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1.  Risk Factors Associated With Sphincter-Preserving Resection in Patients With Low Rectal Cancer 
International Surgery  2014;99(4):330-337.
Abdominoperineal resection (APR) and sphincter-preserving resection (SPR) are the two primary surgical options for rectal cancer. Retrospectively we collected rectal cancer patients for SPR and APR observation between 2005 and 2007. The patient-related, tumor-related, and surgery-related variables of the SPR and APR groups were analyzed by using logistic regression techniques. The mean distance from the anal verge (DAV) of cancer is significantly higher in SPR than that in APR (P < 0.001). In cancers with DAV <40 mm (SPR, 40 versus APR, 110), multivariate analysis shows that surgeon procedure volume (odds ratio [OR] = 0.244; 95% confidence interval [CI]: 0.077–0.772; P = 0.016) and neoadjuvant radiotherapy (OR = 0.031; 95% CI: 0.002–0.396; P = 0.008) are factors influencing SPR. In cancers with DAV ranging from 40 mm to 59 mm (SPR 190 versus APR 50), analysis shows that patient age (OR = 2.139; 95% CI: 1.124–4.069; P = 0.021), diabetes (OR = 2.657; 95% CI: 0.872–8.095; P = 0.086), and colorectal surgeon (OR = 0.122, 95% CI: 0.020–0.758; P = 0.024), are influencing factors for SPR. The local recurrence and disease-free survival reveal no significant difference. A significant difference exists in DAV, surgeon specialization, procedure volume, age, diabetes, and neoadjuvant radiotherapy between SPR and APR.
doi:10.9738/INTSURG-D-13-00217.1
PMCID: PMC4114357  PMID: 25058761
Abdominoperineal resection; Sphincter-preserving resection; Anterior resection; Rectal cancer; Treatment
2.  A cross-population extended haplotype-based homozygosity score test to detect positive selection in genome-wide scans 
Statistics and its interface  2011;4(1):51-63.
In this article, we developed a cross-population comparison test statistic to detect chromosome regions in which there is no significant excess homozygosity in one population but homozygosity remains high in the other. We treated an extended stretch of homozygosity as a surrogate indicator of a recent positive selection. Conditioned on existing linkage disequilibrium, we proposed to test the haplotype version of the Hardy–Weinberg equilibrium (HWE). For each population, we assumed that a random sample of unrelated individuals were typed on a large number of single nucleotide polymorphisms (SNPs). A pooled-test statistic was constructed by comparing the measurements of homozygosity of the two samples around a core SNP. In the chromosome regions where HWE is roughly true in one population and HWE is not true in the other, the pooled-test statistic led to significant results to detect the positive selection. We evaluated the performance of the test statistic by type I error comparison and power evaluation. We showed that the proposed test statistic was very conservative and it had good power when the selected allele remains polymorphic. Then, we applied the test to HapMap Phase II data to make a comparison with previous results and to search for new candidate regions.
doi:10.4310/SII.2011.v4.n1.a6
PMCID: PMC4470573  PMID: 26097641
Extended homozygosity; Linkage disequilibrium; Ositive selection
3.  Methoxy-Directed Aryl-to-Aryl 1,3-Rhodium Migration 
Journal of the American Chemical Society  2013;135(46):17270-17273.
Through-space metal/hydrogen shift is an important strategy for transition metal-catalyzed C-H bond activation. Here we describe the synthesis and characterization of a Rh(I) 2,6-dimethoxybenzoate complex that underwent stoichiometric rearrangement via a highly unusual 1,3- rhodium migration. This aryl-to-aryl 1,3-Rh/H shift was also demonstrated in a Rh(I)-catalyzed decarboxylative conjugate addition to form a C-C bond at a meta position instead of the ipso-carboxyl position. A deuterium-labeling study under the conditions of Rh(I)-catalyzed protodecarboxylation revealed the involvement of an ortho-methoxy group in a multi-step pathway of consecutive sp3 and sp2 C-H bond activations.
