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2.  EMMPRIN Promotes Angiogenesis, Proliferation, Invasion and Resistance to Sunitinib in Renal Cell Carcinoma, and Its Level Predicts Patient Outcome 
PLoS ONE  2013;8(9):e74313.
Extracellular matrix metalloproteinase inducer (EMMPRIN) has been reported to play crucial roles, including in angiogenesis, in several carcinomas. However, the correlation between EMMPRIN levels and angiogenesis expression profile has not been reported, and the role of EMMPRIN in renal cell carcinoma (RCC) is unclear. In the present study, we evaluated the association of EMMPRIN with angiogenesis, its value in prognosis, and its roles in RCC.
Experimental Design
EMMPRIN expression was examined in 50 RCC patients treated with radical nephrectomy. Angiogenesis, proliferation, and invasion activity were evaluated using EMMPRIN knockdown RCC cell lines. The size of EMMPRIN-overexpressing xenografts was measured and the degree of angiogenesis was quantified. EMMPRIN expression was evaluated in RCC patients who received sunitinib therapy and in sunitinib-resistant cells. Further, the relation between EMMPRIN expression and sensitivity to sunitinib was examined.
EMMPRIN score was significantly associated with clinicopathological parameters in RCC patients, as well as being significantly correlated with microvessel area (MVA) in immature vessels and with prognosis. Down-regulation of EMMPRIN by siRNA led to decreased VEGF and bFGF expression, cell proliferation, and invasive potential. EMMPRIN over-expressing xenografts showed accelerated growth and MVA of immature vessels. EMMPRIN expression was significantly increased in patients who received sunitinib therapy as well as in sunitinib-resistant 786-O cells (786-suni). EMMPRIN-overexpressing RCC cells were resistant to sunitinib.
Our findings indicate that high expression of EMMPRIN in RCC plays important roles in tumor progression and sunitinib resistance. Therefore, EMMPRIN could be a novel target for the treatment of RCC.
PMCID: PMC3779201  PMID: 24073208
3.  Immunomodulatory IL-18 binding protein is produced by prostate cancer cells and its levels in urine and serum correlate with tumor status 
Cytokines may play a role in the initiation and progression of prostate cancer. A cytokine antibody array was previously applied to prostatic fluid obtained from patients with prostate cancer, and interleukin 18 binding protein (IL-18BP), a potent inhibitor of interleukin 18, was noted to be significantly upregulated in cases with large volume disease. We sought to further characterize the association of IL-18BP with prostate cancer and determine whether IL-18BP levels in patient serum and urine samples had clinical relevance. IL-18BP was expressed and secreted by the prostate cancer cell lines DU145 and PC3, but not by LNCaP and CWR22, upon interferon-γ (IFN-γ) stimulation. IFN-γ-induced secretion of IL-18BP was enhanced by added TNF-α, IFN-α and IFN-β. The IL-18BP secreted from DU145 and PC3 functionally inhibited IL-18. Immunohistochemical analyses showed positive IL-18BP staining in prostate cancer cells as well as in macrophages in radical prostatectomy specimens. Significant differences in urinary IL-18BP levels (normalized by total protein) collected post-DRE were found between cases with and without cancer on biopsy (P = 0.02) and serum IL-18BP levels correlated with Gleason score (P = 0.03). Our finding of elevated IL-18BP secretion from prostate cancer cells suggests an attempt by cancer to escape immune surveillance. IL-18BP merits further study as a marker of aggressive prostate cancer and as a therapeutic target.
PMCID: PMC3040782  PMID: 20878981
Prostate cancer; IL-18 binding protein; urinary marker
4.  Clinical characteristics and risk factors for septic shock in patients receiving emergency drainage for acute pyelonephritis with upper urinary tract calculi 
BMC Urology  2012;12:4.
Acute pyelonephritis (APN) is a common complication of ureteral obstruction caused by urolithiasis, and it can be lethal if it progresses to septic shock. We investigated the clinical characteristics of patients undergoing emergency drainage and assessed risk factors for septic shock.
A retrospective study was performed of 98 patients (101 events) requiring emergency drainage at our urology department for obstructive APN associated with upper urinary tract calculi from January 2003 to January 2011. Clinical characteristics were summarized, and risk factors for septic shock were assessed by logistic regression analysis.
Objective evidence of sepsis was found in 64 (63.4%) events, and 21 events (20.8%) were categorized as septic shock. Ninety-six patients recovered, but 2 patients died of septic shock. Multivariate analysis revealed that age and the presence of paralysis were independent risk factors for septic shock.
APN associated with upper urinary tract calculi is a severe disease that should be treated with caution, particularly when risk factors are present.
