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Biomedical subjects

Edward M Messing

Publications and source records attributed to Edward M Messing.

At least 19 recordsLinked to original sources
PubMed2006

Long-term outcome of hematuria home screening for bladder cancer in men.

BACKGROUND: The objectives of this study were to determine whether bladder cancer (BC) screening in healthy men could lead to earlier detection and reduced BC mortality compared with unscreened men and to determine long-term outcomes of a geographically defined, unscreened population with newly diagnosed BC. METHODS: In 1987 and from 1998 to 1992, 1575 men ages 50 years and older who were solicited from well patient rosters in clinics in and around Madison, Wisconsin, tested their urine repetitively with a chemical reagent strip for hemoglobin. Participants who had positive test results underwent standard urologic evaluation. BC grades and stages and the outcomes of men with BC detected by screening were compared with the grades, stages, and outcomes of 87% of men ages 50 years and older with newly diagnosed BC who were reported to the Wisconsin Tumor Registry in 1988 (n = 509 men). RESULTS: Two hundred fifty-eight screening participants (16.4%) were evaluated for hematuria, and 21 participants (8.1%) were diagnosed with BC. Proportions of low-grade (Grade 1 and 2) superficial (Stage Ta and T1) versus high-grade (Grade 3) superficial or invasive (Stage > or = T2) cancers in screened men (52.4% vs. 47.7%) and in men from the tumor registry (60.3% vs. 39.7%) were similar (P = .50). The proportion of high-grade superficial or invasive BCs that were invasive were lower in screened men (10%) than in unscreened men (60%; P = .002). At 14 years of follow-up, no men with screen-detected BC had died of BC, whereas 20.4% of men with unscreened BC had died of BC (P = .02). CONCLUSIONS: Screening effected the early detection of BC and may reduce mortality from BC compared with BC that is diagnosed at standard clinical presentation.

Aged↗
PubMed2006

Early detection and measurement of urothelial tumors in mice.

OBJECTIVES: To establish reliable noninvasive in vivo methods to detect, measure, and monitor experimentally induced urothelial tumors in mice. METHODS: UPII-SV40T transgenic mice reliably develop bladder tumors by expression of simian virus 40 large T antigen specifically in bladder urothelium through the use of the uroplakin II promoter. Two wild-type and 10 UPII-SV40T transgenic mice were monitored for microhematuria two to three times weekly using dipstick analysis. A unique flat panel detector-based cone beam computed tomography (FPD-CBCT) system imaged the urinary tracts of anesthetized mice after tail vein injection of an iodinated contrast agent (Omnipaque) that is excreted in urine. Within 10 seconds, the FPD-CBCT system acquired 290 two-dimensional images, which produced three-dimensional volumes with true isotropic resolution (180 microm)3 using a filtered back projection-based modified Feldkamp reconstruction algorithm. Amira, version 3.1.1-1, for MacOSX was used for data analysis and advanced visualization of the three-dimensional reconstructed FPD-CBCT images. RESULTS: Hematuria was present in UPII-SV40T transgenic mice at 32 days of age; the wild-type animals exhibited no hematuria. Filling defects, associated with histologically confirmed tumors, in the bladders of the UPII-SV40T transgenic mice were visualized in the reconstructed FPD-CBCT images 1 to 45 minutes after contrast agent injection. Longitudinal FPD-CBCT imaging sessions showed the tumor position, volume, and growth. CONCLUSIONS: The combination of early detection of hematuria and high-resolution in vivo FPD-CBCT imaging of murine bladder tumors enabled accurate longitudinal assessment of tumor growth and progression in individual animals. This approach could provide an important alternative to serial sacrifice experimental designs, while refining statistical power and reducing animal use.

Animals↗
PubMed2006

Initial observations of reduced uroflow in transgenic adenocarcinoma of murine prostate.

