To investigate whether elevated urinary levels of vascular endothelial growth factor (VEGF), carbonic anhydrase 9 (CA9) and angiogenin are associated with BCa.
This is a case-control study in which voided urines from 127 patients: control subjects (n = 63) and tumor bearing subjects (n = 64) were analyzed. The urinary concentrations of VEGF, CA9, angiogenin and BTA were assessed by enzyme-linked immunosorbent assay (ELISA). We used the area under the curve (AUC) of receiver operating characteristic curves to determine the ability of VEGF, CA9, and angiogenin to detect BCa in voided urine samples. Data were also compared to a commercial ELISA-based BCa detection assay (BTA-Trak©). Sensitivity, specificity, positive and negative predictive values were calculated.
Urinary concentrations of VEGF, CA9, angiogenin and BTA were significantly elevated in BCa. VEGF was the most accurate urinary biomarker (AUC: 0.886; 95% confidence interval [CI]: 0.8301–0.9418). Furthermore, multivariate regression analysis highlighted VEGF (OR: 5.90; 95% CI: 2.60–13.40, p < 0.0001) as an independent variable. The sensitivities and specificities for VEGF (sensitivity, 83% and specificity, 87%) outperformed BTA (sensitivity, 80% and specificity, 84%).
VEGF may be a valuable addition to voided urine sample analysis for the detection of BCa. Larger, prospective studies are needed to determine the clinical utility of urinary VEGF and angiogenin as biomarkers in the non-invasive evaluation of BCa patients.
angiogenin; bladder cancer; biomarkers; diagnosis; VEGF
Pheochromocytoma (paraganglioma) of the urinary bladder is a rare tumor. Herein we sought to review the contemporary literature on pheochromocytomas of the urinary bladder in order to further illustrate the presentation, treatment options and outcomes of patients diagnosed with these tumors.
A comprehensive review of the current literature was conducted according to the PRISMA guidelines by accessing the NCBI PubMed database and using the search terms “paraganglioma, pheochromocytoma, bladder.” This search resulted in the identification of 186 articles published between January 1980 and April 2012 of which 80 articles were ultimately included in our analysis.
Pheochromocytomas usually occurred in young adult Caucasians (mean age, 43.3 years; range,11–84 years). According to the literature, the most common symptoms and signs of pheochromocytomas of the urinary bladder were hypertension, headache, and hematuria. Of the 77 cases that commented on catecholamine production, 65 patients had biochemically functional tumors. Approximately 20% of patients were treated by transurethral resection alone, 70% by partial cystectomy and 10% by radical cystectomy. The 75 patients with follow-up information had a mean follow-up of 35 months. At the time of last follow-up, 15 (14.2%) had disease recurrence, 10 (9.4%) had metastasis, and 65 (61.3%) were alive.
Pheochromocytomas of the urinary bladder tend to be functional and occur mostly in young adult Caucasians. Patients with localized tumors have an extremely favorable prognosis and may be managed by less aggressive modalities, whereas patients with metastatic disease have a significant reduction in survival rates despite aggressive treatment.
Paraganglioma; Pheochromocytoma; Bladder; Treatment; Diagnosis; Prognosis
Bladder cancer is one of the most prevalent cancers worldwide, but the treatment and management of this disease can be very successful if the disease is detected early. The development of molecular assays that could diagnose bladder cancer accurately, and at an early stage, would be a significant advance. Ideally, such molecular assays would be applicable to non-invasively obtained body fluids, and be designed not only for diagnosis but also for monitoring disease recurrence and response to treatment. In this article, we assess the performance of current diagnostic assays for bladder cancer and discuss some of the emerging biomarkers that could be developed to augment current bladder cancer detection strategies.
Mycoplasma hyorhinis is a eubacterium belonging to the Mollicutes class and is responsible for porcine respiratory and arthritic diseases. It is also the major contaminant of mammalian tissue cultures in laboratories worldwide. Here, we report the complete genome sequence of M. hyorhinis strain SK76.
