures of ligand-binding sites to 2D Voronoi diagrams, which are then used as the input to a pretrained convolutional neural network classifier. The ResNet model generalizes well to unseen data achieving the accuracy of 85.6% for nucleotide- and 91.3% for heme-binding pockets. BionoiNet also computes significance scores of pocket atoms, called BionoiScores, to provide meaningful insights into their interactions with ligand molecules. BionoiNet is a lightweight alternative to computationally expensive 3D architectures. AVAILABILITY AND IMPLEMENTATION: BionoiNet is implemented in Python with the source code freely available at: https://github.com/CSBG-LSU/BionoiNet. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Astragaloside IV ameliorates preeclampsia-induced oxidative stress through the Nrf2/HO-1 pathway in a rat model.

Preeclampsia (PE) can cause serious health problems for pregnant women and their infants. Astragaloside IV has been shown to exert cardioprotective, anti-inflammatory, and antioxidative effects on various disorders. We aimed to study the effects of Astragaloside IV on PE symptoms using an NG-nitro-l-arginine methyl ester (l-NAME)-induced rat model of PE. The pregnant rats' physiological features, including blood pressure, urine protein, serum soluble fms-like tyrosine kinase-1(sFlt-1)/placental growth factor (PlGF) ratio, and weight of placenta, as well as the weight, length, and survival of pups, were documented. The expression levels of target genes were analyzed by Western blot and qRT-PCR assays. The levels of target secreted proteins were determined by ELISA. We demonstrated that the administration of Astragaloside IV might exert a multitude of beneficial effects on attenuated PE symptoms in a rat model of PE. We further revealed that the effects of Astragaloside IV on PE rats were achieved, at least partially, through elimination of oxidative stress and stimulation of the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) signaling pathway. Our study indicated that Astragaloside IV may serve as a promising candidate for the development of new therapeutic methods for patients with PE.

Astragaloside IV relieves gestational diabetes mellitus in genetic mice through reducing hepatic gluconeogenesis.

The glucose intolerance developed during pregnancy is called gestational diabetes mellitus (GDM). GDM has become a severe risk for the health of both mother and baby. Astragaloside IV (AS-IV) is the dominant active component in Astragalus membranaceus and has been reported to have anti-inflammation and immune-regulation function. We aimed to demonstrate the function of AS-IV in the therapy of GDM and the molecular mechanism in this process. C57BL/KsJ-Lepdb/+ female mice were used as the GDM model. The mRNA levels of relative genes in this research were detected by quantitative real-time PCR. The protein levels of relative genes were analyzed by Western blot. Serum lipid level was measured with an ILab Chemistry Analyzer 300 PLUS. Glucose, insulin, and lipid profile levels in the GDM mice model were decreased by AS-IV treatment. AS-IV downregulated the expression of inflammatory genes and upregulated the expressions of anti-oxidant genes in the GDM mice model. AS-IV treatment reduced cAMP accumulation in liver and reduced hepatic gluconeogenesis in GDM mice. This study demonstrated that AS-IV treatment has an effective therapeutic function of GDM in a mice model through the regulation of cAMP accumulation and hepatic gluconeogenesis.

Factors influencing postpartum blood glucose screening among women with prior gestational diabetes mellitus in a rural community.

AIMS: The aims of the present study were: a) to investigate the current state of postpartum glucose screening in rural China; and b) to explore the factors influencing postpartum blood glucose screening among women with prior GDM based on Andersen's behavioural model of health service use. DESIGN: A multisite, cross-sectional study design, conducted from November 2017 to January 2018. METHODS: A total of 465 women with prior GDM were included from two county-level hospitals in rural China. The potential influencing factors for postpartum blood glucose screening based on Andersen's behavioural model, including predisposing, enabling, and need factors, were collected by self-reported questionnaires. Chi-square tests and logistic regression were used to explore the influence of these factors on whether screening of blood glucose level after delivery occurred. RESULTS: The mean age of the women was 31.92 years old (SD 5.16) and the mean time after delivery was 16.73 months (SD 15.07). The postpartum glucose screening proportion was 32.7%. Women who did not have a full-time job (p= .011) (predisposing factor), had not received any treatment for GDM (p= .002), and were not informed about screening plans for diabetes by health professionals (p < .001) (enabling factor) were less likely to engage in postpartum glucose screening. The need factor, high actual risk of developing type 2 diabetes mellitus (T2DM), was not associated with postpartum blood glucose screening (p> .05). CONCLUSIONS: In rural China, most women with prior GDM were not screened for T2DM after delivery. The women with prior GDM who did not have a full-time job or had not received any prior treatment for GDM should be the target population for health education on postpartum glucose screening. IMPACT: There is a need for data on postpartum blood glucose testing rates among rural women. Future interventions aimed at increasing postpartum blood glucose screening are needed.

