Mel-18 has been implicated in several processes in tumor progression, in which the Akt pathway is involved as an important key molecular event. However, the function of Mel-18 in human cancers has ...not been fully established yet. Here, we examined the effect of Mel-18 on tumor angiogenesis in human breast cancer, and found that Mel-18 was a novel regulator of HIF-1α. Mel-18 negatively regulated the HIF-1α expression and its target gene VEGF transcription during both normoxia and hypoxia. We demonstrated that Mel-18 regulated the HIF-1α expression and activity via the PI3K/Akt pathway. Loss of Mel-18 downregulated Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) expression, consequently activating the PI3K/Akt/MDM2 pathway, and leading to an increase of HIF-1α protein level. Mel-18 modulated the HIF-1α transcriptional activity via regulating the cytoplasmic retention of FOXO3a, a downstream effector of Akt, and recruitment of HIF-1α/CBP complex to the VEGF promoter. Furthermore, our data shows that Mel-18 blocked tumor angiogenesis both in vitro and in vivo. Mel-18 overexpression inhibited in vitro tube formation in human umbilical endothelial cells (HUVECs). Xenografts in NOD/SCID mice derived from stably Mel-18 knocked down MCF7 human breast cancer cells showed increased tumor volume, microvessel density, and phospho-Akt and HIF-1α expression levels. In conclusion, our findings provide that Mel-18 is a novel regulator of tumor angiogenesis through regulating HIF-1α and its target VEGF expressions mediated by the PTEN/PI3K/Akt pathway, suggesting a new tumor-suppressive role of Mel-18 in human breast cancer.
Abstract Purpose The aim of the present study was to examine the clinical course of nonvascular hepatic ischemia following adult living donor liver transplantation (LDLT). Methods This retrospective ...study reviewed the medical records of 1782 patients who underwent LDLT from January 2003 to September 2010. Nine subjects (0.5%) suffered idiopathic hepatic parenchymal infarcts (IHPI) classified according to the morphology and extent of the infarcted area as peripheral or central. Results Increased levels of liver enzymes were observed in all IHPI patients. Liver cell damage closely correlated with the extent of the infarcted area. Most patients with peripheral-type IHPI showed favoarable spontaneous recovery, occasionally requiring liver support with plasmapheresis or a prolonged period. By contrast, 2 patients with central-type IHPI died due to progressive expansion of the infarcted area with subsequent graft failure. Conclusions In the present study the incidence of IHPI following LDLT was 0.5%. The severity of the infarct depended upon its location and size; central-type IHPI showed a worse prognosis. Thus, special attention should be paid to patients showing a central-type infarction.
Primary cilium is required for mechano-biological signal transduction in chondrocytes, and its interaction with extracellular matrix is critical for cartilage homeostasis. However, the role of ...cilia-associated proteins that affect the function of cilia remains to be elucidated. Here, we show that Dicam has a novel function as a modulator of primary cilia-mediated Indian hedgehog (Ihh) signaling in chondrocytes.
Cartilage-specific Dicam transgenic mouse was constructed and the phenotype of growth plates at embryonic day 15.5 and 18.5 was analyzed. Primary chondrocytes and tibiae isolated from embryonic day 15.5 mice were used in vitro study.
Dicam was mainly expressed in resting and proliferating chondrocytes of the growth plate and was increased by PTHrP and BMP2 in primary chondrocytes. Cartilage-specific Dicam gain-of-function demonstrated increased length of growth plate in long bones. Dicam enhanced both proliferation and maturation of growth plate chondrocytes in vivo and in vitro, and it was accompanied by enhanced Ihh and PTHrP signaling. Dicam was localized to primary cilia of chondrocytes, and increased the number of primary cilia and their assembly molecule, IFT88/Polaris as well. Dicam successfully rescued the knock-down phenotype of IFT88/Polaris and it was accompanied by increased number of cilia in tibia organ culture.
These findings suggest that Dicam positively regulates primary cilia and Ihh signaling resulting in elongation of long bone.
Background
There is little information about clinical outcomes after intraoperative cardiac arrest (IOCA). We determined the incidence and characteristics of 3‐month mortality after IOCA.
Methods
The ...electronic medical records of 238,648 adult surgical patients from January 2005 to December 2014 were reviewed retrospectively. Characteristics of IOCA were documented using the Utstein reporting template.
