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This study was aimed to explore the differential diagnosis value of preinvasive lesions/minimally invasive adenocarcinoma and invasive adenocarcinoma manifesting as small pulmonary nodules under dual source computed tomography (DSCT) imaging. The patients with nodular manifestations of adenocarcinoma in situ (AIS)/microinfiltrating adenocarcinoma (MIA) were selected as group X, including 14 cases. A total of 31 cases with nodular infiltrating adenocarcinoma were selected as group Y. The enhanced dual-energy image obtained by DSCT dual-energy scan was transferred to the software to obtain the energy image and iodine distribution map. SPSS 18.0 was used for statistical analysis. P < 0.05 was considered statistically significant. All measurements were labeled as mean x ͞ ± S standard deviation. In the CT findings of microinfiltrating adenocarcinoma and infiltrating adenocarcinoma, lobulation sign, burr sign, vacuole sign, and pleural depression sign can help the diagnosis of infiltrating adenocarcinoma. The results showed that lobulation sign, burr sign, vacuole sign, and pleural depression sign could be used as the distinguishing feature of preinvasive lesion/microinvasive adenocarcinoma and invasive adenocarcinoma. Receiver-operating characteristic (ROC) curve analysis showed that the critical value, sensitivity, and specificity of lesion diameter ≥1.4 cm and CT value ≥14.14HU for diagnosis of invasive lung adenocarcinoma were 1.32 and 14.14, 88.4% and 94.4%, and 67.3% and 75.8%, respectively. There were substantial differences in CT values between the two groups under low energy level (42-99 kev) ( P < 0.05 ). DSCT dual-energy imaging can quantitatively identify preinvasive pulmonary nodules with multiple parameters.

Periodontitis is the most important oral disease causing human tooth loss. Although supragingival and subgingival scaling is the main strategy of periodontitis clinical treatments, drug treatment has an indispensable auxiliary role to some degree. Periodontitis medical treatment is divided into systemically administered treatments and local periodontally administered treatments. Compared with systemic administration, local administration can increase local drug concentrations, reduce dosages, and prolong action times while also improving patient compliance and avoiding possible adverse effects due to systemic administration responses. However, some studies show that minocycline ointment, a clinical local drug commonly used in periodontal pockets, has an unstable release rate; 80% of the drug is usually released within 2-3 days after pocket placement. This release is not conducive to controlling periodontal infection and may hinder the periodontal tissue repair and regeneration. Therefore, choosing a suitable carrier for minocycline hydrochloride is necessary to control its local release in periodontal tissue. Phase transition lysozyme (PTL) has been widely used in many studies and the development of macromolecular carrier material, and we selected PTL as the carrier for minocycline hydrochloride drugs because of its good biocompatibility, good drug-carrying capacity, and stable release. Due to its release characteristics and simple preparation, PTL is a promising carrier material.

Background:. Histone deacetylase 4 (HDAC4) regulates chondrocyte hypertrophy and bone formation. The aim of the present study was to explore the effects of HDAC4 on Interleukin 1 beta (IL-1β)-induced chondrocyte extracellular matrix degradation and whether it is regulated through the WNT family member 3A (WNT3A)/β-catenin signaling pathway. Methods:. Primary chondrocytes (CC) and human chondrosarcoma cells (SW1353 cells) were treated with IL-1β and the level of HDAC4 was assayed using Western blotting. Then, HDAC4 expression in the SW1353 cells was silenced using small interfering RNA to detect the effect of HDAC4 knockdown on the levels of matrix metalloproteinase 3 (MMP3) and MMP13 induced by IL-1β. After transfection with HDAC4 plasmids, the overexpression efficiency was examined using Real-time quantitative polymerase chain reaction (qRT-PCR) and the levels of MMP3 and MMP13 were assayed using Western blotting. After incubation with IL-1β, the translocation of β-catenin into the nucleus was observed using immunofluorescence staining in SW1353 cells to investigate the activation of the WNT3A/β-catenin signaling pathway. Finally, treatment with WNT3A and transfection with glycogen synthase kinase 3 beta (GSK3β) plasmids were assessed for their effects on HDAC4 levels using Western blotting. Results:. IL-1β downregulated HDAC4 levels in chondrocytes and SW1353 cells. Furthermore, HDAC4 knockdown increased the levels of MMP3 and MMP13, which contributed to the degradation of the extracellular matrix. Overexpression of HDAC4 inhibited IL-1β-induced increases in MMP3 and MMP13. IL-1β upregulated the levels of WNT3A, and WNT3A reduced HDAC4 levels in SW1353 cells. GSK-3β rescued IL-1β-induced downregulation of HDAC4 in SW1353 cells. Conclusion:. HDAC4 exerted an inhibitory effect on IL-1β-induced extracellular matrix degradation and was regulated partially by the WNT3A/β-catenin signaling pathway.

Chronic obstructive pulmonary disease (COPD) is a chronic lung disease and the third leading cause of death in the world. Dexmedetomidine has been reported to effectively inhibit histamine-induced bronchoconstriction. However, the molecular mechanism of dexmedetomidine in COPD has not been found. To explore the role and mechanism of dexmedetomidine in COPD, and to provide theoretical basis for clinical treatment of COPD. The expression of miR-146a was regulated by mimics or inhibitor and the relative expression of apoptotic proteins p53, Bax and Bcl-2 in human bronchial epithelial 16HBE cells was determined by real-time PCR and Western blot. Dexmedetomidine was treated for 16HBE cells and alveolar epithelial type II cells (AEC2), the cell apoptosis was detected by TUNEL and Hoechst33342 staining. A COPD rat model was established by smoking to test the effects of dexmedetomidine on the progression of COPD. The levels of IL-6, IL-1β and TNF-α in serum were measured by ELISA and the protein concentration of bronchoalveolar lavage fluid (BALF) was also detected in dexmedetomidine treated COPD rat model. miR-146a promoted 16HBE cell apoptosis and reduced cell proliferation. Additionally, dexmedetomidine was showed to reduce the 16HBEL cell apoptosis through reducing the expression of miR-146a. Moreover, dexmedetomidine regulated cell apoptosis and cell apoptosis through miR-146a in AEC2 cells. More importantly, dexmedetomidine attenuated the morphology and pathology of COPD rat model. Dexmedetomidine reduced 16HBE cells and AEC2 cell apoptosis and attenuated COPD by down-regulating miR-146a.

Objective. The aim of the study was to investigate the potential effects of waste anesthetic gas (WAG) on oxidative stress, DNA damage, and vital organs. Methods. A total of 150 members of the staff at a hospital were assigned to an exposure group or control group. The 68 operating room (OR) staff in the exposure group were exposed to WAG, and the 82 non-OR staff in the control group were not exposed to WAG. Air samples were collected in the OR, and the sevoflurane concentrations in the samples were determined. Superoxide dismutase (SOD), glutathione peroxidase (GSH-px), and malondialdehyde (MDA) in plasma from the participants were determined to assess oxidative stress. Western blot analysis was used to detect γH2AX in peripheral blood to assess DNA damage. Hematopoietic parameters, liver function, kidney function, and changes in electrophysiology were assessed to identify the effects on the vital organs. Results. The mean (±standard deviation) sevoflurane concentration in 172 air samples from 22 operating rooms was 1.11 ± 0.65 ppm . The superoxide dismutase activity and vital organ parameters (lymphocyte, hemoglobin, and total protein concentrations and heart rate) were significantly lower ( P < 0.05 ) in the exposed group than the control group. The malondialdehyde, total bilirubin, and creatinine concentrations and QT and QTc intervals were significantly higher ( P < 0.05 ) in the exposed group than the control group. There were no significant differences between the glutathione peroxidase activities and γH2AX concentrations for the exposed and control groups. Conclusions. Long-term occupational exposure to waste anesthetic gas may affect the antioxidant defense system and probably affects vital organ functions to some extent. No correlation between DNA damage and chronic exposure to WAG was observed.

The identification of ante- and post-mortem burns is challenging in forensic pathology. In this study, microarray analysis was used to detect the mRNA expression profiles in the skin of an experimental burn mouse model; the results were validated using RT-qPCR. Differentially expressed mRNAs (DE-mRNAs) were assessed using the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases. Our results revealed that mRNA expression of 501 genes was significantly different, of which 273 were upregulated and 228 were downregulated in ante-mortem burned mice skin. The expression levels of eight random mRNAs were consistent when measured using the microarray assay-based method and RT-qPCR. Genes from different functional categories and signalling pathways were enriched, including interleukin-20 binding, type IV hypersensitivity, negative regulation of acute inflammatory response, sensory organ development, endocytosis, neuroactive ligand-receptor interaction, and Jak-STAT signalling pathway. Only five of the eight mRNAs exhibited consistent changes in expression between burned skin samples of mice and human autopsy specimens. Our findings showed that DE-mRNAs revealed using microarray are potential biomarkers of ante-mortem burns. However, DE-mRNAs identified from experimental animal models cannot be directly extended to autopsy specimens without careful validation.