PMCID: PMC3353222  PMID: 22413829
5.  Supplementation of bone marrow aspirate-derived platelet-rich plasma for treating radiation-induced ulcer after cardiac fluoroscopic procedures: A preliminary report 
The frequency of encountering radiodermatitis caused by X-ray fluoroscopic procedures for ischaemic heart disease is increasing. In severe cases, devastating ulcers with pain, for which conservative therapy is ineffective, emerge. Radiation-induced ulcers are notorious for being difficult to treat. Simple skin grafting often fails because of the poor state of the wound bed. A vascularized flap is a very good option. However, the non-adherence of the well-vascularized flap with the irradiated wound bed is frequently experienced.
To ameliorate the irradiated wound bed, bone marrow-derived platelet-rich plasma (bm-PRP) was delivered during the surgery.
Materials and Methods:
Four patients with severe cutaneous radiation injury accompanied by unbearable pain after multiple fluoroscopic procedures for ischaemic heart disease were treated. Wide excision of the lesion and coverage with a skin flap supplemented with bm-PRP injection was performed.
All patients obtained wound closure and were relieved from pain. No complication concerning the bone marrow aspiration and delivery of bm-PRP was observed.
Supplementation of bm-PRP can be an option without major complications, time, and cost to improve the surgical outcome for irradiated wounds.
PMCID: PMC3385373  PMID: 22754164
Bone marrow; cardiac fluoroscopy; platelet-rich plasma; radiation ulcer; skin flap
6.  The Escherichia coli K-12 ORFeome: a resource for comparative molecular microbiology 
BMC Genomics  2010;11:470.
Systems biology and functional genomics require genome-wide datasets and resources. Complete sets of cloned open reading frames (ORFs) have been made for about a dozen bacterial species and allow researchers to express and study complete proteomes in a high-throughput fashion.
We have constructed an open reading frame (ORFeome) collection of 3974 or 94% of the known Escherichia coli K-12 ORFs in Gateway® entry vector pENTR/Zeo. The collection has been used for protein expression and protein interaction studies. For example, we have compared interactions among YgjD, YjeE and YeaZ proteins in E. coli, Streptococcus pneumoniae, and Staphylococcus aureus. We also compare this ORFeome with other Gateway-compatible bacterial ORFeomes and show its utility for comparative functional genomics.
The E. coli ORFeome provides a useful resource for functional genomics and other areas of protein research in a highly flexible format. Our comparison with other ORFeomes makes comparative analyses straighforward and facilitates direct comparisons of many proteins across many genomes.
PMCID: PMC3091666  PMID: 20701780
7.  Specific detection of prostate cancer cells in urine by multiplex immunofluorescence cytology 
Human pathology  2009;40(7):924-933.
Prostate cancer biomarkers are enriched in urine after prostatic manipulation, suggesting whole cells might also be detectable for diagnosis. We tested multiplex staining of urinary sediments as a minimally-invasive method to detect prostate cancer. Urine samples were collected after prostatic massage (attentive digital rectal examination) from 35 men in Urology clinic, and without massage from 15 control men without urologic disease, for a total of 50 specimens (27 cancer positive cases, 23 cancer negative cases). LNCaP prostate cancer cells spiked into urine were used for initial marker optimization. Urine sediments were cytospun onto glass slides and stained. Multiplex urine cytology was compared to conventional urine cytology for cancer detection: anti-alpha-methylacyl CoA racemase (AMACR) antibody was used as a marker of prostate cancer cells, anti-Nkx3.1 as a marker of prostate epithelial cells, anti-nucleolin as a marker of nucleoli, and DAPI to highlight nuclei. Prostate cancer cells were successfully visualized by combined staining for AMACR, Nkx3.1, and nucleolin. Of 25 informative cases with biopsy-proven prostate cancer, 9 were diagnosed as suspicious or positive by multiplex immunofluorescence urine cytology, but only 4 were similarly judged by conventional cytology. All cases without cancer were read as negative by both methods. Multiplex cytology sensitivity for cancer detection in informative cases was 36% (9/25) and specificity was 100% (8/8). In conclusion, we have successfully achieved multiple-staining for AMACR, Nkx3.1, Nucleolin, and DAPI to detect prostate cancer cells in urine. Further refinements in marker selection and technique may increase sensitivity and applicability for prostate cancer diagnosis.