Prostate cancer is the second most commonly diagnosed cancer in American men over the age of 45 years and is the third most common cause of cancer related deaths in American men. In 2012 it is estimated that 241,740 men will be diagnosed with prostate cancer and 28,170 men will succumb to prostate cancer. Currently, radiation therapy is one of the most common definitive treatment options for localized prostate cancer. However, significant number of patients undergoing radiation therapy will develop locally persistent/recurrent tumours. The varying response rates to radiation may be due to 1) tumor microenvironment, 2) tumor stage/grade, 3) modality used to deliver radiation, and 4) dose of radiation. Higher doses of radiation has not always proved to be effective and have been associated with increased morbidity. Compounds designed to enhance the killing effects of radiation, radiosensitizers, have been extensively investigated over the past decade. The development of radiosensitizing agents could improve survival, improve quality of life and reduce costs, thus benefiting both patients and healthcare systems. Herin, we shall review the role and mechanisms of various agents that can sensitize tumours, specifically prostate cancer.
Cancer; Prostate; Radiation; Radiosensitizer
With the stage migration of prostate cancer witnessed in the late 1990’s and early 2000’s along with the persistent morbidities associated with prostatectomy and radiation therapy, the concept of focal prostate cancer treatment remains quite attractive. Herein we evaluate the tolerability and non-oncologic outcomes of a highly select cohort of men that underwent focal cryoablation of the prostate for the treatment of localized prostate cancer.
Pre-operatively, erectile function was assessed by SHIM questionnaire while voiding symptoms were assessed by AUA symptom score. Twenty-six highly select patients (23 low-risk prostate cancer and 3 intermediate-risk prostate cancer) with documented minimal disease on saturation prostate biopsy underwent focal cryoablation of the prostate (24 hemi-ablation and 2 subtotal ablation). Subsequently, serum PSAs were obtained every 3 months for 2 years and then every 6 months thereafter. PSA failure was defined as an increase of 0.50 ng/ml over nadir. Mean follow-up was 19.1 months. Subjective assessment of erectile function and voiding was assessed post-operatively at each visit.
Based on our PSA failure definition, 11.5% (3 patients) of the cohort experienced biochemical failure. In two of the three patients, localized disease was detected on subsequent transrectal ultrasound guided biopsy. These two patients went on to have favorable PSA nadirs after undergoing conventional definitive therapy (one patient had external beam radiation and one patient had whole gland cryoablation). Within the study cohort, 27% (7 patients) reported new post-operative erectile dysfunction requiring therapy while no patients reported new post-operative urinary incontinence or worsening of voiding symptoms.
These preliminary results add to the expanding body of literature that the minimally invasive focal cryosurgical ablation of the prostate is a safe procedure with few side effects. The true extent of cancer control remains in question, but in highly select patients, favorable PSA kinetics have been demonstrated. If confirmed by further studies with long-term follow-up, this treatment approach could have a profound effect on prostate cancer management.
Prostate cancer; Therapy; Focal; Cryoablation
Accurate urinary assays for bladder cancer (BCa) detection would benefit both patients and healthcare systems. Through genomic and proteomic profiling of urine components, we have previously identified a panel of biomarkers that can outperform current urine-based biomarkers for the non-invasive detection of BCa. Herein, we report the diagnostic utility of various multivariate combinations of these biomarkers. We performed a case-controlled validation study in which voided urines from 127 patients (64 tumor bearing subjects) were analyzed. The urinary concentrations of 14 biomarkers (IL-8, MMP-9, MMP-10, SDC1, CCL18, PAI-1, CD44, VEGF, ANG, CA9, A1AT, OPN, PTX3, and APOE) were assessed by enzyme-linked immunosorbent assay (ELISA). Diagnostic performance of each biomarker and multivariate models were compared using receiver operating characteristic curves and the chi-square test. An 8-biomarker model achieved the most accurate BCa diagnosis (sensitivity 92%, specificity 97%), but a combination of 3 of the 8 biomarkers (IL-8, VEGF, and APOE) was also highly accurate (sensitivity 90%, specificity 97%). For comparison, the commercial BTA-Trak ELISA test achieved a sensitivity of 79% and a specificity of 83%, and voided urine cytology detected only 33% of BCa cases in the same cohort. These datashow that a multivariate urine-based assay can markedly improve the accuracy of non-invasive BCa detection. Further validation studies are under way to investigate the clinical utility of this panel of biomarkers for BCa diagnosis and disease monitoring.
