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1.  Angiotensin II Reduces Cardiac AdipoR1 Expression through AT1 Receptor/ROS/ERK1/2/c-Myc Pathway 
PLoS ONE  2013;8(1):e49915.
Adiponectin, an abundant adipose tissue-derived protein, exerts protective effect against cardiovascular disease. Adiponectin receptors (AdipoR1 and AdipoR2) mediate the beneficial effects of adiponectin on the cardiovascular system. However, the alteration of AdipoRs in cardiac remodeling is not fully elucidated. Here, we investigated the effect of angiotensin II (AngII) on cardiac AdipoRs expression and explored the possible molecular mechanism. AngII infusion into rats induced cardiac hypertrophy, reduced AdipoR1 but not AdipoR2 expression, and attenuated the phosphorylations of adenosine monophosphate-activated protein kinase and acetyl coenzyme A carboxylase, and those effects were all reversed by losartan, an AngII type 1 (AT1) receptor blocker. AngII reduced expression of AdipoR1 mRNA and protein in cultured neonatal rat cardiomyocytes, which was abolished by losartan, but not by PD123319, an AT2 receptor antagonist. The antioxidants including reactive oxygen species (ROS) scavenger NAC, NADPH oxidase inhibitor apocynin, Nox2 inhibitor peptide gp91 ds-tat, and mitochondrial electron transport chain complex I inhibitor rotenone attenuated AngII-induced production of ROS and phosphorylation of extracellular signal-regulated kinase (ERK) 1/2. AngII-reduced AdipoR1 expression was reversed by pretreatment with NAC, apocynin, gp91 ds-tat, rotenone, and an ERK1/2 inhibitor PD98059. Chromatin immunoprecipitation assay demonstrated that AngII provoked the recruitment of c-Myc onto the promoter region of AdipoR1, which was attenuated by PD98059. Moreover, AngII-induced DNA binding activity of c-Myc was inhibited by losartan, NAC, apocynin, gp91 ds-tat, rotenone, and PD98059. c-Myc small interfering RNA abolished the inhibitory effect of AngII on AdipoR1 expression. Our results suggest that AngII inhibits cardiac AdipoR1 expression in vivo and in vitro and AT1 receptor/ROS/ERK1/2/c-Myc pathway is required for the downregulation of AdipoR1 induced by AngII.
doi:10.1371/journal.pone.0049915
PMCID: PMC3551944  PMID: 23349663
2.  Therapeutic Potential of Targeting the Oncogenic SHP2 Phosphatase 
Journal of Medicinal Chemistry  2014;57(15):6594-6609.
The Src homology 2 domain containing protein tyrosine phosphatase-2 (SHP2) is an oncogenic phosphatase associated with various kinds of leukemia and solid tumors. Thus, there is substantial interest in developing SHP2 inhibitors as potential anticancer and antileukemia agents. Using a structure-guided and fragment-based library approach, we identified a novel hydroxyindole carboxylic acid-based SHP2 inhibitor 11a-1, with an IC50 value of 200 nM and greater than 5-fold selectivity against 20 mammalian PTPs. Structural and modeling studies reveal that the hydroxyindole carboxylic acid anchors the inhibitor to the SHP2 active site, while interactions of the oxalamide linker and the phenylthiophene tail with residues in the β5–β6 loop contribute to 11a-1’s binding potency and selectivity. Evidence suggests that 11a-1 specifically attenuates the SHP2-dependent signaling inside the cell. Moreover, 11a-1 blocks growth factor mediated Erk1/2 and Akt activation and exhibits excellent antiproliferative activity in lung cancer and breast cancer as well as leukemia cell lines.
doi:10.1021/jm5006176
PMCID: PMC4136714  PMID: 25003231
3.  Growth performance, serum biochemical profile, jejunal morphology, and the expression of nutrients transporter genes in deoxynivalenol (DON)- challenged growing pigs 
BMC Veterinary Research  2015;11:144.
Background
Fusarium infection with concurrent production of deoxynivalenol (DON) causes an increasing safety concern with feed worldwide. This study was conducted to determine the effects of varying levels of DON in diets on growth performance, serum biochemical profile, jejunal morphology, and the differential expression of nutrients transporter genes in growing pigs.
Results
A total of twenty-four 60-day-old healthy growing pigs (initial body weight = 16.3 ± 1.5 kg SE) were individually housed and randomly assigned to receive one of four diets containing 0, 3, 6 or 12 mg DON/kg feed for 21 days. Differences were observed between control and the 12 mg/kg DON treatment group with regards to average daily gain (ADG), although the value for average daily feed intake (ADFI) in the 3 mg/kg DON treatment group was slightly higher than that in control (P<0.01). The relative liver weight in the 12 mg/kg DON treatment group was significantly greater than that in the control (P<0.01), but there were no significant differences in other organs. With regard to serum biochemistry, the values of blood urea nitrogen (BUN), alkaline phosphatase (ALP), alanine aminotransferase (ALT) and aspartate amino transferase (AST) in the 3 treatment groups were higher than those in the control, and the serum concentrations of L-valine, glycine, L-serine, and L-glutamine were significantly reduced in the 3 treatment groups, especially in the 12 mg/kg DON group (P<0.01). Serum total superoxide dismutase (T-SOD), glutathione peroxidase (GSH-Px) were markedly decreased after exposure to DON contaminated feeds (P<0.01). The villi height was markedly decreased and the lymphocyte cell numbers markedly increased in the 3 DON contaminated feeds (P<0.01). The mRNA expression levels of excitatory amino acid transporter-3 (EAAC-3), sodium-glucose transporter-1 (SGLT-1), dipeptide transporter-1 (PepT-1), cationic amino acid transporter-1 (CAT-1) and y+L-type amino acid transporter-1 (LAT-1) in control were slightly or markedly higher than those in the 3 DON treatment groups.