OBJECTIVES: To characterize the voiding function in a transgenic adenocarcinoma of murine prostate (TRAMP) mouse of advanced age, because it might provide a useful model of slow-onset bladder outlet obstruction. Spontaneous death from urinary outlet obstruction occurs in the TRAMP mouse. METHODS: A metabolic cage without a fecal separation screen was placed above a precision balance that reported the mass of the excreta pan every 100 ms. A computational algorithm identified voids suitable for uroflow assessment from other excretory events. A series of images were obtained automatically before and during the excretory events. RESULTS: The TRAMP mouse displayed a pulsatile voiding pattern characterized by a reduction in uroflow, prolongation of voiding, and droplet formation at the tip of the prepuce. Postmortem histologic examination revealed gross enlargement of the prostate, a suburethral tumor, dilation of the lumen of the urethra, and proteinaceous debris in the urethra and bladder. CONCLUSIONS: The observed changes were consistent with urethral obstruction induced by prostate enlargement and/or suburethral tumor. Additional studies are required to ascertain whether prostate enlargement per se is sufficient to produce urethral obstruction in the TRAMP mouse. This transgenic mouse strain may provide a model of slow-onset outlet obstruction that is more representative of bladder outlet obstruction caused by benign prostatic hyperplasia than is the obstruction produced by urethral ligation.

Adenocarcinoma↗
PubMed2006

Immediate versus deferred androgen deprivation treatment in patients with node-positive prostate cancer after radical prostatectomy and pelvic lymphadenectomy.

BACKGROUND: Appropriate timing of androgen deprivation treatment (ADT) for prostate cancer is controversial. Our aim was to determine whether immediate ADT extends survival in men with node-positive prostate cancer who have undergone radical prostatectomy and pelvic lymphadenectomy compared with those who received ADT only once disease progressed. METHODS: Eligible patients from 36 institutes in the USA were randomly assigned in 1988-93 to receive immediate ADT (n=47) or to be observed (n=51), with ADT to be given on detection of distant metastases or symptomatic recurrences. Patients were followed up every 3 months for the first year and every 6 months thereafter. The primary endpoint was progression-free survival; secondary endpoints were overall and disease-specific survival. Analysis was by intention to treat. To ensure that the treatment groups were comparable, we did a retrospective central pathology review of slides and regraded the Gleason scores for available samples. This trial predates the requirement for clinical trial registration. FINDINGS: At median follow-up of 11.9 years (range 9.7-14.5 for surviving patients), men assigned immediate ADT had a significant improvement in overall survival (hazard ratio 1.84 [95% CI 1.01-3.35], p=0.04), prostate-cancer-specific survival (4.09 [1.76-9.49], p=0.0004), and progression-free survival (3.42 [1.96-5.98], p<0.0001). Of 49 histopathology slides received (19 immediate ADT, 30 observation), 16 were downgraded from the original Gleason score (between groups < or = 6, 7, and > or = 8) and five were upgraded. We recorded similar proportions of score changes in each group (p=0.68), and no difference in score distribution by treatment (p=0.38). After adjustment for score, associations were still significant between treatment and survival (overall, p=0.02; disease-specific, p=0.002; progression-free survival, p<0.0001). INTERPRETATION: Early ADT benefits patients with nodal metastases who have undergone prostatectomy and lymphadenectomy, compared with those who receive deferred treatment. The beneficial effects of early ADT, rather than an imbalance in risk factors, are likely to explain the differences in outcomes between treatments.

Aged↗
PubMed2005

Tocopherol-associated protein suppresses prostate cancer cell growth by inhibition of the phosphoinositide 3-kinase pathway.

