Peking Union Medical Hospital

Beijing, China

Peking Union Medical Hospital

Beijing, China

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Shi Y.,Peking Union Medical College | Shi Y.,Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs | Zhang L.,Sun Yat Sen University | Zhang L.,Peking Union Medical Hospital | And 30 more authors.
The Lancet Oncology | Year: 2013

Background: Icotinib, an oral EGFR tyrosine kinase inhibitor, had shown antitumour activity and favourable toxicity in early-phase clinical trials. We aimed to investigate whether icotinib is non-inferior to gefitinib in patients with non-small-cell lung cancer. Methods: In this randomised, double-blind, phase 3 non-inferiority trial we enrolled patients with advanced non-small-cell lung cancer from 27 sites in China. Eligible patients were those aged 18-75 years who had not responded to one or more platinum-based chemotherapy regimen. Patients were randomly assigned (1:1), using minimisation methods, to receive icotinib (125 mg, three times per day) or gefitinib (250 mg, once per day) until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival, analysed in the full analysis set. We analysed EGFR status if tissue samples were available. All investigators, clinicians, and participants were masked to patient distribution. The non-inferiority margin was 1·14; non-inferiority would be established if the upper limit of the 95% CI for the hazard ratio (HR) of gefitinib versus icotinib was less than this margin. This study is registered with ClinicalTrials.gov, number NCT01040780, and the Chinese Clinical Trial Registry, number ChiCTR-TRC-09000506. Findings: 400 eligible patients were enrolled between Feb 26, 2009, and Nov 13, 2009; one patient was enrolled by mistake and removed from the study, 200 were assigned to icotinib and 199 to gefitinib. 395 patients were included in the full analysis set (icotinib, n=199; gefitinib, n=196). Icotinib was non-inferior to gefitinib in terms of progression-free survival (HR 0·84, 95% CI 0·67-1·05; median progression-free survival 4·6 months [95% CI 3·5-6·3] vs 3·4 months [2·3-3·8]; p=0·13). The most common adverse events were rash (81 [41%] of 200 patients in the icotinib group vs 98 [49%] of 199 patients in the gefitinib group) and diarrhoea (43 [22%] vs 58 [29%]). Patients given icotinib had less drug-related adverse events than did those given gefitinib (121 [61%] vs 140 [70%]; p=0·046), especially drug-related diarrhoea (37 [19%] vs 55 [28%]; p=0·033). Interpretation: Icotinib could be a new treatment option for pretreated patients with advanced non-small-cell lung cancer. Funding: Zhejiang Beta Pharma (China), the Chinese National Key Special Program for Innovative Drugs, the 863 Project, and Zhejiang Provincial Key Special Program. © 2013 Elsevier Ltd.


Yang D.,Capital Medical University | Tian C.,Capital Medical University | Liu J.,Capital Medical University | Zheng Y.-H.,Peking Union Medical Hospital | Li H.-H.,Capital Medical University
Cellular Physiology and Biochemistry | Year: 2010

Background: Mild hypothermia (32-34°C) improves resistance to ischemia-reperfusion (I/R) injury. However, the mechanisms by which it affects human cellular function are not fully elucidated. To further test for hypothermic modulation of global biological processes, we used DNA microarray technique to detect the overall gene expression profile. Methods: Human umbilical endothelial cells (HUVECs) were incubated under control condition (37°C) or mild hypothermia (33°C) for 2 hours after stimulated ischemia. Detection of differentially expressed genes was performed with Affymetrix U133 plus 2.0 arrays and PARTEK software. We used DAVID and KEGG Pathways database to identify global trends in gene expression data. Results: Our analysis has identified numerous interesting genes and processes that are differentially presented in hypothermic group when compared with normothermic control. The cell cycle was the most prominent process; several genes involved in cell apoptosis and proliferation displayed significantly differential expression; lower transcriptional level was observed for genes involved in chemokine and cell adhesion processes; genes associated with activity of transmembrane transporter and lipase were also under-expressed. Conclusion: Our data indicated that mild hypothermia altered endothelial expression pattern under the condition of I/R, preferably through varying the expression of genes associated with cell cycle, apoptosis, proliferation, and inflammatory response. Copyright © 2010 S. Karger AG, Basel.