Conclusions
These results showed that feeds containing DON cause a wide range of effects in a dose-dependent manner. Such effects includes weight loss, live injury and oxidation stress, and malabsorption of nutrients as a result of selective regulation of nutrient transporter genes such as EAAC-3, SGLT-1, PepT-1, CAT-1 and LAT-1.
doi:10.1186/s12917-015-0449-y
PMCID: PMC4490653  PMID: 26138080
Deoxynivalenol (DON); Amino acid transporter; Growing pigs; Nutrition
4.  E-Cigarette Prevalence and Correlates of Use among Adolescents versus Adults: A Review and Comparison 
Perceived safer than tobacco cigarettes, prevalence of electronic cigarette (e-cigarette) use is increasing. Analyses of cartridges suggest that e-cigarettes may pose health risks. In light of increased use and the potential for consequences, we searched Google Scholar and Pubmed in July of 2013 using keywords, such as e-cigarette and vaping, to compare differences and similarities in prevalence and correlates of e-cigarette use among adolescents (grades 6-12) versus adults (aged ≥18 years). Twenty-one studies focused on e-cigarette use. Ever-use increased among various age groups. In 2011, ever-use was highest among young adults (college students and those aged 20-28; 4.9%-7.0%), followed by adults (aged ≥18; 0.6%-6.2%), and adolescents (grades 6-12 and aged 11-19; <1%-3.3%). However, in 2012 adolescent ever-use increased to 6.8% and, among high school students, went as high as 10.0%. While the identified common correlate of e-cigarette use was a history of cigarette smoking, a notable proportion of adolescents and young adults who never smoked cigarettes had ever-used e-cigarettes. E-cigarette use was not consistently associated with attempting to quit tobacco among young adults. Adults most often reported e-cigarettes as a substitute for tobacco, although not always to quit. Reviewed studies showed a somewhat different pattern of e-cigarette use among young people (new e-cigarette users who had never used tobacco) versus adults (former or current tobacco users). Research is needed to better characterize prevalences, use correlates, and motives of use in different population groups, including how adolescent and young adult experimentation with e-cigarettes relates to other types of substance use behaviors.
doi:10.1016/j.jpsychires.2014.03.005
PMCID: PMC4055566  PMID: 24680203
adolescent; electronic cigarette; e-cigarette; vaping; vapor; vaper
5.  Pure total flavonoids from Citrus paradisi Macfadyen actmsynergistically with arsenic trioxide in inducingmapoptosis of Kasumi-1 leukemia cells in vitro *  
To investigate the potential effects of pure total flavonoid compounds (PTFCs) from Citrus paradisi Macfadyen separately or combined with arsenic trioxide on the proliferation of human myeloid leukemia cells and the mechanisms underlying the action of PTFCs. The effects of PTFCs separately or combined with arsenic trioxide on the proliferation and apoptosis of leukemia cells were determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), fluorescence microscopy, and flow cytometry. Their effects on the expression levels of apoptosis-related regulators were determined by Western blot assay. PTFCs combined with arsenic trioxide significantly inhibited the growth of Kasumi-1 cells, and apoptosis was confirmed by flow cytometry analysis. Hoechst 33258 staining showed more significant morphological changes and more apoptosis following the combined treatment. Western blots showed changes in the expression of genes for poly ADP-ribose polymerase (PARP), caspase 3/9, and P65. The results indicated that PTFCs separately or combined with arsenic trioxide inhibited proliferation of leukemia cells in vitro and induced their apoptosis by modulating the expression of apoptosis-related regulator genes.
doi:10.1631/jzus.B1400234
PMCID: PMC4506948  PMID: 26160715
Pure total flavonoid compounds; Human myeloid leukemia cells; Growth inhibition; Synergistic effect; Apoptosis
6.  Molecular Basis of Gain-of-Function LEOPARD Syndrome-Associated SHP2 Mutations 
Biochemistry  2014;53(25):4136-4151.
The Src homology 2 (SH2) domain-containing protein tyrosine phosphatase 2 (SHP2) is a critical signal transducer downstream of growth factors that promotes the activation of the RAS-ERK1/2 cascade. In its basal state, SHP2 exists in an autoinhibited closed conformation because of an intramolecular interaction between its N-SH2 and protein tyrosine phosphatase (PTP) domains. Binding to pTyr ligands present on growth factor receptors and adaptor proteins with its N-SH2 domain localizes SHP2 to its substrates and frees the active site from allosteric inhibition. Germline mutations in SHP2 are known to cause both Noonan syndrome (NS) and LEOPARD syndrome (LS), two clinically similar autosomal dominant developmental disorders. NS-associated SHP2 mutants display elevated phosphatase activity, while LS-associated SHP2 mutants exhibit reduced catalytic activity. A conundrum in how clinically similar diseases result from mutations to SHP2 that have opposite effects on this enzyme’s catalytic functionality exists. Here we report a comprehensive investigation of the kinetic, structural, dynamic, and biochemical signaling properties of the wild type as well as all reported LS-associated SHP2 mutants. The results reveal that LS-causing mutations not only affect SHP2 phosphatase activity but also induce a weakening of the intramolecular interaction between the N-SH2 and PTP domains, leading to mutants that are more readily activated by competing pTyr ligands. Our data also indicate that the residual phosphatase activity associated with the LS SHP2 mutant is required for enhanced ERK1/2 activation. Consequently, catalytically impaired SHP2 mutants could display gain-of-function properties because of their ability to localize to the vicinity of substrates for longer periods of time, thereby affording the opportunity for prolonged substrate turnover and sustained RAS-ERK1/2 activation.
doi:10.1021/bi5002695
PMCID: PMC4081049  PMID: 24935154
7.  EphB4 Forward-Signaling Regulates Cardiac Progenitor Development in Mouse ES Cells 
Journal of cellular biochemistry  2015;116(3):467-475.
