The role played by IGF-II in signal transduction through the IGF-II/mannose-6-phosphate receptor (IGF2R) in heart tissue has been poorly understood. In our previous studies, we detected an increased expression of IGF-II and IGF2R in cardiomyocytes that had undergone pathological hypertrophy. We hypothesized that after binding with IGF-II, IGF2R may trigger intracellular signaling cascades involved in the progression of pathologically cardiac hypertrophy. In this study, we used immunohistochemical analysis of the human cardiovascular tissue array to detect expression of IGF2R. In our study of H9c2 cardiomyoblast cell cultures, we used the rhodamine phalloidin staining to measure the cell hypertrophy and western blot to measure the expression of cardiac hypertrophy markers atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) in cells treated with IGF-II. We found that a significant association between IGF2R overexpression and myocardial infarction. The treatment of H9c2 cardiomyoblast cells with IGF-II not only induced cell hypertrophy but also increased the protein level of ANP and BNP. Using Leu27IGF-II, an analog of IGF-II which interacts selectively with the IGF2R, to specifically activate IGF2R signaling cascades, we found that binding of Leu27IGF-II to IGF2R led to an increase in the phosphorylation of protein Kinase C (PKC)-a and calcium/calmodulindependent protein kinase II (CaMKII) in a Gaq-dependent manner. By the inhibition of PKC-a/CaMKII activity, we found that IGF-II and Leu27IGF-II-induced cell hypertrophy and upregulation of ANP and BNP were significantly suppressed. Taken together, this study provides a new insight into the effects of the IGF2R and its downstream signaling in cardiac hypertrophy. The suppression of IGF2R signaling pathways may be a good strategy to prevent the progression of pathological hypertrophy.

Purpose: To examine the effectiveness of a nurse-led self-management program on outcomes of patients with chronic obstructive pulmonary disease (COPD). Design: A randomized controlled, single-blind trial, carried out from October 2017 to December 2018, included 154 participants admitted with COPD to the Affiliated Hospital of Zunyi Medical University in Guizhou, (randomized into intervention (n = 77) and control groups (n = 77)). Materials and Methods: Participants in the intervention group underwent a nurseled self-management program in addition to routine care, and participants of the control group received only routine care. The main outcome measures were COPDrelated readmission and emergency department visits, the 6-minute walk distance (6MWD) test for measurement of exercise capacity, the St George Respiratory Questionnaire (SGRQ) for measurement of health-related quality of life, and the COPD Transitional Care Patient Satisfaction Questionnaire (CTCPSQ) for measurement of satisfaction. Data collection was conducted at baseline (T1) and after 3 (T2), 6 (T3) and 12 mo (T4). FindingsCompared to the control group, participants in the intervention group showed significantly fewer COPD-related hospital admissions (P = 0.03) and emergency department visits (P = 0.001) and higher total CTCPSQ scores (P = 0.001) at 12 mo.Meanwhile, analysis of variance showed a significantly greater improvement in exercise capacity and health status over time in the nurse-led program group than in the control group, P < 0.001. Conclusions: This study demonstrated that the nurse-led self-management program was effective in decreasing hospital readmissions and emergency department visits and improving exercise capacity, health-related quality of life and satisfaction for patients with COPD.

The IGF-II/mannose 6-phosphate receptor (IGF2R) function in extracellular matrix (ECM) remodeling is known to occur as a result of transforming growth factor-b (TGF-b) activation and plasmin in the proteolytic cleavage level caused by the interaction between latent TGF-b and urokinase plasminogen activator receptor (uPAR) respectively. In one of our previous studies, we found IGF-II and IGF2R dose-dependently correlated with the progression of pathological hypertrophy remodeling following complete abdominal aorta ligation. However, how this IGF2R signaling pathway responds specifically to IGF-II and regulates the myocardial ECM remodeling process is unclear. We found that IGF2R was aberrantly expressed in myocardial infarction scars. The matrix metalloproteinase-9 (MMP-9) zymographic activity was elevated in H9c2 cardiomyoblast cells treated with IGF-II, but not IGF-I. Treatment with Leu27IGF-II, an IGF2R specifically binding IGF-II analog, resulted in significant time-dependent increases in the MMP-9, tissue-type plasminogen activator (tPA), and urokinase plasminogen activator (uPA); and a reduction in the tissue inhibitor of matrix metalloproteinases-2 (TIMP-2) protein expression. Furthermore, IGF2R expression inhibition by siRNA blocked the IGF-II-induced MMP-9 activity. We hypothesize that after IGF-II is bound with IGF2R, the resulting signal disrupts the balance in the MMP-9/TIMP-2 expression level and increases plasminogen activator (PAs) expression involved in the development of myocardial remodeling. If so, IGF2R signaling inhibition may have potential use in the development of therapies preventing heart fibrosis progression.