PubMed | Duke University, Peking University and Peking Union Medical Hospital
Type: Journal Article | Journal: PloS one | Year: 2016

It is necessary to develop an effective and low-cost screening tool for identifying Chinese people at high risk of stroke. Transcranial Doppler ultrasound (TCD) is a powerful predictor of stroke in the pediatric sickle cell disease population, as demonstrated in the STOP trial. Our study was conducted to determine the prediction value of peak systolic velocities as measured by TCD on subsequent stroke risk in a prospective cohort of the general population from Beijing, China.In 2002, a prospective cohort study was conducted among 1392 residents from 11 villages of the Shijingshan district of Beijing, China. The cohort was scheduled for follow up with regard to incident stroke in 2005, 2007, and 2012 by a study team comprised of epidemiologists, nurses, and physicians. Univariate and multivariate Cox proportional hazard regression models were used to determine the factors associated with incident stroke.Participants identified by TCD criteria as having intracranial stenosis had a 3.6-fold greater risk of incident stroke (hazard ratio (HR) 3.57, 95% confidence interval (CI) 1.86-6.83, P<0.01) than those without TCD evidence of intracranial stenosis. The association remained significant in multivariate analysis (HR 2.53, 95% CI 1.31-4.87) after adjusting for other risk factors or confounders. Older age, cigarette smoking, hypertension, and diabetes mellitus remained statistically significant as risk factors after controlling for other factors.The study confirmed the screening value of TCD among the general population in urban China. Increasing the availability of TCD screening may help identify subjects as higher risk for stroke.


Zhang Y.,Peking Union Medical College | Zeng Y.,Peking Union Medical Hospital | Wang M.,Peking Union Medical College | Tian C.,Capital Medical University | And 6 more authors.
Basic Research in Cardiology | Year: 2011

Cardiomyocyte death is a major event of myocardial infarction. Previously, we and others have shown that E3 ligase-mediated protein turnover plays a critical role in cardiac injury. In this study, we sought to determine the role of a newly identified E3 ligase, neuregulin receptor degradation protein-1 (Nrdp1), on cardiac ischemia/reperfusion (I/R) injury. I/R injury markedly upregulated Nrdp1 expression in heart tissue. To elucidate the role of Nrdp1 in I/R-induced cardiac injury, neonatal cardiomyocytes were infected with adenoviral constructs expressing wild-type, dominant-negative Nrdp1 genes. Increased Nrdp1 expression enhanced I/R-induced cardiomyocyte apoptosis and inflammation as compared with the green fluorescent protein (GFP) control; these effects were attenuated by overexpression of a dominant-negative Nrdp1 (C34S/H36Q). Furthermore, cardiac-specific Nrdp1 overexpression in vivo in mouse significantly increased infarct size, the number of TUNEL-positive nuclei and inflammatory cells, as well as mortality, as compared with wild-type mice after I/R injury. The mechanisms underlying these effects were associated with the downregulation of an Nrdp1 substrate, ErbB3, accompanied by suppression of its downstream targets AKT, ERK1/2, and activation of p38 and JNK1/2. Together, these results provide evidence for an important role for Nrdp1 in regulating I/R-induced cardiac injury. Nrdp1 may constitute a new therapeutic target for ameliorating the I/R-induced cardiac injury. © 2011 Springer-Verlag.


Zhang Y.,Peking Union Medical College | Kang Y.-M.,Xi'an Jiaotong University | Tian C.,Capital Medical University | Zeng Y.,Peking Union Medical Hospital | And 4 more authors.
PLoS ONE | Year: 2011

Background: Cardiac cell death and generation of oxidative stress contribute to doxorubicin (DOX)-induced cardiac dysfunction. E3 ligase Nrdp1 plays a critical role in the regulation of cell apoptosis, inflammation and production of reactive oxygen species (ROS), which may contribute to heart failure. However, the role of Nrdp1 in DOX-induced cardiac injury remains to be determined. Methods and Results: We examined the effect of Nrdp1 overexpression with DOX treatment in rat neonatal cardiomyocytes and mouse heart tissue. Cardiomyocytes were infected with adenovirus containing GFP (Ad-GFP), Nrdp1 wild-type (Ad-Nrdp1) or the dominant-negative form of Nrdp1 (Ad-Dn-Nrdp1), then treated with DOX for 24 hr. DOX treatment increased cell death and apoptosis, with Ad-Nrdp1 infection enhancing these actions but Ad-Dn-Nrdp1 infection attenuating these effects. Furthermore, 5 days after a single injection of DOX (20 mg/kg, intraperitoneally), Nrdp1 transgenic mice (TG) showed decreased cardiac function and increased apoptosis, autophagy and oxidative stress as compared with wild-type (WT) mice (P<0.01). Survival rate was significantly lower in Nrdp1 TG mice than in WT mice 10 days after DOX injection (P<0.01). Conclusions/Significance: These results were associated with decreased activation of Akt, extracellular signal-regulated kinase 1/2 (ERK1/2) and signal transducer and activator of transcription 3 (STAT3) signaling pathways. Nrdp1 may be a key mediator in the development of cardiac dysfunction after DOX treatment and associated with inhibition of Akt, ERK1/2 and STAT3. Nrdp1 may be a new therapeutic target in protecting against the cardiotoxic effects of DOX. © 2011 Zhang et al.