The commercial NMP-22 urine assays for bladder cancer (BCa) detect nuclear mitotic apparatus protein 1 (NUMA1) using monoclonal antibodies. It remains unclear whether these assays are monitoring a tumor antigen or some other phenomenon associated with the disease state. In this study, we investigated the influence of urinary cellular and protein concentration, and hematuria on the performance of the NMP-22 tests in an experimental model.
Pooled urine from healthy subjects were spiked with varying concentrations of benign (UROtsa) cells, cancer cells (RT4, T24, KU-7 and UM-UC-14), whole blood or serum, prior to analysis with both NMP22® Bladder Cancer ELISA test and the NMP22® BladderChek® point-of-care test.
Urines from control subjects were negative for NMP-22. The addition of whole blood at 50ul/10 ml, but not serum, resulted in a false-positive result. Furthermore, the addition of a high concentration of benign urothelial cells (106) or the cell lysate from these cells (306 μg protein) resulted in a false-positive result. High concentrations of pooled-cancer cells (106) or cell lysate (30.6 μg and above) resulted in a positive NMP-22 assay. Concordance between the NMP-22 ELISA assay and the NMP-22 point of care assay was >90%.
Rather than detecting a specific tumor antigen, urinary NMP-22 assays may be measuring the cellularity or amount of cell turnover that may be introduced into the urine by a variety of conditions, including surface shedding from bladder tumors. The absence of significant urinary cellularity in some cases due to lesion characteristics or the timing of sampling may result in false-negative NMP-2 assays.
Bladder cancer; Urine; NMP-22
The ability to detect and monitor bladder cancer in noninvasively obtained urine samples is a major goal. While a number of protein biomarkers have been identified and commercially developed, none have greatly improved the accuracy of sample evaluation over invasive cystoscopy. The ongoing development of high-throughput proteomic profiling technologies will facilitate the identification of molecular signatures that are associated with bladder disease. The appropriate use of these approaches has the potential to provide efficient biomarkers for the early detection and monitoring of recurrent bladder cancer. Identification of disease-associated proteins will also advance our knowledge of tumor biology, which, in turn, will enable development of targeted therapeutics aimed at reducing morbidity from bladder cancer. In this article, we focus on the accumulating proteomic signatures of urine in health and disease, and discuss expected future developments in this field of research.
biomarker; bladder cancer detection; molecular signature; oncoproteomics; urinalysis
The early detection of bladder cancer (BCa) is pivotal for successful patient treatment and management. Through genomic and proteomic studies, we have identified a number of bladder cancer-associated biomarkers that have potential clinical utility. In a case-control study, we examined voided urines from 127 subjects: 64 tumor-bearing subjects and 63 controls. The urine concentrations of the following proteins were assessed by enzyme-linked immunosorbent assay (ELISA); C-C motif chemokine 18 (CCL18), Plasminogen Activator Inhibitor 1 (PAI-1) and CD44. Data were compared to a commercial ELISA-based BCa detection assay (BTA-Trak©) and voided urinary cytology. We used analysis of the area under the curve of receiver operating characteristic curves to compare the ability of CCL18, PAI-1, CD44, and BTA to detect BCa in voided urine samples. Urinary concentrations of CCL18, PAI-1, and BTA were significantly elevated in subjects with BCa. CCL18 was the most accurate biomarker (AUC; 0.919; 95% confidence interval [CI], 0.8704-0.9674). Multivariate regression analysis highlighted CCL18 (OR; 18.31; 95% CI, 4.95-67.70, p<0.0001) and BTA (OR; 6.43; 95% CI, 1.86-22.21, p = 0.0033) as independent predictors of BCa in voided urine samples. The combination of CCL18, PAI-1 and CD44 improved the area under the curve to0.938. Preliminary results indicate that CCL18 was a highly accurate biomarker for BCa detection in this cohort. Monitoring CCL18 in voided urine samples has the potential to improve non-invasive tests for BCa diagnosis. Furthermore using the combination of CCL18, PAI-1 and CD44 may make the model more robust to errors to detect BCa over the individual biomarkers or BTA.
Cancers of the urinary bladder are the fifth most commonly diagnosed malignancy in the US. Early clinical diagnosis of bladder cancer remains a major challenge and the development of non-invasive methods for detection and surveillance is desirable for both patients and health care providers.
