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1.  Insulin therapy and the risk of colorectal cancer in patients with type 2 diabetes: a meta-analysis of observational studies 
Aims
Several epidemiological studies have reported inconsistent associations between insulin therapy and the risk of colorectal cancer (CRC) in patients with type 2 diabetes mellitus. We performed this meta-analysis of observational studies to evaluate the effect of insulin therapy on the risk of CRC.
Methods
We carried out a systematic search of PubMed, Embase and the Cochrane Library Central database between January 1966 and August 2013. Fixed-effects and random-effects models were used to estimate the pooled relative risk (RR) and corresponding 95% confidence interval (CI).
Results
A total of 12 epidemiological studies were included in the present meta-analysis, involving a total of 7947 CRC cases and 491 384 participants. There was significant heterogeneity among the studies, but no publication bias. Insulin therapy significantly increased the risk of CRC [RR = 1.69, 95% CI (1.25, 2.27)]. When the various studies were stratified by study design, we found that insulin use was associated with a statistically significant 115% higher risk of CRC among case–control studies [RR = 2.15, 95% CI (1.41, 3.26)], but not among cohort studies [RR = 1.25, 95% CI (0.95, 1.65)]. Furthermore, a significant association was noted among studies conducted in USA [RR = 1.73, 95% CI (1.15, 2.60)] and Asia [RR = 2.55, 95% CI (2.14, 3.04)], but not in Europe [RR = 1.20, 95% CI (0.92, 1.57)].
Conclusions
The present meta-analysis suggests that insulin therapy may increase the risk of CRC. More prospective cohort studies with longer follow-up durations are warranted to confirm this association. Furthermore, future studies should report results stratified by gender and race and should adjust the results by more confounders.
doi:10.1111/bcp.12350
PMCID: PMC4137822  PMID: 25099257
colorectal cancer; epidemiology; insulin; meta-analysis
2.  Splenocytes Seed Bone Marrow of Myeloablated Mice: Implication for Atherosclerosis 
PLoS ONE  2015;10(6):e0125961.
Extramedullary hematopoiesis has been shown to contribute to the pathogenesis of a variety of diseases including cardiovascular diseases. In this process, the spleen is seeded with mobilized bone marrow cells that augment its hematopoietic ability. It is unclear whether these immigrant cells that are produced/reprogrammed in spleen are similar or different from those found in the bone marrow. To begin to understand this, we investigated the relative potency of adult splenocytes per se to repopulate bone marrow of lethally-irradiated mice and its functional consequences in atherosclerosis. The splenocytes were harvested from GFP donor mice and transplanted into myeloablated wild type recipient mice without the inclusion of any bone marrow helper cells. We found that adult splenocytes repopulated bone marrow of myeloablated mice and the transplanted cells differentiated into a full repertoire of myeloid cell lineages. The level of monocytes/macrophages in the bone marrow of recipient mice was dependent on the cell origin, i.e., the donor splenocytes gave rise to significantly more monocytes/macrophages than the donor bone marrow cells. This occurred despite a significantly lower number of hematopoietic stem cells being present in the donor splenocytes when compared with donor bone marrow cells. Atherosclerosis studies revealed that donor splenocytes displayed a similar level of atherogenic and atheroprotective activities to those of donor bone marrow cells. Cell culture studies showed that the phenotype of macrophages derived from spleen is different from those of bone marrow. Together, these results demonstrate that splenocytes can seed bone marrow of myeloablated mice and modulate atherosclerosis. In addition, our study shows the potential of splenocytes for therapeutic interventions in inflammatory disease.
doi:10.1371/journal.pone.0125961
PMCID: PMC4454495  PMID: 26038819
3.  CKIP-1 regulates macrophage proliferation by inhibiting TRAF6-mediated Akt activation 
Cell Research  2014;24(6):742-761.
Macrophages play pivotal roles in development, homeostasis, tissue repair and immunity. Macrophage proliferation is promoted by macrophage colony-stimulating factor (M-CSF)-induced Akt signaling; yet, how this process is terminated remains unclear. Here, we identify casein kinase 2-interacting protein-1 (CKIP-1) as a novel inhibitor of macrophage proliferation. In resting macrophages, CKIP-1 was phosphorylated at Serine 342 by constitutively active GSK3β, the downstream target of Akt. This phosphorylation triggers the polyubiquitination and proteasomal degradation of CKIP-1. Upon M-CSF stimulation, Akt is activated by CSF-1R-PI3K and then inactivates GSK3β, leading to the stabilization of CKIP-1 and β-catenin proteins. β-catenin promotes the expression of proliferation genes including cyclin D and c-Myc. CKIP-1 interacts with TRAF6, a ubiquitin ligase required for K63-linked ubiquitination and plasma membrane recruitment of Akt, and terminates TRAF6-mediated Akt activation. By this means, CKIP-1 inhibits macrophage proliferation specifically at the late stage after M-CSF stimulation. Furthermore, CKIP-1 deficiency results in increased proliferation and decreased apoptosis of macrophages in vitro and CKIP-1−/− mice spontaneously develop a macrophage-dominated splenomegaly and myeloproliferation. Together, these data demonstrate that CKIP-1 plays a critical role in the regulation of macrophage homeostasis by inhibiting TRAF6-mediated Akt activation.