Epidemiologic studies suggested that vitamin E has a protective effect against prostate cancer. We showed here that tocopherol-associated protein (TAP), a vitamin E-binding protein, promoted vitamin E uptake and facilitated vitamin E antiproliferation effect in prostate cancer cells. Interestingly, without vitamin E treatment, overexpression of TAP in prostate cancer cells significantly suppressed cell growth; knockdown of endogenous TAP by TAP small interfering RNA (siRNA) in nonmalignant prostate HPr-1 cells increased cell growth. Further mechanism dissection studies suggested that the tumor suppressor function of TAP was via down-regulation of phosphoinositide 3-kinase (PI3K)/Akt signaling, but not by modulating cell cycle arrest or androgen receptor signaling. Immunoprecipitation results indicated that TAP inhibited the interaction of PI3K subunits, p110 with p85, and subsequently reduced Akt activity. Constitutively active Akt could negate the TAP-suppressive activity on prostate cancer cell growth. Moreover, stable transfection of TAP in LNCaP cells suppressed LNCaP tumor incidence and growth rate in nude mice. Furthermore, TAP mRNA and protein expression levels were significantly down-regulated in human prostate cancer tissue samples compared with benign prostate tissues as measured by reverse transcription-PCR, in situ hybridization, and immunohistochemistry. Together, our data suggest that TAP not only mediates vitamin E absorption to facilitate vitamin E antiproliferation effect in prostate cancer cells, but also functions like a tumor suppressor gene to control cancer cell viability through a non-vitamin E manner. Therefore, TAP may represent a new prognostic marker for prostate cancer progression.

Animals↗
PubMed2005

Prostate cancer: three-dimensional sonoelastography for in vitro detection.

PURPOSE: To prospectively evaluate the accuracy of three-dimensional (3D) sonoelastographic imaging, relative to that of gray-scale ultrasonography (US), in the in vitro detection of prostate cancer. MATERIALS AND METHODS: The study was approved by the institutional review board and was HIPAA compliant. Informed consent was obtained from all patients. Nineteen prostatectomy specimens from patients aged 46-70 years with biopsy-proved prostate cancer were scanned in three dimensions by using conventional B-mode US and sonoelastography with vibrations of more than 100 Hz. Step-sectioned whole-mount histologic specimens were used to create a 3D volume of the prostate and the tumors within it. B-mode US scans and regions of low vibration on the sonoelastographic images (hard regions) were formatted in three dimensions. The lesions in the 19 cases were classified into two groups, as follows: G1 lesions were pathologically confirmed tumors with a volume of at least 1.0 cm3, and G2 lesions were pathologically confirmed tumors smaller than 1.0 cm3. G1 lesions were evaluated with B-mode US and sonoelastography and classified as true-positive, false-positive, true-negative, or false-negative; G2 lesions were evaluated only with sonoelastography. Findings at histologic examination were used as the reference standard. True-positive findings necessitated 3D lesion correlation between pathologic and imaging data. Conventional definitions of accuracy and sensitivity were used for statistical analysis. RESULTS: For G1 lesions (seven lesions with a volume of at least 1.0 cm3), sonoelastography had an accuracy of 55% and a sensitivity of 71% and B-mode US had an accuracy of 17% and a sensitivity of 29%. The mean tumor volume was 3.1 cm3 +/- 2.1 (standard deviation). For G2 lesions (22 lesions with a volume of less than 1.0 cm3), the mean tumor volume was 0.32 cm3 +/- 0.21. Sonoelastography had an accuracy of 34% and a sensitivity of 41%; there were six false-positive findings. CONCLUSION: Sonoelastography performed considerably better than did gray-scale US in the depiction of prostate cancer for tumors with volumes of more than 1 cm3.

Aged↗
PubMed2005

The SPRY domain-containing SOCS box protein 1 (SSB-1) interacts with MET and enhances the hepatocyte growth factor-induced Erk-Elk-1-serum response element pathway.