doi:10.1021/ja409049t
PMCID: PMC4447322  PMID: 24171626
4.  Pitavastatin calcium improves endothelial function and delays the progress of atherosclerosis in patients with hypercholesterolemia*  
Background: Statins have proven efficacy in inhibiting the onset and progress of atherosclerosis. The effectiveness of pitavastatin in reversing carotid atherosclerosis associated with hypercholesterolemia (HC) is unknown. Objectives: To explore the simultaneous effects of pitavastatin calcium on brachial arterial flow-mediated vasodilatation (FMD), carotid intima-media thickness (IMT), and arterial stiffness (β), three surrogate markers of atherosclerosis were studied in HC patients. Methods: A randomized, double-blind trial was performed with 40 HC subjects who fulfilled the inclusion/exclusion criteria. Patients were given pitavastatin calcium 1 mg/d (Group 1) or 2 mg/d (Group 2) for 8 weeks. There were 20 patients in each group, and 30 gender- and age-matched healthy subjects as controls were recruited. FMD of the brachial artery, carotid IMT, and arterial stiffness indicated by β were measured at baseline and at 8 weeks after starting pitavastatin calcium therapy using ultrasound techniques. Biochemical tests were also made on all subjects. Results: At baseline, higher total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C), reduced FMD, and increased β and IMT were observed in HC patients (P<0.001 for all) compared with controls. After 8 weeks, TC was decreased by 20.59%/27.56% and LDL-C 30.92%/35.64%, respectively, in comparison to baseline groups; the HC groups had reduced β and improved endothelial function over the 8-week follow-up (P<0.05–0.001); nonetheless, no significant alterations of IMT were found (P>0.05). Significant negative interactions between TC/LDL and FMD (P<0.05–0.001), positive interactions between TC and IMT (P=0.003) and between TC/LDL and β (P<0.001–0.000) were found. Conclusions: Treatment with pitavastatin calcium exerted favorable effects on endothelial function and arterial stiffness. It also improved carotid atherosclerosis in patients with HC.
doi:10.1631/jzus.B1400181
PMCID: PMC4432990  PMID: 25990055
Flow-mediated vasodilatation (FMD); Hypercholesterolemia (HC); Carotid intima-media thickness (IMT); Pitavastatin calcium
5.  Inhibition of STAT3 signaling as critical molecular event in resveratrol-suppressed ovarian cancer cells 
Background
Resveratrol exerts inhibitory effects on ovarian cancer cells, while its underlying mechanism and critical molecular target(s) have been lesser known. Activations of Wnt, Notch and STAT3 signaling are frequent in ovarian cancers/OCs and supposed to be important for OC formation and progression, while the impacts of resveratrol on these signaling pathways in OC cells remain obscure.
Methods
In this study, two human ovarian cancer cell lines, OVCAR-3 and CAOV-3, were treated by 120 μM resveratrol and their responses to the treatment and the statuses of Wnt, Notch and STAT3 signaling in them were analyzed by multiple experimental approaches. Selective inhibitors of Wnt, Notch or STAT3 signaling were employed to treat OVCAR-3 and CAOV-3 cells to elucidate the significance of individual signaling pathways for ovarian cancers.
Results
The results demonstrated distinct inhibitory effects of resveratrol on human ovarian cancer cells in terms of remarkable G1 phase accumulation, increased apoptosis fraction and concurrent suppression of Wnt, Notch and STAT3 signaling as well as their downstream cancer-related gene expression. Treatments with Wnt, Notch or STAT3 selective inhibitor revealed that only AG490, a JAK-specific inhibitor, inhibits OVCAR-3 and CAOV-3 cells in the extent as similar as that of resveratrol.
Conclusion
Our results suggest the significance of STAT3 activation in the maintenance and survival of ovarian cancer cells. The activated STAT3 signaling is the critical molecular target of resveratrol. Resveratrol would be a promising candidate in the management of ovarian cancers, especially the ones with resistance to conventional therapeutic agents.
doi:10.1186/s13048-015-0152-4
PMCID: PMC4409989  PMID: 25896424
Ovarian cancer; Resveratrol; Signal transduction pathway; STAT3; Selective inhibitor; Gene expression
6.  Factors and outcomes associated with ultra-early surgery for poor-grade aneurysmal subarachnoid haemorrhage: a multicentre retrospective analysis 
BMJ Open  2015;5(4):e007410.
Objective
To determine factors and outcomes associated with ultra-early surgery for poor-grade aneurysmal subarachnoid haemorrhage (aSAH).
Design
A multicentre retrospective analysis, observational study.
Setting
High-volume teaching hospitals (more than 150 aSAH cases per year).
Participants
118 patients with World Federation of Neurosurgical Societies (WFNS) grades IV and V underwent surgical treatment. Ultra-early surgery was defined as surgery performed within 24 h of aSAH, and delayed surgery as surgery performed after 24 h. Outcome was assessed by modified Rankin Scale (mRS). The mean time of follow-up was 12.5±3.4 months (range 6–28 months).
Results
47 (40%) patients underwent ultra-early surgery, and 71 (60%) patients underwent delayed surgery. Patients with WFNS grade V (p=0.011) and brain herniation (p=0.004) more often underwent ultra-early surgery. Postoperative complications were similar in ultra-early and delayed surgery groups. Adjusted multivariate analysis showed the outcomes were similar between the two groups. Multivariate analysis of predictors of poor outcome, ultraearly surgery was not an independent predictor of poor outcome, while advanced age, postresuscitation WFNS V grade, intraventricular haemorrhage, brain herniation and non-middle cerebral artery (MCA) aneurysms were associated with poor outcome.
