Junxiang Wan

University of Southern California, Los Angeles, California, United States

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Publications (16)93.07 Total impact

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    ABSTRACT: Aging is influenced by endocrine pathways including the growth hormone/insulin-like growth factor-1 (GH/IGF) axis. Mitochondrial function has also been linked to the aging process, but the relevant mitochondrial signals mediating the effects of mitochondria are poorly understood. Humanin is a novel signaling peptide that acts as a potent regulator of cellular stress responses and protects from a variety of in vitro and in vivo toxic and metabolic insults. The circulating levels of humanin decline with age in mice and humans. Here, we demonstrate a negative correlation between the activity of the GH-IGF axis and the levels of humanin, as well as a positive correlation between humanin and lifespan in mouse models with altered GH/IGF-I axis. Long-lived, GH-deficient Ames mice displayed elevated humanin levels, while short-lived GH-transgenic mice have reduced humanin levels. Furthermore, treatment with GH or IGF-I reduced circulating humanin levels in both mice and human subjects. Our results indicate that GH and IGF are potent regulators of humanin levels and that humanin levels correlate with lifespan in mice. This suggests that humanin represents a circulating mitochondrial signal that participates in modulating the aging process, adding a coordinated mitochondrial element to the endocrine regulation of aging.
    Aging cell 07/2014; · 7.55 Impact Factor
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    ABSTRACT: Attenuated growth hormone and insulin-like growth factor-1 (GH/IGF-1) signaling is associated with extended lifespan in several animal models. However, the effect of diminished GH/IGF-1 activity on survival in humans has not been confirmed. We tested the hypothesis that IGF-1 levels in nonagenarians (n = 184), measured at study enrollment, predict the duration of their incremental survival. In the Kaplan-Meier analysis, females with IGF-1 levels below the median (≤ 96 ng mL(-1) ) had significantly longer survival compared with females with levels above the median, P < 0.01. However, this survival advantage was not observed in males (P = 0.83). On the other hand, in both males and females with a history of cancer, lower IGF-1 levels predicted longer survival (P < 0.01). IGF-1 level remained a significant predictor of survival duration in linear regression models after multivariable adjustment in females (P = 0.01) and individuals with a history of cancer (P < 0.01). We show for the first time that low IGF-1 levels predict life expectancy in exceptionally long-lived individuals.
    Aging cell 03/2014; · 7.55 Impact Factor
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    ABSTRACT: Mice and humans with growth hormone receptor/IGF-1 deficiencies display major reductions in age-related diseases. Because protein restriction reduces GHR-IGF-1 activity, we examined links between protein intake and mortality. Respondents aged 50-65 reporting high protein intake had a 75% increase in overall mortality and a 4-fold increase in cancer death risk during the following 18 years. These associations were either abolished or attenuated if the proteins were plant derived. Conversely, high protein intake was associated with reduced cancer and overall mortality in respondents over 65, but a 5-fold increase in diabetes mortality across all ages. Mouse studies confirmed the effect of high protein intake and GHR-IGF-1 signaling on the incidence and progression of breast and melanoma tumors, but also the detrimental effects of a low protein diet in the very old. These results suggest that low protein intake during middle age followed by moderate to high protein consumption in old adults may optimize healthspan and longevity.