Eph receptor (Eph)-ephrin signaling plays an important role in organ development and tissue regeneration. Bidirectional signaling of EphB4– ephrinB2 regulates cardiovascular development. To assess the role of EphB4–ephrinB2 signaling in cardiac lineage development, we utilized two GFP reporter systems in embryonic stem (ES) cells, in which the GFP transgenes were expressed in Nkx2.5+ cardiac progenitor cells and in α-MHC+ cardiomyocytes, respectively. We found that both EphB4 and ephrinB2 were expressed in Nkx2.5-GFP+ cardiac progenitor cells, but not in α-MHC-GFP+ cardiomyocytes during cardiac lineage differentiation of ES cells. An antagonist of EphB4, TNYL-RAW peptides, that block the binding of EphB4 and ephrinB2, impaired cardiac lineage development in ES cells. Inhibition of EphB4–ephrinB2 signaling at different time points during ES cell differentiation demonstrated that the interaction of EphB4 and ephrinB2 was required for the early stage of cardiac lineage development. Forced expression of human full-length EphB4 or intracellular domain-truncated EphB4 in EphB4-null ES cells was established to investigate the role of EphB4-forward signaling in ES cells. Interestingly, while full-length EphB4 was able to restore the cardiac lineage development in EphB4-null ES cells, the truncated EphB4 that lacks the intracellular domain of tyrosine kinase and PDZ motif failed to rescue the defect of cardiomyocyte development, suggesting that EphB4 intracellular domain is essential for the development of cardiomyocytes. Our study provides evidence that receptor-kinase-dependent EphB4-forward signaling plays a crucial role in the development of cardiac progenitor cells.
doi:10.1002/jcb.25000
PMCID: PMC4452947  PMID: 25359705
EMBRYONIC STEM (ES) CELLS; CARDIOMYOCYTES; EphB4; ephrinB2; CARDIAC PROGENITOR CELLS; Nkx 2.5; α-MHC
8.  Effects of reducing dietary protein on the expression of nutrition sensing genes (amino acid transporters) in weaned piglets*  
The effects of crude protein (CP) levels in the diet on the mRNA expression of amino acid (AA) transporters were studied in a 45-d trial. Eighteen piglets with an initial body weight (BW) of 9.57 kg were assigned to three groups (14%, 17%, and 20% CP in the diet) in a completely randomized design (six replicates per treatment). Diets were supplemented with crystalline AA to achieve equal standardized ileal digestible contents of Lys, Met plus Cys, Thr, and Trp, and were provided ad libitum. After 45 d, all piglets were slaughtered to collect small intestine samples. Compared with the values in the 14% CP group, the expressions of ASCT2, 4F2hc, and ATB0 mRNA in the jejunum were increased by 23.00%, 12.00%, 6.00% and 48.00%, 47.00%, 56.00% in the 17% and 20% CP groups, respectively. These results indicate that a 14% CP diet supplemented with crystalline AA may not transport enough AA into the body and maintain growth performance of piglets. However, a reduction of dietary 17% CP may reduce the excretion of nitrogen into the environment while supporting the development of piglets. Therefore, the 17% CP level is more suitable than 14% CP level.
doi:10.1631/jzus.B1400259
PMCID: PMC4471601  PMID: 26055911
Crude protein; Amino acid balance; Amino acid transporters
9.  A gp130-Src-YAP Module Links Inflammation to Epithelial Regeneration 
Nature  2015;519(7541):57-62.
Summary
Inflammation promotes regeneration of injured tissues through poorly understood mechanisms, some of which involve interleukin (IL)-6 family members whose expression is elevated in many diseases, including inflammatory bowel diseases (IBD) and colorectal cancer (CRC). We show that gp130, a co-receptor for IL-6 cytokines, triggers activation of YAP and Notch, transcriptional regulators that control tissue growth and regeneration, independently of the classic gp130 effector STAT3. Through YAP and Notch, intestinal gp130 signaling stimulates epithelial cell proliferation, causes aberrant differentiation and confers resistance to mucosal erosion. gp130 associates with the related tyrosine kinases Src and Yes, which are activated upon receptor engagement to phosphorylate YAP and induce its stabilization and nuclear translocation. This signaling module is strongly activated upon mucosal injury to promote healing and maintain barrier function.
doi:10.1038/nature14228
PMCID: PMC4447318  PMID: 25731159
10.  Association between Gastroenterological Malignancy and Diabetes Mellitus and Anti-Diabetic Therapy: A Nationwide, Population-Based Cohort Study 
PLoS ONE  2015;10(5):e0125421.
Background
The relationship between diabetes mellitus (DM) and cancer incidence has been evaluated in limited kinds of cancer. The effect of anti-diabetic therapy (ADT) on carcinogenesis among diabetic patients is also unclear.
Materials and Methods
Using population-based representative insurance claims data in Taiwan, 36,270 DM patients and 145,080 comparison subjects without DM were identified from claims from 2005 to 2010. The association between the top ten leading causes of cancer-related death in Taiwan and DM was evaluated. Whether ADT altered the risk of developing cancer was also investigated.
Results
Incidence of cancer at any site was significantly higher in patients with DM than in those without (p<0.001). The risk of carcinogenesis imparted by DM was greatest in gastroenterological malignancies (liver, pancreas, and colorectal cancer) as well as lung, breast and oral cancer (p<0.001). Among the oral types of ADT, metformin decreased the risk of lung and liver cancer, but had less effect on reducing the risk of colorectal cancer. α-glucosidase inhibitor decreased the risk of developing liver, colorectal, and breast cancer. Apart from intermediate-acting insulin, rapid-acting, long-acting, and combination insulin treatment significantly reduced the overall cancer risk among all DM patients. In subgroup analysis, long-acting insulin treatment significantly decreased the risk of lung, liver, and colorectal cancer.
