Design, synthesis, and biological evaluation of thiazole/thiadiazole carboxamide scaffold-based derivatives as potential c-Met kinase inhibitors for cancer treatment.

As part of our continuous efforts to discover novel c-Met inhibitors as antitumor agents, four series of thiazole/thiadiazole carboxamide-derived analogues were designed, synthesised, and evaluated for the in vitro activity against c-Met and four human cancer cell lines. After five cycles of optimisation on structure-activity relationship, compound 51am was found to be the most promising inhibitor in both biochemical and cellular assays. Moreover, 51am exhibited potency against several c-Met mutants. Mechanistically, 51am not only induced cell cycle arrest and apoptosis in MKN-45 cells but also inhibited c-Met phosphorylation in the cell and cell-free systems. It also exhibited a good pharmacokinetic profile in BALB/c mice. Furthermore, the binding mode of 51am with both c-Met and VEGFR-2 provided novel insights for the discovery of selective c-Met inhibitors. Taken together, these results indicate that 51am could be an antitumor candidate meriting further development.

Study on the application of oral digital design in aesthetic restoration of anterior teeth of cleft lip/palate patients.

OBJECTIVES: A study was conducted to investigate the clinical effects of oral digital design on the aesthetic restoration of anterior teeth of cleft lip/palate patients. METHODS: Nine adult cleft lip/palate patients who need aesthetic restoration of anterior teeth were recruited. Digital information of patients' dental arches, the surrounding soft tissue and face were captured by digital camera and scanner. The aesthetic analysis and design were conducted using keynote and 3shape software and were demonstrated to the patients. The optimized treatment plan was ensured by communicating with the patients. Digital wax-up models were exported and printed into resin diagnostic models, which were then utilized in the treatment process to guide the doctors and the technicians in tooth preparation and in making the final restorations, respectively. The adhesive procedure was completed after satisfactory try-in. Aesthetics assessment was conducted in accordance with the anterior esthetic evaluation form. The scores of patient's satisfaction were recorded on a questionnaire containing six items of aesthetic index and doctor-patient communication. Patients were interviewed and examined after 1, 3, 6, and 12 months, respectively, and the clinical effects of restorations were evaluated. RESULTS: All nine patients had satisfactory clinical results. The aesthetic defects of the patients were effectively addressed. All treatments met the requirements of the preoperative digital designs. The patients' scores were all above 90 on the satisfaction scale. At 12 months after the operation, the clinical effects of restorations of all cases achieved A class in each evaluation indicator. CONCLUSIONS: For cleft lip/palate patients with esthetic defect in the anterior teeth, the digital design plays an important role in optimizing the treatment plan and guides the whole treatment process. This design can help clinicians achieve predictable satisfactory aesthetic results.

Combined therapy of intensive statin plus intravenous rt-PA in acute ischemic stroke: the INSPIRE randomized clinical trial.

OBJECTIVE: To investigate the safety and efficacy of intensive statin in the acute phase of ischemic stroke after intravenous thrombolysis therapy. METHODS: A total of 310 stroke patients treated with rt-PA were randomly scheduled into the intensive statin group (rosuvastatin 20 mg daily × 14 days) and the control group (rosuvastatin 5 mg daily × 14 days). The primary clinical endpoint was excellent functional outcome (mRS ≤ 1) at 3 months, and the primary safety endpoint was symptomatic intracranial hemorrhage (sICH) in 90 days. RESULTS: The intensive statin users did not achieve a favorable outcome in excellent functional outcome (mRS ≤ 1) at 3 months compared with controls (70.3% vs. 66.5%, p = 0.464). Intensive statin also not significantly improved the overall distribution of scores on the modified Rankin scale, as compared with controls (p = 0.82 by the Cochran-Mantel-Haenszel test). The incidence of primary safety endpoint events (sICH) in 90 days did not significantly differ between the intensive statin group and control group (0.6% vs. 1.3%, p > 0.999). CONCLUSION: The INSPIRE study indicated that intensive statin therapy may not improve clinical outcomes compared with the low dose of statin therapy in AIS patients undergoing intravenous thrombolysis, and the two groups had similar safety profile. CLINICAL TRIAL REGISTRATION: URL: http://www.chictr.org . Unique identifier: ChiCTR-IPR-16008642.

Expression and antibacterial analysis of galectin-8 and -9 genes in mandarin fish, Siniperca chuatsi.