Essential hypertension has been regarded a significant risk factor for cardiovascular disease across the globe, and a significant escapable causation of early death as well as morbidity in the U.S. When angiotensin II receptor blockers and calcium channel blockers are used to treat essential hypertension, most patients will have inadequate blood pressure management. As a result, including a diuretic in the regimen is necessary. The current study's aim is to investigate the effectiveness as well as safety of levamlodipine besylate combination therapy in treating essential hypertension at varying degrees of severity.In establishing the effectiveness and safety of the mix of levamlodipine besylate and dihydropyridine for essential hypertension, the authors will conduct a systematic review and, where applicable, a meta-analysis of randomized controlled clinical trials. A total of 8 electronic databases will be used in the search, including 4 English databases (PubMed, Web of Science, EMBASE, and Cochrane Library) and 4 Chinese databases (China National Knowledge Infrastructure, Chinese BioMedical Literature database, Chinese Scientific Journal database, and WanFang database). All articles published in the databases will be considered between their inception and January 18, 2022. Only articles published in English or Mandarin Chinese will be picked. A group of writers will independently evaluate each reference to see if it is eligible and whether there are any duplicates. The same authors will do data extraction for all eligible studies and use the Cochrane risk of bias tool to evaluate the risk of bias in the trials chosen for inclusion.The analysis will evaluate the efficiency and level of safeness of levamlodipine besylate combined treatment for essential hypertension.Our systematic review will offer evidence for judging whether levamlodipine besylate combination therapy can be considered an effective intercession for essential hypertension.Ethical approval will not be required as no original data will be collected as part of this review.DOI 10.17605/OSF.IO/H8ZR2.

Objectives This study aimed to explore whether knockdown of cancer-derived IgG (CIgG) could enhance cisplatin-induced anti-cancer effects. Materials and methods Cancer-derived IgG was knocked down by siRNA or Tet-on shRNA in the absence or presence of cisplatin in WSU-HN6 or CAL27 cells. Cell proliferation, apoptosis, and mobility were evaluated using CCK-8, flow cytometry, and transwell assays, respectively. Molecular events were investigated using real-time PCR and Western blot assays. Results Knockdown of CIgG significantly promoted cisplatin-induced apoptosis and inhibition of cell proliferation, migration, and invasion. Cisplatin upregulated CIgG expression and phosphorylation of AKT and PDK1, while knockdown of CIgG downregulated phosphorylation of AKT and PDK1, and blocked cisplatin-induced upregulation of AKT and PDK1 phosphorylation. Moreover, knockdown of CIgG blocked cisplatin-induced upregulation of Src phosphorylation, and knockdown of Src blocked cisplatin-induced upregulation of AKT and PDK1 phosphorylation. Overexpression of Src upregulated AKT and PDK1 phosphorylation. Furthermore, knockdown of CIgG upregulated PTP-BAS mRNA and protein expression, whereas cisplatin downregulated PTP-BAS protein, but not mRNA expression; knockdown of PTP-BAS upregulated phosphorylation of Src, PDK1, AKT, and blocked CIgG knockdown-mediated enhancement of cisplatin-induced inhibition of cell proliferation. Conclusion Knockdown of CIgG enhanced the anti-cancer effects of cisplatin through PTP-BAS/Src/PDK1/AKT signaling pathway in oral squamous cell carcinoma.

Severe inflammation, progressive cartilage, and bone destruction are typical pathologic changes in temporomandibular joint (TMJ) arthritis and lead to great difficulty for treatment. However, current therapy is inefficient to improve degenerative changes in progressive TMJ arthritis. This study investigated the therapeutic effects of human dental pulp stem cells (DPSCs) on severe inflammatory TMJ diseases. Progressive TMJ arthritis in rats was induced by intra-articular injection of complete Freund’s adjuvant and monosodium iodoacetate. DPSCs were injected into the articular cavity to treat rat TMJ arthritis, with normal saline injection as control. Measurement of head withdrawal threshold, micro–computed tomography scanning, and histologic staining were applied to evaluate the severity of TMJ arthritis. Results showed that local injection of DPSCs in rats with TMJ arthritis relieved hyperalgesia and synovial inflammation, attenuated cartilage matrix degradation, and induced bone regeneration. Inflammatory factors TNF-α and IFN-γ were elevated in progressive TMJ arthritis and partially decreased by local injection of DPSCs. MMP3 and MMP13 were elevated in the arthritis + normal saline group and decreased in the arthritis + DPSCs group, which indicated amelioration of matrix degradation. The isolated primary synoviocytes were cocultured with DPSCs after inflammatory factors stimulated to explore the possible biological mechanisms. The expression of MMP3 and MMP13 in synoviocytes was elevated after TNF-α and IFN-γ stimulation and partially reversed by DPSC treatment in the in vitro study. The signal transducer and activator of transcription 1 (STAT1) was activated by inflammatory stimulation and suppressed by DPSC coculture. The upregulation of MMP3 and MMP13 triggered by inflammation was blocked by STAT1-specific inhibitor, suggesting that STAT1 regulated the expression of MMP3 and MMP13. In conclusion, this study demonstrated the possible therapeutic effects of local injection of DPSCs on progressive TMJ arthritis by inhibiting the expression of MMP3 and MMP13 through the STAT1 pathway.

To investigate whether an improved U2-Net model could be used to segment the median nerve and improve segmentation performance, we performed a retrospective study with 402 nerve images from patients who visited Huashan Hospital from October 2018 to July 2020; 249 images were from patients with carpal tunnel syndrome, and 153 were from healthy volunteers. From these, 320 cases were selected as training sets, and 82 cases were selected as test sets. The improved U2-Net model was used to segment each image. Dice coefficients (Dice), pixel accuracy (PA), mean intersection over union (MIoU) and average Hausdorff distance (AVD) were used to evaluate segmentation performance. Results revealed that the Dice, MIoU, PA and AVD values of our improved U2-Net were 72.85%, 79.66%, 95.92% and 51.37 mm, respectively, which were comparable to the actual ground truth; the ground truth came from the labeling of clinicians. However, the Dice, MIoU, PA and AVD values of U-Net were 43.19%, 65.57%, 86.22% and 74.82 mm, and those of Res-U-Net were 58.65%, 72.53%, 88.98% and 57.30 mm. Overall, our data suggest our improved U2-Net model might be used for segmentation of ultrasound median neural images.

BACKGROUND: Meshes play a crucial role in hernia repair. However, the displacement of mesh inevitably leads to various associated complications. This process is difficult to be traced by conventional imaging means. The purpose of this study is to create a contrast-enhanced material with high-density property that can be detected by computed tomography (CT). METHODS: The contrast-enhanced monofilament was manufactured from barium sulfate nanoparticles and medical polypropylene (PP/Ba). To characterize the composite, stress tensile tests and scanning electron microscopy (SEM) was performed. Toxicity and biocompatibility of PP/Ba materials was verified by in vitro cellular assays. Meanwhile, the inflammatory response was tested by protein adsorption assay. In addition, an animal model was established to demonstrate the long-term radiographic effect of the composite material in vivo. Subsequent pathological tests confirmed its in vivo compatibility. RESULTS: The SEM revealed that the main component of the monofilament is carbon. In vitro cell experiments demonstrated that novel material does not affect cell activity and proliferation. Protein adsorption assays indicated that the contrast-enhanced material does not cause additional inflammatory responses. In addition, in vivo experiments illustrated that PP/Ba mesh can be detected by CT and has good in vivo compatibility. CONCLUSION: These results highlight the excellent biocompatibility of the contrast-enhanced material, which is suitable for human abdominal wall tissue engineering. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13770-022-00460-6.

Objectives This study aimed to explore whether RhoG/Rac1 was involved in migration and invasion of salivary adenoid cystic carcinoma (SACC). Materials and methods RhoG and Rac1 were evaluated in two SACC cell lines, namely SACC-83 and SACC-LM, with low and high rates of lung metastasis, respectively. Functional changes were evaluated using cell proliferation, transwell, and wound-healing assays, and molecular events were investigated using real-time PCR and Western blot assays. Results RhoG and Rac1 were highly expressed and more activated in SACC-LM cells than in SACC-83 cells. RhoG overexpression promoted SACC-83 cell migration and invasion through activating Rac1. The knockdown of RhoG or Rac1 partially blocked epiregulin-induced migration and invasion in SACC-83 cells. Epiregulin-induced activation of RhoG/Rac1 in SACC-83 cells was blocked by a Src inhibitor, or an AKT inhibitor or AKT siRNA, or an ERK1/2 inhibitor. Moreover, the epiregulin-induced phosphorylation of AKT and ERK1/2 in SACC-83 cells was blocked by a Src inhibitor, and the epiregulin-induced phosphorylation of ERK1/2 was blocked by an AKT inhibitor or AKT siRNA. Overexpression of activated AKT induced activation of ERK1/2 and RhoG. Conclusions RhoG/Rac1 signaling pathway was involved in SACC cell migration and invasion. RhoG/Rac1 at least partially mediated epiregulin/Src/AKT/ERK1/2 signaling to promote SACC cell migration and invasion.