Conclusion
Our results supported the notion that pre-existing DM increases the incidence of gastroenterological cancer. ADT, especially metformin, α-glucosidase inhibitor, and long-acting insulin treatment, may protect patients with DM against these malignancies. It is crucial that oncologists should closely collaborate with endocrinologists to provide an optimal cancer-specific therapy and diabetic treatment to patients simultaneously with cancer and DM.
doi:10.1371/journal.pone.0125421
PMCID: PMC4433253  PMID: 25978841
11.  Hydroxyindole Carboxylic Acid-Based Inhibitors for Receptor-Type Protein Tyrosine Protein Phosphatase Beta 
Antioxidants & Redox Signaling  2014;20(14):2130-2140.
Abstract
Aims: Protein tyrosine phosphatases (PTPs) play an important role in regulating a wide range of cellular processes. Understanding the role of PTPs within these processes has been hampered by a lack of potent and selective PTP inhibitors. Generating potent and selective probes for PTPs remains a significant challenge because of the highly conserved and positively charged PTP active site that also harbors a redox-sensitive Cys residue. Results: We describe a facile method that uses an appropriate hydroxyindole carboxylic acid to anchor the inhibitor to the PTP active site and relies on the secondary binding elements introduced through an amide-focused library to enhance binding affinity for the target PTP and to impart selectivity against off-target phosphatases. Here, we disclose a novel series of hydroxyindole carboxylic acid-based inhibitors for receptor-type tyrosine protein phosphatase beta (RPTPβ), a potential target that is implicated in blood vessel development. The representative RPTPβ inhibitor 8b-1 (L87B44) has an IC50 of 0.38 μM and at least 14-fold selectivity for RPTPβ over a large panel of PTPs. Moreover, 8b-1 also exhibits excellent cellular activity and augments growth factor signaling in HEK293, MDA-MB-468, and human umbilical vein endothelial cells. Innovation: The bicyclic salicylic acid pharmacophore-based focused library approach may provide a potential solution to overcome the bioavailability issue that has plagued the PTP drug discovery field for many years. Conclusion: A novel method is described for the development of bioavailable PTP inhibitors that utilizes bicyclic salicylic acid to anchor the inhibitors to the active site and peripheral site interactions to enhance binding affinity and selectivity. Antioxid. Redox Signal. 20, 2130–2140.
doi:10.1089/ars.2013.5463
PMCID: PMC3995206  PMID: 24180557
12.  Extended release naltrexone injection is performed in the majority of opioid dependent patients receiving outpatient induction: a very low dose naltrexone and buprenorphine open label trial 
Drug and alcohol dependence  2014;138:83-88.
BACKGROUND
The approval of extended release injectable naltrexone (XR-NTX; Vivitrol®) has introduced a new option for treating opioid addiction, but studies are needed to identify its place within the spectrum of available therapies. The absence of physiological opioid dependence is a necessary and challenging first step for starting XR-NTX. Outpatient detoxification gives poor results and inpatient detoxification is either unavailable or too brief for the physiological effects of opioids to resolve. Here we present findings from an open label study that tested whether the transition from opioid addiction to XR-NTX can be safely and effectively performed in an outpatient setting using very low dose naltrexone and buprenorphine.
METHODS
Twenty treatment seeking opioid addicted individuals were given increasing doses of naltrexone starting at 0.25 mg with decreasing doses of buprenorphine starting at 4 mg during a 7-day outpatient XR-NTX induction procedure. Withdrawal discomfort, craving, drug use, and adverse events were assessed daily until the XR-NTX injection, then weekly over the next month.
RESULTS
Fourteen of the 20 participants received XR-NTX and 13 completed weekly assessments. Withdrawal, craving, and opioid or other drug use were significantly lower during induction and after XR-NTX administration compared with baseline, and no serious adverse events were recorded.
CONCLUSIONS
Outpatient transition to XR-NTX combining upward titration of very low dose naltrexone with downward titration of low dose buprenorphine was safe, well tolerated, and completed by most participants. Further studies with larger numbers of subjects are needed to see if this approach is useful for naltrexone induction.
doi:10.1016/j.drugalcdep.2014.02.002
PMCID: PMC4017322  PMID: 24602363
addiction; detoxification; pharmacotherapy; opioid agonist; opioid antagonist; minority recruitment
13.  Sagittal lip positions in different skeletal malocclusions: a cephalometric analysis 
Background
The objectives of this paper are to (1) study use of soft tissue analyses advocated by Steiner, Ricketts, Burstone, Sushner and Holdway to develop soft tissue cephalometric norms as baseline data for sagittal lip position in Northeast Chinese adult population, (2) compare the sagittal lip positions in different skeletal malocclusions and (3) compare the sagittal lip positions in Northeast Chinese adults with other reported populations.
Methods
Lateral cephalometric radiographs of subjects were taken in natural head position. Radiographs were manually traced and five reference lines - Sushner, Steiner, Burstone, Holdway and Ricketts, were used. The linear distance between the tip of the lips and the five reference lines were measured. Statistical analysis was done using the Statistical Package for Social Sciences (SPSS) 21. Descriptive analysis was done for each variable for each subject. Coefficient of variation between lip positions as assessed by reference lines was determined. Post hoc Tukey’s test was used for comparison of the mean cephalometric values of three skeletal malocclusions. The level of significance for the analysis was set at p < 0.05.
Results
The findings showed significant difference in the sagittal lip positions in different skeletal malocclusions. There was variation in consistent reference line in each skeletal malocclusion. The S2 line was the most consistent reference line in skeletal class I and class II group. The B line was the most consistent line in skeletal class III. In skeletal class II group, upper lips were the most protrusive and lower lips were retrusive than in skeletal class I and class III groups. In case of skeletal class III group, upper lips were retrusive and lower lips were more protrusive than in skeletal class I and class II groups.