Galectin-8 and galectin-9 belong to tandem repeat-type galectins, and in the present study, these two genes were cloned in mandarin fish Siniperca chuatsi. The open reading frame (ORF) of the mandarin fish galectin-8 and galectin-9 contains 942, and 1008 bp, encoding 313 and 335 amino acids, respectively. As a conserved feature, an N-terminal carbohydrate recognition domain (CRD), and a C-terminal CRD were observed in each of the two galectins in mandarin fish. In healthy fish, galectin-8 and -9 were constitutively expressed in all organs/tissues examined, and their expression can be induced following the stimulation of LPS and poly(I:C). It is obvious that galectin-8 had a higher increase at mRNA level following the stimulation of poly(I:C). It is further demonstrated that mandarin fish galectin-8 inhibited the growth of Flavobacterium columnare and Streptococcus agalactiae, and in addition to the two species of bacteria, galectin-9 inhibited also the growth of Edwardsiella piscicida, which provides the basis for further understanding their antibacterial role in immune response of mandarin fish.

Clinical Efficacy and Safety of Major Uterine Wall Resection and Reconstruction of the Uterus Combined with LNG-IUS for the Treatment of Severe Adenomyosis.

Objective Aim of the study was to evaluate the clinical efficacy and safety of major uterine wall resection and reconstruction of the uterus (MURU) combined with a levonorgestrel-releasing intrauterine system (LNG-IUS) for the treatment of adenomyosis. Methods Ninety patients diagnosed with adenomyosis were enrolled in this study. All participants were examined by transvaginal ultrasound (TVU) or magnetic resonance imaging (MRI). Serum levels of cancer antigen 125 (CA 125) were quantitatively measured. All patients underwent MURU in combination with LNG-IUS. The therapeutic safety of MURU was assessed during surgery and the patients' stay in hospital. The clinical efficacy was evaluated by comparatively analyzing changes in dysmenorrhea, volume of menstrual blood, uterine volume and serum levels of CA 125 before, and at 3, 6 and 12 months following MURU. Results All 90 patients enrolled in the study were successfully treated with MURU combined with LNG-IUS. No significant complications were observed during surgery and hospital stay. The mean operation time, intraoperative blood loss and length of hospital stay were 82.4 ± 13.8 min, 53.3 ± 20.3 ml, and 4.3 ± 0.8 days, respectively. Dysmenorrhea completely disappeared in all patients. Uterine volume and serum levels of CA 125 were restored to normal ranges. No recurrence of adenomyosis was observed during postoperative follow-up. Conclusion MURU combined with LNG-IUS is an efficacious and safe treatment for severe adenomyosis. This combined technique is not only effective to manage severe adenomyosis but also preserves as much of the uterus as possible.

Contourlet-based hippocampal magnetic resonance imaging texture features for multivariant classification and prediction of Alzheimer's disease.

The study is aimed to assess whether the addition of contourlet-based hippocampal magnetic resonance imaging (MRI) texture features to multivariant models improves the classification of Alzheimer's disease (AD) and the prediction of mild cognitive impairment (MCI) conversion, and to evaluate whether Gaussian process (GP) and partial least squares (PLS) are feasible in developing multivariant models in this context. Clinical and MRI data of 58 patients with probable AD, 147 with MCI, and 94 normal controls (NCs) were collected. Baseline contourlet-based hippocampal MRI texture features, medical histories, symptoms, neuropsychological tests, volume-based morphometric (VBM) parameters based on MRI, and regional CMgl measurement based on fluorine-18 fluorodeoxyglucose-positron emission tomography were included to develop GP and PLS models to classify different groups of subjects. GPR1 model, which incorporated MRI texture features and was based on GPG, performed better in classifying different groups of subjects than GPR2 model, which used the same algorithm and had the same data as GPR1 except that MRI texture features were excluded. PLS model, which included the same variables as GPR1 but was based on the PLS algorithm, performed best among the three models. GPR1 accurately predicted 82.2% (51/62) of MCI convertors confirmed during the 2-year follow-up period, while this figure was 53 (85.5%) for PLS model. GPR1 and PLS models accurately predicted 58 (79.5%) vs. 61 (83.6%) of 73 patients with stable MCI, respectively. For seven patients with MCI who converted to NCs, PLS model accurately predicted all cases (100%), while GPR1 predicted six (85.7%) cases. The addition of contourlet-based MRI texture features to multivariant models can effectively improve the classification of AD and the prediction of MCI conversion to AD. Both GPR and LPS models performed well in the classification and predictive process, with the latter having significantly higher classification and predictive accuracies. Advances in knowledge: We combined contourlet-based hippocampal MRI texture features, medical histories, symptoms, neuropsychological tests, volume-based morphometric (VBM) parameters, and regional CMgl measurement to develop models using GP and PLS algorithms to classify AD patients.

miR-21 promotes proliferation and inhibits apoptosis of hepatic stellate cells through targeting PTEN/PI3K/AKT pathway.