Conclusions
Although patients with WFNS grade V and brain herniation more often undergo ultra-early surgery, postoperative complications and outcomes in selected patients were similar in the two groups. Patients of younger age, WFNS grade IV, absence of intraventricular haemorrhage, absence of brain herniation and MCA aneurysms are more likely to have a good outcome. Ultra-early surgery could improve outcomes in carefully selected patients with poor-grade aSAH.
doi:10.1136/bmjopen-2014-007410
PMCID: PMC4401840  PMID: 25877280
NEUROSURGERY; VASCULAR SURGERY
7.  Expression of phosphorylated Akt/mTOR and clinical significance in human ameloblastoma 
This study aimed to evaluate the expression of AKT and phosphorylated AKT (p-Akt) in human ameloblastoma (AB). Immunohistochemistry showed human AB was positive for Akt and Akt expression was mainly found in the cytoplasm of epithelial cells. The Akt expression in AB was significantly higher than that in normal oral mucosa (NOM), but still lower than that in oral squamous cell carcinoma (OSCC). NOM was negative for p-Akt, but AB was positive for p-Akt. In some AB tissues, p-Akt expression was found in both cytoplasm and nucleus. Akt expression in AB was significantly different from that in NOM and OSCC. The p-Akt in AB was markedly higher than that in NOM, but lower than that in OSCC. mTOR expressed in cytoplasm in AB, but not in NOM. P-mTOR expressed on cell membrane in NOM, while in cytoplasm and nucleus in Ab. Results of western blot assay showed that Akt expression was found in all the AB tissues, and increased in tissues with malignant transformation. In addition, the p-Akt expression also markedly increased in AB, but was still lower than that in OSCC tissues. Compared to NOM, mTOR and p-mTOR expression significantly increased in AB. BandScan 5.0 software was used to detect the optical density of protein bands. Results showed p-Akt, mTOR and p-mTOR expression in AB was markedly different from that in control group.
PMCID: PMC4483961  PMID: 26131097
Human ameloblastoma; oral squamous cell carcinoma; Akt
8.  Valsartan blocks thrombospondin/transforming growth factor/Smads to inhibit aortic remodeling in diabetic rats 
Diagnostic Pathology  2015;10:18.
Background
Angiotensin II (Ang II) and transforming growth factor β (TGFβ) are closely involved in the pathogenesis of diabetic complications. We aimed to determine whether an aberrant thrombospondin 1 (TSP1)–mediated TGFβ1/Smads signaling pathway specifically affects vascular fibrosis in diabetic rats and whether valsartan, an Ang II subtype 1 receptor blocker, has an anti-fibrotic effect.
Methods
Age-matched male Wistar rats were randomly divided into 3 groups: control (n = 8), diabetes (n = 16) and valsartan (30 mg/kg/day) (n = 16). Type 2 diabetes mellitus (T2DM) was induced by a high-calorie diet and streptozotocin injection. Morphological and biomechanical properties of the thoracic aorta were assessed by echocardiography and cardiac catheterization. Masson staining was used for histological evaluation of extracellular matrix (ECM). The expression of components in the TSP1–mediated TGFβ1/Smads signaling pathway was analyzed by immunohistochemistry and real-time quantitative reverse transcription polymerase chain reaction.
Results
As compared with controls, diabetic aortas showed reduced distensibility and compliance, with excess ECM deposition. Components in the TSP1-mediated TGFβ1/Smads signaling pathway, including TSP1, TGFβ1, TGFβ type II receptor (TβRII), Smad2 and Smad3, were accumulated in vascular smooth muscle cytoplasm of diabetic aortas and their protein and mRNA levels were upregulated. All these abnormalities were attenuated by valsartan.
Conclusions
TSP1-mediated TGFβ1/Smads pathway activation plays an important role in marcovascular remodeling in T2DM in rat. Valsartan can block the pathway and ameliorate vascular fibrosis.