doi:10.1038/cr.2014.53
PMCID: PMC4042176  PMID: 24777252
macrophage proliferation; Akt signaling; TRAF6; GSK3β; CKIP-1
4.  Extent, Nature, and Risk Factors of Workplace Violence in Public Tertiary Hospitals in China: A Cross-Sectional Survey 
Using a cross-sectional survey design from 11 public tertiary hospitals (a specialist hospital, four Chinese medicine hospitals, and six general hospitals) in the urban areas of Heilongjiang, we determined the nature of workplace violence that medical staff have encountered in Chinese hospitals and identified factors associated with those experiences of violence. A total of 1129 health workers participated. The specialist hospital had the highest prevalence of physical violence (35.4%), while the general hospitals had the highest prevalence of non-physical violence (76%). Inexperienced medical staff (p < 0.001) were more likely to suffer non-physical violence than physical violence in Chinese medicine hospitals compared to experienced staff. Medical units (p = 0.001) had a high risk of non-physical violence, while surgical units (p = 0.005) had a high risk of physical violence. In general hospitals, staff with higher levels of anxiety about workplace violence were more vulnerable to both physical violence (1.67, 95% CI 1.36–2.10) and non-physical violence (1.309, 95% CI 1.136–1.508) compared to those with lower levels of anxiety, while rotating shift workers had a higher odds of physical violence (2.2, 95% CI 1.21–4.17) and non-physical violence (1.65, 95% CI 1.13–2.41) compared to fixed day shift workers. Thus, prevention should focus not only on high-risk sections of hospitals, but also on the nature of the hospital itself.
doi:10.3390/ijerph120606801
PMCID: PMC4483731  PMID: 26086703
Chinese medicine hospitals; general hospitals; specialist hospitals; workplace violence; risk factor
5.  The incidence and risk factors of peripherally inserted central catheter-related infection among cancer patients 
Background
As the use of peripherally inserted central catheters (PICCs) increased in chemotherapy, the identification of complications and risk factors became essential to prevent patient harm. But little is known about PICC-related infection and risk factors among patients with cancer. Our study was to identify the prevalence, patterns, and risk factors of catheter-related infections associated with PICCs.
Methods
A 3-year prospective cohort study was conducted in a university-affiliated hospital. All patients with cancer who met inclusion criteria were enrolled. The patients were followed up until catheter removal. Tip cultures were routinely performed at the time of catheter removal. The general information was recorded at the time of PICC insertion, weekly care, and removal. Univariable and multivariable logistic regression analyses were applied for identification of risk factors.
Results
In total, 912 cancer patients with 912 PICCs of 96,307 catheter days were enrolled. Ninety-four developed PICC-related infection; 46 were exit-site infection, 43 were catheter bacterial colonization, and five were PICC-related bloodstream infection. The median time from catheter insertion to infection was 98.26 days. Multivariate analysis showed StatLock fixing (odds ratio [OR] =0.555, 95% confidence interval [CI]: 0.326–0.945) and tip position located in the lower one-third of the superior vena cava (OR =0.340, 95% CI: 0.202–0.571) were associated with lower PICC infection rate. Catheter care delay (OR =2.612, 95% CI: 1.373–4.969) and indwelling mostly in summer (OR =4.784, 95% CI: 2.681–8.538) were associated with higher infection incidence.
Conclusion
StatLock fixing and tip position located in the lower one-third of the superior vena cava were protective factors against PICC-related infection, while catheter care delay and indwelling mostly in summer were risk factors. Policy and measures targeting these factors may be necessary to reduce the risk of infection.
doi:10.2147/TCRM.S83776
PMCID: PMC4447175  PMID: 26045668
PICC; complication; clinical study; catheter-related bloodstream infection
6.  Phase II trial of granulocyte-macrophage colony-stimulating factor plus thalidomide in older patients with castration-resistant prostate cancer 
Molecular and Clinical Oncology  2015;3(4):865-868.
The objective of this study was to assess the efficacy of granulocyte-macrophage colony-stimulating factor (GM-CSF) in combination with thalidomide for prostate-specific antigen (PSA) reduction in older patients (aged ≥70 years, life expectancy of >1 year) with castration-resistant prostate cancer (CRPC). A total of 11 CRPC patients were treated with 300 µg GM-CSF administered subcutaneously on days 1, 3 and 6 of weeks 1 and 2 of each cycle. Thalidomide was gradually increased to reach the study dose of 100 mg/day. The patients were assessed every 4 weeks with therapy continuing to 4 months. All 11 patients exhibited a decrease in PSA levels and 3 patients (27.2%) exhibited a PSA decrease of >50% in cycle 1. In cycle 2, 8 patients exhibited decreasing PSA levels. A total of 3 patients (27.2%) had a PSA rebound, with 1 patient exhibiting a PSA rebound of >50%. In cycle 3, 10 patients exhibited continuously decreasing PSA levels, with 2 patients (18.2%) exhibiting a PSA decrease of >50%; 1 patient (27.2%) had a PSA rebound of <50%. In cycle 4, 9 patients exhibited continuously decreasing PSA levels and 2 patients (18.2%) had a PSA rebound of >50%. All 11 patients in this study exhibited a decrease in PSA levels, with a median decrease of 92.2%. Therapy was well tolerated, with the majority of the patients experiencing only one adverse event. In conclusion, the combination of GM-CSF with thalidomide was found to be clinically effective and well tolerated by elderly CRPC patients. Therefore, GM-CSF plus thalidomide may be considered a viable treatment option for such patients.
doi:10.3892/mco.2015.571
PMCID: PMC4487031  PMID: 26171197
castration-resistant prostate cancer; thalidomide; granulocyte-macrophage colony-stimulating factor
7.  Ecto-5′-nucleotidase expression is associated with the progression of renal cell carcinoma 
Oncology Letters  2015;9(6):2485-2494.