To investigate the effect of microRNA 21 (miR-21) on hepatic stellate cells (HSCs) proliferation and apoptosis, and further to study its potential mechanisms. LX-2 cells were divided into miR-21 mimic group (Mimic), miR-21 mimic negative control group (NM), miR-21 inhibitor group (Inhibitor), miR-21 inhibitor negative control group (NC), and blank control group (Control). The cell proliferation was detected by CCK-8 assay and the cell migration and invasion were detected by scratch and transwell assay. Cell cycle and apoptosis were detected by flow cytometry. The levels of interleukin (IL)-6, tumor necrosis factor (TNF)-α, and transforming growth factor (TGF)-ß1 were detected by enzyme-linked immunosorbent assay (ELISA). Proliferation, apoptosis, and phosphatase and tensin homolog (PTEN)/phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway related genes and proteins were detected by quantitative real-time polymerase chain reaction (qRT-PCR) and western blot, respectively. The cells proliferation, migration, and invasion were promoted in Mimic group. The levels of IL-6, TNF-α, and TGF-ß1 were increased after miR-21 administration. The expression of α-smooth muscle actin (SMA) and collagen 1 (Colla1) were increased, while Bax/B-cell lymphoma (Bcl)-2 ratio and programed cell death 4 (PDCD4) were reduced after miR­21 treatment. Meanwhile, the mRNA and protein expression of PTEN were reduced and PI3K/AKT pathway been promoted. Our study demonstrated that miR-21 could promote proliferation and inhibit apoptosis of HSCs, and its mechanism may be related to PTEN/PI3K/AKT pathway.

[Investigation of related risk factors of temporomandibular disorders in 109 patients].

PURPOSE: To investigate the related risk factors of temporomandibular disorders(TMD), and to provide evidences for clinical prevention. METHODS: One hundred and nine TMD patients were included in the study as case group, while 109 people with no TMJ symptoms and signs were selected randomly as control group. All subjects fulfilled questionaires. Logistics regression analysis was used to analyze the data with SPSS 22.0 software package. RESULTS: Females patients were more common than males, with 20~29 age group accounting for 44%. The proportions of patients with habits of bruxism or clenching, unilateral mastication and maxillofacial injure history were significantly greater than those of control group (P<0.05). The proportions of patients with life stress and habits of stay-up late, chewing hard food and orthodontic treatment history showed no significant difference compared with the control group (P>0.05). CONCLUSIONS: TMD has a higher prevalence in female than in male, with a peak incidence in 20-29 age group. Habits of bruxism or clenching, unilateral mastication and maxillofacial injury history may be risk factors of TMD, while life stress, habits of stay-up late, chewing hard food and orthodontic treatments show no significant correlation with TMD.

Experimental study on ablation of leiomyoma by combination high-intensity focused ultrasound and iodized oil in vitro.

AIM: The aim of the current study was to investigate whether iodized oil (IO) enhances high-intensity focused ultrasound (HIFU) ablation of uterine leiomyoma and to determine the features of hyperechoic changes in the target region. METHODS: Forty samples of uterine leiomyoma were randomly divided into an experimental group and a control group. In the experimental group, the leiomyoma was ablated by HIFU 30 min after 1 mL of iodized oil had been injected into the center of the myoma. The hyperechoic values and areas in the target region were observed by B-modal ultrasound after HIFU ablation. The samples were cut successively into slices and stained by triphenyltetrazolium chloride (TTC) solution within 1 h after HIFU ablation. The diameters of TTC-non-stained areas were measured and tissues in the borderline of the TTC-stained and -non-stained areas were observed pathologically. All procedures in the control group were the same as those in the experimental group except IO was replaced by physiological saline. RESULTS: The hyperechoic value in the target region in the experimental group was higher than that in the control group 4 min after HIFU ablation (P < 0.05). Hyperechoic areas in the target region as well as TTC-non-stained volumes in the experimental group were greater than those in the control group (P < 0.05). Routine pathologic observation showed that coagulation necrosis of leiomyoma occurred in the target region in both groups. CONCLUSION: IO causes coagulation necrosis, enlarges tissue damage, and postpones the attenuation of hyperechoic changes in the target region when HIFU ablation is carried out for leiomyoma in vitro.

Viral encephalitis complicated by acute retinal necrosis syndrome: A case report.