Phosphorylation of Runx2, induced by cyclic mechanical tension via ERK1/2 pathway, contributes to osteodifferentiation of human periodontal ligament fibroblasts.

Occlusal force is an important stimulus for maintaining periodontal homeostasis. This is attributed to the quality of human periodontal ligament fibroblasts (hPDLFs) that could transfer occlusal force into biological signals modulating osteoblst differentiation. However, few studies investigated the mechanism of occlusal force-induced osteodifferentiation of hPDLFs. In our study, we used the cyclic mechanical tension (CMT) at 10% elongation with 0.5 Hz to mimic occlusal force, and explored its effects on osteogenesis of hPDLFs. Firstly, elevated expressions of several osteoblast marker genes (Runx2, ATF4, SP7, OCN, and BSP), as well as activated ERK1/2 pathway were detected during CMT loading for 1, 3, 6, 12, 18, and 24 h. To gain further insight into how CMT contributed to those effects, we focused on the classic ERK1/2-Runx2 pathway by inhibiting ERK1/2 and overexpressing Runx2. Our results reflected that Runx2 overexpression alone could induce osteodifferentiation of hPDLFs. Meanwhile, CMT loading could intensify while combined ERK1/2 blockage could weaken this process. Furthermore, we found that CMT promoted Runx2 transcription and phosphorylation via ERK1/2; protein level of phospho-Runx2 (p-Runx2), rather than Runx2, was in parallel with mRNA expressions of SP7, OCN, and BSP. Taken together, our study proved that p-Runx2, elevated by CMT via ERK1/2 pathway, is the predominate factor in promoting osteoblast differentiation of hPDLFs.

Expression and Function of Hypoxia Inducible Factor-1α and Vascular Endothelial Growth Factor in Pulp Tissue of Teeth under Orthodontic Movement.

Orthodontic force may lead to cell damage, circulatory disturbances, and vascular changes of the dental pulp, which make a hypoxic environment in pulp. In order to maintain the homeostasis of dental pulp, hypoxia will inevitably induce the defensive reaction. However, this is a complex process and is regulated by numerous factors. In this study, we established an experimental animal model of orthodontic tooth movement to investigate the effects of mechanical force on the expression of VEGF and HIF-1α in dental pulp. Histological analysis of dental pulp and expressions of HIF-1α and VEGF proteins in dental pulp were examined. The results showed that inflammation and vascular changes happened in dental pulp tissue in different periods. Additionally, there were significant changes in the expression of HIF-1α and VEGF proteins under orthodontic force. After application of mechanical load, expression of HIF-1α and VEGF was markedly positive in 1, 3, 7 d, and 2 w groups, and then it weakened in 4 w group. These findings suggested that the expression of HIF-1α and VEGF was enhanced by mechanical force. HIF-1α and VEGF may play an important role in retaining the homeostasis of dental pulp during orthodontic tooth movement.

Two different classes of vector beams that have the same paraxial approximation.

It is observed that there exist two different classes of vector light beams that have the same first-order paraxial approximation. They are characterized by the axial and transverse orientations of a constant unit vector that comes from the constraint of transversality condition. Their vectorial structures in the nonparaxial regime and angular momentum properties are compared.

Induction immunochemotherapy followed by definitive chemoradiotherapy for unresectable locally advanced non-small cell lung cancer: a multi-institutional retrospective cohort study.