In order to identify urinary proteins with potential clinical utility we enriched and profiled the glycoprotein component of urine samples using a dual-lectin affinity chromatography and LC-MS/MS platform.
From a primary sample set obtained from 54 cancer patients and 46 controls a total of 265 distinct glycoproteins were identified with high confidence, and changes in glycoprotein abundance between groups were quantified by a label-free spectral counting method. Validation of candidate biomarker alpha-1-antitrypsin (A1AT) for disease association was performed on an independent set of 70 samples (35 cancer cases) using an ELISA. Increased levels of urinary alpha-1-antitrypsin (A1AT) glycoprotein were indicative of the presence of bladder cancer (p value < 0.0001) and augmented voided urine cytology results. A1AT detection classified bladder cancer patients with a sensitivity of 74% and specificity of 80%.
The described strategy can enable higher resolution profiling of the proteome in biological fluids by reducing complexity. Application of glycoprotein enrichment provided novel candidates for further investigation as biomarkers for the non-invasive detection of bladder cancer.
bladder cancer; glycoprotein profiling; diagnostic profile; A1AT
Current urine-based assays for bladder cancer (BCa) diagnosis lack accuracy, so the search for improved biomarkers continues. Through genomic and proteomic profiling of urine, we have identified a panel of biomarkers associated with the presence of BCa. In this study, we evaluated the utility of three of these biomarkers, interleukin 8 (IL-8), Matrix metallopeptidase 9 (MMP-9) and Syndecan in the diagnosis of BCa through urinalysis.
Voided urines from 127 subjects, cancer subjects (n = 64), non-cancer subjects (n = 63) were analyzed. The protein concentrations of IL-8, MMP-9, and Syndecan were assessed by enzyme-linked immunosorbent assay (ELISA). Data were also compared to a commercial ELISA-based BCa detection assay (BTA-Trak©) and urinary cytology. We used the area under the curve of a receiver operating characteristic (AUROC) to compare the performance of each biomarker.
Urinary protein concentrations of IL-8, MMP-9 and BTA were significantly elevated in BCa subjects. Of the experimental markers compared to BTA-Trak©, IL-8 was the most prominent marker (AUC; 0.79; 95% confidence interval [CI], 0.72-0.86). Multivariate regression analysis revealed that only IL-8 (OR; 1.51; 95% CI, 1.16-1.97, p = 0.002) was an independent factor for the detection of BCa.
These results suggest that the measurement of IL-8 in voided urinary samples may have utility for urine-based detection of BCa. These findings need to be confirmed in a larger, prospective cohort.
IL-8; Biomarkers; Diagnosis; Bladder cancer
Mycoplasma genitalium is one of the smallest organisms capable of self-replication and its sequence is considered a starting point for understanding the minimal genome required for life. MG289, a putative phosphonate substrate binding protein, is considered to be one of these essential genes. The crystal structure of MG289 has been solved at 1.95 Å resolution. The structurally identified thiamine binding region reveals possible mechanisms for ligand promiscuity. MG289 was determined to be an extracytoplasmic thiamine binding lipoprotein. Computational analysis, size exclusion chromatography, and small angle X-ray scattering indicates that MG289 homodimerizes in a concentration-dependant manner. Comparisons to the thiamine pyrophosphate binding homolog Cypl reveal insights into the metabolic differences between mycoplasmal species including identifying possible kinases for cofactor phosphorylation and describing the mechanism of thiamine transport into the cell. These results provide a baseline to build our understanding of the minimal metabolic requirements of a living organism.
p37; Cypl; substrate binding protein; extracytoplasmic lipoprotein; sexually transmitted infection; X-ray crystallography; small angle X-ray scattering
Single orthorhombic crystals of M. genitalium protein MG289 have been grown and shown to diffract X-rays to 2.8 Å resolution with good statistics. The structure obtained from these data will help to provide insight into the function of the protein as well as improving the understanding of its role in this human pathogen.
Mycoplasma genitalium is a human pathogen that is associated with nongonococcal urethritis in men and cervicitis in women. The cloning, expression, purification and crystallization of the protein MG289 from M. genitalium strain G37 are reported here. Crystals of MG289 diffracted X-rays to 2.8 Å resolution. The crystals belonged to the orthorhombic space group P212121, with unit-cell parameters a = 49.7, b = 90.9, c = 176.1 Å. The diffraction data after processing had an overall R
merge of 8.7%. The crystal structure of Cypl, the ortholog of MG289 from M. hyorhinis, has recently been determined, providing a reasonable phasing model; molecular replacement is currently under way.