Renal cell carcinoma (RCC) is a common tissue tumor that occurs across all age groups and has become one of the types of cancer with the fastest increasing incidence. Due to the resistance of RCC chemo- and radiotherapy, surgery is the only currently effective treatment. Therefore, specific markers for the diagnosis and prognosis of RCC are expected to result in novel methods of treatment. Ecto-5′-nucleotidase, also termed cluster of differentiation (CD)73, is a protein that is activated in several types of aggressive cancer and may promote cancer progression. CD73 was examined in the present study to determine the association between the protein and RCC. The expression levels of CD73 in 159 RCC tissue sections and 30 paratumorous normal renal tissue samples obtained from 235 patients that underwent nephrectomy were examined by immunohistochemical staining. By contrast, the expression level of P-glycoprotein (P-gp), a potential prognostic factor in RCC, was also examined in 85 RCC and 13 normal tissue samples. Intense CD73 expression was identified in 75 out of 159 RCC cell membranes compared with normal renal tissues. In contrast, there was high P-gp expression in the blood vessels of 42 out of 85 RCC tissues and there was no significant difference between the P-gp expression identified in RCC cells (34 out of 85) and the cell membrane of normal renal cells (2 out of 13). The expression level of CD73 in RCC cells was significantly associated with tumor type, tumor node metastasis (TNM) stage, and tumor grade. However, the expression of P-gp in RCC cells was only associated with the TNM stage and tumor grade. Using a multivariable Cox regression analysis, it was found that the median survival rate of RCC patients with intense CD73 expression in RCC cells was 62.06±5.35 months, which was drastically shorter compared with rare CD73 expression (103.72±3.67 months). In conclusion, the expression level of CD73 is significantly associated with RCC tumor progression and may serve as a favorable marker for the diagnosis and prognosis of RCC, in addition to being a therapeutic target for the treatment of RCC.
doi:10.3892/ol.2015.3138
PMCID: PMC4473655  PMID: 26137095
renal cell carcinoma; CD73; P-glycoprotein; tumor progression; prognosis
8.  Portable and Reusable Optofluidics-Based Biosensing Platform for Ultrasensitive Detection of Sulfadimidine in Dairy Products 
Sensors (Basel, Switzerland)  2015;15(4):8302-8313.
Sulfadimidine (SM2) is a highly toxic and ubiquitous pollutant which requires rapid, sensitive and portable detection method for environmental and food monitoring. Herein, the use for the detection of SM2 of a portable optofluidics-based biosensing platform, which was used for the accurate detection of bisphenol A, atrazine and melamine, is reported for the first time. The proposed compact biosensing system combines the advantages of an evanescent wave immunosensor and microfluidic technology. Through the indirect competitive immunoassay, the detection limit of the proposed optofluidics-based biosensing platform for SM2 reaches 0.05 μg·L−1 at the concentration of Cy5.5-labeled antibody of 0.1 μg·mL−1. Linearity is obtained over a dynamic range from 0.17 μg·L−1 to 10.73 μg·L−1. The surface of the fiber probe can be regenerated more than 300 times by means of 0.5% sodium dodecyl sulfate solution (pH = 1.9) washes without losing sensitivity. This method, featuring high sensitivity, portability and acceptable reproducibility shows potential in the detection of SM2 in real milk and other dairy products.
doi:10.3390/s150408302
PMCID: PMC4431307  PMID: 25860072
optofluidics-based biosensing platform; optic fiber; sulfadimidine; dairy products
9.  Neuroprotective effects of SMADs in a rat model of cerebral ischemia/reperfusion 
Neural Regeneration Research  2015;10(3):438-444.
Previous studies have shown that up-regulation of transforming growth factor β1 results in neuroprotective effects. However, the role of the transforming growth factor β1 downstream molecule, SMAD2/3, following ischemia/reperfusion remains unclear. Here, we investigated the neuroprotective effects of SMAD2/3 by analyzing the relationships between SMAD2/3 expression and cell apoptosis and inflammation in the brain of a rat model of cerebral ischemia/reperfusion. Levels of SMAD2/3 mRNA were up-regulated in the ischemic penumbra 6 hours after cerebral ischemia/reperfusion, reached a peak after 72 hours and were then decreased at 7 days. Phosphorylated SMAD2/3 protein levels at the aforementioned time points were consistent with the mRNA levels. Over-expression of SMAD3 in the brains of the ischemia/reperfusion model rats via delivery of an adeno-associated virus containing the SMAD3 gene could reduce tumor necrosis factor-α and interleukin-1β mRNA levels, down-regulate expression of the pro-apoptotic gene, capase-3, and up-regulate expression of the anti-apoptotic protein, Bcl-2. The SMAD3 protein level was negatively correlated with cell apoptosis. These findings indicate that SMAD3 exhibits neuroprotective effects on the brain after ischemia/reperfusion through anti-inflammatory and anti-apoptotic pathways.