To investigate the effect of RITA on TP53 mutant human mantle cell lymphoma (MCL) cell line Mino and its possible mechanism.Mino cells were cultured in RPMI-1640 and treated with RITA at a concentration of 0-16 μmol/L for 24,48,72 hours. Cell viability was assessed by CCK-8 assay. The cells were treated by RITA (0-8 μmol/L) for 48 h, the cell apoptosis induced by RITA was detected by annexin V/PI flow cytometry. Western blot was performed to evaluate the expression of protein BCL-2, Caspase-3, Cleaved Caspase-3, PARP, MDM2, and P53 in Mino cells.After treatment with 0.5, 1, 2, 4, 8, and 16 μmol/L RITA for 48 h, the proliferation inhibition rate of Mino cells was (1.2±5.6)%, (14.9±4.9)%, (41.7±5.0)%, (61.8±2.4)%, (70.2±2.8)%, and (70.8±2.4)%, respectively. RITA could inhibit the proliferation of Mino cells significantly, and statistical analysis showed that the inhibition rate was increased with the increasing of RITA concentration (r=0.767). After the cells were treated by 4 μmol/L RITA for 24, 48, and 72 h, the proliferation inhibition rate was (25.2±3.8)%, (61.8±2.4)%, and (87.0±0.7)%, respectively. Satistical analysis showed that the inhibition rate was also increased with the increasing of treatment time (r=0.978). The apoptosis rate of Mino cells treated by 0, 2, 4, and 8 μmol/L RITA for 48 h was (5.4±0.4)%, (15.3±0.6)%, (38.7±1.7)%, and (50.8±1.1)%, respectively, and it showed dose-dependent manner (r=0.961). Western blot showed that with the increasing of RITA concentration, the BCL-2 protein expression was decreased in a dose-dependent manner (r=0.932), moreover, PARP cleavage and Caspase-3 activation were found, while the protein expression of MDM2 and P53 showed no change.RITA can inhibit the proliferation and induce the apoptosis of Mino cells significantly. The mechanism may be dependent on the Caspase pathway, but independent on the P53 pathway.RITA对TP53突变人套细胞淋巴瘤细胞株的作用及调控机制研究.研究RITA对TP53突变的人套细胞淋巴瘤细胞株Mino的作用及其调控机制.体外培养Mino细胞，不同浓度（0-16 μmol/L）RITA作用于Mino细胞24、48、72 h后，采用CCK-8法检测RITA对Mino细胞的增殖抑制作用； 0-8 μmol/L浓度RITA作用于Mino细胞48 h，采用Annexin V/PI流式细胞术检测RITA对Mino细胞的凋亡诱导作用，采用Western blot法检测蛋白BCL-2、Caspase-3、Cleaved Caspase-3、PARP、MDM2、P53的表达.RITA能显著抑制TP53突变细胞株Mino增殖，经0.5、1、2、4、8、16 μmol/L的RITA作用Mino细胞48 h后，细胞的增殖抑制率分别为（1.2±5.6）%、（14.9±4.9）%、（41.7±5.0）%、（61.8±2.4）%、（70.2±2.8）%和（70.8±2.4）%，随着RITA作用浓度的增加，抑制率也增加（r=0.767）。Mino细胞经4 μmol/L的RITA作用24、48和72 h后的增殖抑制率分别为（25.2±3.8）%、（61.8±2.4）%和（87.0±0.7）%，随着RITA作用时间增加，抑制率亦增加（r=0.978）。细胞凋亡检测结果显示，Mino细胞经0、2、4、8 μmol/L的RITA作用48 h后的凋亡率分别为（5.4±0.4）%、（15.3±0.6）%、（38.7±1.7）%和（50.8±1.1）%，随着RITA作用浓度增加，诱导Mino细胞凋亡的作用增强（r=0.961）。Western blot检测结果显示，随着RITA浓度的增加，BCL-2蛋白表达下降（r=0.932），出现PARP切割和Caspase-3激活，而MDM2、P53蛋白表达无变化.P53小分子RITA对套细胞淋巴瘤TP53突变细胞株Mino有显著的增殖抑制和诱导凋亡的作用，其机制可能依赖于Caspase途径，而与P53通路无关.

Obesity, especially central obesity, is a strong risk factor for developing type 2 diabetes (T2D). However, the mechanism underlying the progression from central obesity to T2D remains unknown. Therefore, we analyzed the gut microbial profiles of central obese individuals with or without T2D from a Chinese population. Here we reported both the microbial compositional and gene functional alterations during the progression from central obesity to T2D. Several opportunistic pathogens were enriched in obese T2D patients. We also characterized thousands of genes involved in sugar and amino acid metabolism whose abundance were significantly depleted in obese T2D group. Moreover, the abundance of those genes was negatively associated with plasma glycemia level and percentage of individuals with impaired plasma glucose status. Therefore, our study indicates that the abundance of those depleted genes can be used as a potential biomarker to identify central obese individuals with high risks of developing T2D.

Reactive oxygen species (ROS), especially hydrogen peroxide (H2O2), have recently been reported to cause a significant increase in the production and expression of matrix metalloproteinases (MMPs), which are closely correlated with lung cancer metastasis. The aim of the present study is to determine the inhibitory effects of a polysaccharide isolated from Ulva prolifera O.F. Müller (U. prolifera) on the invasive potential of non-small cell lung cancer (NSCLC) cells, and further to explore the underlying mechanisms connected to that potential. The data showed that increased MMP-9 resulting from H2O2 exposure was mediated by activating mitogen-activated protein kinases (MAPKs). Pre-treatment with polysaccharides suppressed the activation of H2O2-mediated MAPK pathways and cell invasion. Hence, MMP-9 production triggered by H2O2 was demonstrated by activating MAPK signaling in a Myc-dependent manner. Taken together, these results suggested that polysaccharides suppress H2O2-induced cell invasion by inhibiting Myc-mediated MMP-9 gene transcription through the MAPK signaling pathway in A549 and NCI-H1650 cells. Our data also suggested that polysaccharides may be useful in minimizing the development of lung cancer metastasis. In the future, pretreatment with polysaccharides because of their antioxidant properties might be beneficial to enhance surgical outcomes.

Purpose: Aberrant activation of MET (hepatocyte growth factor receptor) signaling is implicated in the tumorigenesis of human cancers. This phase I study assessed the safety, tolerability, and MTD of the potent and selective MET inhibitor, savolitinib (AZD6094, HMPL-504, volitinib). Patients and Methods: This open-label, multicenter dose-escalation and -expansion study evaluated oral savolitinib for patients with locally advanced or metastatic solid tumors. A 3 + 3 design assessed repeated daily (QD) and twice daily (BID) dosing schedules. The dose-expansion phase included 12 patients. Primary objectives were to evaluate the safety, tolerability, MTD, and dose-limiting toxicities (DLT) of savolitinib. Secondary and exploratory objectives included pharmacokinetics, biomarker research, and antitumor activity. Results: Overall, 48 patients were enrolled. Four patients had DLTs following QD savolitinib (600 mg N = 1, 800 mg N = 1, and 1,000 mg N = 2); the MTD was 800 mg QD and not reached for BID dosing. The recommended phase II dose (RP2D) was 600 mg QD. The most frequent adverse events were nausea (30 patients, 63%), vomiting (20 patients, 42%), fatigue (20 patients, 42%), and peripheral edema (15 patients, 31%). At 600 mg QD, Cmax was 2,414.8 ng/mL, AUC was 17053.9 h·ng/mL, and there was no apparent drug accumulation. Three patients with papillary renal cell carcinoma (PRCC) and MET aberrations had partial responses with durations from 39 to 147 weeks. Conclusions: The tolerability profile of savolitinib was acceptable and the RP2D was established as 600 mg QD. Preliminary antitumor activity was demonstrated supporting further study in patients with PRCC.

OBJECTIVE This study primarily aims to explore the value of combining the measurement of plasma α-synuclein oligomer levels with enhanced T2 star-weighted angiography (ESWAN) in the early diagnosis of Parkinson's disease. METHODS Sixty patients with early Parkinson's disease and 30 normal adults, with similar ages and genders, were enrolled in the study. Their levels of plasma α-synuclein oligomers were measured, and ESWAN was performed. The amplitudes, phases and R2* values of the head, body and tail of the ipsilateral and contralateral substantia nigra pars compacta (SNc) were measured, at the side of the limb with severe symptoms or early symptoms. The receiver operating characteristic (ROC) curve was used to explore the value of these indexes in the early diagnosis of Parkinson's disease. RESULTS The plasma level of α-synuclein oligomer was significantly higher in the experimental group than in the control group (P

The aim of this study was to identify the function of the Mg2+ transporter protein solute carrier family 41 member 1 SLC41A1 in pancreatic ductal adenocarcinoma and the underlying mechanisms. A total of 27 solute carrier proteins were differentially expressed in pancreatic ductal adenocarcinoma. Three of these proteins were correlated with clinical outcomes in patients, among which SLC41A1 was downregulated in tumour. Overexpression of SLC41A1 suppressed orthotopic tumour growth in a mouse model and reduced the cell proliferation, colony formation, and invasiveness of KP3 and Panc-1 cells, which may have been associated with the increased population of apoptotic-prone cells. Overexpression of SLC41A1 reduced the mitochondrial membrane potential, induced Bax while suppressed Bcl-2 expression. Suppression of Bax abrogated the tumour-suppressive effects of SLC41A1. Furthermore, overexpression of SLC41A1 promoted Mg2+ efflux and suppressed Akt/mTOR activity, which is the upstream regulator of Bax and Bcl-2. An increase in Akt activity and supplementation with Mg2+ abolished SLC41A1-induced tumour suppression. The results of this study suggest that SLC41A1 may be a potential target for the treatment of pancreatic ductal adenocarcinoma.