Fei Y.,Peking Union Medical Hospital | Li X.,Beijing General Hospital | Lin S.,Zaozhuang Hospital of Traditional Chinese Medicine | Song X.,Peking Union Medical Hospital | And 7 more authors.
Clinical Rheumatology | Year: 2013

Behçet's disease (BD) is a multi-systemic inflammatory disorder which can affect all types and sizes of blood vessels. This study aims to evaluate the prevalence and characteristics of vascular involvement in BD. Among 796 patients diagnosed with BD, 102 patients (81 male, 21 female) with vascular involvement were included, whose detailed clinical characteristics were recorded. The diagnosis of vascular lesions was made on clinical signs, by Doppler ultrasonography, and/or angiography using computed tomographic or magnetic resonance techniques. Vascular involvement occurred in 12.8 % of BD patients. Male to female ratio was 3.86:1. Mean age at onset of vascular involvement was 29.5 ± 11.3 years. Vascular lesion was the initial sign of BD in 28 patients, accounting for 27.5 %. Of 102 BD patients with vascular involvement, 72 had venous lesions (70.6 %) and 56 had arterial lesions (54.9 %), among which 26 (25.5 %) patients had both venous and arterial involvements. Female BD patients were more often involved with arterial lesions, whereas male BD patients developed venous lesions more often than females, P = 0.000. The most common type of vascular involvement was deep venous thrombosis in lower extremities (n = 49), other affected venous sites including inferior vena cava, superior vena cava, and cerebral venous. The prominent type of arterial lesions was dilatation (n = 25, including 24 cases of aneurysms); other types included eight cases of occlusion and 23 cases of stenosis. The main locations of arterial lesions were the aorta (n = 19), lower extremity arteries (n = 15), pulmonary arteries (n = 13), coronary arteries (n = 5), and subclavian arteries (n = 5). Compared with those without vascular lesions, ocular involvement, genital ulcers, and arthritis were significantly less frequent among patients with vasculo-BD (23.5 vs 35.2 %, P = 0.024; 54.9 vs 76.5 %, P = 0.000; 19.6 vs 30.5 %, P = 0.026), whereas a higher frequency of cardiac involvement was found in vasculo-BD patients (20.6 vs 3.6 %, P = 0.000). Vascular involvement is a complication in BD patients. This study illustrated that venous lesions are more frequently involved than arterial lesions. Vascular lesions correlated with a high frequency of cardiac involvement and a low incidence of ocular lesions, genital ulcers, and arthritis. © 2013 Clinical Rheumatology.


Zheng Y.-H.,Peking Union Medical Hospital | Li F.-D.,Peking Union Medical Hospital | Tian C.,Capital Medical University | Tian C.,Beijing Institute of Heart | And 5 more authors.
PLoS ONE | Year: 2013

Abdominal aortic aneurysm (AAA) is a life-threatening aortic disease in the elderly. Activation of Notch1 pathway plays a critical role in the development of AAA, but the underlying mechanisms remain poorly understood. In the present study, we explored the mechanisms by which Notch1 activation regulates angiotensin II (Ang II)-induced AAA formation and evaluated the therapeutic potential of a new Notch γ-secretase inhibitor, dibenzazepine (DBZ), for the treatment of AAA. Apolipoprotein E knockout (Apo E-/-) mice infused for 4 weeks with Ang II (1000 ng/kg/min, IP) using osmotic mini-pumps were received an intraperitoneal injection of either vehicle or 1 mg/kg/d DBZ. Notch1 signaling was activated in AAA tissue from both Ang II-infused Apo E -/- mice and human undergoing AAA repair in vivo, with increased expression of Notch intracellular domain (NICD) and its target gene Hes1, and this effect was effectively blocked by DBZ. Moreover, infusion of Ang II markedly increased the incidence and severity of AAA in Apo E-/- mice. In contrast, inhibition of Notch activation by DBZ prevented AAA formation in vivo. Furthermore, DBZ markedly prevented Ang II-stimulated accumulation of macrophages and CD4+ T cells, and ERK-mediated angiogenesis, simultaneously reversed Th2 response, in vivo. In conclusion, these findings provide new insight into the multiple mechanisms of Notch signaling involved in AAA formation and suggest that γ-secretase inhibitor DBZ might be a novel therapeutic drug for treating AAAS. © 2013 Zheng et al.