The suppressor of cytokine signaling (SOCS) protein family includes a SPRY (repeats in splA and RyR) domain-containing SOCS box protein (SSB) subfamily, which consists of four members, SSB-1, SSB-2, SSB-3, and SSB-4. These proteins contain a central SPRY domain and a C-terminal SOCS box. Although some of the SOCS protein subfamilies function as adaptors for a large family of ubiquitin-protein isopeptide ligases to regulate certain signaling pathways, the function of the SSB subfamily remains to be determined. In our previous studies, we have found that two SPRY domain-containing proteins, RanBP9 and RanBP10, interact with MET through the SPRY domain. In the present study, we explored the function of SSB proteins in the regulation of the hepatocyte growth factor (HGF)-MET signaling. Our results showed that all four SSB proteins also interacted with the MET. The MET interaction with SSB-1 was further investigated. We demonstrated that SSB-1 bound to MET tyrosine kinase domain through its SPRY domain. MET interacted with SSB-1 in both the absence and the presence of HGF, but HGF treatment resulted in the recruitment of more SSB-1 by MET. We showed that overexpression of SSB-1 but not other SSB proteins enhanced the HGF-induced serum response element (SRE)-luciferase activity. Overexpression of SSB-1 exhibited no effect on the basal level or epidermal growth factor-induced SRE-luciferase activity. SSB-1 also enhanced HGF-induced Erk phosphorylation. Suppression of SSB-1 by the RNA interference method down-regulated HGF-induced SRE-luciferase activity and decreased Elk-1 activation. These results suggest that SSB-1 may play an important role in enhancing the HGF-induced Erk-Elk-1-SRE pathway. Furthermore, we demonstrated that in response to HGF stimulation, the SSB-1 protein became phosphorylated at tyrosine residue 31. The phosphorylated SSB-1 protein bound to p120Ras-GTPase-activating protein (GAP) but did not promote the degradation of p120RasGAP, indicating that enhanced HGF-MET signaling by overexpression of SSB-1 was not dependent on p120RasGAP degradation.

Amino Acid Sequence↗
PubMed2005

Inhibition of the Akt, cyclooxygenase-2, and matrix metalloproteinase-9 pathways in combination with androgen deprivation therapy: potential therapeutic approaches for prostate cancer.

Prostate cancer cells are generally dependent on androgen stimulation mediated by the androgen receptor (AR) for growth and survival, and, therefore, hormonal manipulation, such as castration and/or the use of AR antagonists, results in a regression of the cancer. However, this treatment very rarely leads to the "cure" of advanced disease, and cancers eventually become androgen-independent. A number of genes/pathways have been reported to be activated in prostate cancer, most of which are possibly associated with disease progression. In this article, among them, we focus on Akt (also known as protein kinase B), cyclooxygenase (COX)-2, and matrix metalloproteinase (MMP)-9, whose activities or expressions have been found to be regulated by androgens/AR. Previous studies by us and others, with androgen-sensitive prostate cancer cell lines, have demonstrated that androgen deprivation results in activation/overexpression of Akt, COX-2, and MMP-9 in cells. This suggests that androgen deprivation in clinical settings activates the Akt, COX-2, and MMP-9 pathways in prostate cancer, which may increase cell growth and in turn promote the transition to the androgen-independent state. We hypothesize that androgen deprivation, in combination with inhibition of the Akt, COX-2, and MMP-9 pathways, delays the androgen-independent transition and has more beneficial effects than hormonal therapy alone.

Androgens↗
PubMed2005

VHL protein-interacting deubiquitinating enzyme 2 deubiquitinates and stabilizes HIF-1alpha.

Hypoxia-inducible factor (HIF)-1alpha is a short-lived protein and is ubiquitinated and degraded through the von Hippel-Lindau protein (pVHL)-E3 ubiquitin ligase pathway at normoxia. Deubiquitination, by reversing ubiquitination, has been recognized as an important regulatory step in ubiquitination-related processes. Here, we show that pVHL-interacting deubiquitinating enzyme 2, VDU2, but not VDU1, interacts with HIF-1alpha. VDU2 can specifically deubiquitinate and stabilize HIF-1alpha and, therefore, increase expression of HIF-1alpha targeted genes, such as vascular endothelial growth factor (VEGF). These findings suggest that ubiquitination of HIF-1alpha is a dynamic process and that ubiquitinated HIF-1alpha might be rescued from degradation by VDU2 through deubiquitination. Although pVHL functions as a master control for HIF-1alpha stabilization, as pVHL-E3 ligase mediates the ubiquitination of both HIF-1alpha and VDU2, the balance between the pVHL-mediated ubiquitination and VDU2-mediated deubiquitination of HIF-1alpha provides another level of control for HIF-1alpha stabilization.