Objective The present study aimed to investigate the clinical significance and prognostic value of LINC01793 in OSCC patients, and to explore its role in the modulation of OSCC development. Methods LINC01793 expression was analyzed in 80 cases of OSCC patients and SCC9, SCC25, Cal27, and HN6 cell lines by qRT-PCR. The association of LINC01793 expression with clinicopathological features and prognosis in OSCC patients was analyzed. The effects of LINC01793 on cell proliferation, cell cycle, migration, and invasion of SCC9 and Cal27 cells were detected by MTT, flow cytometry, and Transwell assays in vitro, respectively. Results LINC01793 level was upregulated in cancer tissues and cell lines of OSCC, and its expression was increased in cancer tissues from patients with lymph node metastasis. ROC curve for LINC01793 expression and lymph node metastasis revealed a significant AUC of 0.84 (95 % CI: 0.75–0.93), with 76.51 % sensitivity and 83.69 % specificity. Moreover, high LINC01793 level was positively correlated with T category, TNM stage, lymph node metastasis, and local recurrence. OSCC patients with high level of LINC01793 was followed by low overall survival rate, and LINC01793 expression was an independent prognostic indicator for overall survival in patients with OSCC. Functionally, cell proliferation, invasion and migration of SCC9 and Cal27 cells were decreased after knockdown of LINC01793. Consistently, silence of LINC01793 induced G0/G1 cell cycle arrest in OSCC cells. Conclusion High LINC01793 level is correlated with adverse clinicopathological features and poor prognosis of patients with OSCC. LINC01793 act as an oncogenic role in the development of OSCC.

Introduction: Primary yolk sac tumor (YST) is an infrequently-diagnosed malignant extragonadal germ cell tumors. It is likely to recur locally and may present with widespread metastases once diagnosed. Primary YST of the head is uncommon but can cause severe complications, such as loss of vision once the tumor mass invades the optic nerve. Patient concerns: A 20-month-old boy presented to the general clinic of the local children's hospital with a complaint of swelling of left face for 1 year and proptosis of the left eye for over 2 weeks as stated by his parents. Initially, he did have some vision, as he could walk by himself, but a special ophthalmologic examination was not performed. Diagnoses: Cranial computed tomography and magnetic resonance imaging revealed a large tumor accompanied by peripheral bone destruction in the left pterygopalatine fossa that extended to sphenoid, ethmoid, left maxillary sinuses, left nasoethmoid, and left orbit. The optic nerve was invaded on both sides. Chest and abdominal imaging were normal. A primary diagnosis of Langerhans cell hyperplasia was made. However, blood tests on the second day of hospitalization revealed significantly elevated serum alpha-fetoprotein levels. On the third day, the boy lost his eyesight, with loss of pupillary and no light sensation during flashlight stimulation on both sides. Interventions: Nasal endoscopy was performed on the fourth day, the vast majority of soft tissue mass was resected for biopsy. Histopathological examination revealed features of endodermal sinus tumor. A final diagnosis of primary YST of pterygopalatine fossa was made. Because the mass could not be resected completely, he received combined chemotherapy with bleomycin, etoposide, and carboplatin for 6 cycles over six months. Outcomes: The patient recovered with significant tumor shrinkage and without secondary metastasis after 18 months but left permanently blind. Conclusion: The worst complication of loss of vision after Primary YST of pterygopalatine fossa alerts us that close physical examination during the initial investigation should be performed, which is especially important in young children who cannot express complaints well. Early detection and treatment with surgical resection and chemotherapy may contribute to satisfactory outcomes and avoidance of visual impairment.

Intracellular adenosine monophosphate (AMP) is indispensable for cellular metabolic processes, and it is interconverted to ADP and/or ATP or activates AMP-activated protein kinase (AMPK). However, the specific biological function of extracellular AMP has not been identified. We evaluated the effect of extracellular AMP using in vivo and in vitro models of endotoxemia. We found that AMP inhibited inflammation and neutrophil activation in lipopolysaccharide (LPS)-induced endotoxemic mice. The effects of extracellular AMP were abolished by an adenosine 1 receptor (A1R) antagonist but were not influenced by inhibiting the conversion of AMP to adenosine (ADO), indicating that AMP inhibited inflammation by directly activating A1R. In addition, in vitro experiments using LPS-stimulated mouse neutrophils showed that AMP inhibited LPS-induced reactive oxygen species (ROS) production, degranulation, and cytokine production, while the effects were reversed by an A1R antagonist. Further research showed that AMP regulated LPS-stimulated neutrophil functions by inhibiting the p38 MAPK pathway. These findings were also confirmed in primary neutrophils derived from healthy human blood. Moreover, we collected serum samples from septic patients. We found that AMP levels were increased compared with those of healthy volunteers and that AMP levels were negatively correlated with disease severity. Together, these data provide evidence that extracellular AMP acts on A1R to suppress endotoxemia-induced inflammation by inhibiting neutrophil overactivation and that the p38 MAPK signaling pathway is involved.

Stomachache is not only disease name of Traditional Chinese medicine (TCM) but also the clinical symptom. It is a common and multiple diseases. TCM has its particular advantage in clinical treatment of stomachache. Syndrome differentiation is an important concept in TCM practice. The therapeutic process is virtually a nonlinear mapping process from clinical symptom to syndrome diagnosis with processing and seeking rules from mass data. Artificial neutral network has strong learning ability for nonlinear relationship. Artificial neutral network has been widely used to TCM area where the multiple factors, multilevel, nonlinear problem accompanied by a large number of optimization exist.We present an original experimental method to apply the improved third-order convergence LM algorithm to intelligent syndrome differentiation for the first time, and compare the predicted ability of Levenberg-Marquardt (LM) algorithm and the improved third-order convergence LM algorithm in syndrome differentiation.In this study, 2436 cases of stomachache electronic medical data from hospital information system, and then the real world data were normalized and standardized. Afterwards, LM algorithm and the improved third-order convergence LM algorithm were used to build the Back Propagation (BP) neural network model for intelligent syndrome differentiation of stomachache on Matlab, respectively. Finally, the differentiation performance of the 2 models was tested and analyzed.The testing results showed that the improved third-order convergence LM algorithm model has better average prediction and diagnosis accuracy, especially in predicting "liver-stomach disharmony" and "stomach yang deficiency", is above 95%.By effectively using the self-learning and auto-update ability of the BP neural network, the intelligent syndrome differentiation model of TCM can fully approach the real side of syndrome differentiation, and shows excellent predicted ability of syndrome differentiation.

Background: Although many studies have reported the effects of dexmedetomidine on cognitive function (CF) in elderly patients after laparoscopic cholecystectomy (LCT), to this date, its effects are still not well understood. The aim of this study is to produce a qualitative synthesis of assessing the effects of dexmedetomidine on CF in elderly patients after LCT. Methods: We will conduct a comprehensive search in Cochrane Library, MEDLINE, EMBASE, CINAHL, PsycINFO, Scopus, VIP Database, WANGFANG Database, Chinese Biomedical Literature Database, and China National Knowledge Infrastructure from the commencement to March 31, 2020 without restrictions of language and publication status. In addition, we will also search grey literature, including conference abstracts, dissertations, reference lists of included studies and relevant reviews. All potential studies will be identified independently by 2 authors to determine their inclusion against previously defined eligibility criteria. The quality of selected papers will be assessed using Cochrane risk of bias tool. All statistical analysis will be performed using RevMan 5.3 software. Results: This study will provide a synthesis of the current available data on assessing the effects of dexmedetomidine on CF in elderly patients after LCT. Conclusions: Its findings will provide qualitative evidence to better understand the effects of dexmedetomidine on CF in elderly patients after LCT. INPLASY Registration Number: INPLASY202040030.

Summary We assessed the pharmacokinetics and safety of a single oral administration of selatinib to healthy Chinese subjects and evaluated the potential bioavailability advantage of selatinib relative to lapatinib. Healthy subjects aged 18–40 years were enrolled in this two-part study: Part 1, a single ascending dose (50–500 mg), randomized, double-blind, placebo-control study with 64 subjects; and Part 2, an open-label, positive control, randomized, three-treatment, three-period, three-sequence crossover design study, with 6 subjects administered a single 500-mg dose of selatinib tablets (A), selatinib suspension (B), or lapatinib tablets C) per cycle. In part 1, selatinib was well-tolerated up to the planned maximum dose of 500 mg; thus the maximum tolerated dose was not attained. Twenty-two adverse events were observed in 19 (36.5%) of the 52 subjects administered the test drug. The most common drug-related adverse event was diarrhea. The mean selatinib peak plasma concentration was 69.4–494 ng/mL, which was achieved in a median peak time of 3.5–4.5 h, with a mean elimination half-life between 13.8 and 15.8 h. In Part 2, A and B showed similar bioavailability. Plasma exposure to the active drug (selatinib plus the metabolite, lapatinib) after A intake was more than two-fold higher than that of the same dose of C. In the dose range of 50–500 mg, selatinib was safe and well-tolerated by healthy Chinese subjects, and it conformed with linear pharmacokinetics. Active exposure to selatinib was much greater than that to lapatinib, supporting its development as an adjuvant for anticancer treatment. Electronic supplementary material The online version of this article (10.1007/s10637-020-00959-6) contains supplementary material, which is available to authorized users.