This study aimed to evaluate the efficacy and safety of induction immunochemotherapy followed by definitive chemoradiotherapy (CRT) for unresectable locally advanced non-small cell lung cancer (LA-NSCLC). We identified unresectable stage III NSCLC patients who received induction immunochemotherapy. Overall survival (OS) and progression-free survival (PFS) were the primary endpoints. From February 2019 to August 2022, 158 patients were enrolled. Following the completion of induction immunochemotherapy, the objective response rate (ORR) and disease control rate (DCR) were 52.5% and 83.5%, respectively. The ORR of CRT was 73.5%, representing 68.4% of the total cohort. The median PFS was 17.8 months, and the median OS was 41.9 months, significantly higher than in patients who received CRT alone (p < 0.001). Patients with concurrent CRT demonstrated markedly improved PFS (p = 0.012) and OS (p = 0.017) than those undergoing sequential CRT. Additionally, those with a programmed-death ligand 1 (PD-L1) expression of 50% or higher showed significantly elevated ORRs (72.2% vs. 47.2%, p = 0.011) and superior OS (median 44.8 vs. 28.6 months, p = 0.004) compared to patients with PD-L1 expression below 50%. Hematologic toxicities were the primary severe adverse events (grade ≥ 3) encountered, with no unforeseen treatment-related toxicities. Thus, induction immunochemotherapy followed by definitive CRT demonstrated encouraging efficacy and tolerable toxicities for unresectable LA-NSCLC.

Clinical predictors of severe radiation pneumonitis in patients undergoing thoracic radiotherapy for lung cancer.

Background: Severe radiation pneumonitis (RP), one of adverse events in patients with lung cancer receiving thoracic radiotherapy, is more likely to lead to more mortality and poor quality of life, which could be predicted by clinical information and treatment scheme. In this study, we aimed to explore the clinical predict model for severe RP. Methods: We collected information on lung cancer patients who received radiotherapy from August 2020 to August 2022. Clinical features were obtained from 690 patients, including baseline and treatment data as well as radiation dose measurement parameters, including lung volume exceeding 5 Gy (V5), lung volume exceeding 20 Gy (V20), lung volume exceeding 30 Gy (V30), mean lung dose (MLD), etc. Among them, 621 patients were in the training cohort, and 69 patients were in the test cohort. Three models were built using different screening methods, including multivariate logistics regression (MLR), backward stepwise regression (BSR), and random forest regression (RFR), to evaluate their predictive power. Overoptimism in the training cohorts was evaluated by four validation methods, including hold-out, 10-fold, leave-one-out, and bootstrap methods, and test cohort was used to evaluate the predictive performance of the model. Model calibration, decision curve analysis (DCA), and evaluation of the nomograms for the three models were completed. Results: Severe RP was up to 9.4%. The results of multivariate analysis of logistics regression in all patients showed that patients with subclinical (untreated and asymptomatic) interstitial lung disease (ILD) could increase the risk of severe RP, and patients with a better lung diffusion function and received standardized steroids treatment could decrease the risk of severe RP. The three models built by MLR, BSR, and RFR all had good accuracy (>0.850) and moderate κ value (>0.4), and the model 2 built by BSR had the highest area under the receiver operating characteristic (ROC) curve (AUC) in three models, which was 0.958 [95% confidence interval (CI): 0.932-0.985]. The calibration curve showed good agreement between the predicted and actual values, and the DCA showed a positive net benefit for the model 2 which drew the nomogram. The model 2 included subclinical ILD, diffusing capacity of the lung for carbon monoxide (DLCO), ipsilateral lung V20, and standardized steroid treatment, which could affect the incidence of severe RP. Conclusions: Subclinical ILD, DLCO, ipsilateral lung V20, and with or not standardized steroid treatment could affect the incidence of severe RP. Strict lung dose limitation and standardized steroid treatment could contribute to a decrease in severe RP.

Natural Flavonoid Quercetin Enhances the Anti-inflammatory Effects of Aspirin in a Preeclampsia-like Rat Model Induced by Lipopolysaccharide.