Virtual slides
The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1053842818141195
doi:10.1186/s13000-015-0246-8
PMCID: PMC4460645  PMID: 25884585
Diabetes; Macrovascular remodeling; Thrombospondin 1; Transforming growth factor β1; Smads; valsartan
9.  PEDF Improves Cardiac Function in Rats with Acute Myocardial Infarction via Inhibiting Vascular Permeability and Cardiomyocyte Apoptosis 
Pigment epithelium-derived factor (PEDF) is a pleiotropic gene with anti-inflammatory, antioxidant and anti-angiogenic properties. However, recent reports about the effects of PEDF on cardiomyocytes are controversial, and it is not known whether and how PEDF acts to inhibit hypoxic or ischemic endothelial injury in the heart. In the present study, adult Sprague-Dawley rat models of acute myocardial infarction (AMI) were surgically established. PEDF-small interfering RNA (siRNA)-lentivirus (PEDF-RNAi-LV) or PEDF-LV was delivered into the myocardium along the infarct border to knockdown or overexpress PEDF, respectively. Vascular permeability, cardiomyocyte apoptosis, myocardial infarct size and animal cardiac function were analyzed. We also evaluated PEDF’s effect on the suppression of the endothelial permeability and cardiomyocyte apoptosis under hypoxia in vitro. The results indicated that PEDF significantly suppressed the vascular permeability and inhibited hypoxia-induced endothelial permeability through PPARγ-dependent tight junction (TJ) production. PEDF protected cardiomyocytes against ischemia or hypoxia-induced cell apoptosis both in vivo and in vitro via preventing the activation of caspase-3. We also found that PEDF significantly reduced myocardial infarct size and enhanced cardiac function in rats with AMI. These data suggest that PEDF could protect cardiac function from ischemic injury, at least by means of reducing vascular permeability, cardiomyocyte apoptosis and myocardial infarct size.
doi:10.3390/ijms16035618
PMCID: PMC4394496  PMID: 25768344
pigment epithelium-derived factor (PEDF); myocardial infarction; cardiac function; vascular permeability; PPARγ; apoptosis
10.  Incidence and Mortality of Anastomotic Dehiscence Requiring Reoperation After Rectal Carcinoma Resection 
International Surgery  2014;99(2):112-119.
Anastomotic dehiscence (AD) requiring reoperation is the most severe complication following anterior rectal resection. We performed a systematic review on studies that describe AD requiring reoperation and its subsequent mortality after anterior resection for rectal carcinoma. A systematic search was performed on published literature. Data on the definition and rate of AD, the number of ADs requiring reoperation, the mortality caused by AD, and the overall postoperative mortality were pooled and analyzed. A total of 39 studies with 24,232 patients were analyzed. The studies varied in incidence and definition of AD. Systematic review of the data showed that the overall rate of AD was 8.6%, and the rate of AD requiring reoperation was 5.4%. The postoperative mortality caused by AD was 0.4%, and the overall postoperative mortality was 1.3%. We found considerable risk and mortality for AD requiring reoperation, which largely contributed to the overall postoperative mortality.
doi:10.9738/INTSURG-D-13-00059
PMCID: PMC3968835  PMID: 24670019
Anastomotic dehiscence; Anterior resection; Rectal carcinoma; Complication; Mortality; Treatment
11.  Clinical effect of postconditioning in ST-elevation myocardial infarction patients treated with primary percutaneous coronary intervention: a meta-analysis of randomized controlled trials*  
Objective: To evaluate the clinical effect of postconditioning on patients with ST-elevation myocardial infarction (STEMI) treated with primary percutaneous coronary intervention (PCI). Methods: Randomized controlled trials were identified by searching relevant databases published up to April 2nd, 2014. A meta-analysis of eligible studies was performed by Stata 12.0 and Review Manager 5.2 with a fixed-effect model. Results: Ten studies providing adverse cardiac events in a total of 1346 STEMI patients treated with primary PCI were identified. The occurrence of heart failure was significantly reduced in patients treated with postconditioning compared with usual care (risk ratio (RR) 0.533; 95% confidence intervals (CI) 0.368–0.770), whereas non-fatal reinfarction slightly increased in the postconditioning group (RR 2.746; 95% CI 1.007–7.488). No significant difference in total major adverse cardiac events (MACEs) was observed between the two groups (RR 0.876; 95% CI 0.671–1.144). Conclusions: Postconditioning in STEMI patients undergoing primary PCI significantly reduces the risk of heart failure, but fails to decrease the incidence of total MACEs and the risk of non-fatal reinfarction.
doi:10.1631/jzus.B1400237
PMCID: PMC4357369  PMID: 25743121
Myocardial infarction; Postconditioning; Coronary intervention
12.  Expression variations of connective tissue growth factor in pulmonary arteries from smokers with and without chronic obstructive pulmonary disease 
Scientific Reports  2015;5:8564.