Purpose The study aimed to investigate whether isocitrate dehydrogenase 1 (IDH1) mutation status in gliomas can be estimated by volume-based histogram analysis of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). Materials and methods Preoperative DCE-MRI data of 85 pathologically confirmed glioma patients including 33 carrying IDH1 mutant type (IDH1mut) and 52 with IDH1 wildtype (IDH1wt) were reviewed in a retrospective approach. Regions of interest (ROI) covering entire tumor volume were manually delineated using O.K. software (OmniKinetics, GE Healthcare, China). Histogram parameters of volume transfer constant (Ktrans) and volume of extravascular /extracellular space per unit volume of tissue (Ve) derived from DCE-MRI were obtained. Mann-Whitney U tests were made to compare the differences in histogram parameters of Ktrans and Ve between IDH1mut and IDH1wt in all gliomas and high-grade gliomas (HGGs, grade III and IV). Receiver operator characteristic (ROC) analysis were implemented to assess the diagnostic performance. Results In histogram parameters of Ktrans and Ve, pairwise comparisons demonstrated statistically significant differences in mean, standard deviation (SD), 90th and 95th percentiles (90%, 95%) values between IDH1mut and IDH1wt in all cases of gliomas and HGGs (P Conclusion Volume-based histogram analysis of DCE-MRI performs well in identification of IDH1mut gliomas.

We wished to evaluate whether epigenetic modifiers have a beneficial effect on treating experimental periodontitis and mechanisms for regulating the cell fate of mesenchymal stem cells (MSCs) in inflammatory microenvironments. We isolated MSCs from healthy and inflamed gingival tissues to investigate whether trichostatin A (TSA) could improve osteogenic differentiation and resolve inflammation in vitro. The tissue regenerative potentials were evaluated when treated with a temperature-dependent, chitosan-scaffold-encapsulated TSA, in a rat model of periodontitis. After induction with the conditioned medium, TSA treatment increased the osteogenic differentiation potential of inflamed MSCs and healthy MSCs. In addition, interleukin-6 and interleukin-8 levels in supernatants were significantly decreased after TSA treatment. Moreover, TSA promoted osteogenic differentiation by inhibiting nuclear factor-κB (p65) DNA binding in MSCs. In rats with experimental periodontitis, 7 weeks after local injections of chitosan-scaffold-encapsulated TSA, histology and microcomputed tomography showed a significant increase in alveolar bone volume and less inflammatory infiltration compared with vehicle-treated rats. The concentrations of interferon-γ and interleukin-6 were significantly decreased in the gingival crevicular fluid after TSA treatment. This study demonstrated that TSA had anti-inflammatory properties and could promote periodontal tissue repair, which indicated that epigenetic modifiers hold promise as a potential therapeutic option for periodontal tissue repair.

BACKGROUND The present work was performed to detect the potential inhibitory effect of cyclic guanosine monophosphate (cGMP)-dependent protein kinase II (PKG II) on epidermal growth factor (EGF) receptor-induced biological activity and related signal cascades in osteosarcoma cells. MATERIAL AND METHODS We transfected the osteosarcoma MG-63 cell line with an adenoviral vector encoding PKG II cDNA (Ad-PKGII) and incubated the transfected cells with 250 μM 8-pCPT-cGMP to activate the PKG II. We stimulated the MG-63 cells with100 ng/ml EGF, and then detected their proliferation using a CCK-8 assay. Transwell assay was used to examine MG-63 cell migration; and Western blot analysis was used to detect expression of matrix metalloproteinase 9 (MMP-9) and activation of ERK and Akt. RESULTS Stimulating cells by 100 ng/ml EGF promoted MG-63 cell proliferation and migration, ERK and Akt phosphorylation, and MMP-9 expression. These effects of EGF were inhibited in MG-63 cells infected with Ad-PKGII and incubated with 8-pCPT-cGMP. CONCLUSIONS Our results demonstrate that Ad-PKGII infection significantly inhibited EGF-induced proliferation and migration, as well as the associated-signal cascades; which indicates that PKG II might be a potential anti-cancer factor.

Sortilin is found to regulate proliferation and death of different cells, while its role in regulating keratinocyte proliferation and apoptosis is still unknown. In this study, we found that sortilin levels significantly increased in psoriasis patients, and sortilin suppression eliminated the proliferation of HaCaT cells induced by M5 cocktail solution and enhanced the levels of cleaved caspase 3 protein and the Bax/Bcl-2 ratio; however, levels of p-PI3K and p-AKT were decreased. In addition, sortilin silencing remitted the characteristic changes associated with psoriasis-like skin lesions. In summary, suppressed sortilin expression helped inhibit keratinocyte proliferation in HaCaT cells by inactivating PI3K/AKT signaling, which provides a new target for the therapy of psoriasis.

Chemotherapy is one of the most effective non-surgical treatments for various types of tumor. Identifying different combinations of antitumor agents that can produce synergistic antitumor effects remains an important clinical strategy. In the present study, we showed that the combination of histone deacetylase 6 (HDAC6) inhibitor tubastatin A together with cyclooxygenase-2 (COX-2) inhibitor celecoxib resulted in synergistic antitumor effects in CAL 27 and SACC-83 cells. Treatment with celecoxib alone promoted the membrane translocation of phosphatase and tensin homolog (PTEN), indicating PTEN activation, and consequently led to protein kinase B (AKT) dephosphorylation (inactivation). Similarly, treatment with an HDAC6 inhibitor alone promoted PTEN membrane translocation and correspondingly dephosphorylated AKT. The combination of celecoxib and an HDAC6 inhibitor synergistically increased PTEN membrane translocation and inactivated AKT. Moreover, celecoxib enhanced the HDAC6 inhibitor-induced antitumor effects in PTEN-deficient U-87 MG cells that had been stably transfected with wild-type PTEN, but not in the same cell line stably transfected with mutant PTEN-K163R, which cannot be activated by HDAC6 inhibitors. In summary, the results indicated that the COX-2 inhibitor celecoxib enhanced the HDAC6 inhibitor-induced antitumor effects by activating the PTEN/AKT signaling pathway.

Cerebrotendinous xanthomatosis (CTX) is a lipid-storage disease caused by mutations in CYP27A1. Current publications of Chinese CTX were mainly based on case reports. Here we investigated the clinical manifestations, genetic features in Chinese CTX patients. The clinical materials of 4 Chinese CTX pedigrees were collected. The genetic testing was done by polymerase chain reaction plus Sanger sequencing. The features of Chinese CTX patients reported previously were also reviewed. Three novel mutations of p.Arg513Cys, c.1477-2A > C in family 1 and p.Arg188Stop in family 4 (NM 000784.3) in CYP27A1 were found. The probands in our study manifested cerebellar ataxia, tendon xanthoma and spastic paresis in family 1 and 4, tendon xanthoma plus spastic paraparesis in family 2, asymptomatic tendon xanthoma in family 3. Three known mutations of p.Arg137Gln, p.Arg127Trp and p.Arg405Gln were found respectively in Family 2, 3 and 4. For the Chinese patients reviewed, the most common findings were xanthomatosis (100%), pyramidal signs (100%), cerebellar ataxia (66.7%), cognitive impairment (66.7%), cataracts (50.0%), and peripheral neuropathy (33.3%). Chronic diarrhea was infrequently seen (5.6%). No mutation was found associated with any given clinical features. We identified 3 novel mutations in CYP27A1. In Chinese CTX patients, xanthomatosis was the most common symptom while cataracts and chronic diarrhea were less frequent. The special features in Chinese CTX patients might caused by the lack of serum cholestanol test and should be confirmed in larger number of patients in the future.

Objective The aim of this study was to investigate the effects of rinsing with arginine or urea solution on initial enamel lesions in situ. Methods Fourteen subjects who wore mandibular removable partial dentures embedded with bovine enamel blocks with artificial enamel lesions were included. The experiment included four 4-week rinsing periods with a 10-day washout period between each rinsing period. In each rinsing period, the subjects rinsed after meal or snack using water, or 2% arginine bicarbonate, or 1% urea, or 0.05% NaF solution, five times daily. The mineralization changes of the enamel lesions were assessed using quantitative light-induced fluorescence. Results All groups except the water group showed a statistically significant decrease in the fluorescence loss after treatment, compared with their respective baseline. Although both the arginine group and urea group showed more decrease in fluorescence loss than that of the water group, the decrease was not statistically significantly different from that of the water group. The decrease in fluorescence loss of the NaF group was statistically significant than that of the water group, arginine group, and urea group. Conclusion Rinsing with arginine or urea solution offers limited remineralizing benefit to enamel lesions over a period of 4-week time.