BACKGROUND: Preeclampsia is a disorder of hypertension and proteinuria accompanied by abnormal inflammatory responses. Both aspirin and quercetin possess anti-inflammatory and anti-hypertensive properties. A low dose of aspirin is recommended for the prevention of preeclampsia in patients with preeclampsia history. Whether quercetin can enhance the effect of aspirin on preeclampsia remains elusive. METHODS: Female Sprague-Dawley pregnant rats were treated with daily administration of aspirin, quercetin, or a combination of aspirin and quercetin and subsequently received lipopolysaccharides (LPS) injection to induce preeclampsia-like symptoms. The systolic blood pressure and proteinuria from all groups of rats were assessed. RESULTS: Our results demonstrated that the combination of quercetin and aspirin exerted significantly stronger effects than aspirin alone on decreasing systolic blood pressure and proteinuria, reducing pro-inflammatory cytokine production, and inhibiting M1-type decidual macrophages polarization in an LPS-induced rat model of preeclampsia. CONCLUSION: This study suggested that quercetin may serve as an excellent supplement to aspirin in preventing or treating patients with preeclampsia.

Five-year follow-up after stereotactic body radiotherapy for medically inoperable early-stage non-small cell lung cancer: a multicenter study.

Background: Stereotactic body radiotherapy (SBRT) has proven to provide high rates of tumor control for patients with early-stage non-small cell lung cancer (NSCLC). We are reporting a multicenter experience of long-term clinical outcomes and adverse effect profiles of patients with medically inoperable early-stage NSCLC treated with SBRT. Methods: A total of 145 early-stage NSCLC patients underwent SBRT at the Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Shandong Cancer Hospital and Institute, and Shanghai Pulmonary Hospital between October 2012 and March 2019. Four-dimensional computed tomography (4D-CT) simulation was used for all patients. All received a biologically effective dose (BED; α/ß=10) of 96-120 Gy with the prescribed isodose line covering >95% of the planning target volume (PTV). Survival was analyzed by the Kaplan-Meier method. Survival was estimated using the Kaplan-Meier method. Results: The median tumor diameter was 2.2 (range, 0.5-5.2) cm. The median follow-up was of 65.6 months. Thirty-five patients (24.1%) developed disease recurrence. The rates of local, regional, and distant disease recurrence were, respectively, 5.1%, 7.4%, and 13.2% at 3 years; and 9.6%, 9.8%, and 15.8% at 5 years. Progression-free survival (PFS) rates at 3 and 5 years were 69.2% and 60.5% respectively; the overall survival (OS) rates were 78.1% and 70.1%, respectively. Five patients (3.4%) experienced grade 3 treatment-related adverse events (AEs). No patient experienced grade 4 or 5 toxicity. Conclusions: From our retrospective analysis with long-term follow-up in Chinese population, SBRT achieved high rate of local control (LC) and low toxicity in patients with early-stage NSCLC. This study offered robust long-term outcome data of SBRT in the Chinese population, which was very rarely reported in China before.

Effect and stability of miniscrew-assisted rapid palatal expansion: A systematic review and meta-analysis.

Objective: This study aimed to systematically analyze the effect and stability of miniscrew-assisted rapid palatal expansion (MARPE) to provide a reference for the clinical treatment of patients with maxillary transverse deficiency (MTD). Methods: We searched PubMed, Science Direct, Web of Science, Embase, Cochrane Library, CNKI, and Wanfang Database for relevant studies published before February 18, 2021 and selected them according to the eligibility criteria. The Cochrane Handbook for Systematic Reviews (version 5.1.0) criteria were used for the quality assessment of randomized controlled trials, while the scoring protocol of the methodological index for non-randomized studies was used for non-randomized controlled trials. Statistical analysis was performed using the RevMan5.3 software. Results: All the included studies showed a relatively high success rate of expansion. The changes in both the intermolar and alveolar widths after MARPE were statistically significant. MARPE exhibited greater skeletal expansion effects than did conventional RPE. The midpalatal suture was opened in parallel after MARPE. A small amount of relapse was observed 1 year after expansion. MARPE caused tooth inclination and a decrease in alveolar height, but it was less significant than in conventional RPE. Conclusions: MARPE may be an effective treatment modality for patients with MTD. It causes great transverse skeletal expansion in late adolescence. In comparison to conventional RPE, MARPE has lower detrimental periodontal effects and has certain clinical advantages.

Quercetin Supplement to Aspirin Attenuates Lipopolysaccharide-Induced Pre-eclampsia-Like Impairments in Rats Through the NLRP3 Inflammasome.

