No abstract

Proprotein convertases (PCs) are serine proteases with an active role in the post-translational processing of numerous inactive proteins to active proteins including many substrates of paramount importance in cancer development and progression. Furin (PCSKC3), a well-studied member of this family, is overexpressed in numerous human and experimental malignancies. In the present communication we treated two furin-overexpressing non-small cell carcinoma (NSCLC) cell lines (Calu-6 and HOP-62) with the PC inhibitor CMK (Decanoyl-Arg-Val-Lys-Argchloromethylketone). This resulted in a diminished IGF-1R processing and a simultaneous decrease in cell proliferation of two NSCLC lines. Similarly, growth and proliferation of subcutaneous xenografts of both cell lines, were partially inhibited by an in vivo treatment with the same drug. These observations point to a potential role of PC inhibitors in cancer therapy.

946S ilent cerebral infarction (SCI) is a cerebral infarction that is evident on brain imaging but is not associated with a clinical symptom. In most cases, SCI is found as a lacunar infarction, that is, a small, deep cerebral infarct caused by occlusion of small penetrating cerebral arteries. Recent studies demonstrated that the presence of SCI predicts transient ischemia attack, clinically overt stroke, cardiovascular disease, and dementia. 1-3 See accompanying editorial on page 702A large body of evidence has highlighted a role for oxidative stress in atherosclerosis. Oxidative stress is induced by increased production of reactive oxygen species or decreased antioxidant capacity of endogenous antioxidant systems. Bilirubin is an effective antioxidant molecule that suppresses the oxidation of lipids and prevents the formation of plaque. 4 In several cross-sectional studies, bilirubin levels were found to be decreased in carotid intima-media thickness, cardiovascular disease, stroke, and peripheral arterial disease.5-8 A meta-analysis further confirmed that bilirubin levels were reduced in coronary artery disease. 9 To the best of our knowledge, the relationship between bilirubin levels and SCI has not yet been reported. We, therefore, conducted this study to assess the bilirubin levels in general population. Materials and MethodsMaterials and Methods are available in the online-only Supplement. ResultsClinical and laboratory data of participants with and without SCI are shown in Table 1. Of the 2865 participants enrolled, 1831 (63.91%) were men and 1034 (36.09%) were women. Median (interquartile range) of total bilirubin (TB) concentration was 10.5 (7.8-13.8; range, 2.1-33.4) μmol/L in the whole cohort of individuals. Three hundred forty-three participants (11.97%; 274 men and 69 women) presented SCI. The patients with SCI were older and had higher body mass index (BMI), systolic blood pressure, diastolic blood pressure (DBP), total cholesterol (TC), triglyceride, low-density lipoprotein cholesterol (LDL-C), fasting plasma glucose (FPG), and brachial-ankle pulse wave velocity (baPWV) levels and reduced TB, indirect bilirubin, direct bilirubin, estimated glomerular filtration rate (eGFR), and high-density lipoprotein cholesterol levels compared with the subjects without SCI. However, the levels of aspartate aminotransferase, alanine aminotransferase, γ-glutamyl transpeptidase, and current use of statins and calcium channel blocker drugs in the 2 groups had no difference. Male sex, smoking, alcohol consumption, type 2 diabetes mellitus (DM), hypertension, and current use of angiotensin-converting enzyme inhibitor/angiotensin II receptor antagonist, aspirin, and hypoglycemic drugs had a higher prevalence in SCI group.The demographic and biochemical characteristics of the study population according to TB quartiles are shown in Table 2 FPG, triglyceride, LDL-C, FPG, aspartate aminotransferase, alanine aminotransferase, γ-glutamyl transpeptidase, and baPWV decreased gradually as TB increased. Also, the percentage ...

PACE4 is a proprotein convertase (PC) responsible for cleaving and activating proteins that contribute to enhance tumor progression. PACE4 overexpression significantly increased the susceptibility to carcinogenesis, leading to enhanced tumor cell proliferation and premature degradation of the basement membrane. In the present study, we sought to evaluate a novel approach to retard skin tumor progression based on the inhibition of PACE4. We used decanoyl-RVKR-chloromethylketone (CMK), a small-molecule PC inhibitor, for in vitro and in vivo experiments. We found that CMK-dependent blockage of PACE4 activity in skin squamous cell carcinoma cell lines resulted in impaired insulin-like growth factor 1 receptor maturation, diminished its intrinsic tyrosine kinase activity, and decreased tumor cell proliferation. Two-stage skin chemical carcinogenesis experiments, together with topical applications of CMK, demonstrated that this PC inhibitor markedly reduced tumor incidence, tumor multiplicity, and metastasis, pointing to a significant delay in tumor progression in wild-type and PACE4 transgenic mice. These results identify PACE4, together with other PCs, as suitable targets to slow down or block tumor progression, suggesting that PC inhibition is a potential approach for therapy for solid tumors.