To observe the therapeutic effects of electro-acupuncture (EA) combined with psychological intervention on the symptom of somzatization or obsession and mental symptom of depression or anxiety and P50 of Auditory Evoked Potential (AEP) on internet addiction disorder (IAD).One hundred and twenty cases of IAD ere randomly divided into an EA group, a psycho- intervention (PI) group and a comprehensive therapy (EA plus PI) group. Patients in the EA group were treated with EA. Patients in the PI group were treated with cognition and behavior therapy. Patients in the EA plus PI group were treated with electro-acupuncture plus psychological intervention. Scores of IAD, scores of the symptom checklist 90 (SCL-90), latency and amplitude of P50 of AEP were measured before and after treatment.The scores of IAD after treatment significantly decreased in all groups (P0.05), and the scores of IAD in the EA plus PI group were significantly lower than those in the other two groups (P0.05). The scores of SCL-90 assembled and each factor after treatment in the EA plus PI group significantly decreased (P0.05). After treatment in the EA plus PI group, the amplitude distance of S1P50 and S2P50 (S1-S2) significantly increased (P0.05).EA combined with PI could relieve the mental symptoms of IAD patients, and the mechanism is possibly related to the increase of cerebrum sense perception gating function.

// Jian Ming Xu 1 , Yan Wang 1 , Yu Ling Chen 1 , Ru Jia 1 , Jie Li 2 , Ji Fang Gong 2 , Jing Li 3 , Chuan Qi 3 , Ye Hua 3 , Cui Rong Tan 3 , Jian Wang 4 , Ke Li 4 , Yang Sai 4 , Feng Zhou 5 , Yong Xin Ren 5 , Wei Guo Qing 5 , Hong Jia 6 , Wei Guo Su 6 and Lin Shen 2 1 Department of Gastrointestinal Oncology, The Affiliated Hospital Cancer Center (The 307th Hospital of Chinese People’s Liberation Army), Academy of Military Medical Sciences, Beijing, China 2 Department of Gastrointestinal Oncology, Peking University Cancer Hospital, Beijing, China 3 Clinical and Regulatory Department, Hutchison MediPharma Limited, Shanghai, China 4 Drug Metabolism and Pharmacokinetic Department, Hutchison MediPharma Limited, Shanghai, China 5 Oncology Department, Hutchison MediPharma Limited, Shanghai, China 6 Chemistry Department, Hutchison MediPharma Limited, Shanghai, China Correspondence to: Jian Ming Xu, email: jmxu2003@yahoo.com Lin Shen, email: lin100@medmail.com.cn Keywords: phase I clinical trial, neuroendocrine tumor, solid tumor, sulfatinib, tyrosine kinase inhibitor Received: October 28, 2016 Accepted: December 05, 2016 Published: February 01, 2017 ABSTRACT Sulfatinib is a small molecule kinase inhibitor that targets tumor angiogenesis and immune modulation. This phase I study (NCT02133157) investigated the safety, pharmacokinetic characteristics, and preliminary anti-tumor activity of sulfatinib in patients with advanced solid tumors. The study included a dose-escalation phase (50-350 mg/day, 28-day cycle) with a Fibonacci (3+3) design, and a tumor-specific expansion phase investigating the tumor response to treatment. Two sulfatinib formulations were assessed: formulation 1 (5, 25, and 50 mg capsules) and formulation 2 (50 and 200 mg capsules). Seventy-seven Chinese patients received oral sulfatinib; the maximum tolerated dose was not reached. Dose-limiting toxicities included abnormal hepatic function and coagulation tests, and upper gastrointestinal hemorrhage. The most common treatment-related adverse events were proteinuria, hypertension and diarrhea. Among 34 patients receiving sulfatinib formulation 2, one patient with hepatocellular carcinoma and eight with neuroendocrine tumors exhibited a partial response; 15 had stable disease. The objective response rate was 26.5% (9/34) and the disease control rate was 70.6% (24/34). Pharmacokinetic, safety, and efficacy data supported continuous oral administration of sulfatinib at 300 mg as the recommended phase II dose. Sulfatinib exhibited an acceptable safety profile and encouraging antitumor activity in patients with advanced solid tumors, particularly neuroendocrine tumors.

Background To assess the efficacy and safety of fruquintinib, a vascular endothelial growth factor receptor (VEGFR) inhibitor, in metastatic colorectal cancer (mCRC) patients. Methods A phase Ib open-label study and phase II randomized, placebo-controlled trial compared the efficacy of fruquintinib plus best supportive care (BSC) with placebo plus BSC in mCRC patients with ≥2 lines of prior therapies. The primary endpoint was progression-free survival (PFS). Results In the phase Ib study, 42 patients took fruquintinib 5 mg for 3 weeks on/1 week off. The median PFS was 5.80 months, and the median overall survival (OS) was 8.88 months. In the phase II study, 71 patients were randomized (47 to fruquintinib, 24 to placebo). PFS was significantly improved with fruquintinib plus BSC (4.73 months; 95% confidence interval [CI] 2.86–5.59) versus placebo plus BSC (0.99 months; 95% CI 0.95–1.58); (hazard ratio [HR] 0.30; 95% CI 0.15–0.59; P

Objective: To examine the role of cadherin-11, an integral membrane adhesion molecule, in periodontal ligament cells (PDLCs) under mechanical stimulation.Materials and Methods: Human PDLCs were cultured and subjected to mechanical stress. Cadherin-11 expression and cell morphology of PDLCs were investigated via immunofluorescence staining. The mRNA and protein expressions of cadherin-11 and type I collagen (Col-I) of PDLCs were evaluated by quantitative real-time polymerase chain reaction and Western blot, respectively. Small interfering RNA was used to knock down cadherin-11 expression in PDLCs. The collagen matrix of PDLCs was examined using toluidine blue staining.Results: Cadherin-11 was expressed in PDLCs. Mechanical stress suppressed cadherin-11 expression in PDLCs with prolonged force treatment time and increased force intensity, accompanied by suppressed β-catenin expression. Simultaneously, mechanical stress altered cell morphology and repressed Col-I expression in a time- and dose-dependent manner in PDLCs. Moreover, knockdown of cadherin-11 with suppressed β-catenin expression resulted in altered PDLC morphology and repressed collagen expression, which were consistent with the changes observed under mechanical stress.Conclusions: Results of this study suggest that cadherin-11 is expressed in PDLCs and modulates PDLC morphology and collagen synthesis in response to mechanical stress, which may play an important role in the homeostasis and remodeling of the PDL under mechanical stimulation.

The exact mechanism underlying chronic masticatory myalgia (CMM), a conspicuous symptom in temporomandibular disorders, remains unclear. This investigation compared gene expression profiles between CMM patients and healthy subjects. Peripheral blood leukocytes were collected in 8 cases and 8 controls and subjected to whole genome microarray analyses. Data were analyzed with Gene Ontology and interactive pathways analyses. According to Gene Ontology analysis, categories such as ion transport, response to stimuli, and metabolic process were upregulated. The pathway analysis suggested overexpression of the mitogen-activated protein kinase (MAPK) pathway in CMM patients and to a higher degree in a pathway network. Overexpression of representative members of the MAPK pathway—including MAPK kinase 3 ( MEK3), calcium voltage-gated channel auxiliary subunit gamma 2 ( CACNG2), and growth arrest and DNA damage–inducible gamma ( GADD45G)—was validated with real-time polymerase chain reaction. The upregulation of MEK3 was negatively correlated with the age of the CMM group. In the next step, the authors focused on MEK3, the gene that exhibited the greatest degree of differential expression, and its downstream target protein p38 MAPK. The results revealed upregulation of MEK3, as well as phosphorylated MEK3 and phosphorylated p38 MAPK, in CMM patients. These results provide a “fingerprint” for mechanistic studies of CMM in the future and highlight the importance of MEK3–p38 MAPK activation in CMM.

Background MiRNAs have been demonstrated to be important regulators during osteogenic differentiation in multiple types of stem cells. In the study, the interaction between miR-375 and TOB2 was analyzed to identify their functions on the proliferation and osteogenic differentiation of hPDLSCs. Methods hPDLSCs were isolated from human first premolars, and hPDLSCs stably expressing and silenced miR-375 were constructed using miR-375-ago and miR-375-antago, respectively. miR-375 and RUNX2 mRNA expression levels in hPDLSCs during osteogenic differentiation were investigated using qRT-PCR. The impact of miR-375 expression on hPDLSCs proliferation and osteogenic differentiation was determined using MTT assay, ALP assay, and alizarin red S staining. The protein expression levels of COL1A1, RUNX2 and OCN were detected using Western blot. The targeting of TOB2 by miR-375 was validated using dual luciferase reporter assay. Results The expression levels of miR-375 were increased in hPDLSCs during osteogenic differentiation in a time-dependant manner, and was positively correlated with RUNX2 mRNA expression. miR-375 facilitated the proliferation and osteogenic differentiation of hPDLSCs, and promoted the protein expression levels of COL1A1, RUNX2 and OCN. Moreover, TOB2 protein expression was reduced in hPDLSCs during osteogenic differentiation in a time-dependant manner, and miR-375 directly targeted TOB2 expression. In addition, targeting TOB2 expression in hPDLSCs could rescue the suppression of cell proliferation and osteogenic differentiation by miR-375-antago. Conclusion In summary, miR-375 promotes proliferation and osteogenic differentiation of hPDLSCs by targeting TOB2, which reveals a new regulatory mechanism underlying osteogenic differentiation of hPDLSCs by miR-375/TOB2 axis.