Results
IOCA occurred in 50 patients (21/100,000 surgeries). Nineteen patients died in the operating room, and further 12 patients died within 3 months post‐arrest (total mortality: 62%). Three survivors at 3 months post‐arrest had unfavourable neurological outcome. Finally, 34 patients showed unfavourable clinical outcomes at 3 months post‐arrest. The incidences of non‐cardiac surgery, emergency, pre‐operative intubation state, non‐shockable initial cardiac rhythm, hypovolaemic shock, pre‐operative complications‐induced cardiac arrest, non‐anaesthetic cause of cardiac arrest, intra‐ and post‐arrest transfusion, and continuous infusion of inotrope or vasopressor in intensive care unit (ICU) were significantly higher in non‐survivors at 3 months post‐arrest. Total epinephrine dose administrated during arrest was higher, and the duration of cardiac compressions was longer in non‐survivors at 3 months post‐arrest.
Conclusions
In this study, the incidence of IOCA was 21/100,000 surgeries and the 3‐month mortality rate after IOCA was 62%. Several factors including surgical emergency, non‐shockable initial cardiac rhythm, pre‐operative complications, surgical complications, long duration of cardiac compressions, high total epinephrine dose, transfusion, and continuous infusion of inotropes or vasopressors in ICU seemed to be risk factors for 3‐month mortality after IOCA. These risk factors should be considered in the light of relatively small sample size of this study.
Aim
To investigate the molecular mechanisms of nitric oxide (NO)‐induced cytotoxic effect in human gingival fibroblast (HGF) cells.
Methodology
After sodium nitroprusside (SNP), as NO donor, was ...treated to HGF, viability was measured by MTT assay and apoptosis was determined by TUNEL and DNA fragmentation assay. Mitochondrial membrane potential was detected using confocal microscopy, and caspase activity assay was measured by spectrophotometer. Mitogen‐activated protein kinases (MAPK) activation, Bax/Bcl‐2 ratio and cytochrome c release were analysed by Western blot analyses. Cells were exposed to MAPK inhibitors (U0126, SB203580 and SP600125) before SNP treatment to investigate the effects of MAPK kinases on the NO‐induced apoptosis in HGF. Statistical analysis was performed using one‐way analysis of variance with the Student–Newman–Keuls post hoc test for multiple group comparison.
Results
Apoptosis was significantly increased (P = 0.011 and 0.0004, respectively) in the presence of SNP (1 and 3 mmol L−1) after 12 h in HGF. However, 1H‐1,2,4 oxadiatolo 4, 3‐a cluinoxaline‐1‐one (ODQ), a soluble guanylate cyclase inhibitor, did not block the decrement of cell viability by NO. SNP treatment induced the loss of mitochondrial membrane potential, release of cytochrome c, increased Bax/Bcl‐2 ratio and activation of caspases in HGF. Also, SNP treatment increased phosphorylation of MAPKinases and c‐Jun N‐terminal kinase (JNK) inhibitor (5 and 10 μmol L−1) rescued cell viability decreased by SNP in HGF (P = 0.024 and 0.0149, respectively).
Conclusion
Nitric oxide induced apoptosis in human gingival fibroblast through the mitochondria‐mediated pathway by regulation of Bcl‐2 family and JNK activation.
This paper is concerned with the stability analysis of discrete‐time systems with a time‐varying delay. The conservatism and computation burden are two important factors to evaluate a stability ...condition. By taking the relationship of two reciprocally convex parts into consideration, a new combined matrix‐separation‐based inequality is proposed that involves only a few free matrices. Moreover, an improved matrix‐injection‐based transformation lemma with the parameter varying within a closed interval is proposed by introducing only one free matrix. By constructing an appropriate Lyapunov–Krasovskii functional and applying the improved methods, a relaxed stability condition is consequently obtained with a small number of decision variables. Two numerical examples are given to show the merits of the proposed methods.
This paper studiesthe stability problem for discrete‐time systems with a time‐varying delay by developing a new combined summation inequality and improving a transformation lemma. Numerical examples show that, compared to several recently reported results, the obtained stability condition not only produces larger maximal allowable upper bounds but also involves a relatively smaller number of decision variables.
Autoimmune pancreatitis (AIP) is distinct from calcifying and obstructive forms of chronic pancreatitis. Clinically and histologically it has two distinct subsets: (i) lymphoplasmacytic sclerosing ...pancreatitis or type 1 AIP which appears to be a systemic disease characterised by abundant infiltration of affected organs with immunoglobulin G4 (IgG4)-positive plasma cells and (2) duct-centric or type 2 AIP characterised by granulocyte epithelial lesions in the pancreas without systemic involvement. In AIP a marked lymphoplasmacytic infiltrate that responds dramatically to steroid therapy suggests an autoimmune aetiology. However, the target autoantigen(s) and the effector cells in AIP remain speculative. Despite the consistent elevation in serum IgG4 levels and tissue infiltration with IgG4-positive plasma cells in type 1 AIP, the role of IgG4 in its pathogenesis remains unknown. Recent development of animal models of AIP will help improve our understanding of the pathogenesis of these newly described forms of chronic pancreatitis.