Cigarette smoking contributes to the development of pulmonary hypertension (PH) complicated with chronic obstructive pulmonary disease (COPD), and the pulmonary vascular remodeling, the structural basis of PH, could be attributed to abnormal proliferation of pulmonary artery smooth muscle cells (PASMCs).In this study, morphometrical analysis showed that the pulmonary vessel wall thickness in smoker group and COPD group was significantly greater than in nonsmokers. In addition, we determined the expression patterns of connective tissue growth factor (CTGF) and cyclin D1 in PASMCs harvested from smokers with normal lung function or mild to moderate COPD, finding that the expression levels of CTGF and cyclin D1 were significantly increased in smoker group and COPD group. In vitro experiment showed that the expression of CTGF, cyclin D1 and E2F were significantly increased in human PASMCs (HPASMCs) treated with 2% cigarette smoke extract (CSE), and two CTGF siRNAs with different mRNA hits successfully attenuated the upregulated cyclin D1 and E2F, and significantly restored the CSE-induced proliferation of HPASMCs by causing cell cycle arrest in G0. These findings suggest that CTGF may contribute to the pathogenesis of abnormal proliferation of HPASMCs by promoting the expression of its downstream effectors in smokers with or without COPD.
doi:10.1038/srep08564
PMCID: PMC4338434  PMID: 25708588
13.  A medical costs study of older patients with acute myocardial infarction and metabolic syndrome in hospital 
Background
Older patients with acute myocardial infarction (AMI) usually have a poor prognosis, but whether this poor prognosis leads to high hospital costs remains unclear. This study investigated the clinical outcomes of and costs incurred by older patients with AMI and metabolic syndrome (MS) in hospital.
Methods and results
Patients with AMI seen at Qilu Hospital of Shandong University between January 2011 and May 2013 were separated into four groups: young non-MS patients (n=282), older non-MS patients (n=324), young MS patients (n=217), and older MS patients (n=174). We found that advanced age was significantly associated with worse clinical outcomes, and that the clinical outcomes in patients with AMI and MS are also worsened. At the same cost (RMB¥10,000), older patients with and without MS had a markedly increased number of cardiovascular incidences compared with younger patients without MS. In a comparison of the incremental cost-effectiveness ratio (ICER) of percutaneous coronary intervention, older patients without MS had a lower ICER for cardiovascular incidences and a higher ICER for cardiac event-free survival rate when compared with young patients without MS, but a lower ICER for cardiovascular incidences and a higher ICER for cardiac event-free survival rate when compared with older MS patients.
Conclusion
Older AMI patients have poor clinical outcomes and their treatment is not cost-effective; however, the results are worse in patients with AMI and MS. Percutaneous coronary intervention is a cost-effective therapy in older patients with AMI, but its cost-effectiveness decreases in patients with AMI and MS.
doi:10.2147/CIA.S70372
PMCID: PMC4315548  PMID: 25670890
metabolic syndrome; aging; vascular; acute myocardial infarction; cost-effectiveness
14.  Time-dependent changes of plasma inflammatory biomarkers in type A aortic dissection patients without optimal medical management 
Objectives
To investigate the time-dependent changes in plasma levels of interleukin-6, C-reactive protein, and tumor necrosis factor-α in patients with type A aortic dissection (TAAD) who received unoptimal medical management since the onset of dissections.
Design and methods
Plasma levels of interleukin-6, C-reactive protein, and tumor necrosis factor-α were detected by ELISA and immuno-turbidimetric assay in 92 TAAD patients at hospital admission. Blood samples from 78 patients with uncontrolled hypertension and 82 healthy volunteers were also analyzed as controls. The occurrence of TAAD-related complication and its relationship with the plasma levels of these inflammatory biomarkers was also investigated.
Results
The concentrations of inflammatory mediators were significant higher in TAAD than those in the uncontrolled hypertension and the healthy group. The time to peak plasma level of IL-6.and TNF-α was shorter than that of CRP in TAAD group. In the TAAD group, 51 patients suffered TAAD-related complications, and their plasma level of CRP was significantly higher than that in patients without TAAD-related complications (94.5 ± 58.8 mg/L versus 47.4 ± 47.8 mg/L, p < 0.001). Also, CRP levels strongly correlated with the value of PaO2/FiO2 ratio (r = −0.69, p < 0.001) and creatinine (r = 0.60, p < 0.001). The time to the peak level of CRP was shorter and the duration of persistently high CRP level was longer in the complication group than those in the complication-free group.
Conclusions
Elevated and persistently high levels of plasma CRP, IL-6 and TNF-α were associated with progressively development of the TAAD. The changing pattern of CRP might be a marker for diagnosis and prophylactic treatment of complications. Our findings suggested a critical role of the inflammation in the progression of dissection and TAAD-related complications.