Microporous membranes support the growth of neurites into and through micro-channels, providing a different type of neural growth platform to conventional dish cultures. Microporous membranes are used to support various types of culture, however, the role of pore diameter in relation to neurite growth through the membrane has not been well characterised. In this study, the human cell line (SH-SY5Y) was differentiated into neuron-like cells and cultured on track-etched microporous membranes with pore and channel diameters selected to accommodate neurite width (0.8 µm to 5 µm). Whilst neurites extended through all pore diameters, the extent of neurite coverage on the non-seeded side of the membranes after 5 days in culture was found to be directly proportional to channel diameter. Neurite growth through membrane pores reduced significantly when neural cultures were non-confluent. Scanning electron microscopy revealed that neurites bridged pores and circumnavigated pore edges – such that the overall likelihood of a neurite entering a pore channel was decreased. These findings highlight the role of pore diameter, cell sheet confluence and contact guidance in directing neurite growth through pores and may be useful in applications that seek to use physical substrates to maintain separate neural populations whilst permitting neurite contact between cultures.

Purpose: No antiangiogenic treatment is yet approved for extrapancreatic neuroendocrine tumors (NET). Surufatinib (HMPL-012, previously named sulfatinib) is a small-molecule inhibitor targeting vascular endothelial growth factor receptors, fibroblast growth factor receptor 1 and colony-stimulating factor 1 receptor. We conducted a single-arm phase Ib/II study of surufatinib in advanced NETs. Patients and Methods: Patients with histologically well-differentiated, low or intermittent grade, inoperable or metastatic NETs were enrolled into a pancreatic or extrapancreatic NET cohort. Patients were treated with surufatinib 300 mg orally, once daily. The primary endpoints were safety and objective response rate (ORR) according to Response Evaluation Criteria in Solid Tumors (version 1.1). Results: Of the 81 patients enrolled, 42 had pancreatic NETs and 39 had extrapancreatic NETs. Most patients had radiologic progression within 1 year prior to enrollment (32 patients in each cohort). In the pancreatic and extrapancreatic NET cohorts, ORRs were 19% [95% confidence intervals (CI), 9–34] and 15% (95% CI, 6–31), disease control rates were 91% (95% CI, 77–97) and 92% (95% CI, 79–98), and median progression-free survival was 21.2 months (95% CI, 15.9–24.8) and 13.4 months (95% CI, 7.6–19.3), respectively. The most common grade ≥3 treatment-related adverse events were hypertension (33%), proteinuria (12%), hyperuricemia (10%), hypertriglyceridemia, and diarrhea (6% for each), and increased alanine aminotransferase (5%). Conclusions: Surufatinib showed encouraging antitumor activity and manageable toxicities in patients with advanced NETs. Two ongoing phase III studies, validating the efficacy of surufatinib in patients with NETs, will contribute to the clinical evidence.

Rationale and Objectives This study aimed to investigate whether volume transfer constant (Ktrans) and volume of extravascular extracellular space per unit volume of tissue (Ve) derived from dynamic contrast-enhanced magnetic resonance imaging (DCE MRI) could quantitatively assess the tumor proliferation index (Ki-67) of gliomas noninvasively. Materials and Methods The preoperative DCE MRI data of 69 patients with pathologically confirmed glioma (28, 8, and 33 cases in grades Ⅱ, Ⅲ, and Ⅳ) were retrospectively reviewed. The maximal Ktrans and Ve were measured in the tumor body. The immunohistochemistry was used to detect the expression of Ki-67 proteins in glioma specimens. The Mann–Whitney U test was applied to analyze the differences in Ktrans, Ve, and Ki-67 index across histologically defined glioma grades. Spearman correlation was performed between Ktrans, Ve, and Ki-67 index. The receiver operating characteristic curve analysis was used to determine the cutoff values of Ktrans and Ve in distinguishing different Ki-67 index expression levels. Results Ktrans, Ve, and Ki-67 index of grade Ⅱ (0.027 min−1, 0.065, 4.04%) were significantly lower than those of grade Ⅲ (0.093 min−1, 0.297, 25.13%) and Ⅳ (0.100 min−1, 0.299, 25.37%). Both Ktrans and Ve significantly correlated with the Ki-67 index in all tumors and high-grade gliomas (HGGs, grade Ⅲ and Ⅳ). The receiver operating characteristic curve analysis revealed that the cutoff values for Ktrans (0.079 min−1) and Ve (0.249) provided the best combination of sensitivity and specificity to distinguish the gliomas with high Ki-67 index from those with low Ki-67 index. Conclusion The DCE MRI-derived parameters were valuable in assessing the tumor cell proliferation in HGG noninvasively.

Cisplatin is still one of the first-line drugs for chemotherapy of head and neck squamous cell carcinoma (HNSCC) and shows a survival advantage for HNSCC. However, a substantial proportion of HNSCC eventually becomes resistance to cisplatin and the underlying mechanisms remain to be fully understood. Yin Yang 1 (YY1) is a multifunctional protein regulating both gene transcription and protein modifications and also plays a role in chemotherapy resistance. Here, we reported that knockdown of YY1 by lentivirus-mediated short hairpin RNA or tetracycline-inducible short hairpin RNA enhanced cisplatin-induced apoptosis and inhibition of cell proliferation, migration and invasion in the HNSCC cell lines, and inhibition of the xenograft tumor growth. The underlying mechanisms were revealed that knockdown of YY1 downregulated both S473 and T308 phosphorylation of AKT (protein kinase B), which was mainly responsible for cisplatin resistance, whereas overexpression of YY1 upregulated both S473 and T308 phosphorylation. Cisplatin upregulated YY1 mRNA and protein expression and both S473 and T308 phosphorylation of AKT. In the presence of cisplatin, knockdown of YY1 not only blocked cisplatin-induced increase in S473 and T308 phosphorylation of AKT, but still downregulated T308 phosphorylation. Moreover, protein phosphatase 2A (PP2A) antagonist, okadaic acid, upregulated T308, but not S473, phosphorylation, and simultaneously abolished YY1 knockdown-mediated enhancement of cisplatin-induced inhibition of cell proliferation. In addition, knockdown of YY1 promoted PP2A activity through upregulating mRNA and protein expressions of PP2A catalytic subunit alpha (PPP2CA) through the binding of YY1 in the promoter of PPP2CA. Conversely, activating PP2A by forskolin also promoted YY1 degradation and subsequently inhibited T308 phosphorylation. These results suggested that knockdown of YY1 enhanced anticancer effects of cisplatin through PP2A mediating T308 dephosphorylation of AKT, and that targeting YY1 or PP2A would enhance the efficiency of cisplatin chemotherapy in treatment of HNSCC.

Veratridine is a lipid-soluble neurotoxin derived from plants in the family Liliaceae. It has been broadly investigated for its action as a sodium channel agonist. However, the effects of veratridine on subtypes of sodium channels, especially Nav1.7, remain to be studied. Here, we investigated the effects of veratridine on human Nav1.7 ectopically expressed in HEK293A cells and recorded Nav1.7 currents from the cells using whole-cell patch clamp technique. We found that veratridine exerted a dose-dependent inhibitory effect on the peak current of Nav1.7, with the half-maximal inhibition concentration (IC(50)) of 18.39 µM. Meanwhile, veratridine also elicited tail current (linearly) and sustained current [half-maximal concentration (EC(50)): 9.53 µM], also in a dose-dependent manner. Veratridine (75 µM) shifted the half-maximal activation voltage of the Nav1.7 activation curve in the hyperpolarized direction, from −21.64 ± 0.75 mV to −28.14 ± 0.66 mV, and shifted the half-inactivation voltage of the steady-state inactivation curve from −59.39 ± 0.39 mV to −73.78 ± 0.5 mV. An increased frequency of stimulation decreased the peak and tail currents of Nav1.7 for each pulse along with pulse number, and increased the accumulated tail current at the end of train stimulation. These findings reveal the different modulatory effects of veratridine on the Nav1.7 peak current and tail current.

IMPORTANCE: Patients with metastatic colorectal cancer (CRC) have limited effective and tolerable treatment options. OBJECTIVE: To evaluate the efficacy and safety of oral fruquintinib, a vascular endothelial growth factor receptor (VEGFR) inhibitor, as third-line or later therapy in patients with metastatic CRC. DESIGN, SETTING, AND PARTICIPANTS: FRESCO (Fruquintinib Efficacy and Safety in 3+ Line Colorectal Cancer Patients) was a randomized, double-blind, placebo-controlled, multicenter (28 hospitals in China), phase 3 clinical trial. From December 2014 to May 2016, screening took place among 519 patients aged 18 to 75 years who had metastatic CRC that progressed after at least 2 lines of chemotherapy but had not received VEGFR inhibitor therapy; 416 met the eligibility criteria and were stratified by prior anti-VEGF therapy and K-ras status. The final date of follow-up was January 17, 2017. INTERVENTIONS: Patients were randomized in a 2:1 ratio to receive either fruquintinib, 5 mg (n = 278) or placebo (n = 138) orally, once daily for 21 days, followed by 7 days off in 28-day cycles, until disease progression, intolerable toxicity, or study withdrawal. MAIN OUTCOMES AND MEASURES: The primary end point was overall survival. Key secondary efficacy endpoints were progression-free survival (time from randomization to disease progression or death), objective response rate (confirmed complete or partial response), and disease control rate (complete or partial response, or stable disease recorded ≥8 weeks postrandomization). Duration of response was also assessed. Safety outcomes included treatment-emergent adverse events. RESULTS: Of the 416 randomized patients (mean age, 54.6 years; 161 [38.7%] women), 404 (97.1%) completed the trial. Median overall survival was significantly prolonged with fruquintinib compared with placebo (9.3 months [95% CI, 8.2-10.5] vs 6.6 months [95% CI, 5.9-8.1]); hazard ratio (HR) for death, 0.65 (95% CI, 0.51-0.83; P