Animals↗
PubMed2005

A randomized controlled trial of intravesical bacillus calmette-guerin for treatment refractory interstitial cystitis.

PURPOSE: We compared intravesical bacillus Calmette-Guerin (BCG) to placebo instillations in patients with treatment refractory interstitial cystitis (IC). MATERIALS AND METHODS: Subjects who met the National Institutes of Health-National Institute for Diabetes and Digestive and Kidney Diseases criteria for IC, and reported at least moderate pain and frequency for a minimum of 6 months before study entry, were randomized to 6 weekly double-blinded intravesical instillations of either BCG or placebo, and then followed for a total of 34 weeks. The primary outcome was a patient reported global response assessment at week 34, supplemented with medications for IC during weeks 31 to 34. Secondary outcomes included a 24-hour voiding diary, pain, urgency, validated IC symptom indexes and adverse events. The target sample size was 260 participants, designed to detect a difference in response rates between placebo and BCG of 30% and 50%, respectively. RESULTS: A total of 265 participants were randomized and 17 (6%) patients withdrew from study. The response rates for the primary outcome were 12% for placebo and 21% for BCG (p = 0.062). Small improvements were observed for all secondary outcomes, some more so with BCG, but these differences were of borderline statistical significance. Although a large number of adverse events were reported in the BCG arm, there was no statistically significant difference between the treatment arms in overall adverse event rates. CONCLUSIONS: Although the BCG safety profile was acceptable, the response rate for the primary outcome was low. Effective medical treatment for patients with moderate to severe interstitial cystitis remains elusive.

Administration, Intravesical↗
PubMed2005

Performance of urine test in patients monitored for recurrence of bladder cancer: a multicenter study in the United States.

PURPOSE: We assessed the performance of the ImmunoCyt immunocytochemical test for detecting bladder cancer recurrence in patients with prior superficial bladder cancers compared with cystoscopic and histological findings. MATERIALS AND METHODS: A total of 341 patients with a history of bladder cancer undergoing monitoring were evaluated at 4 sites. The results of cytology and/or ImmunoCyt were analyzed for sensitivity and specificity compared with biopsy confirmed cancer. RESULTS: The overall sensitivity of cytology alone, ImmunoCyt alone and the 2 methods combined was 23%, 81% and 81%, respectively. The specificity of cytology alone, ImmunoCyt alone and of the 2 methods combined was 93%, 75% and 73%, respectively. The immunocytochemical test was more sensitive than cytology for detecting grades 1 and 2, and stages Ta, T1, and T2 urothelial carcinoma, and it was equally sensitive for detecting grade 3 cancers and carcinoma in situ (CIS). The sensitivity of the combined tests for grades 1 to 3/CIS was 79%, 90% and 82%, while for stages Ta, T1, T2+ and CIS it was 83%, 75%, 100% and 100%, respectively. The overall positive and negative predictive values of the combined tests were 37% and 95%, respectively. Importantly the immunocytochemical test could detect 71% of small (less than 1 cm) tumors. CONCLUSIONS: ImmunoCyt is a sensitive test for detecting bladder cancer. Because of its high sensitivity for detecting small tumors, even those of low histological grade, and its high negative predictive value, this test may have a role in decreasing the frequency of cystoscopic examinations for monitoring patients with low risk bladder cancer.

Antibodies, Monoclonal↗
PubMed2004

Androgen deprivation therapy for prostate cancer: current status and future prospects.