VILIP-1, a member of the neuronal Ca++ sensor protein family, acts as a tumor suppressor gene in an experimental animal model by inhibiting cell proliferation, adhesion and invasiveness of squamous cell carcinoma cells. Western Blot analysis of human tumor cells showed that VILIP-1 expression was undetectable in several types of human tumor cells, including 11 out of 12 non-small cell lung carcinoma (NSCLC) cell lines. The down-regulation of VILIP-1 was due to loss of VILIP-1 mRNA transcripts. Rearrangements, large gene deletions or mutations were not found. Hypermethylation of the VILIP-1 promoter played an important role in gene silencing. In most VILIP-1-silent cells the VILIP-1 promoter was methylated. In vitro methylation of the VILIP-1 promoter reduced its activity in a promoter-reporter assay. Transcriptional activity of endogenous VILIP-1 promoter was recovered by treatment with 5′-aza-2′-deoxycytidine (5′-Aza-dC). Trichostatin A (TSA), a histone deacetylase inhibitor, potently induced VILIP-1 expression, indicating that histone deacetylation is an additional mechanism of VILIP-1 silencing. TSA increased histone H3 and H4 acetylation in the region of the VILIP-1 promoter. Furthermore, statistical analysis of expression and promoter methylation (n = 150 primary NSCLC samples) showed a significant relationship between promoter methylation and protein expression downregulation as well as between survival and decreased or absent VILIP-1 expression in lung cancer tissues (p<0.0001). VILIP-1 expression is silenced by promoter hypermethylation and histone deacetylation in aggressive NSCLC cell lines and primary tumors and its clinical evaluation could have a role as a predictor of short-term survival in lung cancer patients.

Background: Systemic inflammation is related to disease progression in asthma. Activated platelets play a critical role in atherogenesis, inflammation, and atherothrombosis. The mean platelet volume (MPV) is an early marker of platelet activation. Objectives: The aim of this study is to clarify the relevance of MPV levels in patients with stable and exacerbated asthma. Methods: We investigated the peripheral blood cell count parameters, C-reactive protein (CRP), lung function parameters, and arterial blood gas in patients with asthma and control subjects. Eighty-five stable asthma patients and 85 asthmatics with exacerbations were investigated. Eighty-five controls matched for age, gender, body mass index (BMI), and smoking status were recruited. Results: Patients with exacerbated asthma had lower MPV and higher CRP levels and white blood cell (WBC) counts compared to patients with stable asthma and control subjects. Furthermore, the MPV was reduced in patients with stable asthma compared to control subjects. Negative correlations between MPV and CRP were present in stable and exacerbated asthma. Although there was no relationship between MPV and WBC count in stable asthma, there was an inverse relationship between MPV and WBC count in exacerbated asthma. Conclusions: These findings show that patients with stable asthma had a lower MPV compared to controls and the MPV levels in asthmatic patients with exacerbations were lower compared to those in patients with stable asthma. Further investigations regarding the role of MPV in asthma may be beneficial in the search for therapeutic targets.

Osteoporosis (OP) has been associated with cardiovascular disease. More specifically, osteoporosis was found to be an independent predictor of cardiovascular mortality. Recent studies revealed that platelets play a critical role in bone remodeling. Mean platelet volume (MPV) is an early marker of platelet activation, which is involved in the pathophysiology of coronary heart disease. However, little research has been conducted to investigate the relationship between MPV and OP. In this cross-sectional study, we investigated the relationship between platelet count, MPV, and bone mineral density (BMD) in 410 subjects in the geriatric department of the Second Affiliated Hospital, Harbin, China. Different biochemical parameters, platelet count, and MPV were determined, and bone mineral density (BMD) (g/cm(2)) was measured in the osteoporosis, osteopenia, and normal BMD groups. Mean age, systolic blood pressure (SBP), total cholesterol (TC), triglyceride (TG), low density lipoprotein cholesterol (LDL-C), fasting plasma glucose (FPG), and MPV increased gradually, and body mass index (BMI), decreased as BMD decreased. A negative correlation was present between MPV and the lumbar spine (L2-L4) and femoral neck BMD after adjusting other risk factors. Univariate analysis and multivariate analysis showed that MPV was significantly associated with lumbar spine L2-L4 BMD and femoral neck BMD (β = -0.285, P < 0.001 for lumbar spine L2-L4 BMD; β = -0.207, P < 0.001 for femoral neck BMD in multivariate model). The findings show that MPV is negatively correlated with BMD. Further studies on the involvement of MPV in osteoporosis may contribute to the evaluation of thrombotic risk in elderly patients with osteoporosis.

Unmanned aerial vehicle (UAV) remote sensing and deep learning provide a practical approach to object detection. However, most of the current approaches for processing UAV remote-sensing data cannot carry out object detection in real time for emergencies, such as firefighting. This study proposes a new approach for integrating UAV remote sensing and deep learning for the real-time detection of ground objects. Excavators, which usually threaten pipeline safety, are selected as the target object. A widely used deep-learning algorithm, namely You Only Look Once V3, is first used to train the excavator detection model on a workstation and then deployed on an embedded board that is carried by a UAV. The recall rate of the trained excavator detection model is 99.4%, demonstrating that the trained model has a very high accuracy. Then, the UAV for an excavator detection system (UAV-ED) is further constructed for operational application. UAV-ED is composed of a UAV Control Module, a UAV Module, and a Warning Module. A UAV experiment with different scenarios was conducted to evaluate the performance of the UAV-ED. The whole process from the UAV observation of an excavator to the Warning Module (350 km away from the testing area) receiving the detection results only lasted about 1.15 s. Thus, the UAV-ED system has good performance and would benefit the management of pipeline safety.