INTRODUCTION Low high-density lipoprotein cholesterol (HDL-C) and high low-density lipoprotein cholesterol (LDL-C) levels are associated with incidence of cardiovascular disease (CVD). Alirocumab has been considered as an efficacious, safe and promising therapeutic modality for hypercholesterolemia. The purpose of this study is to compare the differences of the three different doses of alirocumab in patients with hypercholesterolemia. EVIDENCE ACQUISITION Randomized controlled trials were identified from PubMed, EMBASE, PMC and Cochrane-library databases. The inter-comparison of different doses were performed by subgroups analysis. Meta-analyses were performed by the Review Manager 5.3 and STATA 13.0 software. EVIDENCE SYNTHESIS A total of nine studies involving 3870 patients were included in this meta-analysis. Alirocumab administered at 75-150 mg every 2 weeks (Q2W) resulted in a greater percent change from baseline in LDL-C concentrations (MD, -55.17; 95% CI: -64.35 to -45.99; P

Purpose Patients with advanced non‒small-cell lung cancer (NSCLC) who fail two lines of chemotherapy have unmet medical needs. The kinase inhibitor fruquintinib selectively targets vascular endothelial growth factor receptors and, hence, tumor angiogenesis and lymphogenesis. This randomized, double-blind, placebo-controlled, multicenter phase II trial evaluated the efficacy and safety of fruquintinib in patients with advanced nonsquamous NSCLC who experienced disease progression after second-line chemotherapy. Patients and Methods Eligible patients were randomly assigned (two to one; stratified by epidermal growth factor receptor status) to receive fruquintinib or placebo, both in combination with best supportive care. Oral fruquintinib (5 mg once daily) was given in 4-week cycles of 3 weeks of treatment followed by 1 week off. Tumor response was assessed using Response Evaluation Criteria in Solid Tumors version 1.1. The primary end point was progression-free survival (PFS) evaluated by a blinded image central review (BICR) committee. Secondary end points included investigator-evaluated PFS, objective response rate, disease control rate, overall survival, and safety. Results Ninety-one patients from 12 hospitals received treatment with fruquintinib (n = 61) or placebo (n = 30). Median PFS was 3.8 months with fruquintinib by both BICR and investigators’ evaluations (hazard ratio by BICR, 0.34; 95% CI, 0.20 to 0.57; P < .001). Three- and 6-month survival rates were 90.2% and 67.2% in the fruquintinib group and 73.3% and 58.8% in the placebo group, respectively. The objective response rate and disease control rate were 13.1% and 60.7% with fruquintinib, compared with 0% and 13.3% with placebo ( P = .041 and < .001), respectively. The most common treatment-emergent adverse events with fruquintinib (≥ grade 3) were hypertension (8.2%), hand-foot syndrome (4.9%), and proteinuria (4.9%). Conclusion Third- and fourth-line fruquintinib for advanced NSCLC was superior to placebo and had an acceptable safety profile.

Objective The aim of this study was to evaluate the carious status and the microbial profiles of supragingival plaque in patients with chronic kidney disease undergoing hemodialysis. Methods This study included 30 patients with chronic kidney disease undergoing hemodialysis as well as 30 control subjects. Dental examination was performed and the decayed-missing-filled-teeth was recorded. Supragingival plaque was taken and analyzed using 16S rRNA gene amplicon by Illumina MiSeq sequencing to detect microbial composition and community diversity and structure. Results The level of decayed-missing-filled-teeth was higher in the hemodialysis group than that in the control group. Microbial analysis showed a decrease in α diversity and a increase in relative abundance and prevalence of many acidogenic and aciduric caries related species in the supragingival plaque samples of the hemodialysis patients, including Streptococcus mutans, Lactobacillus salivarius, Lactobacillus fermentum, Lactobacillus vaginalis, Scardovia wiggsiae F0424, and Actinomyces naeslundii. Conclusion Our results suggested that the hemodialysis patients were more susceptible to caries. More attentions for caries prevention and treatment should be paid to improve their life quality, and even to reduce their cardiovascular events and survival.

There is increasing evidence to suggest that matrix metalloproteinases (MMPs) play a crucial role in vascular remodeling. It has been reported that hypoxia stimulated MMP-9 expression in brain endothelial cells and MMP-9 plays an important role in cerebral vascular remodeling. However, little is known about MMP-2 in the cerebral vessels remodeling. Herein, the aim of this study is to examine the class of vessel and cell type expressing MMP-2 in cerebral vessels and to investigate its potential role in vascular remodeling. In the present study, dual-immunofluorescence assay showed that MMP-2 was mainly expressed in arterioles. In addition, we found that MMP-2 expression in cerebral vessels was derived from endothelial cells, not astrocyte cells. Notably, in the normoxic central nervous system (CNS), there was no effect on vascular development, integrity, or endothelial proliferation when MMP-2 was knocked out, but lack of MMP-2 led to defective arteriolar remodeling and associated with transforming growth factor β1 (TGF-β1) signaling in CNS. Moreover, blocking TGF-β with SB431542, a specific TGF-β inhibitor, significantly reduced the messenger RNA (mRNA) and protein expression levels of MMP-2 in human umbilical vein endothelial cells (HUVECs). Our findings reveal that the level of MMP-2 is high in arteriolar endothelial cells and demonstrate a novel connection between MMP-2 and TGF-β1 signaling in cerebral vascular remodeling.

Phosphatase and tensin homologue deleted on chromosome 10 (PTEN), an important tumour-suppressor gene, is mutated, downregulated or dysfunctional in many tumours. The phosphatase activity of PTEN depends on membrane translocation (activation). As promising anti-cancer agents, histone deacetylase (HDAC) inhibitors, particularly trichostatin A (TSA), can promote PTEN membrane translocation, but the underlying mechanism remains unknown. In this study, we revealed that non-selective HDAC inhibitors, namely, TSA or suberoylanilide hydroxamic acid (SAHA), induced PTEN membrane translocation through PTEN acetylation at K163 by inhibiting HDAC6. K163 acetylation inhibited the interaction of the PTEN C-tail with the remaining part of PTEN, resulting in PTEN membrane translocation. Overexpression of wild-type PTEN, but not K163-mutated PTEN, facilitated the inhibition of cell proliferation, migration and invasion, as well as xenograft tumour growth, induced by SAHA or tubastatin A, an HDAC6-specific inhibitor. These results indicated that PTEN activation by inhibiting HDAC6 significantly contributed to tumour inhibition. Therefore, non-selective HDAC or HDAC6-specific inhibitors may be more clinically suitable to treat tumours without PTEN mutations or deletions.

Mandibular prognathism is a facial skeletal malocclusion. Until now, the genetic mechanism has been unclear. The goal of this study was to identify candidate genes or genomic regions directly associated with mandibular prognathism development, by employing whole genome sequencing. A large Chinese family was recruited, composed of 9 affected and 12 unaffected individuals, and the inheritance pattern of this family tends to be autosomal dominant. A single-nucleotide missense mutation in the ADAMTS1 gene (c. 742I>T) was found to segregate in the family, given that the affected individuals must be heterozygous for the mutation. For mutation validation, we screened this candidate mutation and 15 tag single-nucleotide polymorphisms in the coding sequence of ADAMTS1 among 230 unrelated cases and 196 unrelated controls using Sequenom Massarray and found that 3 in 230 cases carried this mutation and none of the controls did. Final results suggested that 2 single-nucleotide polymorphisms (rs2738, rs229038) of ADAMTS1 were significantly associated with mandibular prognathism.

Temporomandibular joint osteoarthritis (TMJOA) is a complex disease and has a strong genetic component in its pathogenesis. Experimental evidence suggests the involvement of biological pathway in the disease. This case-control study was designed to investigate whether five common single nucleotide polymorphisms (SNPs) in GDF5, SMAD3, RUNX2, TGFβ1 and CHST11, respectively, are associated with TMJOA in female Han Chinese patients. A total of 240 participants were evaluated comprising 114 female patients diagnosed with TMJOA based on Research Diagnostic Criteria for Temporomandibular Disorders and 126 healthy female controls. The SNPs of the five genes in the genomic DNA were examined by sequencing, and their allelic, genotypic and carriage rate frequency distributions, as well as the triple combination of the risk genotypes, were analysed using the logistic regression model. The SNP in GDF5 or SMAD3 showed significant association with TMJOA, a relatively weak association was observed in RUNX2. In the triple combinational analysis, the risk of TMJOA grew 5·09 times in the patients with five or six risk alleles (P 0·01). This is the first study to evaluate the association of GDF5, SMAD3, RUNX2, TGFβ1 and CHST11 with TMJOA in female Han Chinese. Our study suggests that the SNPs of genes related to TGFβ family might contribute to the risk of TMJOA.