BACKGROUND AND OBJECTIVES: Aspirin is a common drug for the treatment of pre-eclampsia. We aimed to explore whether quercetin as a supplement to aspirin could enhance the therapeutic outcome in pre-eclampsia rat models. We further aimed to evaluate the nucleotide-binding oligomerization domain-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome as a potential pre-eclampsia-related molecular mechanism, which can be affected by quercetin treatment. METHODS: Rat pre-eclampsia models were established using an intravenous lipopolysaccharide injection after gestation. Rats were treated with aspirin and quercetin at 6-18 days after pregnancy. On day 20, blood, fetus, and placenta were harvested. Blood pressure and the level of proteinuria were measured every 4 days. Fetal outcomes were analyzed by pup body weight. Serum soluble Fms-like tyrosine kinase-1, PIGF, interleukin-6, and interleukin-10 levels were measured using the enzyme-linked immunosorbent assay. Caspase-1, NLRP3, apoptosis-associated speck-like protein containing a caspase recruitment domain, and p-caspase-1 levels in the placenta were assessed using western blot or quantitative real-time polymerase chain reaction analyses. RESULTS: Pre-eclampsia rat models showed a pronounced increase in systolic blood pressure and proteinuria after 4 days of pregnancy, while aspirin, quercetin, and aspirin/quercetin combinatory treatment significantly attenuated the blood pressure and proteinuria abnormalities. Notably, the aspirin/quercetin combinatory treatment showed the highest efficacy in attenuating pre-eclampsia-like symptoms. Placental caspase-1 and NLRP3 levels also showed the greatest attenuation in pre-eclampsia rats after aspirin/quercetin treatment. CONCLUSIONS: Our data suggested that quercetin supplementation to aspirin is more effective in attenuating symptoms of pre-eclampsia and improving pregnancy outcomes compared with quercetin or aspirin alone. Quercetin can ameliorate placental NLRP3 inflammasome activation, which might serve as an underlying mechanism for its therapeutic efficacies in pre-eclampsia.

Mechanical force-sensitive lncRNA SNHG8 inhibits osteogenic differentiation by regulating EZH2 in hPDLSCs.

Long non-coding RNAs (lncRNAs) play important roles in various physiological and pathophysiological processes. However, the effect of mechanical force on lncRNAs and their role in osteogenic differentiation of periodontal ligament stem cells (PDLSCs) remains unclear. Here, we showed that the expression of lncRNA small nucleolar RNA host gene 8 (SNHG8) was steadily declined in PDLSCs under mechanical force. This reduced expression of SNHG8 promoted osteogenic differentiation of PDLSCs under mechanical force. After knockdown of SNHG8 by shRNA, the expression of osteogenic-related genes was increased in PDLSCs under mechanical force. Regarding the osteogenic regulatory ability of SNHG8, PDLSCs with lower level of expression of SNHG8 under osteogenic induction had a higher level of expression of osteogenic-related genes, higher level of alkaline phosphatase (ALP), and more mineralised nodules. In rats, the expression of the homolog, Smim4, was decreased during tooth movement. PDLSCs with lower expression of SNHG8 in nude mice also showed better bone formation ability during ectopic osteogenesis. Mechanistically, downregulation of SNHG8 led to lower expression of enhancer of zeste homolog 2 (EZH2), which negatively regulated the osteogenic differentiation of PDLSCs. Our study indicated that the mechanically sensitive lncRNA SNHG8 regulates the osteogenic differentiation of PDLSCs through epigenetic pathways. Our results provided solid evidence for the regulation of cell differentiation by non-coding genes, which might serve as potential therapeutic targets for bone reconstruction or periodontal tissue regeneration during orthodontics.

Characterization of vector diffraction-free beams.

It is observed that a constant unit vector denoted by I is needed to characterize a complete orthonormal set of vector diffraction-free beams. The previously found diffraction-free beams are shown to be included as special cases. The I-dependence of the longitudinal component of diffraction-free beams is also discussed.

A comparative study of auto-contouring softwares in delineation of organs at risk in lung cancer and rectal cancer.