It is known, from the zymogram method of nuclease activity assay, that the crude extracts of Cunninghamella echinulata var. echinulata contained at least three distinct extracellular nucleases. Among them, the major form was 30 kDa in molecular mass and termed nuclease C1. In this report, nuclease C1 was purified to apparent homogeneity by chromatography on Cibacron blue-3GA, phenyl-Sepharose 4B and HiTrap Heparin. Nuclease C1 acquired enzymatic activity in the presence of Mn 2ϩ or Mg 2ϩ and was inhibited by EDTA. The activity was maximal at pH 7Ϫ8.5. The primary structure of nuclease C1 was completely determined using enzymatic digestion and gene cloning. The N-terminal 49 residues of nuclease C1 were first elucidated from a tryptic digest. Two degenerate upstream primers were subsequently designed to amplify the cDNA encoding nuclease C1. The resulting protein sequence of nuclease C1 was shown to be composed of 252 residues. It was intriguing to find that the protein sequence of nuclease C1 showed significant similarities with the sequences of the mitochondrial nucleases of Saccharomyces cerevisiae (44% identity) and Schizosaccharomyces pombe (42 % identity). Residue His87 of nuclease C1 was postulated to be located at the active site from sequence similarity with secreted nuclease from Serratia marcescens.Keywords : nuclease C1; mitochondrial nuclease ; Cunninghamella echinulata ; Saccharomyces cerevisiae; Schizosaccharomyces pombe.Nucleases act on both DNA and RNA to release products containing 5′-or 3′-phosphates [1]. Several fungal species are known to produce both extracellular and intracellular nucleases. Representatives of extracellular fungal nucleases are nuclease S1 of Aspergillus oryzae [2,3] and nuclease P1 of Penicillium citrinum [4,5]. The properties and the structures of these two nucleases are well characterized. Other fungi also secrete nucleases, e.g. Neurospora crassa and Aspergillus nidulans, which are referred to as DNase (deoxyribonuclease) A [6] and DNase 4 [7], respectively.Clinically, some Cunninghamella species cause severe syndromes and even led to death in humans. For example, several reports have indicated that Cunninghamella bertholletiae can infect patients with cancer and immunocompromise children [8,9]. Diseases including paranasal sinusitus [10] and mucormycosis [11] have been relatively correlated with Cunninghamella infection. The most important risk factors for C. bertholletiae infection include corticosteroid administration and pro-

The survivals of gastric cancer (GC) patients are associated with early diagnosis and effective treatments. Therefore, it is urgent for the discovery of early GC biomarkers and tumor-targeting therapeutics. The aim of this study was to uncover putative tissue biomarkers of GC using 2D DIGE and then apply one of these specific markers in GC treatment. We found three putative biomarkers of GC with significant differences in expression level compared to adjacent normal tissue, including glucose-regulated protein 78 (GRP78) and glutathione s-transferase pi (GSTpi) with increased expression level, and alpha-1 antitrypsin (A1AT) with reduced expression level. The overexpressed GRP78 was used as a targeted protein for guiding the drugs to tumor cells, leading to more effective treatment for GC xenografts. Our results demonstrated that the designated GRP78-binding peptide based on the sequence, WIFPWIQL, was selectively prone to recognize and bind to GC MKN45 cells in vitro, and also improve the delivery efficiency of polymeric micelles-encapsulated drugs into tumor cells and displayed better therapeutic outcome in experimental animals. This strategy of GRP78-mediated drug targeting system may bring chemotherapeutic drugs with more precise targeting to tumor cells, leading to minimize side effects on patients after chemotherapy.

Increased expression of cellular membrane bound glucose-regulated protein 78 (GRP78) is considered to be one of the biomarkers for gastric cancers. Therefore, peptides or molecules with specific recognition to GRP78 can act as a guiding probe to direct conjugated imaging agents to localized cancers. Based on this rationale, GRP78-guided polymeric micelles were designed and manufactured for nuclear imaging detection of tumors. Thiolated GRP78 binding peptide (GRP78BP) was first labeled with maleimide-terminated poly(ethylene glycol)-poly(ε-caprolactone) and then mixed with diethylenetriaminepentaacetic acid (DTPA)-linked poly(ethylene glycol)-poly(ε-caprolactone) to form DTPA/GRP78BP-conjugated micelles. The coupling efficiency of micelles with radioisotope indium-111 ( 111 In) was measured and analyzed by instant thin layer chromatography. The coupling efficiency of DTPA-conjugated micelles and DTPA/GRP78BP-conjugated micelles with 111 In was 85% and 93%, respectively.For characterization and trace imaging, the radioisotope 111In-targeting tumors were detected and imaged in a xenograft murine model using nano single photon emission computed tomography/ computed tomography. The results revealed that the radioactive intensity measured in the animals administered with GRP78BP-guided 111 In-labeled micelles was statistically higher than that in animals administered with 111 In-labeled micelles, demonstrating that GRP78BP more than doubled the accumulation of micelles to the tumor tissue (P , 0.05). The results indicate that the gastric cancer biomarker GRP78 is a probing target in the application of nuclear imaging for tumor diagnosis. This novel GRP78BP-guided micelle agent may be applied in clinical practice to complement the histological diagnosis.

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The aim of this study was to compare the efficacy and safety of laparoscopic primary closure of the common bile duct (CBD) combined with percutaneous transhepatic cholangiographic drainage (PTCD) and laparoscopic choledocholithotomy with T-tube placement for the treatment of CBD stones. Between January 1991 and July 2002, 50 patients with choledocholithiasis and a CBD diameter larger than or equal to 1 cm underwent laparoscopic CBD explorations. The study group consisted of 10 patients undergoing laparoscopic primary closure of the CBD combined with PTCD. The control group consisted of 40 patients undergoing laparoscopic choledocholithotomy with T-tube placement. Parameters were compared statistically. The study group showed higher female/male ratio (6/4 vs 8/32, P = 0.02), less stone numbers (1.90 ± 0.88 vs 3.40 ± 1.65, P = 0.0078), shorter operation time (138 ± 37 minutes vs 191 ± 75 minutes, P = 0.014), and shorter postoperative stays (7 ± 3 days vs 10 ± 3 days, P = 0.0013). It seems that laparoscopic primary closure of the CBD combined with PTCD can shorten the operation time and postoperative stays as compared with laparoscopic choledocholithotomy with T-tube placement for the treatment of CBD stones.