The accuracy of computed tomography for clavicle non-union evaluation.

BACKGROUND: The primary aim of this study is to determine the accuracy of CT scanning when evaluating non-union of the clavicle. METHODS: A retrospective review was performed of all CT scans undertaken for suspected nonunion of midshaft clavicle fractures over a 10-year period. The influence of scan timing, callus and patient characteristics was evaluated. RESULTS: One hundred eighty-four CT scans were analysed. No patient was incorrectly diagnosed with union (n = 85). Ninety-nine scans were reported as non-union with inadequate bridging callus, 19 of which were united at operation or on repeat CT imaging and represented delayed unions. Atrophic callus was found in 57 patients and all of which had a confirmed non-union (positive predictive value 100%). A hypertrophic callus was found in 42 patients, all of the delayed unions were found in this group (positive predictive value for non-union 55%, p < 0.001). CT compared to radiographs showed greater inter-observer agreement for union (weighted kappa 0.75 vs. 0.50 respectively). Overall, CT is 100% sensitive and 81.7% specific for non-union diagnosis. DISCUSSION: CT has excellent accuracy to determine clavicle union but approximately one in five suspected non-unions went onto unite. Hypertrophic callus finding resulted in a delayed union in approximately half of the cases in our study.

Prostate Cancer Screening in Men of African Descent: 15-year Results of the Tobago Prostate Cancer Survey / Tamización del cáncer de próstata en hombres de ascendencia africana: resultados de 15 años de la Encuesta de Cáncer de Próstata de Tobago

ABSTRACT Objective: To compare all-cause-mortality in screening-detected prostate cancer cases versus non-cases after a median 12.2-year follow-up. Methods: In this prospective, population-based study of 3089 Afro-Caribbean men aged 40-79 years in Tobago, Trinidad and Tobago, West Indies, all men were screened for prostate cancer (serum prostate specific antigen and/or digital rectal exam) one to three times between 1997 and 2007 and followed for mortality to 2012. Among 502 men diagnosed with prostate cancer, 81 younger men underwent radical retropubic prostatectomy. Minimal treatment was available for older men. Survival curves compared all-cause-mortality in cases versus non-cases within 10-year age groups at first screening. Results: There were 350 all-cause-deaths over 34 089 person-years of follow-up. All-cause-survival curves in men aged 60 years or above at first screening did not diverge between cases and non-cases until after 10-12 years of follow-up (p > 0.36). In contrast, among men first screened at age 50-59 years, survival was lower in cases, with survival curves diverging at seven years (p = 0.003). Survival in men aged 50-59 years who underwent prostatectomy was similar to survival in non-cases (p = 0.63). Conclusion: Among men aged 60 years or above, the absence of excess all-cause-mortality among screening-detected prostate cancer cases provides argument against the utility of routine prostate cancer screening in this older population of African descent. However, the significantly poorer survival in men aged 50-59 years with screening-detected prostate cancer, compared with screened men without prostate cancer, along with the potential for prostate cancer treatment to improve survival, supports the continuation of prostate cancer screening in this age group, pending further research to assess the risks and benefits.

RESUMEN Objetivo: Comparar la mortalidad por todas las causas en casos de cáncer de próstata frente a no casos tras un seguimiento medio de 12.2 años. Métodos: En este estudio prospectivo poblacional de 3089 hombres afrocaribeños de 40-79 años en Tobago, Trinidad y Tobago, West Indies, todos los hombres fueron expuestos a tamizaje de cáncer de próstata (antígeno prostático específico en suero y/o examen rectal digital) de una a tres veces entre 1997 y 2007, y a un seguimiento de la mortalidad hasta 2012. De entre los 502 hombres diagnosticados con cáncer de próstata, a 81 hombres de los más jóvenes se les practicó una prostatectomía retropúbica radical. El tratamiento mínimo estuvo disponible para los hombres mayores. Las curvas de supervivencia compararon la mortalidad por todas las causas en los casos frente a los no casos dentro de los grupos de edades de 10 años en la primera tamización. Resultados: Hubo 350 muertes por todas las causas con más de 34 089 persona-años de seguimiento. Las curvas de supervivencia por todas las causas en hombres de 60 años o más en el primer tamizaje, no divergieron entre casos y no casos hasta después de 10 a 12 años de seguimiento (p > 0.36). En cambio, entre los hombres tamizados por primera vez a la edad 50-59 años, la supervivencia fue menor en los casos, con curvas de supervivencia divergentes a los siete años (p = 0.003). La supervivencia en los hombres de 50-59 años que tuvieron prostatectomía fue similar a la supervivencia en los no casos (p = 0.63). Conclusión: Entre los hombres de 60 años o más, la ausencia de exceso de mortalidad por todas las causas entre los casos de cáncer de próstata detectados por tamizaje proporciona argumentos contra la utilidad de la tamización rutinaria del cáncer de próstata en esta población mayor de ascendencia africana. Sin embargo, la supervivencia significativamente más pobre en hombres de 50 a 59 años con cáncer de próstata detectado mediante tamizaje - en comparación con los hombres tamizados sin cáncer de próstata, además de las posibilidades de tratamiento del cáncer de próstata para mejorar la supervivencia - respalda la continuación del tamizaje del cáncer de próstata en este grupo etario, quedando pendiente una investigación ulterior a fin de evaluar sus riesgos y beneficios.