Conclusions
The sagittal lip positions were found to be associated with the skeletal malocclusion pattern. Northeast Chinese population has protrusive upper and lower lip in comparison to Caucasians. Each skeletal malocclusion group showed different preferable reference lines for analysis of sagittal lip position.
Electronic supplementary material
The online version of this article (doi:10.1186/s40510-015-0077-x) contains supplementary material, which is available to authorized users.
doi:10.1186/s40510-015-0077-x
PMCID: PMC4416099  PMID: 26061982
Northeast Chinese population; Skeletal class; Reference lines; Sagittal; Lip
14.  Operative Treatment of Terrible Triad of the Elbow via Posterolateral and Anteromedial Approaches 
PLoS ONE  2015;10(4):e0124821.
The aim of the study was to explore the clinical outcome of posterolateral and anteromedial approaches in treatment of terrible triad of the elbow. The study involved 12 patients with closed terrible triad of the elbow treated by posterolateral and anteromedial approaches between January 2010 and June 2012. The mechanism of injury included fall from height in 9 patients and traffic accident in 3. According to O’Driscoll classification for fractures of the ulnar coronoid, there were 11 patients with type Ⅰ and 1 with type Ⅱ fractures. According to Mason classification for fractures of the radial head, there were 3 patients with type Ⅰ, 7 with type Ⅱ and 2 with type Ⅲ fractures. All patients were followed up for 12-27 months (average 15.5 months), which showed no pain or severe pain in all patients except for 2 patients with mild pain. At the last follow-up, the mean flexion was for 125°(range, 90°-140°), the mean extension loss for 20°(range, 0°-70°), the mean pronation for 66°(range, 20°-85°) and the mean supination for 60°(range, 30°-85°). The bony union time was 8-14 weeks (average 11 weeks) and the elbows were stable in flexion-extension and varus-valgus in all patients. The elbows maintained a concentric reduction of both the ulnotrochlear and the radiocapitellar articulation. Mild heterotopic ossification of the elbow occurred in 3 patients at 6 months after operation and mild degenerative change in 1 patient at 18 months after operation. The Broberg and Morrey elbow performance score was 82 points (range, 58-98 points). The results were excellent in 6 patients, good in 4, fair in 1 and poor in 1, with excellence rate of 83.3%. The results showed that the combined posterolateral and anteromedial approaches can facilitate the reduction and fixation of terrible triad of the elbow. Repair of radial head, coronoid, medial and lateral collateral ligaments can sufficiently restore the elbow stability, allow early postoperative motion and enhance the functional recovery.
doi:10.1371/journal.pone.0124821
PMCID: PMC4409296  PMID: 25910196
15.  Sexual risk behaviors and HIV risk among Americans aged 50 years or older: a review 
Although HIV-related sexual risk behaviors have been studied extensively in adolescents and young adults, there is limited information about these behaviors among older Americans, which make up a growing segment of the US population and an understudied population. This review of the literature dealing with sexual behaviors that increase the risk of becoming HIV-infected found a low prevalence of condom use among older adults, even when not in a long-term relationship with a single partner. A seminal study by Schick et al published in 2010 reported that the prevalence of condom use at last intercourse was highest among those aged 50–59 years (24.3%; 95% confidence interval, 15.6–35.8) and declined with age, with a 17.1% prevalence among those aged 60–69 years (17.1%; 95% confidence interval, 7.3–34.2). Studies have shown that older Americans may underestimate their risk of becoming HIV-infected. Substance use also increases the risk for sexual risk behaviors, and studies have indicated that the prevalence of substance use among older adults has increased in the past decade. As is the case with younger adults, the prevalence of HIV infections is elevated among ethnic minorities, drug users (eg, injection drug users), and men who have sex with men. When infected, older adults are likely to be diagnosed with HIV-related medical disorders later in the course of illness compared with their younger counterparts. Physicians are less likely to discuss sexual risk behaviors with older adults and to test them for HIV compared with younger adults. Thus, it is important to educate clinicians about sexual risk behaviors in the older age group and to design preventive interventions specifically designed for older adults.
doi:10.2147/SAR.S78808
PMCID: PMC4410899  PMID: 25960684
HIV/AIDS; older adults; aging; sexual risk behaviors; condom use
16.  Evaluation of the Medicinal Herb Graptopetalum paraguayense as a Treatment for Liver Cancer 
PLoS ONE  2015;10(4):e0121298.
Background
Hepatocellular carcinoma (HCC) is the fifth most common malignancy and the third most common cause of cancer-related death worldwide. Sorafenib is the only drug for patients with advanced-stage hepatocellular carcinoma (HCC) that has been shown to confer a survival benefit to patients with HCC; however, it has many side effects. Thus, alternate therapeutic strategies with improved safety and therapeutic efficacy for the management of HCC should be developed.
Methods and Findings
We demonstrate that an extract of Graptopetalum paraguayense (GP) down-regulated the expression levels of several onco-proteins, including AURKA, AURKB, and FLJ10540, in HCC cells. To isolate the active components in the GP extracts, we prepared extracts fractions and assessed their effects on the expression of onco-proteins in HCC cells. The fraction designated HH-F3 was enriched in active ingredients, exhibited cytotoxic effects, and suppressed the expression of the onco-proteins in HCC cells. The structure of the main active compound in HH-F3 was found to be similar to that of the proanthocyanidin compounds derived from Rhodiola rosea. In addition, a distinct new compound rich in 3, 4, 5-trihydroxy benzylic moieties was identified in the HH-F3 preparations. Mechanistic studies indicated that HH-F3 induced apoptosis in HCC cells by promoting the loss of mitochondrial membrane potential and the production of reactive oxygen species. HH-F3 also enhanced PTEN expression and decreased AKT phosphorylation at Ser473 in a concentration-dependent manner in HCC cells. Moreover combination of GP or HH-F3 and sorafenib synergistically inhibits the proliferation of Huh7 cells. The treatment of a rat model with diethylnitrosamine (DEN)-induced liver cancer with extracts of GP and HH-F3 decreased hepatic collagen contents and inhibited tumor growth.