Mycoplasma genitalium; MG289; p37; extracytoplasmic thiamine-binding lipoprotein; Cypl
Recent epidemiologic, genetic, and molecular studies suggest infection and inflammation initiate certain cancers, including cancers of the prostate. Over the past several years, our group has been studying how mycoplasmas could possibly initiate and propagate cancers of the prostate. Specifically, Mycoplasma hyorhinis encoded protein p37 was found to promote invasion of prostate cancer cells and cause changes in growth, morphology and gene expression of these cells to a more aggressive phenotype. Moreover, we found that chronic exposure of benign human prostate cells to M. hyorhinis resulted in significant phenotypic and karyotypic changes that ultimately resulted in the malignant transformation of the benign cells. In this study, we set out to investigate another potential link between mycoplasma and human prostate cancer.
We report the incidence of men with prostate cancer and benign prostatic hyperplasia (BPH) being seropositive for M. hyorhinis. Antibodies to M. hyorhinis were surveyed by a novel indirect enzyme-linked immunosorbent assay (ELISA) in serum samples collected from men presenting to an outpatient Urology clinic for BPH (N = 105) or prostate cancer (N = 114) from 2006-2009.
A seropositive rate of 36% in men with BPH and 52% in men with prostate cancer was reported, thus leading us to speculate a possible connection between M. hyorhinis exposure with prostate cancer.
These results further support a potential exacerbating role for mycoplasma in the development of prostate cancer.
Mycoplasma hyorhinis; ELISA; cancer; prostate
Chemokines, including chemokine (C-X-C motif) ligand 1 (CXCL1), may regulate tumor epithelial-stromal interactions that facilitate tumor growth and invasion. Studies have linked CXCL1 expression to gastric, colon and skin cancers, but limited studies to date have described CXCL1 protein expression in human bladder cancer (BCa).
CXCL1 protein expression was examined in 152 bladder tissue specimens (142 BCa) by immunohistochemical staining. The expression of CXCL1 was scored by assigning a combined score based on the proportion of cells staining and intensity of staining. CXCL1 expression patterns were correlated with clinicopathological features and follow-up data.
CXCL1 protein expression was present in cancerous tissues, but was entirely absent in benign tissue. CXCL1 combined immunostaining score was significantly higher in high-grade tumors relative to low-grade tumors (p = 0.012). Similarly, CXCL1 combined immunostaining score was higher in high stage tumors (T2-T4) than in low stage tumors (Ta-T1) (p < 0.0001). An increase in the combined immunostaining score of CXCL1 was also associated with reduced disease-specific survival.
To date, this is the largest study describing increased CXCL1 protein expression in more aggressive phenotypes in human BCa. Further studies are warranted to define the role CXCL1 plays in bladder carcinogenesis and progression.
Bladder Cancer; Chemokine Ligand 1 (CXCL1); Tumor Grade; Tumor Stage
Bladder cancer is one of the most prevalent cancers worldwide. Furthermore, nonmuscle invasive bladder cancer has a 70% rate of recurrence, making it a considerable strain to the healthcare system. Patients with bladder cancer require repeat cystoscopic examinations of the bladder to monitor for tumor recurrence. The reason these patients have to undergo these costly, painful, invasive procedures is owing to the absence of accurate urine-based assays to detect the presence of bladder cancer noninvasively. Consequently, the development of a urine-based test to detect bladder cancer would be of tremendous benefit to both patients and healthcare systems. This article reports some of the more prominent urine markers in use today. In addition, the article will highlight some new technologies that are used to investigate novel urinary markers.
bladder cancer; genomics; marker; NMP 22; proteomics; urinary cytology; urine
Gefitinib remains an excellent treatment option for patients with a variety of cancers, including non small cell lung cancer (NSCLC). However, clinicians must be aware of the potential of gefitinib to cause an inflammatory reaction in the skin, lungs and bladder.
We present a case on hemorrhagic cystitis and severaly contracted bladder in a patient with NSCLC on gefitinib.