Acute retinal necrosis syndrome (ARN) is a viral infection characterized by focal retinal necrosis. Viral meningitis complicated by ARN is relatively rare. In the present case study, a 44-year-old male presented with fever, headache and mental disorder. After four days, the patient developed blurred vision. The patient was diagnosed with viral encephalitis complicated by bilateral ARN, based on the examination results. After treatment with antivirals and systemic glucocorticoids, the symptoms of the patient improved. Viral encephalitis may be an important risk factor for ARN. For a patient with viral encephalitis who experiences decreased visual acuity or vitreous opacification, the possibility of ARN should be considered.

Characteristics of blood chemistry, hematology, and lymphocyte subsets in pregnant rhesus monkeys.

The present study was designed to characterize the blood chemistry, hematology, and lymphocyte subsets in pregnant rhesus monkeys and provide baseline parameters for future studies of reproductive and developmental toxicity and developmental immunotoxicity. Harem-mating was used in 96 female and 16 male rhesus monkeys. Pregnancy was confirmed on gestation day (GD)18 by ultrasound. The blood samples of rhesus monkeys were collected at various times (20 days before pregnancy and GD20, 100 and 150). The analyses of blood chemistry, hematology, and lymphocyte subsets were performed. Compared with 20 days before pregnancy, Significant decreases (P < 0.05) were observed in HCT and RBC on GD20, GD150 and in HGB on GD150, Significant increases in NEUT and decreases in LYMPH on GD20 were observed. Significant decreases in ALB from GD20 to GD150 were observed, significant decreases in TP was observed on GD100. Significant increases in mean GLU were observed on GD20 and GD150 during pregnancy. Significant decreases (P < 0.05) in CD20(+) subsets on GD100, GD150 and CD4(+)/CD8(+)ratio on GD150 were observed, The significant changes of MCV, MCHC, RDW-SD, MCV, MONO, ALT, AST, GLB, ALP, TBIL, DBIL, IBIL, GGT, CR-S, URIC, TC, TG and CK were observed during the pregnant period, but no biologic change were observed, There were no significant changes in MCH, RDW-CV, MPV, BUN, CD3(+), CD4(+) and CD8(+) during pregnancy. These data provide a database for preclinical study in rhesus monkeys. Physiological anemia, hyperglycemia, and immune suppression may occur in pregnant rhesus monkey which is similar to that found in human, and it is essential to distinguish the physiological changes from the pharmacological effects in reproductive and developmental toxicity and developmental immunotoxicity studies of pharmaceuticals.

Tenuigenin attenuates α-synuclein-induced cytotoxicity by down-regulating polo-like kinase 3.

BACKGROUND AND AIMS: Tenuigenin (Ten) is a Chinese herbal extract with antioxidative and antiinflammatory effects on toxin-induced cell models of Parkinson's disease (PD); however, its effects on α-synuclein toxicity-based PD models remain unknown. α-synuclein hyperphosphorylation is a key event in PD pathogenesis and potential target of therapeutic interventions. We tested whether Ten alleviates α-synuclein-induced cytotoxicity via reducing kinases that phosphorylate α-synuclein. METHODS: SH-SY5Y cells transiently transfected with wild-type or A53T mutant α-synuclein were used to evaluate the effect of Ten on the levels of α-synuclein phosphorylation-related kinases. Cells treated with 10 µM Ten for 24 h were measured for viability (proliferation and apoptosis assays) and cellular proteins harvested and fractioned. The levels of total and phosphorylated α-synuclein and five associated kinases (polo-like kinase [PLK] 1-3, casein kinase [CK] 1-2) were evaluated by Western blotting. RESULTS: Overexpression of either wild-type or A53T mutant α-synuclein decreased cell viability and increased α-synuclein phosphorylation. Ten treatment-protected cells from this α-synuclein-induced toxicity and dramatically reduced α-synuclein phosphorylation and PLK3 (but not other kinase) levels. CONCLUSION: In α-synuclein cell model of PD, Ten is effective in attenuating α-synuclein-induced toxicity and α-synuclein phosphorylation probably via targeting PLK3, suggesting it could be an efficient therapeutic drug to treat α-synuclein-related neurodegeneration.

Ablation of leiomyomas using a combination of HIFU and iodized oil in vitro.