PMCID: PMC2757169  PMID: 19368959
prostate cancer; urine cytology; biomarkers; diagnosis; multiplex staining
8.  Endoglin (CD105) as a Urinary and Serum Marker of Prostate Cancer 
We have previously shown that endoglin (CD105) is upregulated in prostatic fluid of men with large volume prostate cancer. We chose to assess endoglin levels in urine and serum from men with prostate cancer or at increased risk for the disease: Urine samples were collected after DRE from 99 men whose cancer status was confirmed by biopsy, and serum samples were collected from 20 men without prostate cancer at low risk for the disease, and from 69 men diagnosed with prostate cancer that subsequently underwent radical prostatectomy (30 pT2, 39 pT3). Endoglin levels were assessed by ELISA. Urinary endoglin was elevated in men with biopsy-positive prostate cancer compared to biopsy-negative men (p=0.0014). Urinary endoglin levels in men with prostate cancer correlated with radical prostatectomy tumor volume. The area under the receiver-operator characteristics (ROC) curve was 0.72 for urinary endoglin and 0.50 for serum prostate-specific antigen PSA (sensitivity for cancer detection 73%, specificity 63%). There were no differences in serum endoglin between normal and cancer cases, but there were increases in serum endoglin in non-organ confined (NOC, pT3+) vs. organ-confined (OC, pT2) cases (p=0.0004). The area under the ROC curve was 0.75 for serum endoglin and 0.63 for PSA for predicting NOC status, with a sensitivity of 67% and a specificity of 80%. In conclusion, elevations in post-DRE urinary endoglin suggest there may be value in further studying endoglin as a urinary biomarker of prostate cancer. Endoglin levels in both urine and serum may aid in prostate cancer detection and prognostication.
PMCID: PMC2666305  PMID: 19004009
Endoglin; CD105; Prostate Cancer; Biological Markers; Clinical Markers
9.  Cytokine Profiling of Prostatic Fluid from Cancerous Prostate Glands 
The Prostate  2008;68(8):872-882.
Cytokines are key mediators of inflammation that may play important roles in prostate cancer initiation and progression. Cytokines found in cancerous prostates may provide further insight into the mechanisms of cancer initiation and progression, and facilitate the exploration of new markers of prostatic neoplasia and inflammation. We describe the cytokine profile of prostatic fluids obtained from cancerous prostate glands and correlate it to both cancer status and inflammation grade.
Prostatic fluid was collected from fresh radical prostatectomy specimens and analyzed by human cytokine antibody microarray. Cases were selected from patients with either minimal or extensive cancer volume on final pathology. Among the cytokines with the greatest difference between the tumor volume groups, eight had their levels quantitated by ELISA and correlated with cancer status and grade of inflammation by neutrophils, macrophages and lymphocytes.
Among 174 cytokines analyzed, HGF was the most increased (6.57-fold), and HGF and IL18Bpa were significantly elevated in patients with extensive prostate cancer. IL17, GITR, ICAM-1, and IL-18Bpa were elevated in specimens with neutrophilic inflammation into gland lumina, and IL18Bpa, IL17, GITR, ICAM-1 were elevated in specimens with lymphocytic inflammation in prostatic stroma.
Prostatic fluid cytokines were identified that may be useful in early detection and prognostication efforts for prostate cancer, particularly if they can be found not only in prostatic fluids obtained ex vivo, but in expressed prostatic secretions or urine samples from patients with their prostates still in situ.
PMCID: PMC2562260  PMID: 18361406
cancer; inflammation; cytokine
10.  Transplantation of spermatogonial stem cells isolated from leukemic mice restores fertility without inducing leukemia 
Journal of Clinical Investigation  2005;115(7):1855-1861.
More than 70% of patients survive childhood leukemia, but chemotherapy and radiation therapy cause irreversible impairment of spermatogenesis. Although autotransplantation of germ cells holds promise for restoring fertility, contamination by leukemic cells may induce relapse. In this study, we isolated germ cells from leukemic mice by FACS sorting. The cell population in the high forward-scatter and low side-scatter regions of dissociated testicular cells from leukemic mice were analyzed by staining for MHC class I heavy chain (H-2Kb/H-2Db) and for CD45. Cells that did not stain positively for H-2Kb/H-2Db and CD45 were sorted as the germ cell–enriched fraction. The sorted germ cell–enriched fractions were transplanted into the testes of recipient mice exposed to alkylating agents. Transplanted germ cells colonized, and recipient mice survived. Normal progeny were produced by intracytoplasmic injection of sperm obtained from recipient testes. When unsorted germ cells from leukemic mice were transplanted into recipient testes, all recipient mice developed leukemia. The successful birth of offspring from recipient mice without transmission of leukemia to the recipients indicates the potential of autotransplantation of germ cells sorted by FACS to treat infertility secondary to anticancer treatment for childhood leukemia.
PMCID: PMC1150287  PMID: 15965502

Results 1-10 (10)