Further studies are needed to substantiate the association of gefitinib therapy with hemorrhagic cystitis and contracted bladder.
Recently a convincing body of evidence has accumulated, suggesting that the over-expression of carbonic anhydrase isozyme IX (CA IX) in some cancers contributes to the acidification of the extracellular matrix, which in turn promotes the growth and metastasis of the tumor. These observations have made CA IX an attractive drug target for the selective treatment of certain cancers. Currently there is no available x-ray crystal structure of CA IX and this has hampered the rational design of selective CA IX inhibitors. In light of these observations and based on structural alignment homology, using the crystal structure CA II and the sequence of CA IX, a double mutant of CA II with Ala 65 replaced by Ser and Asn 67 replace by Gln has been constructed to resemble the active site of CA IX. This CA IX mimic has been characterized kinetically using 18O-exchange and structurally using x-ray crystallography, alone and in complex with five CA sulfonamide based inhibitors; acetazolamide, benzolamide, chlorzolamide, ethoxzolamide, and methazolamide, and compared to CA II. This structural information has been evaluated in relationship to inhibition studies and in vitro cytotoxicity assays and shows a correlated structure-activity relationship. Kinetic and structural studies of CA II and CA IX mimic reveal chlorzolamide to be a more potent inhibitor of CA IX inducing an active site conformational change upon binding. Additionally, chlorzolamide appears to be cytotoxic to prostate cancer cells. This preliminary study demonstrates that the CA IX mimic may provide a useful model to design more isozyme specific CA IX inhibitors which may lead to development of new therapeutic treatments of some cancers.
Bladder cancer is the fifth most commonly diagnosed malignancy in the United States and one of the most prevalent worldwide. It harbors a probability of recurrence of >50%, thus rigorous, long-term surveillance of patients is advocated. Flexible cystoscopy coupled with voided urine cytology (VUC) is the primary diagnostic approach, but cystoscopy is an uncomfortable, invasive procedure and the sensitivity of VUC is poor in all but high-grade tumors. Thus, improvements in non-invasive urinalysis assessment strategies would benefit patients. We applied gene expression microarray analysis to exfoliated urothelia recovered from bladder washes obtained prospectively from 46 patients with subsequently confirmed presence or absence of bladder cancer. Data from microarrays containing 56,000 targets was subjected to a panel of statistical analyses to identify bladder cancer-associated gene signatures. Hierarchical clustering and supervised learning algorithms were used to classify samples on the basis of tumor burden. A differentially expressed geneset of 319 gene probes was associated with the presence of bladder cancer (P<0.01), and visualization of protein interaction networks revealed VEGF and AGT as pivotal factors in tumor cells. Supervised machine learning and a cross-validation approach were used to build a 14-gene molecular classifier that was able to classify patients with and without bladder cancer with an overall accuracy of 76%. Our results show that it is possible to achieve the detection of bladder cancer using molecular signatures present in exfoliated tumor urothelia. Further investigation and validation of the cancer-associated profiles may reveal important biomarkers for the non-invasive detection and surveillance of bladder cancer.
Urinary bladder cancer; diagnostic signature; microarray profiling; urinalysis; VEGF
Zoledronic acid (ZOL) is a new generation bisphosphonate with improved efficacy benefits over pamidronate in preclinical testing. In addition, ZOL is superior to pamidronate in the treatment of hypercalcemia of malignancy. ZOL is also the first bisphosphonate to demonstrate efficacy in patients with bone metastases from solid tumors other than breast cancer, such as prostate cancer. In this study, we investigated ZOL treatment in 17 Japanese men with advanced prostate cancer, treated at the Aichi Medical University Hospital between August 2006 and November 2007. The 17 patients had biopsy-confirmed prostate cancer and were found to harbor bone metastasis upon bone scintigraphy. ZOL was administered intravenously at a dose of 4 mg over 15 min every 4 weeks. ZOL was well tolerated with mild renal dysfunction in 2 patients (11.8%), while 1 patient (5.8%) developed skin rash. No significant side effects were observed. Subjective improvement in bone pain was reported in 14 patients (32.4%). ZOL, therefore, is a safe and effective drug that remains an important component of the urologist’s armamentarium against advanced prostate cancer.