Conclusions
These results indicate that GP extracts and HH-F3 can protect the liver by suppressing tumor growth; consequently, these compounds could be considered for the treatment of HCC.
doi:10.1371/journal.pone.0121298
PMCID: PMC4388720  PMID: 25849560
17.  Substance use disorders and psychiatric comorbidity in mid and later life: a review 
Background Globally, adults aged 65 years or older will increase from 516 million in 2009 to an estimated 1.53 billion in 2050. Due to substance use at earlier ages that may continue into later life, and ageing-related changes in medical conditions, older substance users are at risk for substance-related consequences.
Methods MEDLINE and PsychInfo databases were searched using keywords: alcohol use disorder, drug use disorder, drug misuse, substance use disorder, prescription drug abuse, and substance abuse. Using the related-articles link, additional articles were screened for inclusion. This review focused on original studies published between 2005 and 2013 to reflect recent trends in substance use disorders. Studies on psychiatric comorbidity were also reviewed to inform treatment needs for older adults with a substance use disorder.
Results Among community non-institutionalized adults aged 50+ years, about 60% used alcohol, 3% used illicit drugs and 1–2% used nonmedical prescription drugs in the past year. Among adults aged 50+, about 5% of men and 1.4% of women had a past-year alcohol use disorder. Among alcohol users, about one in 14 users aged 50–64 had a past-year alcohol use disorder vs one in 30 elder users aged 65+. Among drug users aged 50+, approximately 10–12% had a drug use disorder. Similar to depressive and anxiety disorders, substance use disorders were among the common psychiatric disorders among older adults. Older drug users in methadone maintenance treatment exhibited multiple psychiatric or medical conditions. There have been increases in treatment admissions for illicit and prescription drug problems in the United States.
Conclusions Substance use in late life requires surveillance and research, including tracking substance use in the racial/ethnic populations and developing effective care models to address comorbid medical and mental health problems.
doi:10.1093/ije/dyt173
PMCID: PMC3997371  PMID: 24163278
Epidemiology; substance use disorders; older adults; comorbidity
18.  Seipin mutation at glycosylation sites activates autophagy in transfected cells via abnormal large lipid droplets generation 
Acta Pharmacologica Sinica  2015;36(4):497-506.
Aim:
Seipin is a protein that resides in endoplasmic reticulum, and involved in both lipid metabolic disorders and motor neuropathy. The aim of this study was to investigate the effects of mutant seipin on autophagy system and the morphology of lipid droplets in vitro.
Methods:
HEK-293, H1299 and MES23.5 cells were transfected with the plasmids of mutated seipin at glycosylation sites (N88S or S90L) and GFP-LC3 plasmids. The cells were subjected to immunofluorescence and flow cytometry assays, and the cell lysates were subjected to immunoblot analysis. Nile Red was used to stain the lipid droplets in the cells.
Results:
Overexpression of the mutated seipin proteins N88S or S90L activated autophagy in the 3 cell lines, and substantially altered the sub-cellular distribution of the autophagosome marker GFP-LC3, leading to a number of large vacuoles appearing in the cytoplasm. The sub-cellular location of GFP-LC3 and mutated seipin proteins highly overlapped. Moreover, and the mutated seipin proteins caused diffuse small lipid droplets to fuse into larger lipid droplets. Treatment of mutated seipin-transfected cells with the autophagy inhibitor 3-MA (5 mmol/L) facilitated the fusion of mutated seipin-induced large vacuoles. The protein glycosylation inhibitor tunicamycin could mimic the mutated seipin-induced effects, and treatment of the wild-type seipin-transfected cells with tunicamycin (2.5 μg/mL) produced similar morphological and biochemical properties as in the mutated seipin-transfected cells.
Conclusion:
The mutation of seipin at glycosylation sites disrupt its function in regulating lipid droplet metabolism, and the autophagy acts as an adaptive response to break down abnormal lipid droplets. The interruption of autophagy would accelerate the fusion of abnormal lipid droplets.
doi:10.1038/aps.2014.164
PMCID: PMC4387305  PMID: 25832430
seipin; lipodystrophy; motor neuron disease; glycosylation; lipid droplets; autophagy; 3-MA; tunicamycin; endoplasmic reticulum
19.  Dietary l-Arginine Supplementation Protects Weanling Pigs from Deoxynivalenol-Induced Toxicity 
Toxins  2015;7(4):1341-1354.
This study was conducted to determine the positive effects of dietary supplementation with l-arginine (Arg) on piglets fed a deoxynivalenol (DON)-contaminated diet. A total of eighteen, 28-day-old healthy weanling pigs were randomly assigned into one of three groups: uncontaminated basal diet (control group), 6 mg/kg DON-contaminated diet (DON group) and 6 mg/kg DON + 1% l-arginine (DON + ARG group). After 21 days of Arg supplementation, piglets in the DON and DON + ARG groups were challenged by feeding 6 mg/kg DON-contaminated diet for seven days. The results showed that DON resulted in damage to piglets. However, clinical parameters, including jejunal morphology, amino acid concentrations in the serum, jejunum and ileum, were improved by Arg (p < 0.05). Furthermore, the mRNA levels for sodium-glucose transporter-1 (SGLT-1), glucose transporter type-2 (GLUT-2) and y+l-type amino acid transporter-1 (y+LAT-1) were downregulated in the DON group, but the values were increased in the DON + ARG group (p < 0.05). Collectively, these results indicate that dietary supplementation with Arg exerts a protective role in pigs fed DON-contaminated diets.