    Cell metabolism 03/2014; 19(3):407-417. · 17.35 Impact Factor
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    ABSTRACT: Humanin (HN) is a novel 24-amino acid mitochondrial-derived peptide that has demonstrated diverse cytoprotective effects, including an emerging role in diabetes. The purpose of this study was to examine the pharmacokinetics of humanin analogues, which show great potential as therapeutic agents (HNG and the nonIGFBP-3 binding, HNGF6A). 11-week-old male IGFBP-3(-/-) and wild type (WT) mice were divided into three groups: WT mice treated with HNG, WT mice treated with HNGF6A, and IGFBP-3(-/-)mice treated with HNG. Plasma was obtained from mice following intraperitonial (IP) injection with HN analogues, and HN levels were measured with ELISA. WT mice treated with HNGF6A and IGFBP-3(-/-)mice treated with HNG displayed a longer half-life of HN compared with WT mice treated with HNG. Following HNG injection, both IGF-1 and IGFBP-3 levels decreased over time. Adult male Sprague Dawley rats were also IP injected with HNG, and HN levels were measured in various tissues (plasma, liver, heart, and brain) by ELISA. The half-life of HN was found to be longer in rats compared with mice. In rats, HN levels were found to be highest in plasma, present in liver, and undetectable in brain or heart. The current study provides evidence of HN and IGFBP-3 association in the circulation, and suggests that native HN may modulate the distribution of IGF-1 and IGFBP-3. The results also demonstrate varying kinetic profiles of HN analogues and interspecies variation in rodents. Sustainable levels of circulating HN measured in plasma underline the potential value of HN analogues as a new therapeutic intervention in the treatment of diabetes.
    Endocrinology 07/2013; · 4.72 Impact Factor
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    ABSTRACT: Context:Prostate cancer patients at increased risk for relapse after prostatectomy were treated in a neo-adjuvant study with androgen deprivation therapy (ADT) in combination with cixutumumab, an inhibitory fully human monoclonal antibody against insulin-like growth factor receptor 1 (IGF-IR).Objective:A clinical trial with prospective collection of serum and tissue was designed to test the potential clinical efficacy of neoadjuvant IGF-IR blockade combined with ADT in these patients. Effect of body mass index (BMI) on response of IGF-IR/insulin components to IGF-IR blockade was also examined.Design:Eligibility for the trial required the presence of high-risk prostate adenocarcinoma. Treatment consisted of bicalutamide, goserelin, and cixutumumab for thirteen weeks before prostatectomy. Here we report on an analysis of serum samples from 29 enrolled patients. Changes in IGF and glucose homeostasis pathways were compared to control samples from patients in a concurrent clinical trial of neoadjuvant ADT alone.Results:Significant increases were seen in growth hormone (p = 0.001), IGF-I (p < 0.0001), IGF-II (p = 0.003), IGFBP-3 (p < 0.0001), C-peptide (p = 0.0038), and insulin (p = 0.05) compared to patients treated with ADT alone. IGFBP-1 levels were significantly lower in the cixutumumab+ADT cohort (p = 0.001). No significant changes in blood glucose were evident. Patients with BMIs in the normal range had significantly higher growth hormone (p < 0.05) and IGFBP-1 (p < 0.05) levels compared to overweight and obese patients.Conclusions:Patients with IGF-IR blockade in combination with ADT demonstrated significant changes in IGF and glucose homeostasis pathway factors compared to patients receiving ADT alone. In the patients receiving combination therapy, patients with normal BMI had serum levels of glucose homeostasis components similar to individuals in the ADT alone cohort, while patients with overweight and obese BMIs had serum levels that differed from the ADT cohort.
    The Journal of clinical endocrinology and metabolism 03/2013; · 6.50 Impact Factor
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    ABSTRACT: In laboratory animals Calorie Restriction (CR) protects against aging, oxidative stress and neurodegenerative pathologies. Reduced levels of growth hormone and IGF-1, which mediate some of the protective effects of CR, can also extend longevity and protect against age-related diseases in rodents and humans. However, severely restricted diets are difficult to maintain and are associated with chronically low weight and other major side effects. Here, we show that four months of periodic protein restriction cycles (PRC) with supplementation of non-essential amino acids in mice already displaying significant cognitive impairment and AD-like pathology reduced circulating IGF-1 levels by 30-70% and caused an 8-fold increase in IGFBP-1. Whereas PRC did not affect the levels of β amyloid (Aβ) they decreased tau phosphorylation in the hippocampus and alleviated the age-dependent impairment in cognitive performance. These results indicate that periodic protein restriction cycles without CR can promote changes in circulating growth factors and tau phosphorylation associated with protection against age-related neuropathologies. © 2013 The Authors Aging Cell © 2013 Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland.