doi:10.1186/s13019-014-0199-0
PMCID: PMC4302155  PMID: 25592634
Type A aortic dissection; Inflammatory mediator; Interleukin-6; C-reactive protein; Tumor necrosis factor-α; Complication
15.  rs17501976 polymorphism of CLDN1 gene is associated with decreased risk of colorectal cancer in a Chinese population 
The purpose of this study was to determine the relationship between polymorphisms in Claudin-1 (CLDN1) and the risk of colorectal cancer in a Chinese population. In this study, a case-control study was conducted in which polymorphisms in CLDN1 were analyzed in 50 patients with colorectal cancer (CRC) and 50 healthy individuals as controls. No rs16865344 and rs17429833 polymorphism were found among all analyzed samples. For the rs17501976 polymorphism, the TC genotype (OR = 0. 41, 95% CI = 0.18-0.91, and P = 0.045) was closely associated with the risk of colorectal cancer compared with the more common TT genotype. And the TC + CC genotypes (OR = 0.41, 95% CI = 0.18-0.91, and P = 0.045) were also significantly associated with the risk of CRC compared with the TT genotype. However, a C > T change of the rs17501976 polymorphism did not show a difference in transcription factor binding to the promoter region of CLDN1. For rs12696600 polymorphism, no significant difference was found in colorectal cancer risk between cases and controls in corresponding genotypes. Collectively, our data suggest that rs17501976 polymorphism significantly associated with a decreased susceptibility to CRC in a Chinese population.
PMCID: PMC4358575  PMID: 25785120
Colorectal cancer; Claudin 1; rs17501976; single nucleotide polymorphism
16.  Identification of PLXDC1 and PLXDC2 as the transmembrane receptors for the multifunctional factor PEDF 
eLife  null;3:e05401.
Pigment Epithelium Derived Factor (PEDF) is a secreted factor that has broad biological activities. It was first identified as a neurotrophic factor and later as the most potent natural antiangiogenic factor, a stem cell niche factor, and an inhibitor of cancer cell growth. Numerous animal models demonstrated its therapeutic value in treating blinding diseases and diverse cancer types. A long-standing challenge is to reveal how PEDF acts on its target cells and the identities of the cell-surface receptors responsible for its activities. Here we report the identification of transmembrane proteins PLXDC1 and PLXDC2 as cell-surface receptors for PEDF. Using distinct cellular models, we demonstrate their cell type-specific receptor activities through loss of function and gain of function studies. Our experiments suggest that PEDF receptors form homooligomers under basal conditions, and PEDF dissociates the homooligomer to activate the receptors. Mutations in the intracellular domain can have profound effects on receptor activities.
DOI: http://dx.doi.org/10.7554/eLife.05401.001
eLife digest
Many cells in our body release signals that trigger responses in other cells. A protein called PEDF is a signal released from a variety of cells that can prevent the formation of new blood vessels, protect cells in the retina and brain from damage and stop cancer cells from growing. Experiments using model animals have also demonstrated that PEDF could be used to treat a variety of eye diseases that lead to blindness and many types of cancer.
PEDF is found in tissues including the brain, eye, liver, heart and lung, but it was not known how cells sense this signal. Cells are expected to have specific proteins called receptors on the cell surface membrane to detect PEDF and transmit the signal into the cell; however, the identity of these receptors has remained a long-standing unsolved puzzle.
Cheng, Zhong, Kawaguchi et al. have now identified two human proteins that act as receptors for PEDF. These proteins—known as PLXDC1 and PLXDC2—span the cell surface membrane, and bind to PEDF on the outside of the cell. PLXDC1 and PLXDC2 are expressed on different types of cells that respond to PEDF. Furthermore, PEDF was unable to act upon cells that had been engineered to make less of these two receptors.
This study also revealed that each receptor can play different roles in different cell types. For example, exposing one type of cell from blood vessels to PEDF would normally kill them, but cells without PLXDC2 (but not those without PLXDC1) could survive PEDF treatment. Furthermore, PEDF treatment protects a type of neuron against environmental damage, and this activity depends on PLXDC1, but not PLXDC2.
How do the receptors transmit the PEDF signal from the outside of the cell to the inside of the cell? Cheng, Zhong, Kawaguchi et al. found that when PEDF is not present, both PLXDC1 and PLXDC2 form complexes containing more than one copy of either receptor. When PEDF binds to the receptors, it causes these complexes to disassemble and this activates further downstream signaling events inside the cell.
Understanding PEDF receptors and their mechanisms will open the way to developing new drugs that target these receptors to treat human diseases.
DOI: http://dx.doi.org/10.7554/eLife.05401.002
doi:10.7554/eLife.05401
PMCID: PMC4303762  PMID: 25535841
membrane receptors; signal transduction; human disease; none
17.  Visceral adiposity index score indicated the severity of coronary heart disease in Chinese adults 
Background
Visceral adiposity contributes to cardiometabolic risk, and visceral adiposity index (VAI) had significant correlation with visceral adiposity. We aimed to explore whether VAI was associated with cardiac structure and function and assess the impact of the cut-off points of VAI defining visceral adipose dysfunction (VAD) on the severity of coronary heart disease (CHD).