doi:10.3390/toxins7041341
PMCID: PMC4417970  PMID: 25884909
deoxynivalenol (DON); l-arginine; amino acid transporter; weanling pigs
20.  LRIG1 enhances the radiosensitivity of radioresistant human glioblastoma U251 cells via attenuation of the EGFR/Akt signaling pathway 
The radiotherapy as a local and regional modality is widely applied in treatment of glioma, but most glioblastomas are commonly resistant to irradiation treatment. It remains challengeable to seek out efficient strategies to conquer the resistance of human glioblastoma cells to radiotherapy. Leucine-rich repeats and immunoglobulin-like domains protein 1 (LRIG1) is a newly discovered tumor suppressor which involved in regulation of chemosensitivity in various human cancer cells. In the present study, we established a radioresistant U251 cell line (U251R) to investigate the role of LRIG1 in regulation of radiosensitivity in human glioblastoma cells. Significantly decreased expression level of LRIG1 and enhanced expression of EGFR and phosphorylated Akt were detected in U251R cells compared with the parental U251 cells. U251R cells exhibited an advantage in colony formation ability, which accompanied by remarkably reduced X-ray-induced γ-H2AX foci formation and cell apoptosis. LRIG1 overexpression significantly inhibited the colony formation ability of U251R cells and obviously enhanced X-ray-inducedγ-H2AX foci formation and cell apoptosis. In addition, up-regulated expression of LRIG1 suppressed the expression level of EGFR and phosphorylated Akt protein. Our results demonstrated that LRIG1 expression was related to the radiosensitivity of human glioblastoma cells and may play an important role in the regulation of cellular radiosensitivity of human glioblastoma cells through the EGFR/Akt signaling pathway.
PMCID: PMC4466927  PMID: 26097540
LRIG1; glioblastoma; radiosensitivity; γ-H2AX; apoptosis; EGFR signaling
21.  Gallic Acid Induces Necroptosis via TNF–α Signaling Pathway in Activated Hepatic Stellate Cells 
PLoS ONE  2015;10(3):e0120713.
Gallic acid (3, 4, 5-trihydroxybenzoic acid, GA), a natural phenolic acid widely found in gallnuts, tea leaves and various fruits, possesses several bioactivities against inflammation, oxidation, and carcinogenicity. The beneficial effect of GA on the reduction of animal hepatofibrosis has been indicated due to its antioxidative property. However, the cytotoxicity of GA autoxidation causing cell death has also been reported. Herein, we postulated that GA might target activated hepatic stellate cells (aHSCs), the cell type responsible for hepatofibrosis, to mitigate the process of fibrosis. The molecular cytotoxic mechanisms that GA exerted on aHSCs were then analyzed. The results indicated that GA elicited aHSC programmed cell death through TNF–α–mediated necroptosis. GA induced significant oxidative stress through the suppression of catalase activity and the depletion of glutathione (GSH). Elevated oxidative stress triggered the production of TNF–α facilitating the undergoing of necroptosis through the up-regulation of key necroptotic regulatory proteins TRADD and receptor-interacting protein 3 (RIP3), and the inactivation of caspase–8. Calmodulin and calpain–1 activation were engaged, which promoted subsequent lysosomal membrane permeabilization (LMP). The TNF–α antagonist (SPD–304) and the RIP1 inhibitor (necrostatin–1, Nec–1) confirmed GA-induced TNFR1–mediated necroptosis. The inhibition of RIP1 by Nec–1 diverted the cell death from necroptosis to apoptosis, as the activation of caspase 3 and the increase of cytochrome c. Collectively, this is the first report indicating that GA induces TNF signaling–triggered necroptosis in aHSCs, which may offer an alternative strategy for the amelioration of liver fibrosis.
doi:10.1371/journal.pone.0120713
PMCID: PMC4376672  PMID: 25816210
22.  Obstacles to the coordination of delivering integrated prenatal HIV, syphilis and hepatitis B testing services in Guangdong: using a needs assessment approach 
Background
Integration of services for Prevention of Mother-To-Child Transmission of HIV (PMTCT) into routine maternal and child health care is promoted as a priority strategy by the WHO to facilitate the implementation of PMTCT. Integration of services emphasizes inter-sectoral coordination in the health systems to provide convenient services for clients. China has been integrating prenatal HIV, syphilis and hepatitis B testing services since 2009. However, as the individual health systems are complex, effective coordination among different health agencies is challenging. Few studies have examined the factors that affect the coordination of such complex systems. The aim of this study is to assess the effectiveness of and examine challenges for integrated service delivery. Findings will provide the basis for strategy development to enhance the effective delivery of integrated services.
Methods
The research was conducted in Guangdong province in 2013 using a needs assessment approach that includes qualitative and quantitative methods. Quantitative data was collected through a survey and from routine monitoring for PMTCT and qualitative data was collected through stakeholder interviews.
Results
Routine monitoring data used to assess key indicators of coordination suggested numerous coordination problems. The rates of prenatal HIV (95%), syphilis (47%) and hepatitis B (47%) test were inconsistent. An average of only 20% of the HIV positive mothers was referred in the health systems. There were no regular meetings among different health agencies and the clients indicated complicated service processes. The major obstacles to the coordination of delivering these integrated services are lack of service resource integration; and lack of a mechanism for coordination of the health systems, with no uniform guidelines, clear roles or consistent evaluation.
Conclusions
The key obstacles that have been identified in this study hinder the coordination of the delivery of integrated services. Our recommendations include: 1) Facilitate integration of the funding and information systems by fully combining the service resources of different health agencies into one unit; 2) Establish regular meetings to facilitate exchange of information and address problems; 3) Establish a client referral network between different health agencies with agreed guidelines, clear roles and consistent evaluation.
doi:10.1186/s12913-015-0760-0
PMCID: PMC4378261  PMID: 25889645
Integrated prenatal testing services; Prevention of mother-to-child transmission of HIV
23.  Prevalence and Associated Factors of Myopia in High-School Students in Beijing 
PLoS ONE  2015;10(3):e0120764.