Radiotherapy requires the target area and the organs at risk to be contoured on the CT image of the patient. During the process of organs-at-Risk (OAR) of the chest and abdomen, the doctor needs to contour at each CT image. The delineations of large and varied shapes are time-consuming and laborious. This study aims to evaluate the results of two automatic contouring softwares on OARs definition of CT images of lung cancer and rectal cancer patients. The CT images of 15 patients with rectal cancer and 15 patients with lung cancer were selected separately, and the organs at risk were manually contoured by experienced physicians as reference structures. And then the same datasets were automatically contoured based on AiContour (version 3.1.8.0, Manufactured by Linking MED, Beijing, China) and Raystation (version 4.7.5.4, Manufactured by Raysearch, Stockholm, Sweden) respectively. Deep learning auto-segmentations and Atlas were respectively performed with AiContour and Raystation. Overlap index (OI), Dice similarity index (DSC) and Volume difference (Dv) were evaluated based on the auto-contours, and independent-sample t-test analysis is applied to the results. The results of deep learning auto-segmentations on OI and DSC were better than that of Atlas with statistical difference. There was no significant difference in Dv between the results of two software. With deep learning auto-segmentations, auto-contouring results of most organs in the chest and abdomen are good, and with slight modification, it can meet the clinical requirements for planning. With Atlas, auto-contouring results in most OAR is not as good as deep learning auto-segmentations, and only the auto-contouring results of some organs can be used clinically after modification.

PERK-eIF2α-ATF4 signaling contributes to osteogenic differentiation of periodontal ligament stem cells.

Protein kinase-like endoplasmic reticulum kinase (PERK) is a type I transmembrane protein located in the endoplasmic reticulum (ER). The PERK-eukaryotic initiation factor 2α (eIF2α)-activating transcription factor 4 (ATF4) pathway has been proved to be involved in osteoblast differentiation, but the involvement of the PERK-eIF2α-ATF4 signaling pathway in osteogenic differentiation of human periodontal ligament stem cells (hPDLSCs) has remained unclear. Therefore, the aim of this study was to explore the role of PERK in osteogenic differentiation of hPDLSCs and to assess whether PERK-eIF2α-ATF4 contributes to the process of osteogenic differentiation in hPDLSCs. In our study, we constructed PERK-overexpressed and PERK-silenced hPDLSCs by lentiviral transduction. Furthermore, lentivirus-transfected cells were induced to differentiate into osteoblast cells for different days. Alkaline phosphatase (ALP) activity and Alizarin Red staining were used to evaluate the mineralization capacity, and the expression levels of related genes-ATF4, ALP, bone sialoprotein, runt-related transcription factor 2 (Runx2), and osteocalcin were measured to evaluate the osteogenic differentiation of hPDLSCs. The results showed that over-expression of PERK greatly increased ALP activity and the expression levels of related osteogenic genes, which displayed the strongest osteogenesis capacity. However, suppression of PERK caused decreased ALP activity and the weakest osteogenesis capacity, and the levels of ATF4 and p-eIF2α in PERK-silenced hPDLSCs were also decreased. Our results indicated that the PERK gene plays an important role in the differentiation of hPDLSCs to osteoblast-like cells. The PERK-eIF2α-ATF4 signaling pathway contributes to osteoblast differentiation of hPDLSCs.

Astragaloside IV alleviates placental oxidative stress and inflammation in GDM mice.

BACKGROUND: Our previous study revealed that astragaloside IV (AS-IV) effectively improved gestational diabetes mellitus (GDM) by reducing hepatic gluconeogenesis. Due to the importance of placental oxidative stress, we further explored the protective role of AS-IV on placental oxidative stress in GDM. METHODS: First, non-pregnant mice were orally administrated with AS-IV to evaluate its safety and effect. Then GDM mice were orally administered with AS-IV for 20 days and its effect on the symptoms of GDM, placental oxidative stress, secretions of inflammatory cytokines, as well as toll-like receptor 4 (TLR4)/NF-κB signaling pathway, were evaluated. RESULTS: AS-IV had no adverse effect on non-pregnant mice. On the other hand, AS-IV significantly attenuated the GDM-induced hyperglycemia, glucose intolerance, insulin resistance, placental oxidative stress, productions of inflammatory cytokines and the activation of TLR4/NF-κB pathway. CONCLUSION: AS-IV effectively protected against GDM by alleviating placental oxidative stress and inflammation, in which TLR4/NF-κB might be involved.