doi:10.4103/1673-5374.153693
PMCID: PMC4396107  PMID: 25878593
nerve regeneration; brain injury; neuroprotection; inflammation; apoptosis; cerebral ischemia; SMAD3; transforming growth factor β1; NSFC grant; neural regeneration
10.  Effect of Different Tumbling Marination Treatments on the Quality Characteristics of Prepared Pork Chops 
The effect of different tumbling marination treatments (control group, CG; conventional static marination, SM; vacuum continuous tumbling marination, CT; vacuum intermittent tumbling marination, IT) on the quality characteristics of prepared pork chops was investigated under simulated commercial conditions. The CT treatment increased (p<0.05) the pH value, b* value, product yield, tenderness, overall flavor, sensory juiciness and overall acceptability in comparison to other treatments for prepared boneless pork chops. The CT treatment decreased (p<0.05) cooking loss, shear force value, hardness, gumminess and chewiness compared with other treatments. In addition, CT treatment effectively improved springiness and sensory color more than other treatments. However, IT treatment achieved the numerically highest (p<0.05) L* and a* values. These results suggested that CT treatment obtained the best quality characteristics of prepared pork chops and should be adopted as the optimal commercial processing method for this prepared boneless pork chops.
doi:10.5713/ajas.14.0511
PMCID: PMC4283172  PMID: 25557823
Tumbling; Continuous; Intermittent; Quality Characteristic; Prepared Pork Chop
11.  Peripherally inserted central catheter thrombosis incidence and risk factors in cancer patients: a double-center prospective investigation 
Background
Peripherally inserted central catheters (PICCs) are widely used in chemotherapy, but the reported PICC thrombosis incidence varies greatly, and risks of PICC thrombosis are not well defined. This study was to investigate the incidence and risk factors of PICC-related upper extremity vein thrombosis in cancer patients.
Methods
This was a prospective study conducted in two tertiary referral hospitals from May 2010 to February 2013. Cancer patients who were subject to PICC placement were enrolled and checked by Doppler ultrasound weekly for at least 1 month. Univariable and multivariable logistic regression analyses were applied for identification of risk factors.
Results
Three hundred and eleven cancer patients were enrolled in the study. One hundred and sixty (51.4%) developed PICC thrombosis, of which 87 (54.4%) cases were symptomatic. The mean time interval from PICC insertion to thrombosis onset was 11.04±5.538 days. The univariable logistic regression analysis showed that complications (odds ratio [OR] 1.686, P=0.032), less activity (OR 1.476, P=0.006), obesity (OR 3.148, P=0.000), and chemotherapy history (OR 3.405, P=0.030) were associated with PICC thrombosis. Multivariate analysis showed that less activity (OR 9.583, P=0.000) and obesity (OR 3.466, P=0.014) were significantly associated with PICC thrombosis.
Conclusions
The incidence of PICC thrombosis is relatively high, and nearly half are asymptomatic. Less activity and obesity are risk factors of PICC-related thrombosis.
doi:10.2147/TCRM.S73379
PMCID: PMC4321638  PMID: 25673995
PICC; complication; clinical study; catheter-related thrombosis; upper extremity vein thrombosis
12.  Induction of H2AX phosphorylation in tumor cells by gossypol acetic acid is mediated by phosphatidylinositol 3-kinase (PI3K) family 
Background
H2AX is phosphorylated (γH2AX) by members of the phosphatidylinositol 3-kinase (PI3K) family, including Ataxia telangiectasia-mutated (ATM), ATM- and Rad3-related (ATR) and DNA-PK in response to DNA damage. Our study shows that gossypol acetic acid (GAA) alone can induce γH2AX in Human mucoepidermoid carcinoma cell line (MEC-1) in vitro. Thus, we further examined the possible mechanisms of GAA to induce γH2AX in tumor cells.
Materials and methods
The PI3K inhibitors caffeine and wortmannin were used in an effort to identify the kinase(s) responsible for GAA -induced γH2AX in MEC-1 cells. DNA dependent protein kinase (DNA-PK) - proficient and –deficient cells, human glioma cell lines M059K and M059J, were also used to evaluate the kinases responsible for GAA induced H2AX phosphorylation. γH2AX expression was detected by immunofluorescent microscopy. Flow cytometry assay was used to assay γH2AX and cell cycle.
Results
GAA induced H2AX phosphorylation in a cell cycle-dependent manner and a significant G0/G1 phase arrest in MEC-1 cells was shown. Caffeine and wortmannin significantly inhibited GAA-induced H2AX phosphorylation in MEC-1 cells. GAA induced H2AX phosphorylation in M059K, but not in M059J. Taken together, these data suggested that GAA treatment alone could induce H2AX phosphorylation in a cell cycle dependent manner in MEC-1 and M059K, but not in M059J cells. A significant G0/G1 phase arrest was shown in MEC-1.
Conclusions
The member of PI3K family, DNA-PK, ATM and ATR are involved in the H2AX phosphorylation of MEC-1 cells.
doi:10.1186/s12935-014-0141-5
PMCID: PMC4272777  PMID: 25530717
Gossypol acetic acid; H2AX phosphorylation; DNA-PK; ATM; ATR
13.  Fabrication of Electrospun Poly(L-Lactide-co-ɛ-Caprolactone)/Collagen Nanoyarn Network as a Novel, Three-Dimensional, Macroporous, Aligned Scaffold for Tendon Tissue Engineering 
Tissue Engineering. Part C, Methods  2013;19(12):925-936.