Methods
A total of 95 patients with CHD were divided into Control (nondiabetic CHD patients) and DM group (diabetic CHD patients). Then the two groups were respectively divided into VAD absent and VAD groups. Clinical, echocardiographic and coronary artery angiographic indexes were acquired to examine in relation to VAI.
Results
A significant increasing trend among the four groups of patients (Control + VAD absent, Control +VAD, DM + VAD absent and DM +VAD groups) were observed for waist circumference (WC), body mass index (BMI), systolic blood pressure (SBP), glucose, VAI and Gensini score (P<0.05 for all). The following variables were associated with VAI: total cholesterol, nonesterified fatty acid, Waist-Hip ratio and SBP. VAI was independently associated with Gensini score.
Conclusions
The extent of CHD was more severe in diabetes, and VAI as a simple indicator of visceral adipose mass was strongly associated with the severity of CHD. The cut-off points of VAI used for defining VAD were more useful in diabetic CHD patients in identifying the severity of CHD.
doi:10.1186/1758-5996-6-143
PMCID: PMC4292995  PMID: 25587360
Visceral adiposity index; Coronary heart disease; Diabetes
18.  High levels of SIRT1 expression enhance tumorigenesis and associate with a poor prognosis of colorectal carcinoma patients 
Scientific Reports  2014;4:7481.
SIRT1, a NAD+ dependent class III deacetylase, takes part in many important biological processes. Previous studies show that SIRT1 is overexpressed in some cancers and plays an essential role in tumorigenesis. However, the association between SIRT1 and colorectal cancer (CRC) is still unclear. We found that many CRC specimens had strong SIRT1 expression, which had an obvious correlation with poor prognosis of CRC patients. Meanwhile, SIRT1 expression had a co-localization with CD133, a current universal marker to characterize colorectal cancer stem cells (CSCs). In vitro studies also revealed that SIRT1 was overexpressed in colorectal CSC-like cells. Moreover, SIRT1 deficiency decreased percentage of CD133+ cells, attenuated the abilities of colony and sphere formation, and inhibited tumorigenicity in vivo in CRC cells. Further study demonstrated that the expressions of several stemness-associated genes, including Oct4, Nanog, Cripto, Tert and Lin28, were reduced by SIRT1 knockdown in CRC cells. Taken together, our findings suggest that SIRT1 plays a crucial role in keeping the characteristics of CSCs cells. SIRT1 is a potential independent prognostic factor of CRC patients after tumor resection with curative intent, and will contribute to providing a promising new approach to target at CSCs in CRC treatment.
doi:10.1038/srep07481
PMCID: PMC4265776  PMID: 25500546
20.  Apo-RBP, Holo-RBP, and Insulin Resistance 
Molecular and Cellular Biology  2014;34(11):2105-2106.
doi:10.1128/MCB.01425-12
PMCID: PMC4019056  PMID: 24803600
21.  Neurogenesis in Adult Human Brain after Traumatic Brain Injury 
Journal of Neurotrauma  2013;30(22):1872-1880.
Abstract
While much work has been conducted regarding the neurogenesis response to traumatic brain injury (TBI) in rodents, it remains largely unknown whether neurogenesis in adult human brain also responds to TBI in a similar manner. Here, we performed immunocytochemistry on 11 brain specimens from patients with traumatic brain injury, who underwent surgical intervention. We found that expression of neural stem/progenitor cell (NSC) protein markers, including DCX, TUC4, PSA-NCAM, SOX2 and NeuroD, was increased in the perilesional cortex of human brain after TBI compared to that of normal brain. Confocal images showed that these NSC proteins were expressed in one single cell. We also found that proliferative markers were expressed in NSC protein-positive cells after TBI, and the number of proliferative NSCs was significantly increased after TBI. Our data suggest that TBI may also induce neurogenesis in human brain.
doi:10.1089/neu.2010.1579
PMCID: PMC3815038  PMID: 21275797
brain trauma; human; injury; neurogenesis; stem cells
22.  Notch4 is Activated in Endothelial and Smooth Muscle Cells in Human Brain Arteriovenous Malformations 
Journal of cellular and molecular medicine  2013;17(11):10.1111/jcmm.12115.