Use of municipal solid waste incineration bottom ashes in alkali-activated materials, ceramics and granular applications: A review.

This paper presents a literature review on the incorporation of municipal solid waste incinerated bottom ash as raw material in several markets, other than those where it is conventionally used, such as geotechnical applications and road pavement construction. The main findings of an ample selection of experimental investigations on the use of the bottom ash as precursor of alkali-activated materials, as an adsorbent material for the removal of hazardous elements from wastewater and landfill gases, as soil replacement in agricultural activities, as partial or complete substitute of raw materials for the manufacture of ceramic-based products, as landfill cover and as biogas production enhancer, were gathered, collated and analysed.

Concomitant loss of EAF2/U19 and Pten synergistically promotes prostate carcinogenesis in the mouse model.

Multiple genetic alterations are associated with prostate carcinogenesis. Tumor-suppressor genes phosphatase and tensin homolog deleted on chromosome 10 (Pten) and androgen upregulated gene 19 (U19), which encodes ELL-associated factor 2 (EAF2), are frequently inactivated or downregulated in advanced prostate cancers. Previous studies showed that EAF2 knockout caused tumors in multiple organs and prostatic intraepithelial neoplasia (PIN) in mice. However, EAF2-knockout mice did not develop prostate cancer even at 2 years of age. To further define the roles of EAF2 in prostate carcinogenesis, we crossed the Pten+/- and EAF2+/- mice in the C57/BL6 background to generate EAF2-/-Pten+/-, Pten+/-, EAF2-/- and wild-type mice. The prostates from virgin male mice with the above four genotypes were analyzed at 7 weeks, 19 weeks and 12 months of age. Concomitant loss of EAF2 function and inactivation of one Pten allele induced spontaneous prostate cancer in 33% of the mice. Prostatic tissues from intact EAF2-/- Pten+/- mice exhibited higher levels of phospho-Akt, -p44/42 and microvessel density. Moreover, phospho-Akt remained high after castration. Consistently, there was a synergistic increase in prostate epithelial proliferation in both intact and castrated EAF2-/-Pten+/- mice. Using laser-capture microdissection coupled with real-time reverse transcription-PCR, we confirmed that co-downregulation of EAF2 and Pten occurred in >50% clinical prostate cancer specimens with Gleason scores of 8-9 (n=11), which is associated with poor prognosis. The above findings together demonstrated synergistic functional interactions and clinical relevance of concurrent EAF2 and Pten downregulation in prostate carcinogenesis.

Clinical integration of next-generation sequencing technology.

Recent advances in next-generation sequencing (NGS) methods and technology have substantially reduced costs and operational complexity leading to production of benchtop sequencers and commercial software solutions for implementation in small research and clinical laboratories. This article addresses requirements and limitations to successful implementation of these systems, including (1) calibration and validation of the instrumentation, experimental paradigm, and primary readout, (2) secure data transfer, storage, and secondary processing, (3) implementation of software tools for targeted analysis, and (4) training of research and clinical personnel to evaluate data fidelity and interpret the molecular significance of the genomic output.

Proteins secreted by embryonic stem cells activate cardiomyocytes through ligand binding pathways.