Tissue engineering techniques using novel scaffolding materials offer potential alternatives for managing tendon disorders. An ideal tendon tissue engineered scaffold should mimic the three-dimensional (3D) structure of the natural extracellular matrix (ECM) of the native tendon. Here, we propose a novel electrospun nanoyarn network that is morphologically and structurally similar to the ECM of native tendon tissues. The nanoyarn, random nanofiber, and aligned nanofiber scaffolds of a synthetic biodegradable polymer, poly(l-lactide-co-ɛ-caprolactone) [P(LLA-CL)], and natural collagen I complex were fabricated using electrospinning. These scaffolds were characterized in terms of fiber morphology, pore size, porosity, and chemical and mechanical properties for the purpose of culturing tendon cells (TCs) for tendon tissue engineering. The results indicated a fiber diameter of 632±81 nm for the random nanofiber scaffold, 643±97 nm for the aligned nanofiber scaffold, and 641±68 nm for the nanoyarn scaffold. The yarn in the nanoyarn scaffold was twisted by many nanofibers similar to the structure and inherent nanoscale organization of tendons, indicating an increase in the diameter of 9.51±3.62 μm. The nanoyarn scaffold also contained 3D aligned microstructures with large interconnected pores and high porosity. Fourier transform infrared analyses revealed the presence of collagen in the three scaffolds. The mechanical properties of the sample scaffolds indicated that the scaffolds had desirable mechanical properties for tissue regeneration. Further, the results revealed that TC proliferation and infiltration, and the expression of tendon-related ECM genes, were significantly enhanced on the nanoyarn scaffold compared with that on the random nanofiber and aligned nanofiber scaffolds. This study demonstrates that electrospun P(LLA-CL)/collagen nanoyarn is a novel, 3D, macroporous, aligned scaffold that has potential application in tendon tissue engineering.
doi:10.1089/ten.tec.2012.0328
PMCID: PMC3833310  PMID: 23557537
14.  Cell Surface Vimentin Is an Attachment Receptor for Enterovirus 71 
Journal of Virology  2014;88(10):5816-5833.
ABSTRACT
Enterovirus 71 (EV71) is a highly transmissible pathogenic agent that causes severe central nervous system diseases in infected infants and young children. Here, we reported that EV71 VP1 protein could bind to vimentin intermediate filaments expressed on the host cell surface. Soluble vimentin or an antibody against vimentin could inhibit the binding of EV71 to host cells. Accompanied with the reduction of vimentin expression on the cell surface, the binding of EV71 to cells was remarkably decreased. Further evidence showed that the N terminus of vimentin is responsible for the interaction between EV71 and vimentin. These results indicated that vimentin on the host cell surface may serve as an attachment site that mediated the initial binding and subsequently increased the infectivity of EV71.
IMPORTANCE This study delivers important findings on the roles of vimentin filaments in relation to EV71 infection and provides information that not only improves our understanding of EV71 pathogenesis but also presents us with potentially new strategies for the treatment of diseases caused by EV71 infections.
doi:10.1128/JVI.03826-13
PMCID: PMC4019121  PMID: 24623428
15.  MiR-451 is decreased in hypertrophic cardiomyopathy and regulates autophagy by targeting TSC1 
The molecular mechanisms that drive the development of cardiac hypertrophy in hypertrophic cardiomyopathy (HCM) remain elusive. Accumulated evidence suggests that microRNAs are essential regulators of cardiac remodelling. We have been suggested that microRNAs could play a role in the process of HCM. To uncover which microRNAs were changed in their expression, microRNA microarrays were performed on heart tissue from HCM patients (n = 7) and from healthy donors (n = 5). Among the 13 microRNAs that were differentially expressed in HCM, miR-451 was the most down-regulated. Ectopic overexpression of miR-451 in neonatal rat cardiomyocytes (NRCM) decreased the cell size, whereas knockdown of endogenous miR-451 increased the cell surface area. Luciferase reporter assay analyses demonstrated that tuberous sclerosis complex 1 (TSC1) was a direct target of miR-451. Overexpression of miR-451 in both HeLa cells and NRCM suppressed the expression of TSC1. Furthermore, TSC1 was significantly up-regulated in HCM myocardia, which correlated with the decreased levels of miR-451. As TSC1 is a known positive regulator of autophagy, we examined the role of miR-451 in the regulation of autophagy. Overexpression of miR-451 in vitro inhibited the formation of the autophagosome. Conversely, miR-451 knockdown accelerated autophagosome formation. Consistently, an increased number of autophagosomes was observed in HCM myocardia, accompanied by up-regulated autophagy markers, and the lipidated form of LC3 and Beclin-1. Taken together, our findings indicate that miR-451 regulates cardiac hypertrophy and cardiac autophagy by targeting TSC1. The down-regulation of miR-451 may contribute to the development of HCM and may be a potential therapeutic target for this disease.
doi:10.1111/jcmm.12380
PMCID: PMC4224559  PMID: 25209900
hypertrophic cardiomyopathy; microRNA-451; tuberous sclerosis complex 1; autophagy; microRNAs microarray
16.  Uniaxial Cyclic Stretch Promotes Osteogenic Differentiation and Synthesis of BMP2 in the C3H10T1/2 Cells with BMP2 Gene Variant of rs2273073 (T/G) 
PLoS ONE  2014;9(9):e106598.