    Aging cell 01/2013; · 7.55 Impact Factor
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    ABSTRACT: Calorie restriction (CR) inhibits prostate cancer progression, partially through modulation of the IGF axis. IGF-1 receptor (IGF-1R) blockade reduces prostate cancer xenograft growth. We hypothesized that combining calorie restriction with IGF-1R blockade would have an additive effect on prostate cancer growth. Severe combined immunodeficient mice were subcutaneously injected with 22Rv1 cells and randomized to: (1) Ad libitum feeding/intraperitoneal saline (Ad-lib); (2) Ad-lib/20 mg/kg twice weekly, intraperitoneal ganitumab [anti-IGF-1R antibody (Ad-lib/Ab)]; (3) 40% calorie restriction/intraperitoneal saline (CR); (4) CR/ intraperitoneal ganitumab, (CR/Ab). CR and ganitumab treatment were initiated one week after tumor injection. Euthanasia occurred 19 days post treatment. Results showed that CR alone decreased final tumor weight, plasma insulin and IGF-1 levels, and increased apoptosis. Ganitumab therapy alone reduced tumor growth but had no effect on final tumor weight. The combination therapy (CR/Ab) further decreased final tumor weight and proliferation, increased apoptosis in comparison to the Ad-lib group, and lowered plasma insulin levels relative to the Ad-lib and Ad-lib/Ab groups. Tumor AKT activation directly correlated with plasma IGF-1 levels. In conclusion, whereas ganitumab therapy modestly affected 22Rv1 tumor growth, combining IGF-1R blockade with calorie restriction resulted in a significant decrease in final tumor weight and improved metabolic profile.
    International Journal of Molecular Sciences 01/2013; 14(7):13782-95. · 2.46 Impact Factor
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    ABSTRACT: Humanin is a small endogenous anti-apoptotic peptide, originally identified as protective against Alzheimer's disease but subsequently also found on human endothelium as well as carotid artery plaques. Endothelial dysfunction is a precursor to the development of atherosclerotic plaques, which are characterized by a highly pro-inflammatory, reactive oxygen species, and apoptotic milieu. Previous animal studies demonstrated that humanin administration may improve endothelial function. Thus, the aim of this study was to test the hypothesis that patients with coronary endothelial dysfunction have reduced systemic levels of humanin. Forty patients undergoing coronary angiography and endothelial function testing were included and subsequently divided into two groups based on coronary blood flow (CBF) response to intracoronary acetylcholine (normal > 50% increase from baseline, n=20 each). Aortic plasma samples were obtained at the time of catheterization for the analysis of humanin levels and traditional biomarkers of atherosclerosis including C-reactive protein, Lp-Pla2, and homocysteine. Baseline characteristics were similar in both groups. Patients with coronary endothelial dysfunction (change in CBF = -33±25%) had significantly lower humanin levels (1.3±1.1 ng/ml vs. 2.2±1.5 ng/ml, p=0.03) compared to those with normal coronary endothelial function (change in CBF = 194±157%). There was a significant and positive correlation between improved CBF and humanin levels (p=0.0091) not seen with changes in coronary flow reserve (p=0.76). C-reactive protein, Lp-Pla(2), and homocysteine were not associated with humanin levels. We observed that preserved human coronary endothelial function is uniquely associated with higher systemic humanin levels, introducing a potential diagnostic and/or therapeutic target for patients with coronary endothelial function.