Human embryonic stem cells (hESC) underlie embryogenesis but paracrine signals associated with the process are unknown. This study was designed to 1) profile native proteins secreted by undifferentiated hESC and 2) determine their biological effects on primary neonatal cardiomyocytes. We utilized multi-analyte, immunochemical assays to characterize media conditioned by undifferentiated hESC versus unconditioned media. Expression profiling was performed on cardiomyocytes subjected to these different media conditions and altered transcripts were mapped to critical pathways. Thirty-two of 109 proteins were significantly elevated in conditioned media ranging in concentration from thrombospondin (57.2+/-5.0 ng/ml) to nerve growth factor (7.4+/-1.2pg/ml) and comprising chemokines, cytokines, growth factors, and proteins involved in cell adhesion and extracellular matrix remodeling. Conditioned media induced karyokinesis, cytokinesis and proliferation in mono- and binucleate cardiomyocytes. Pathway analysis revealed comprehensive activation of the ROCK 1 and 2 G-protein coupled receptor (GPCR) pathway associated with cytokinesis, and the RAS/RAF/MEK/ERK receptor tyrosine kinase (RTK) and JAK/STAT-cytokine pathway involved in cell cycle progression. These results provide a partial database of proteins secreted by pluripotent hESC that potentiate cell division in cardiomyocytes via a paracrine mechanism suggesting a potential role for these stem cell factors in cardiogenesis and cardiac repair.

The effects of a soluble activin type IIB receptor on obesity and insulin sensitivity.

BACKGROUND: Myostatin, also known as Growth and Differentiation Factor 8, is a secreted protein that inhibits muscle growth. Disruption of myostatin signaling increases muscle mass and decreases glucose, but it is unclear whether these changes are related. We treated mice on chow and high-fat diets with a soluble activin receptor type IIB (ActRIIB, RAP-031), which is a putative endogenous signaling receptor for myostatin and other ligands of the TGF-beta superfamily. RESULTS: After 4 weeks, RAP-031 increased lean and muscle mass, grip strength and contractile force. RAP-031 enhanced the ability of insulin to suppress glucose production under clamp conditions in high-fat fed mice, but did not significantly change insulin-mediated glucose disposal. The hepatic insulin-sensitizing effect of RAP-031 treatment was associated with increased adiponectin levels. RAP-031 treatment for 10 weeks further increased muscle mass and drastically reduced fat content in mice on either chow or high-fat diet. RAP-031 suppressed hepatic glucose production and increased peripheral glucose uptake in chow-fed mice. In contrast, RAP-031 suppressed glucose production with no apparent change in glucose disposal in high-fat-diet mice. CONCLUSION: Our findings show that disruption of ActRIIB signaling is a viable pharmacological approach for treating obesity and diabetes.

Glycan stem-cell markers are specifically expressed by spermatogonia in the adult non-human primate testis.

BACKGROUND: The glycan cell surface molecules, stage-specific embryonic antigen (SSEA)-1, -3 and -4 and tumor-rejection antigen (TRA)-1-60 and -1-81, are expressed in specific combinations by undifferentiated pluripotent cells, i.e. embryonic stem cells, induced pluripotent stem cells, embryonal carcinoma cells, primordial germ cells and embryonic germ cells. Upon differentiation of the cells, these markers vanish. Recently, it has been shown that also neonatal and adult mouse testes contain pluripotent cells. Here, we aimed at identifying in situ possibly pluripotent cells in the adult primate testis. METHODS: Monoclonal antibodies raised against the glyco-epitopes SSEA-1, -3 and -4 and TRA-1-60 and -1-81, respectively, were tested to detect cells expressing the antigens, by immunohistochemistry on Bouin's-fixed and paraffin-embedded adult primate testes. Man, the new-world monkey, Callithrix jacchus (common marmoset), and the old-world monkey species, Macaca mulatta (Rhesus macaque) and Macaca silenus (Lion-tailed macaque), were included. The percentage of SSEA-4-positive cells in three adult marmoset testes was determined using flow cytometry. RESULTS: Spermatogonia in the testes of C. jacchus were labeled by SSEA-4, TRA-1-60 and -1-81-antibodies. In the macaques, spermatogonia were detected by SSEA-4 and TRA-1-81-antibodies. TRA-1-61 did not bind to macaque spermatogonia. Also, SSEA-1 and -3 did not bind to spermatogonia in any species. In human testes, we never obtained any clear staining. The total percentage of SSEA-4-positive cells in marmoset testes was 8.6 +/- 1.61%. CONCLUSIONS: SSEA-4 and TRA-1-81-antibodies may be very well suited for the identification and isolation of spermatogonia, and possibly also germline stem cells, in the non-human primate testis.

U19/Eaf2 knockout causes lung adenocarcinoma, B-cell lymphoma, hepatocellular carcinoma and prostatic intraepithelial neoplasia.