Ossification of the posterior longitudinal ligament of the cervical spine (OPLL) is characterized by the replacement of ligament tissues with ectopic bone formation, and this result is strongly affected by genetic and local factors. Two single nucleotide polymorphisms (SNPs) of rs2273073 (T/G) and rs235768 (A/T) of bone morphogenetic protein 2 (BMP2) gene which are associated with OPLL have been reported in our previous report. In this study, we confirmed the connection in 18 case samples analysis of BMP2 gene in OPLL patients; additionally, it was also shown from the OPLL patients with ligament tissues that enchondral ossification and expression of BMP2 were significantly higher compared with the non-OPLL patients by histological examination, immunohistochemistry and Western blotting analysis. To investigate the underlying mechanism, we studied the effect of SNPs in cell model. The C3H10T1/2 cells with different BMP2 gene variants were constructed and then subjected to uniaxial cyclic stretch (0.5 Hz, 10% stretch). In the presence of mechanical stress, the expression of BMP2 protein in C3H10T1/2 cells transfected by BMP2 (rs2273073 (T/G)) and BMP2 (rs2273073 (T/G), rs235768 (A/T)) were significantly higher than the corresponding static groups (P<0.05). In conclusion, these results suggested that BMP2 gene variant of rs2273073 (T/G) could not only increase cell susceptibility to bone transformation similar to pre-OPLL change, but also increase the sensibility to mechanical stress which might play an important role during the progression of OPLL.
doi:10.1371/journal.pone.0106598
PMCID: PMC4156358  PMID: 25191703
17.  Chemotherapy for transarterial chemoembolization in patients with unresectable hepatocellular carcinoma 
World Journal of Gastroenterology : WJG  2014;20(31):10960-10968.
AIM: To compare the efficacy of different chemotherapeutic agents during conventional transarterial chemoembolization (cTACE) in the treatment of unresectable hepatocellular carcinoma (HCC).
METHODS: A retrospective review was undertaken of patients with unresectable HCC undergoing cTACE from May 2003 to November 2011. A total of 107 patients were treated with at least one cTACE session. Irinotecan (CPT-11) was used as a chemotherapeutic agent in 24 patients, gemcitabine (GEM) in 24 and doxorubicin in 59.
RESULTS: The time to progression and overall survival rates were significantly superior in patients treated with CPT-11 compared with the GEM or doxorubicin treated groups (11.4, 8.2, 9.5 mo, P = 0.02 and 21.7, 12.7, 14.5 mo, P = 0.004, respectively). Subgroup analysis showed that for intermediate-stage HCC, CPT-11 resulted in a significantly longer time to progression and overall survival compared with the GEM or doxorubicin treated groups (P = 0.022; P = 0.003, respectively). There were no significant differences in adverse events among the three groups (P > 0.05).
CONCLUSION: For patients treated with cTACE, the chemotherapeutic agent CPT-11 was significantly associated with improved overall survival and delayed tumor progression compared with GEM or doxorubicin. There were no significant differences in clinical adverse events between the three agents. CPT-11 thus appears to be a promising agent when combined with cTACE for the treatment of HCC.
doi:10.3748/wjg.v20.i31.10960
PMCID: PMC4138477  PMID: 25152600
Irinotecan; Gemcitabine; Transarterial chemoembolization; Hepatocellular carcinoma; Overall survival
18.  Advanced abdominal pregnancy: an increasingly challenging clinical concern for obstetricians 
Advanced abdominal pregnancy is rare. The low incidence, high misdiagnosis rate, and lack of specific clinical signs and symptoms explain the fact that there are no standard diagnostic and treatment options available for advanced abdominal pregnancy. We managed a case of abdominal pregnancy in a woman who was pregnant for the first time. This case was further complicated by a concurrent singleton intrauterine pregnancy; the twin pregnancy was not detected until 20 weeks of pregnancy. The case was confirmed at 26 weeks gestational age using MRI to be an abdominal combined with intrauterine pregnancy. The pregnancy was terminated by cesarean section at 33 + 5 weeks gestation. We collected the relevant data of the case while reviewing the advanced abdominal pregnancy-related English literature in the Pubmed, Proquest, and OVID databases. We compared and analyzed the pregnancy history, gestational age when the diagnosis was confirmed, the placental colonization position, the course of treatment and surgical processes, related concurrency rate, post-operative drug treatment programs, and follow-up results with the expectation to provide guidance for other physicians who might encounter similar cases.
PMCID: PMC4203159  PMID: 25337188
Advanced abdominal pregnancy; obstetricians; clinical
19.  Female Sex Is Associated with Worse Prognosis in Patients with Hypertrophic Cardiomyopathy in China 
PLoS ONE  2014;9(7):e102969.
Background
Sex plays an important role in the clinical expression and prognosis of various cardiovascular diseases. This study was designed to observe the effects of sex on hypertrophic cardiomyopathy (HCM).
Methods and Results
A total of 621 unrelated patients with HCM without heart failure (460 males) were enrolled from 1999 to 2011. Compared to male patients, at baseline female patients were older at diagnosis (49.6±17.2 years vs. 46.7±14.4 years, P = 0.033), and had greater frequency of left ventricular outflow tract obstruction (72/161, 44.7% vs. 149/460, 32.4%, P = 0.005). During the average four year follow-up period (range 2–7 years), survival analysis showed that the incidences of mortality from all causes, cardiovascular death and progression to chronic heart failure were greater in women than in men (P = 0.031, 0.040 and 0.012, respectively). After adjustment for multiple factors that may confound survival and cardiac function, female sex remained an independent risk factor for all-cause mortality, cardiovascular death, and chronic heart failure [hazard ratio (HR) 2.19, 95% confidence interval (CI) 1.21–3.95, P = 0.010; HR 2.19, 95% CI 1.17–4.09, P = 0.014; HR 1.73, 95% CI 1.12–2.69, P = 0.014, respectively] in HCM patients. Subgroup analysis revealed that female sex as a risk factor was identified only in patients younger than 50 years old (P = 0.011, 0.011 and 0.009, respectively), but not for those 50 years or older.