    AJP Heart and Circulatory Physiology 12/2012; · 3.63 Impact Factor
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    ABSTRACT: Context:GH receptor (GHR) exon 3-deleted/full-length (d3/fl) polymorphism has been proposed to affect the responsiveness to GH therapy. Conventional multiplex PCR genotyping method for this polymorphism detection requires DNA samples, which may be difficult to obtain due to ethical and procedural issues and may limit further studies into the role of this polymorphism in health and disease.Objective:The objective of the study was to develop a simple genotyping-alternative method for GHRd3 identification by directly measuring serum levels of total GH binding protein (tGHBP) and exon 3-positive GHBP[(E3((+))GHBP] by immunoassay and thereby assess the GHRd3 status.Design:The GHRd3 genotype was determined by PCR, and tGHBP and E3((+))GHBP levels were measured in serum of 88 healthy adults.Main Outcome Measures:The GHRd3 chemotype by ELISA was compared with the genotype by conventional PCR.Results:The concordance rate of GHR exon 3 status identification between PCR genotyping and ELISA chemotyping was shown to be 100%. There were negligible detectable serum levels of E3((+))GHBP in d3/d3 subjects. The ratio of serum levels E3((+))GHBP vs. tGHBP in fl/fl and d3/fl subjects was (mean ± sd) 96.6 ± 5.1 and 57.1 ± 8.4%, respectively (P < 0.0001). Interestingly, we observed that d3/d3 subjects had significantly lower serum levels of tGHBP compared with fl/fl and d3/fl genotypes.Conclusions:This dual ELISA against tGHBP and E3((+))GHBP can be used as an alternative method for determining GHRd3 polymorphism status. The implications of differences in serum levels of tGHBP among different genotypes and responsiveness to GH therapy need to be further investigated.
    The Journal of clinical endocrinology and metabolism 11/2012; · 6.50 Impact Factor
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    ABSTRACT: In preclinical models, both dietary fat reduction and insulin-like growth factor I receptor (IGF-1R) blockade individually inhibit prostate cancer xenograft growth. We hypothesized that a low-fat diet combined with IGF-1R blockade would cause additive inhibition of prostate cancer growth and offset possible untoward metabolic effects of IGF-1R blockade antibody therapy. Fifty severe combined immunodeficient mice were injected with 22Rv1 cells subcutaneously. Ten days postinjection, the animals were randomized to four groups: (i) high-fat diet + saline (HF); (ii) high-fat diet + IGF-1R blocking antibody, ganitumab (HF/Ab); (iii) low-fat diet + saline (LF); and (iv) low-fat diet + ganitumab (LF/Ab). After 19 days of treatment, the animals were euthanized, serum was collected, and tumors were weighed. Tumor Ki67, Akt and extracellular signal-regulated kinase (ERK) activation, serum insulin, IGF-I and TNF-α were measured. In vitro, ganitumab treatment inhibited growth and induced apoptosis in several prostate cancer cell lines. In vivo, tumor weights and volumes were unaffected by the different treatments. The LF/Ab therapy significantly reduced proliferation (Ki67) and ERK activation in tumors. The HF/Ab group had significantly higher serum insulin levels than the HF group. However, LF/Ab combination significantly reduced serum insulin back to normal levels as well as normalizing serum TNF-α level. Whereas the combination of low-fat diet and IGF-1R blockade did not have additive inhibitory effects on tumor weight, it led to reduced tumor cell proliferation and a reduction in serum insulin and TNF-α levels.
    Molecular Cancer Therapeutics 05/2012; 11(7):1539-46. · 5.60 Impact Factor
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    ABSTRACT: Preclinical studies suggest lowering dietary fat and decreasing the ratio of omega-6 to omega-3 polyunsaturated fatty acids decreases the risk of prostate cancer development and progression. We conducted a phase II randomized trial to test the effect of decreasing dietary fat combined with decreasing the dietary omega-6:omega-3 ratio on biomarkers related to prostate cancer development and progression. Patients undergoing radical prostatectomy were randomly assigned to receive a low-fat diet with 5 grams of fish oil daily (dietary omega-6:omega-3 ratio of 2:1) or a control Western diet (omega-6:omega-3 ratio of 15:1) for four to six weeks prior to surgery. The primary endpoint was change in serum insulin-like growth factor I (IGF-1) between arms. Secondary endpoints were serum IGFBP-1, prostate prostaglandin E2 levels, omega-6:omega-3 fatty acid ratios, COX-2, and markers of proliferation and apoptosis. Fifty-five patients were randomized and 48 completed the trial. There was no treatment difference in the primary outcome. Positive secondary outcomes in the low-fat fish oil versus Western group were reduced benign and malignant prostate tissue omega-6:omega-3 ratios, reduced proliferation (Ki-67 index), and reduced proliferation in an ex vivo bioassay when patient sera was applied to prostate cancer cells in vitro. In summary, four to six weeks of a low-fat diet and fish oil capsules to achieve an omega-6:omega-3 fatty acid ratio of 2:1 had no effect on serum IGF-1 levels, though in secondary analyses, the intervention resulted in decreased prostate cancer proliferation and decreased prostate tissue omega-6:omega-3 ratios. These results support further studies evaluating reduction of dietary fat with fish oil supplementation on modulating prostate cancer biology.