Androgens play a major role in promoting the development and progression of prostate cancer. As a result, androgen ablation or blockade of androgen action through the androgen receptor (AR) has been the cornerstone of treatment of advanced prostate cancer. Different strategies involving this hormonal therapy produce a significant clinical response in most of the patients, but most responders eventually lose dependency, resulting in mortality. Thus, whether hormonal therapy contributes to the improvement of overall survival rates, especially in patients with advanced prostate cancer, remains controversial. However, patients with advanced disease clearly have a benefit from androgen deprivation-based treatment for palliating their symptoms and for improving the quality of their lives. In order to improve overall survival, novel treatment strategies that prolong the androgen-dependent state and that are useful for androgen-independent disease based on specific molecular mechanisms need to be identified.

Androgen Antagonists↗
PubMed2004

Interstitial cystitis antiproliferative factor (APF) as a cell-cycle modulator.

BACKGROUND: Interstitial cystitis (IC) is a chronic bladder disorder of unknown etiology. Antiproliferative factor (APF), a peptide found in the urine of IC patients, has previously been shown to decrease incorporation of thymidine by normal bladder epithelial cells. This study was performed to determine the effect of APF on the cell cycle of bladder epithelial cells so as to better understand its antiproliferative activity. METHODS: Explant cultures from normal bladder biopsy specimens were exposed to APF or mock control. DNA cytometry was performed using an automated image analysis system. Cell cycle phase fractions were calculated from the DNA frequency distributions and compared by two-way analysis of variance (ANOVA). RESULTS: APF exposure produced statistically significant increases in the proportion of tetraploid and hypertetraploid cells compared to mock control preparations, suggesting a G2 and/or M phase cell cycle block and the production of polyploidy. CONCLUSIONS: APF has a specific effect on cell cycle distributions. The presence of a peptide with this activity may contribute to the pathogenesis of interstitial cystitis through disruption of normal urothelial proliferation and repair processes.

Adult↗
PubMed2004

A novel MET-interacting protein shares high sequence similarity with RanBPM, but fails to stimulate MET-induced Ras/Erk signaling.

MET is a receptor protein tyrosine kinase for hepatocyte growth factor, a multifunctional cytokine controlling cell growth, morphogenesis, and motility. In our previous study, RanBPM/RanBP9, whose name originated from its ability to interact with Ran, was identified as a MET-interacting protein. RanBPM/RanBP9 activates the Ras/Erk signaling pathway by serving as an adaptor protein of MET to recruit Sos. In this study, we identify a protein sharing a high amino acid sequence identity with RanBPM/RanBP9, especially in its SPRY domain, the region responsible for MET binding. This protein lacks the N-terminal poly-proline and poly-glutamine (Poly-PQ) stretch present in RanBPM/RanBP9 and has less homology with RanBPM/RanBP9 in its mid-region. We subsequently named this protein RanBP10 after demonstrating its interaction with Ran. We show that, like RanBPM/RanBP9, RanBP10 interacts with the tyrosine kinase domain of MET via its SPRY domain and these two proteins can compete with each other to bind to MET. Interestingly, unlike RanBPM/RanBP9, overexpression of RanBP10 cannot induce Erk1/2 phosphorylation and serum response element-luciferase (SRE-LUC) reporter gene expression. More importantly, co-transfection of RanBPM/RanBP9 and RanBP10 significantly represses SRE-LUC reporter gene expression induced by overexpression of RanBPM/RanBP9. Additional binding assays demonstrate that RanBP10 fails to interact with Sos, which explains its inability to activate the Ras/Erk pathway. Furthermore, we show that the N-terminus of RanBPM/RanBP9 with the Poly-PQ stretch is required for recruiting Sos and a truncated RanBPM/RanBP9 lacking this region fails to recruit Sos, indicating that the functional difference between RanBP10 and RanBPM/RanBP9 lies in their sequence difference in their N-termini.

Adaptor Proteins, Signal Transducing↗