Zheng Y.-H.,Peking Union Medical Hospital | Tian C.,Capital Medical University | Meng Y.,Capital Medical University | Qin Y.-W.,Capital Medical University | And 3 more authors.
Journal of Cellular Physiology | Year: 2012

Osteopontin (OPN) exerts pro-inflammatory effect and is associated with the development of abdominal aortic aneurysm (AAA). However, the molecular mechanism underlying this association remains obscure. In the present study, we compared gene expression profiles of AAA tissues using microarray assay, and found that OPN was the highest expressed gene (>125-fold). Furthermore, the expression of LC3 protein and autophagy-related genes including Atg4b, Beclin1/Atg6, Bnip3, and Vps34 was markedly upregulated in AAA tissues. To investigate the ability of OPN to stimulate autophagy as a potential mechanism involved in the pathogenesis of this disease, we treated vascular smooth muscle cells (SMCs) with OPN, and found that OPN significantly increased the formation of autophagosomes, expression of autophagy-related genes and cell death, whereas blocking the signal by anti-OPN antibody markedly inhibited OPN-induced autophagy and SMC death. Furthermore, inhibition of integrin/CD44 and p38 MAPK signaling pathways markedly abrogated the biological effects of OPN on SMCs. These data for the first time demonstrate that OPN sitmulates autophagy directly through integrin/CD44 and p38 MAPK-mediated pathways in SMCs. Thus, inhibition of OPN-induced autophagy might be a potential therapeutic target in the treatment of AAA disease. © 2011 Wiley Periodicals, Inc.


Chai Y.,Wesley Neurology Clinic in Memphis | Chai Y.,University of Tennessee Health Science Center | Bertorini T.E.,Wesley Neurology Clinic in Memphis | Bertorini T.E.,University of Tennessee Health Science Center | And 3 more authors.
Neuromuscular Disorders | Year: 2011

Dermatomyositis is an autoimmune disorder that causes proximal muscle weakness and skin changes which include generalized erythema, heliotrope rash and/or Gottron's papules. Generalized or limb edema is an uncommon manifestation of dermatomyositis. Here, we report four cases who presented with generalized or limb edema, proximal muscle weakness, erythematous skin rash and/or dysphagia. Muscle biopsy revealed perifascicular fiber atrophy, a characteristic finding of dermatomyositis. The absence of other causes indicated that the generalized or limb edema was caused by dermatomyositis. None of our patients showed significant improvement with steroids alone, and more aggressive immunotherapy eventually resolved the edema. We concluded that generalized or limb edema may be a hallmark of a severe form of dermatomyositis and requires prompt and aggressive therapies. © 2011 Elsevier B.V.


PubMed | Capital Medical University and Peking Union Medical Hospital
Type: | Journal: Journal of diabetes and its complications | Year: 2016

The present study investigated the association of serum levels of angiopoietin-related growth factor (AGF) with lower extremity peripheral arterial disease (LEPAD).The study group is comprised of 105 patients with lower extremity peripheral arterial disease. The control group consisted of 80 individuals without lower extremity peripheral arterial disease. Serum AGF concentrations were determined by enzyme-linked immunosorbent assay. The relationship between AGF and clinical and biochemical parameters was studied. Besides, this study analyzed AGF levels in LEPAD patients according to disease severity and evaluated the prognostic value of AGF for amputation and mortality in LEPAD patients after a follow-up period of 1.7years.Median serum AGF levels were significantly higher in LEPAD group (103.7064.69ng/mL) as compared with control group (53.8337.87ng/mL) (P<0.001). In addition, T2DM patients with LEPAD exhibited markedly higher serum AGF concentrations (118.760.90ng/mL) than those without LEPAD (60.2332.62ng/mL) (P<0.0001). Moreover, LEPAD positively predicted AGF concentrations in multivariate linear regression analysis (P<0.0001). Serum AGF levels were independently associated with LEPAD in binary logistic regression analysis model. Among LEPAD patients, those with critical limb ischemia (n=43) showed higher AGF levels (124.973.9 vs. 88.9853.26ng/mL, P=0.01) compared with those with intermittent claudication (n=62). Furthermore, patients with the highest AGF tertile had an increased all-cause mortality and cardiovascular mortality (P=0.033 and P=0.025, respectively).Our results suggested that lower extremity peripheral artery disease was positively associated with AGF serum levels. High serum AGF level was a potential risk factor for LEPAD and associates with disease severity and poor outcome in LEPAD patients.

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