    Cancer Prevention Research 12/2011; 4(12):2062-71. · 4.89 Impact Factor
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    ABSTRACT: Circulating insulin-like growth factor binding protein 1 (IGFBP1) levels vary in response to nutritional status, and pre-clinical studies suggest that elevated IGFBP1 may be protective against the development and progression of prostate cancer. We hypothesized that global deletion of Igfbp1 would accelerate the development of prostate cancer in a c-Myc transgenic mouse model. To test our hypothesis, c-Myc transgenic mice (Myc/BP-1 wild-type (WT)) were crossed and interbred with the Igfbp1 knockout mice (Myc/BP-1 KO). The animals were placed on a high-protein diet at weaning, weighed every 2 weeks, and euthanized at 16 weeks of age. Prostate histopathology was assessed and proliferation status was determined by Ki-67 and proliferating cell nuclear antigen analyses. IGF-related serum biomarkers and body composition were measured. No significant difference in the incidence of prostate cancer was observed between the Myc/BP-1 KO and the Myc/BP-1 WT mice (65 and 80% respectively, P=0.48). Proliferation was significantly decreased by 71% in prostate tissue of Myc/BP-1 KO mice compared with Myc/BP-1 WT mice. Myc/BP-1 KO mice exhibited a significant 6.7% increase in body weight relative to the Myc/BP-1 WT mice that was attributed to an increase in fat mass. Fasting insulin levels were higher in the Myc/BP-1 KO mice without any difference between the groups in fasting glucose concentrations. Thus, contrary to our hypothesis, global deletion of Igfbp1 in a c-Myc transgenic mouse model did not accelerate the development of prostate cancer. Global Igfbp1 deletion did result in a significant increase in body weight and body fat mass. Further studies are required to understand the underlying mechanisms for these metabolic effects.
    Journal of Endocrinology 09/2011; 211(3):297-304. · 4.06 Impact Factor
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    ABSTRACT: Insulin-like growth factor (IGF) signaling is essential for achieving optimal body size during fetal development, peak bone mass during puberty, and maximal fecundity in the reproductive period. IGF-II is considered the main fetal IGF, whereas IGF-I is more important postnatally. Pregnancy-associated plasma protein-A (PAPP-A) enhances local IGF signaling through cleavage of inhibitory IGF binding proteins. Conversely, inhibition of PAPP-A results in reduced local IGF action. Thus, PAPP-A knock-out (KO) mice are born as proportional dwarfs due to the dysregulation of IGF-II signaling during early embryogenesis that impacts body size. Relaxation of IgfII imprinting through mutation of a reciprocally imprinted downstream gene, H19, which allowed transcription of IGF-II from the normally silent maternal allele, rescued the dwarf phenotype of PAPP-A KO mice. To determine the effect of increased IGF-II expression on postnatal phenotypes of PAPP-A KO mice. Young adult wild-type (WT), PAPP-A KO, H19 mutant (ΔH19/WT) and ΔH19/PAPP-A KO mice were characterized for skeletal phenotype (peripheral quantitative computed tomography at the midshaft and distal metaphysis of the femur) and reproductive phenotype (time to first litter, time between litters, pups per litter). Serum IGF-II levels were significantly increased in ΔH19/WT and ΔH19/PAPP-A KO mice compared to WT and PAPP-A KO mice; serum IGF-I levels were not affected by H19 mutation. PAPP-A KO mice had reductions in cortical thickness and in cortical and trabecular area, bone mineral content and bone mineral density compared to WT mice. There were no significant differences between PAPP-A KO and ΔH19/PAPP-A KO mice in any of the bone parameters. PAPP-A KO crossed with (×) PAPP-A KO had a longer time until first litter, normal time between subsequent litters, and significantly reduced number of pups per litter compared to WT×WT. ΔH19/PAPP-A KO×ΔH19/PAPP-A KO had an even longer time to first litter, but also longer time between litters. This phenotype was associated with female ΔH19/PAPP-A KO mice. Furthermore, these ΔH19/PAPP-A KO mouse mothers failed to care for their pups. An increase in IGF-II expression did not rescue the skeletal and reproductive deficiencies associated with reduced local IGF-I signaling in PAPP-A KO mice. In addition, the data suggest a potential new role for genomic imprinting at the IgfII/H19 locus affecting maternal behavior.