Upregulation of Notch4 was observed in the endothelial cells in the arteriovenous malformations (AVMs) in mice. However, whether Notch4 is also involved in brain AVMs in humans remains unclear. Here, we performed immunohistochemistry on normal brain vascular tissue and surgically-resection brain AVMs and found that Notch4 was upregulated in the subset of abnormal vessels of the brain AVM nidus, compared with control brain vascular tissue. Two-photon confocal images show that Notch4 was expressed not only in the endothelial but also in the smooth muscle cells of the vascular wall in brain AVMs. Western blotting shows that Notch 4 was activated in brain AVMs, but not in middle cerebral artery of normal human brain, which was confirmed by immunostaining. Our findings suggest a possible contribution of Notch4 signaling to the development of brain AVMs in human.
doi:10.1111/jcmm.12115
PMCID: PMC3877925  PMID: 24373503
Notch4; AVM; human; brain; signaling
23.  Decreased expression of interleukin-36α predicts poor prognosis in colorectal cancer patients 
Interleukin-36α (IL-36α), previously designated as IL-1F6, has been found to have a pathogenic role in psoriasis. However, possible functions of IL-36α in cancer remain unclear. In present study, we investigate the possible role of interleukin-36α involved in the pathogenesis of colorectal cancer. IL-36α expression was detected in 345 colorectal cancer tissue samples by immunohistochemical staining, and its relation with clinicopathologic parameters and prognosis of colorectal cancer patients were analyzed. IL-36α was highly expressed in nearly half of all tested colorectal cancer patients. However, low expression level of IL-36α significantly correlated with larger tumor size and advanced TNM stage. Kaplan-Meier survival analysis showed that low expression level of IL-36α resulted in a remarkably poor prognosis of colorectal cancer patients. Multivariate Cox’s analysis revealed that the IL-36α expression level was a significant and independent prognostic factor for overall survival rate of colorectal cancer patients. Thus, our study may provide insight into the application of IL-36α as a novel predictor of prognosis and a potential therapeutic drug for colorectal cancer.
PMCID: PMC4270616  PMID: 25550854
Interleukin-36α; colorectal cancer; prognosis; therapy
24.  OsAAP6 functions as an important regulator of grain protein content and nutritional quality in rice 
Nature Communications  2014;5:4847.
Grains from cereals contribute an important source of protein to human food, and grain protein content (GPC) is an important determinant of nutritional quality in cereals. Here we show that the quantitative trait locus (QTL) qPC1 in rice controls GPC by regulating the synthesis and accumulation of glutelins, prolamins, globulins, albumins and starch. qPC1 encodes a putative amino acid transporter OsAAP6, which functions as a positive regulator of GPC in rice, such that higher expression of OsAAP6 is correlated with higher GPC. OsAAP6 greatly enhances root absorption of a range of amino acids and has effects on the distribution of various amino acids. Two common variations in the potential cis-regulatory elements of the OsAAP6 5′-untranslated region seem to be associated with GPC diversity mainly in indica cultivars. Our results represent the first step toward unravelling the mechanism of regulation underlying natural variation of GPC in rice.
Grain protein content (GPC) contributes to the nutritional quality of cereals. Here, the authors show that the OsAAP6 quantitative trait locus in rice controls GPC by regulating the synthesis and accumulation of several grain storage proteins and starch.
doi:10.1038/ncomms5847
PMCID: PMC4175581  PMID: 25209128
25.  Natakalim improves post-infarction left ventricular remodeling by restoring the coordinated balance between endothelial function and cardiac hypertrophy 
Endothelial dysfunction can lead to congestive heart failure and the activation of endothelial ATP-sensitive potassium (KATP) channels may contribute to endothelial protection. Therefore, the present study was carried out to investigate the hypothesis that natakalim, a novel KATP channel opener, ameliorates post-infarction left ventricular remodeling and failure by correcting endothelial dysfunction. The effects of myocardial infarction were assessed 8 weeks following left anterior descending coronary artery occlusion in male Wistar rats. Depressed blood pressure, cardiac dysfunction, evidence of left ventricular remodeling and congestive heart failure were observed in the rats with myocardial infarction. Treatment with natakalim at daily oral doses of 1, 3 or 9 mg/kg/day for 8 weeks prevented these changes. Natakalim also prevented the progression to cardiac failure, which was demonstrated by the increase in right ventricular weight/body weight (RVW/BW) and relative lung weight, signs of cardiac dysfunction, as well as the overexpression of atrial and brain natriuretic peptide mRNAs. Our results also demonstrated that natakalim enhanced the downregulation of endothelium-derived nitric oxide, attenuated the upregulation of inducible nitric oxide synthase-derived nitric oxide (NO), inhibited the upregulated endothelin system and corrected the imbalance between prostacyclin and thromboxane A2. Overall, our findings suggest that natakalim prevents post-infarction hypertrophy and cardiac failure by restoring the coordinated balance between endothelial function and cardiac hypertrophy.
doi:10.3892/ijmm.2014.1931
PMCID: PMC4199399  PMID: 25215478
natakalim; myocardial infarction; left ventricular remodeling; cardiac hypertrophy; congestive heart failure; endothelial function

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