Conclusion
Our results suggest that female sex is associated with worse survival and heart failure in HCM patients. Further studies are required to determine whether female hormones modify the clinical expression and prognosis of HCM.
doi:10.1371/journal.pone.0102969
PMCID: PMC4105411  PMID: 25047602
20.  Rare Variants in Genes Encoding MuRF1 and MuRF2 Are Modifiers of Hypertrophic Cardiomyopathy 
Modifier genes contribute to the diverse clinical manifestations of hypertrophic cardiomyopathy (HCM), but are still largely unknown. Muscle ring finger (MuRF) proteins are a class of muscle-specific ubiquitin E3-ligases that appear to modulate cardiac mass and function by regulating the ubiquitin-proteasome system. In this study we screened all the three members of the MuRF family, MuRF1, MuRF2 and MuRF3, in 594 unrelated HCM patients and 307 healthy controls by targeted resequencing. Identified rare variants were confirmed by capillary Sanger sequencing. The prevalence of rare variants in both MuRF1 and MuRF2 in HCM patients was higher than that in control subjects (MuRF1 13/594 (2.2%) vs. 1/307 (0.3%), p = 0.04; MuRF2 22/594 (3.7%) vs. 2/307 (0.7%); p = 0.007). Patients with rare variants in MuRF1 or MuRF2 were younger (p = 0.04) and had greater maximum left ventricular wall thickness (p = 0.006) than those without such variants. Mutations in genes encoding sarcomere proteins were present in 19 (55.9%) of the 34 HCM patients with rare variants in MuRF1 and MuRF2. These data strongly supported that rare variants in MuRF1 and MuRF2 are associated with higher penetrance and more severe clinical manifestations of HCM. The findings suggest that dysregulation of the ubiquitin-proteasome system contributes to the pathogenesis of HCM.
doi:10.3390/ijms15069302
PMCID: PMC4100095  PMID: 24865491
hypertrophic cardiomyopathy; muscle ring finger protein; rare variant; modifier
21.  Nanolayer encapsulation of insulin-chitosan complexes improves efficiency of oral insulin delivery 
Current oral insulin formulations reported in the literature are often associated with an unpredictable burst release of insulin in the intestine, which may increase the risk for problematic hypoglycemia. The aim of the study was to develop a solution based on a nanolayer encapsulation of insulin-chitosan complexes to afford sustained release after oral administration. Chitosan/heparin multilayer coatings were deposited onto insulin-chitosan microparticulate cores in the presence of poly(ethylene) glycol (PEG) in the precipitating and coating solutions. The addition of PEG improved insulin loading and minimized an undesirable loss of the protein resulting from redissolution. Nanolayer encapsulation and the formation of complexes enabled a superior loading capacity of insulin (>90%), as well as enhanced stability and 74% decreased solubility at acid pH in vitro, compared with nonencapsulated insulin. The capsulated insulin administered by oral gavage lowered fasting blood glucose levels by up to 50% in a sustained and dose-dependent manner and reduced postprandial glycemia in streptozotocin-induced diabetic mice without causing hypoglycemia. Nanolayer encapsulation reduced the possibility of rapid and erratic falls of blood glucose levels in animals. This technique represents a promising strategy to promote the intestinal absorption efficiency and release behavior of the hormone, potentially enabling an efficient and safe route for oral insulin delivery of insulin in diabetes management.
doi:10.2147/IJN.S59075
PMCID: PMC4014370  PMID: 24833901
oral insulin; diabetes mellitus; insulin-chitosan complexes; multilayer nanoencapsulation; polyethylene glycol; chitosan; heparin
22.  Tenascin-C Deficiency in Apo E−/− Mouse Increases Eotaxin Levels: Implications for Atherosclerosis 
Atherosclerosis  2013;227(2):267-274.
Aim
To investigate the potential role of inflammatory cytokines in apo E−/− mouse in response to deletion of Tenascin-C (TNC) gene.
Methods and results
We used antibody array and ELISA to compare the profile of circulating inflammatory cytokines in apo E−/− mice and apo E−/− TNC−/− double knockout mice. In addition, tissue culture studies were performed to investigate the activity of cells from each mouse genotype in vitro. Cytokine array analysis and subsequent ELISA showed that circulating eotaxin levels were selectively and markedly increased in response to TNC gene deletion in apo E−/− mice. In addition, considerable variation was noted in the circulating level of eotaxin among the control apo E−/− mouse group. Inbreeding of apo E−/− mice with high or low levels of plasma eotaxin showed that the level of eotaxin per se determines the extent of atherosclerosis in this mouse genotype. While endothelial cells from apo E−/− mice had low level of eotaxin expression, cells derived from apo E−/−TNC−/− mice expressed a high level of eotaxin. Transient transfection of eotaxin promoter-reporter constructs revealed that eotaxin expression is regulated at the transcriptional level by TNC. Histochemical analysis of aortic sections revealed the massive accumulation of mast cells in the adventitia of double KO mice lesions whereas no such accumulation was detected in the control group. Plasma from the apo E−/−TNC−/− mice markedly stimulated mast cell migration whereas plasma from the apo E−/− mice had no such effect.