    Growth hormone & IGF research: official journal of the Growth Hormone Research Society and the International IGF Research Society 07/2011; 21(5):243-7. · 2.35 Impact Factor
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    ABSTRACT: Humanin (HN) is a cytoprotective peptide derived from endogenous mitochondria, expressed in the endothelial layer of human vessels, but its role in atherogenesis in vivo is not known. In vitro study, however, HN reduced oxidized low-density lipoprotein induced formation of reactive oxygen species and apoptosis. The present study tested the hypothesis that long term treatment with HN will have a protective role against endothelial dysfunction and progression of atherosclerosis in vivo. Daily intraperitonial injection of the HN analogue HNGF6A for 16 weeks prevented endothelial dysfunction and decreased atherosclerotic plaque size in the proximal aorta of ApoE-deficient mice fed on a high cholesterol diet, without showing direct vasoactive effects or cholesterol-reducing effects. HN was expressed in the endothelial layer on the aortic plaques. HNGF6A treatment reduced apoptosis and nitrotyrosine immunoreactivity in the aortic plaques without affecting the systemic cytokine profile. HNGF6A also preserved expression of endothelial nitric oxide synthase in aorta. HN may have a protective effect on endothelial function and progression of atherosclerosis by modulating oxidative stress and apoptosis in the developing plaque.
    Atherosclerosis 06/2011; 219(1):65-73. · 3.71 Impact Factor
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    ABSTRACT: The insulin-like growth factor binding protein IGFBP-3 is a proapoptotic and antiangiogenic protein in prostate cancer (CaP). Epidemiologic studies suggest that low IGFBP-3 is associated with greater risk of aggressive, metastatic prostate cancers, but in vivo functional data are lacking. Here we show that mice that are genetically deficient in IGFBP-3 exhibit weaker growth of primary prostate tumors but higher incidence of metastatic disease. Prostates in IGFBP-3 knockout mice (IGFBP-3KO mice) failed to undergo apoptosis after castration. Spontaneous prostate tumors did not develop in IGFBP-3KO mice, but splenic lymphomas occurred in 23% of female IGFBP-3KO mice by 80 weeks of age. To assess the effects of IGFBP-3 deficiency on prostate cancer development, we crossed IGFBP-3KO mice with a c-Myc-driven model of CaP that develops slow-growing, nonmetastatic tumors. By 24 weeks of age, well-differentiated prostate cancers were observed in all mice regardless of IGFBP-3 status. However, by 80 weeks of age IGFBP-3KO mice tended to exhibit larger prostate tumors than control mice. More strikingly, lung metastases were observed at this time in 55% of the IGFBP-3KO mice but none in the control animals. Cell lines established from IGFBP-3KO:Myc tumors displayed more aggressive phenotypes in proliferation, invasion, and colony formation assays, relative to control Myc tumor cell lines. In addition, Myc:IGFBP-3KO cells exhibited evidence of epithelial-mesenchymal transition. Our findings established a function for IGFBP-3 in suppressing metastasis in prostate cancer, and they also offered the first reported transgenic model of spontaneous metastatic prostate cancer for studies of this advanced stage of disease.
    Cancer Research 06/2011; 71(15):5154-63. · 8.65 Impact Factor
  • Journal of Urology - J UROL. 01/2011; 185(4).