This study investigates the enhancement effects of iodized oil and the features of hyperechoic focus changes in a target region of high-intensity focused ultrasound (HIFU) ablated uterine fibroids. Leiomyomas in the experimental group of 20 randomly assigned patients were ablated by HIFU under certain parameters 30 min after 1 mL of iodized oil was injected into the center of the myomas. The value of the gray scale and its area were observed by B-mode ultrasound in the target region and were carefully recorded at 0, 2, 4, and 5 min, respectively, after HIFU ablation. The samples were sectioned successively in a thickness of 1∼2 mm and stained by 2,3,5-triphenyltetrazolium chloride solution within 1 h after HIFU ablation. The TTC non-staining volumes were measured afterwards. All procedures in the control group of the other 20 randomly assigned patients were the same except that iodized oil was replaced by physiologic saline. The hyperechoic areas in the target region were observed in all fibroids of both groups. Compared with the control group, the gray scale values in the target region of the experimental group were higher 4 min after HIFU ablation. The enhanced gray scale area in the target region and the 2,3,5-triphenyltetrazolium chloride non-staining volumes in the experimental group were bigger. Based on our experience, HIFU sonication of leiomyomas injected with iodized oil produces hyperechoic foci that are greater than areas injected with saline. More studies are required to understand the clinical implications of these observations.

Heterozygote genotypes at rs2222823 and rs2811712 SNP loci are associated with cerebral small vessel disease in Han Chinese population.

AIMS: With developments of etiology of cerebral small vessel disease (CSVD) and genome-wide association study (GWAS) of stroke, the genetic studies of CSVD are focused on genes related to blood-brain barrier (BBB) and aging. The project aims to investigate the association between CSVD and susceptibility loci and candidate genes. METHODS: All study subjects admitted Beijing Tiantan Hospital from June 2009 to September 2010 including 197 cerebral small vessel disease patients(S), 198 large artery atherosclerosis control individuals (vascular stenotic rate ≥50% diameter reduction) (L), 200 hypertensive intracerebral hemorrhage control individuals (H) and 197 stroke-free control individuals (C). 15 SNPs in 4 genes (MYLK, AQP4, NINJ2, and INK4/ARF) were genotyped using Multiplex Snapshot assay. Each SNP was first examined between the groups S and C in different genetic models (codominant, dominant, recessive, overdominant, and log-additive). Permutation correction was used to adjust for multiple testing. The significant SNP loci were further analyzed in comparing S with L and H, respectively. Subgroup analysis was also performed for each risk-factor category. RESULTS: Among the 15 SNPs, rs2222823 and rs2811712 were found to be significantly associated with CSVD after multiple-testing adjustment. The heterozygote (A/T) of rs2222823 of MYLK has an odds ratio of 0.52 (95% CI =[0.35, 0.79], P= 0.002, adjusted P= 0.031) when compared with homozygotes. The heterozygote (C/T) of rs2811712 of INK4/ARF has an odds ratio of 1.75 (95% CI =[1.13-2.71], P= 0.004, adjusted P= 0.050). The SNP rs2222823 was significant (P= 0.035) in comparing S with H. In comparing S versus L, it is significant for the subgroups of patients without diabetes (P= 0.012) and drinking (P= 0.018). rs2811712 was significant in comparing S with L for the subgroups of patients with hyperlipidemia (P= 0.029) and drinking (P= 0.04). CONCLUSION: The heterozygotes (T/A) at the rs2222823 SNP locus of MYLK gene decreases the risk of having cerebral small vessel disease, while the heterozygotes (C/T) at the rs2811712 SNP locus of INK4/ARF gene increases the risk, suggesting that the MYLK and INK4/ARF are the associated genes of cerebral small vessel disease in Han Chinese population.

Intracranial malignant meningioma with cerebrospinal fluid dissemination: a case report.

Malignant meningiomas are uncommon intracranial tumors. The metastasis of malignant meningiomas to distant extracranial sites are well known. However, dissemination of the tumours in the cerebrospinal fluid (CSF) is rare and few cases have been reported. We present a case of histologically proven malignant meningioma with CSF dissemination at the remote intracranial area and into the spinal canal detected with magnetic resonance imaging.

Multilevel binomial logistic prediction model for malignant pulmonary nodules based on texture features of CT image.

PURPOSE: To introduce multilevel binomial logistic prediction model-based computer-aided diagnostic (CAD) method of small solitary pulmonary nodules (SPNs) diagnosis by combining patient and image characteristics by textural features of CT image. MATERIALS AND METHODS: Describe fourteen gray level co-occurrence matrix textural features obtained from 2171 benign and malignant small solitary pulmonary nodules, which belongs to 185 patients. Multilevel binomial logistic model is applied to gain these initial insights. RESULTS: Five texture features, including Inertia, Entropy, Correlation, Difference-mean, Sum-Entropy, and age of patients own aggregating character on patient-level, which are statistically different (P<0.05) between benign and malignant small solitary pulmonary nodules. CONCLUSION: Some gray level co-occurrence matrix textural features are efficiently descriptive features of CT image of small solitary pulmonary nodules, which can profit diagnosis of earlier period lung cancer if combined patient-level characteristics to some extent.