Purpose
To evaluate prevalence and associated factors for myopia in high school students in Beijing.
Methods
Grade 10 and 11 high school students were randomly selected from nine randomly selected districts of Beijing. The students underwent non-cylcoplegic auto-refractometry and an interview.
Results
Out of 4798 eligible students, 4677 (93.4%) students (mean age:16.9±0.7years;range:16–18 years) participated. Mean refractive error of right eyes and left eyes was −2.78±2.29 diopters and −2.59±2.50 diopters, respectively. Prevalence of myopia (defined as ≤ −1.00 diopters in the worse eye) was 80.7% (95% Confidence Interval (CI): 79.6–81.8%). Out of 3773 students with myopia, 1525 (40.4%) wore glasses daily. In multiple logistic regression analysis, a higher prevalence of myopia was associated with female sex (odds ratio (OR) = 1.31;95%CI:1.11–1.55), Han ethnicity (OR = 1.64;95%CI:1.28–2.11), attending key schools (OR = 1.48;95%CI:1.24,1.77), higher family income (OR = 1.37;95%CI:1.09–1.71), longer time spent for near work (OR = 1.43;95%CI:1.06–1.93), shorter near work distance (OR = 1.87;95%CI:1.55–2.26), lower frequency of active rest during studying (OR = 1.40;95%CI:1.16–1.70), and parental myopia (OR = 2.28;95%CI:1.80–2.87). The interaction between distance from near work and time spent for near work was statistically (P = 0.03) significant. In multiple logistic regression analysis, higher prevalence of high myopia (≤-6.0 diopters) was associated with studying in key schools (OR = 1.38;95%CI:1.05,1.81), lower frequency of active rest during studying (OR = 1.40;95%CI:1.09,1.79), and a higher number of myopic parents (OR = 2.66;95%CI:2.08,3.40).
Conclusions
A prevalence of about 80% for myopia and a prevalence of about 10% for high myopia in students aged 16 to 18 years and attending classes of grade 10 and 11 in a Chinese metropolitan region is another example of the high prevalence of moderate and high myopia in metropolitan areas of China. With this young myopic generation getting older, myopia as cause for visual impairment and blindness may further increase in importance. Future studies may address whether active rests during studying with looking into the distance are preventive against myopia development or progression.
doi:10.1371/journal.pone.0120764
PMCID: PMC4372519  PMID: 25803875
24.  Improving Target Coverage and Organ-at-Risk Sparing in Intensity-Modulated Radiotherapy for Cervical Oesophageal Cancer Using a Simple Optimisation Method 
PLoS ONE  2015;10(3):e0121679.
Purpose
To assess the performance of a simple optimisation method for improving target coverage and organ-at-risk (OAR) sparing in intensity-modulated radiotherapy (IMRT) for cervical oesophageal cancer.
Methods
For 20 selected patients, clinically acceptable original IMRT plans (Original plans) were created, and two optimisation methods were adopted to improve the plans: 1) a base dose function (BDF)-based method, in which the treatment plans were re-optimised based on the original plans, and 2) a dose-controlling structure (DCS)-based method, in which the original plans were re-optimised by assigning additional constraints for hot and cold spots. The Original, BDF-based and DCS-based plans were compared with regard to target dose homogeneity, conformity, OAR sparing, planning time and monitor units (MUs). Dosimetric verifications were performed and delivery times were recorded for the BDF-based and DCS-based plans.
Results
The BDF-based plans provided significantly superior dose homogeneity and conformity compared with both the DCS-based and Original plans. The BDF-based method further reduced the doses delivered to the OARs by approximately 1–3%. The re-optimisation time was reduced by approximately 28%, but the MUs and delivery time were slightly increased. All verification tests were passed and no significant differences were found.
Conclusion
The BDF-based method for the optimisation of IMRT for cervical oesophageal cancer can achieve significantly better dose distributions with better planning efficiency at the expense of slightly more MUs.
doi:10.1371/journal.pone.0121679
PMCID: PMC4358965  PMID: 25768733
25.  Elevated expression of NEDD9 is associated with metastatic activity in gastric cancer 
OncoTargets and therapy  2015;8:633-640.
Objective
To investigate the protein and mRNA expression of NEDD9 in gastric cancer (GC) tissues, adjacent atypical hyperplasia tissues, and normal gastric mucosa tissues, and analyze its relationship with the pathological features and prognosis of GC.
Methods
Forty cases of GC tissues, 20 cases of adjacent atypical hyperplasia tissues, and 40 cases of normal gastric mucous tissues were collected. Immunohistochemistry and Western blot were used to examine the expression of NEDD9 protein in various tissues. Situ hybridization and reverse transcription polymerase chain reaction were applied to detect the expression of NEDD9 mRNA in various tissues. The correlation of NEDD9 expression with invasion and metastasis of GC was analyzed.
Results
The protein expression level of NEDD9 was significantly higher in GC tissues than in adjacent atypical hyperplasia tissues and normal gastric mucous tissues (P<0.05). The protein expression level of NEDD9 was positively related to the invasion depth of carcinoma and tumor lymph node metastasis (P<0.05), but unrelated to age, sex, tumor size, and clinical classification of cancer (P<0.05). The mRNA expression level of NEDD9 was also significantly higher in GC tissues than in adjacent atypical hyperplasia tissues and normal gastric mucous tissues (P<0.05), and positively related with the tumor lymph node metastasis and invasion depth of carcinoma (P<0.05).
Conclusion
NEDD9 is involved in the occurrence and development of GC, and it may be an important biological marker of GC metastasis and infiltration.
doi:10.2147/OTT.S77904
PMCID: PMC4360801  PMID: 25792847
immunohistochemistry (IHC); invasion; metastasis

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