zoledronic acid; advanced prostate cancer; bone metastasis
The Mycoplasma hyorhinis protein p37 has been implicated in tumorigenic transformation for more than 20 years. Though there are many speculations as to its function, based solely on sequence homology, the issue has remained unresolved. Presented here is the 1.6-Å-resolution refined crystal structure of M. hyorhinis p37, renamed the extracytoplasmic thiamine-binding lipoprotein (Cypl). The structure shows thiamine pyrophosphate (TPP) and two calcium ions are bound to Cypl and give the first insights into possible functions of the Cypl-like family of proteins. Sequence alignments of Cypl-like proteins between several different species of mycoplasma show that the thiamine-binding site is likely conserved and structural alignments reveal the similarity of Cypl to various binding proteins. While the experimentally determined function of Cypl remains unknown, the structure shows that the protein is a TPP-binding protein, opening up many avenues for future mechanistic studies and making Cypl a possible target for combating mycoplasma infections and tumorigenic transformation.
We determine the utility of serial urinary cytologies in patients presenting with microscopic hematuria who were evaluated with upper and lower urinary tract studies to rule out a malignancy.
Two hundred and thirty-seven patients with the diagnosis of microscopic hematuria were evaluated at an inner-city tertiary care hospital. Of these 239 patients, 182 patients had 405 cytologies obtained as part of their evaluation for hematuria. In addition, all patients had their lower urinary tract and upper tract thoroughly evaluated.
Two hundred and seventy four cytology samples were read as normal, 104 (26%) as atypia, 7 (2%) as suspicious/malignant, and 20 (5%) as unsatisfactory. Seventeen patients (9.3%) had biopsy confirmed bladder cancer. Of these 17 patients, 2 had normal cytology, 11 had atypia, and 5 had suspicious/malignant. No patient had a positive cytology and a negative biopsy. Overall the number of hematuric patients harboring bladder cancer was small (7%). Cytology #1 detected 4 cases of cancer, cytology #2 detected an additional case and cytology #3 did not detect any additional cancers.
Because of this low prevalence of bladder cancer in patients presenting with microscopic hematuria and the low sensitivity of detecting bladder cancers, the utility of urinary cytology in the initial evaluation of patients with hematuria may be minimal. The exact role of urinary cytology in the evaluation of hematuria is unknown.
Recent epidemiologic, genetic, and molecular studies suggest infection and inflammation initiate certain cancers, including those of the prostate. The American Cancer Society, estimates that approximately 20% of all worldwide cancers are caused by infection. Mycoplasma, a genus of bacteria that lack a cell wall, are among the few prokaryotes that can grow in close relationship with mammalian cells, often without any apparent pathology, for extended periods of time. In this study, the capacity of Mycoplasma genitalium, a prevalent sexually transmitted infection, and Mycoplasma hyorhinis, a mycoplasma found at unusually high frequency among patients with AIDS, to induce a malignant phenotype in benign human prostate cells (BPH-1) was evaluated using a series of in vitro and in vivo assays. After 19 weeks of culture, infected BPH-1 cells achieved anchorage-independent growth and increased migration and invasion. Malignant transformation of infected BPH-1 cells was confirmed by the formation of xenograft tumors in athymic mice. Associated with these changes was an increase in karyotypic entropy, evident by the accumulation of chromosomal aberrations and polysomy. This is the first report describing the capacity of M. genitalium or M. hyorhinis infection to lead to the malignant transformation of benign human epithelial cells and may serve as a model to further study the relationship between prostatitis and prostatic carcinogenesis.
Radiation therapy continues to be one of the more popular treatment options for localized prostate cancer. One major obstacle to radiation therapy is that there is a limit to the amount of radiation that can be safely delivered to the target organ. Emerging evidence suggests that therapeutic agents targeting specific molecules might be combined with radiation therapy for more effective treatment of tumors. Recent studies suggest that modulation of these molecules by a variety of mechanisms (e.g., gene therapy, antisense oligonucleotides, small interfering RNA) may enhance the efficacy of radiation therapy by modifying the activity of key cell proliferation and survival pathways such as those controlled by Bcl-2, p53, Akt/PTEN and cyclooxygenase-2. In this article, we summarize the findings of recent investigations of radiosensitizing agents in the treatment of prostate cancer.