Conclusion
These observations support the emerging hypothesis that TNC expression controls eotaxin level in apo E−/− mice and that this chemokine plays a key role in the development of atherosclerosis.
doi:10.1016/j.atherosclerosis.2013.01.039
PMCID: PMC3621962  PMID: 23433402
Tenascin-C; Eotaxin; Atherosclerosis; Mast cells; Chemokines; Matricellular protein; Extracellular matrix
23.  rAAV/ABAD-DP-6His attenuates oxidative stress-induced injury of PC12 cells 
Neural Regeneration Research  2014;9(5):481-488.
Our previous studies have revealed that amyloid β (Aβ)-binding alcohol dehydrogenase (ABAD) decoy peptide antagonizes Aβ42-induced neurotoxicity. However, whether it improves oxidative stress injury remains unclear. In this study, a recombinant adenovirus constitutively secreting and expressing Aβ-ABAD decoy peptide (rAAV/ABAD-DP-6His) was successfully constructed. Our results showed that rAAV/ABAD-DP-6His increased superoxide dismutase activity in hydrogen peroxide-induced oxidative stress-mediated injury of PC12 cells. Moreover, rAAV/ABAD-DP-6His decreased malondialdehyde content, intracellular Ca2+ concentration, and the level of reactive oxygen species. rAAV/ABAD-DP-6His maintained the stability of the mitochondrial membrane potential. In addition, the ATP level remained constant, and apoptosis was reduced. Overall, the results indicate that rAAV/ABAD-DP-6His generates the fusion peptide, Aβ-ABAD decoy peptide, which effectively protects PC12 cells from oxidative stress injury induced by hydrogen peroxide, thus exerting neuroprotective effects.
doi:10.4103/1673-5374.130065
PMCID: PMC4153500  PMID: 25206842
nerve regeneration; neurodegenerative disease; gene therapy; Alzheimer's disease; amyloid beta peptide; amyloid beta binding alcohol dehydrogenase; adeno-associated virus; hydrogen peroxide; oxidative stress; mitochondrial dysfunction; NSFC grant; neural regeneration
24.  Dab2 attenuates brain injury in APP/PS1 mice via targeting transforming growth factor-beta/SMAD signaling 
Neural Regeneration Research  2014;9(1):41-50.
Transforming growth factor-beta (TGF-β) type II receptor (TβRII) levels are extremely low in the brain tissue of patients with Alzheimer's disease. This receptor inhibits TGF-β1/SMAD signaling and thereby aggravates amyolid-beta deposition and neuronal injury. Dab2, a specific adapter protein, protects TβRII from degradation and ensures the effective conduction of TGF-β1/SMAD signaling. In this study, we used an adenoviral vector to overexpress the Dab2 gene in the mouse hippocampus and investigated the regulatory effect of Dab2 protein on TGF-β1/SMAD signaling in a mouse model of Alzheimer's disease, and the potential neuroprotective effect. The results showed that the TβRII level was lower in APP/PS1 mouse hippocampus than in normal mouse hippocampus. After Dab2 expression, hippocampal TβRII and p-SMAD2/3 levels were significantly increased, while amyloid-beta deposition, microglia activation, tumor necrosis factor-α and interleulin-6 levels and neuronal loss were significantly attenuated in APP/PS1 mouse brain tissue. These results suggest that Dab2 can exhibit neuroprotective effects in Alzheimer's disease by regulating TGF-β1/SMAD signaling.
doi:10.4103/1673-5374.125328
PMCID: PMC4146324  PMID: 25206742
nerve regeneration; transforming growth factor-β1; Dab2; Alzheimer's disease; amyolid-beta; neuron; SMAD2; SMAD3; microglia; neural regeneration
25.  Genome-wide multi-omics profiling of colorectal cancer identifies immune determinants strongly associated with relapse 
Frontiers in Genetics  2013;4:236.
The use and benefit of adjuvant chemotherapy to treat stage II colorectal cancer (CRC) patients is not well understood since the majority of these patients are cured by surgery alone. Identification of biological markers of relapse is a critical challenge to effectively target treatments to the ~20% of patients destined to relapse. We have integrated molecular profiling results of several “omics” data types to determine the most reliable prognostic biomarkers for relapse in CRC using data from 40 stage I and II CRC patients. We identified 31 multi-omics features that highly correlate with relapse. The data types were integrated using multi-step analytical approach with consecutive elimination of redundant molecular features. For each data type a systems biology analysis was performed to identify pathways biological processes and disease categories most affected in relapse. The biomarkers detected in tumors urine and blood of patients indicated a strong association with immune processes including aberrant regulation of T-cell and B-cell activation that could lead to overall differences in lymphocyte recruitment for tumor infiltration and markers indicating likelihood of future relapse. The immune response was the biologically most coherent signature that emerged from our analyses among several other biological processes and corroborates other studies showing a strong immune response in patients less likely to relapse.
doi:10.3389/fgene.2013.00236
PMCID: PMC3834519  PMID: 24312117
colorectal cancer; relapse; variant analysis; integrative analysis; multi-omics; exome sequencing; systems biology; immune response

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