MicroRNA-21 affects mechanical force-induced midpalatal suture remodelling.

OBJECTIVES: miR-21 can promote osteoblast differentiation of periodontal ligament stem cells. However, the effect of miR-21 on bone remodelling in the midpalatal suture is unclear. This study aimed to elucidate the effects of miR-21 on the midpalatal suture bone remodelling by expanding the palatal sutures. MATERIALS AND METHODS: miR-21 deficient (miR-21-/- ) and wild-type (WT) mice were used to establish animal models by expanding the palatal sutures. Micro-CT, haematoxylin-eosin (HE) staining, tartrate-resistant acid phosphatase (TRAP) staining, fluorescence labelling and immunohistochemistry were used to investigate the function of miR-21 in midpalatal suture bone remodelling. Besides, bone mesenchymal stem cells (BMSCs) derived from both miR-21-/- and WT mice were cultured. The MTT, CCK8, EdU analysis, transwell and wound healing test were used to assess the effects of miR-21 on the characteristics of cells. RESULTS: The expression of ALP was suppressed in miR-21-/- mice after expansion except 28 days. The expression of Ocn in WT mice was much higher than that of miR-21-/-  mice. Besides, with mechanical force, miR-21 deficiency downregulated the expression of Opg, upregulated the expression of Rankl, and induced more osteoclasts as TRAP staining showed. After injecting agomir-21  to miR-21-/- mice, the expression of Alp, Ocn and Opg/Rankl were rescued. In vitro, the experiments suggested that miR-21 deficiency reduced proliferation and migration ability of BMSCs. CONCLUSIONS: The results showed that miR-21 deficiency reduced the rate of bone formation and prolonged the process of bone formation. miR-21 regulated the bone resorption and osteoclastogenesis by affecting the cell abilities of proliferation and migration.

Pretreatment systemic inflammation response index (SIRI) is an independent predictor of survival in unresectable stage III non-small cell lung cancer treated with chemoradiotherapy: a two-center retrospective study.

BACKGROUND: Circulating immune cells influence the efficacy of cancer therapy. This study aimed to investigate the prognostic values of different peripheral blood leukocyte (PBL) biomarkers in non-small lung cancer (NSCLC) patients treated with chemoradiotherapy. METHODS: An independent cohort of 176 stage III NSCLC patients who were diagnosed at Shanghai Pulmonary Hospital and Zhejiang Cancer Hospital between April, 2010, and September, 2018, and had available pretreatment peripheral blood tests was enrolled. The patients were all treated with concurrent or sequential chemoradiotherapy according to international clinical guidelines, with conventional fractionated radical radiotherapy. The receiver operating characteristic curve and the Youden index were used to determine the optional cutoff values of PBL biomarkers for distinguishing prognosis. Univariate and multivariate Cox proportional hazards regression analyses were performed to identify the factors significantly correlated with overall survival. RESULTS: The cohort had a median follow-up time of 21.7 (3.1-121) months. The 3- and 5-year OS rates of all patients were 34.7% and 27.5%, respectively. Univariate analysis showed that gender (P=0.011), smoking (P=0.011), tumor-node-metastasis (TNM) stage (P=0.002), pretreatment peripheral blood neutrophil-to-leukocyte ratio (P=0.013), and systemic inflammation response index (SIRI, P<0.001) were all correlated with OS in NSCLC patients. Moreover, multivariate analysis revealed that TNM stage (HR =1.541, 95% CI: 1.166-2.036, P=0.010) and SIRI (HR =1.868, 95% CI: 1.016-3.436, P=0.018) were significantly and independently associated with OS. However, the median OS of stage IIIB NSCLC patients with low SIRI (≤2.0) was longer than that of stage IIIA NSCLC patients with high SIRI (>2.0) (33.9±4.1 vs. 19.6±2.5 months). CONCLUSIONS: Pretreatment peripheral blood SIRI was found to be a simple independent predictor of OS in stage III NSCLC patients who underwent chemoradiotherapy. As a novel prognostic marker, the prognostic value of the SIRI is superior to that of the NLR. Low SIRI could be a better prognostic stratification factor for NSCLC patients with different TNM stages.