Excessive glucose causes various diseases and decreases lifespan by altering metabolic processes, but underlying mechanisms remain incompletely understood. Here, we show that Lipin 1/LPIN‐1, a ...phosphatidic acid phosphatase and a putative transcriptional coregulator, prevents life‐shortening effects of dietary glucose on Caenorhabditis elegans. We found that depletion of lpin‐1 decreased overall lipid levels, despite increasing the expression of genes that promote fat synthesis and desaturation, and downregulation of lipolysis. We then showed that knockdown of lpin‐1 altered the composition of various fatty acids in the opposite direction of dietary glucose. In particular, the levels of two ω‐6 polyunsaturated fatty acids (PUFAs), linoleic acid and arachidonic acid, were increased by knockdown of lpin‐1 but decreased by glucose feeding. Importantly, these ω‐6 PUFAs attenuated the short lifespan of glucose‐fed lpin‐1‐inhibited animals. Thus, the production of ω‐6 PUFAs is crucial for protecting animals from living very short under glucose‐rich conditions.
LPIN‐1, phosphatidic acid phosphatase and potential transcriptional regulator, ameliorates lifespan‐shortening effects of dietary glucose by maintaining lipidostasis. Genetic inhibition of lpin‐1 causes lipidostasis imbalance, including substantial reduction in the levels of ω‐6 polyunsaturated fatty acids (PUFAs), linoleic acid and arachidonic acid, in glucose‐rich conditions. This leads to substantially decreased lifespan due to increased glucose toxicity.
Elderly subjects have been historically underrepresented in clinical trials involving antiviral hepatitis C therapies. The aim of this analysis was to retrospectively evaluate the safety and efficacy ...of ledipasvir/sofosbuvir (LDV/SOF) by age groups of <65 years versus ≥65 years among subjects enrolled in phase 3 trials. Four open‐label phase 3 clinical trials evaluated the safety and efficacy of LDV/SOF with or without ribavirin (RBV) for the treatment of genotype 1 chronic hepatitis C virus. Sustained virological response at 12 weeks, treatment‐emergent adverse events (AEs), and graded laboratory abnormalities were analyzed according to age group. Of the 2293 subjects enrolled in four phase 3 trials, 264 (12%) were ≥65 years of age, of whom 24 were aged ≥75 years. Sustained virological response at 12 weeks was achieved by 97% (1965/2029) of subjects aged <65 years and 98% (258/264) of subjects aged ≥65 years. The most common AEs in both LDV/SOF groups that occurred in ≥10% of subjects were headache and fatigue. The rate of study discontinuation due to AEs was similar in the two age cohorts. The use of RBV in 1042 (45%) subjects increased the number of AEs, treatment‐related AEs, and AEs leading to study drug modification/interruption, particularly among elderly subjects. Conclusions: LDV/SOF with or without RBV was highly effective for treatment of genotype 1 chronic hepatitis C virusin subjects aged 65 and older. Addition of RBV did not increase sustained virological response at 12 weeks rates but led to higher rates of AEs, especially in elderly subjects. (Hepatology 2016;63:1112–1119)
Summary
We evaluated the effect of pre‐operative serratus anterior plane block on postoperative pain and opioid consumption after thoracoscopic surgery. We randomly allocated 89 participants to block ...with 30 ml ropivacaine 0.375% (n = 44), or no block without placebo or sham procedure (n = 45). We analysed results from 42 participants in each group. Serratus anterior plane block reduced mean (SD) remifentanil dose during surgery, 0.12 (0.06) mg.h−1 vs. 0.16 (0.06) mg.h−1, p = 0.016, and reduced mean (SD) fentanyl consumption in the first 24 postoperative hours, 3.8 (1.9) μg.kg−1 vs. 5.7 (1.6) μg.kg−1, p = 0.000004. Block also reduced the worst median (IQR range) pain scores reported in the first 24 postoperative hours: 6 (5–7 3–10) vs. 7 (6–7 3–10), p = 0.027. Block decreased dissatisfaction with pain management, categorised as ‘highly unsatisfactory’, ‘unsatisfactory’, ‘neutral’, ‘satisfactory’ or ‘highly satisfactory’: 1/2/21/18/0 vs. 1/14/15/11/1, p = 0.0038. There were no differences in the rates of nausea, vomiting, dizziness or length of hospital stay. Serratus anterior plane block may be used to reduce pain and opioid use after thoracoscopic lung surgery.
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