Upregulated gene 19 (U19)/ELL-associated factor 2 (Eaf2) is a potential human tumor suppressor that exhibits frequent allelic loss and downregulation in high-grade prostate cancer. U19/Eaf2, along with its homolog Eaf1, has been reported to regulate transcriptional elongation via interaction with the eleven-nineteen lysine-rich leukemia (ELL) family of proteins. To further explore the tumor-suppressive effects of U19/Eaf2, we constructed and characterized a murine U19/Eaf2-knockout model. Homozygous or heterozygous deletion of U19/Eaf2 resulted in high rates of lung adenocarcinoma, B-cell lymphoma, hepatocellular carcinoma and prostate intraepithelial neoplasia. Within the mouse prostate, U19/Eaf2 deficiency enhanced cell proliferation and increased epithelial cell size. The knockout mice also exhibited cardiac cell hypertrophy. These data indicate a role for U19/Eaf2 in growth suppression and cell size control as well as argue for U19/Eaf2 as a novel tumor suppressor in multiple mouse tissues. The U19/Eaf2 knockout mouse also provides a unique animal model for three important cancers: lung adenocarcinoma, B-cell lymphoma and hepatocellular carcinoma.

Practical aspects of planning, building, and interpreting tissue microarrays: the Cooperative Prostate Cancer Tissue Resource experience.

This is a review of several new approaches developed at or adopted by the Cooperative Prostate Cancer Tissue Resource (CPCTR) to resolve issues involved in tissue microarray (TMA) construction and use. CPCTR developed the first needle biopsy TMA, allowing researchers to obtain 200 or more consecutive cancer sections from a single biopsy core. Using radiographs of original paraffin blocks to measure tissue thickness we developed a method to produce TMAs with a larger number of usable sections. The modular approach to plan TMA construction is also a novel concept wherein TMAs of different types, such as tumor grade TMAs, metastasis TMA and hormone refractory tumors TMA can be combined to form an ensemble of TMAs with expanded research utility, such as support for tumor progression studies. We also implemented an open access TMA Data Exchange Specification that allows TMA data to be organized in a self-describing XML document annotated with well-defined common data elements. It ensures inter-laboratory reproducibility because it offers information describing the preparation of TMA blocks and slides. There are many important aspects that may be missed by both beginners and experienced investigators in areas of TMA experimental design, human subjects protection, population sample size, selection of tumor areas to sample, strategies for saving tissues, choice of antibodies for immunohistochemistry, and TMA data management.

DNA methylation paradigm shift: 15-lipoxygenase-1 upregulation in prostatic intraepithelial neoplasia and prostate cancer by atypical promoter hypermethylation.

Fifteen (15)-lipoxygenase type 1 (15-LO-1, ALOX15), a highly regulated, tissue- and cell-type-specific lipid-peroxidating enzyme has several functions ranging from physiological membrane remodeling, pathogenesis of atherosclerosis, inflammation and carcinogenesis. Several of our findings support a possible role for 15-LO-1 in prostate cancer (PCa) tumorigenesis. In the present study, we identified a CpG island in the 15-LO-1 promoter and demonstrate that the methylation status of a specific CpG within this island region is associated with transcriptional activation or repression of the 15-LO-1 gene. High levels of 15-LO-1 expression was exclusively correlated with one of the CpG dinucleotides within the 15-LO-1 promoter in all examined PCa cell-lines expressing 15-LO-1 mRNA. We examined the methylation status of this specific CpG in microdissected high grade prostatic intraepithelial neoplasia (HGPIN), PCa, metastatic human prostate tissues, normal prostate cell lines and human donor (normal) prostates. Methylation of this CpG correlated with HGPIN, PCa and metastatic human prostate tissues, while this CpG was unmethylated in all of the normal prostate cell lines and human donor (normal) prostates that either did not display or had minimal basal 15-LO-1 expression. Immunohistochemistry for 15-LO-1 was performed in prostates from PCa patients with Gleason scores 6, 7 [(4+3) and (3+4)], >7 with metastasis, (8-10) and 5 normal (donor) individual males. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was used to detect 15-LO-1 in PrEC, RWPE-1, BPH-1, DU-145, LAPC-4, LNCaP, MDAPCa2b and PC-3 cell lines. The specific methylated CpG dinucleotide within the CpG island of the 15-LO-1 promoter was identified by bisulfite sequencing from these cell lines. The methylation status was determined by COBRA analyses of one specific CpG dinucleotide within the 15-LO-1 promoter in these cell lines and in prostates from patients and normal individuals. Fifteen-LO-1, GSTPi and beta-actin mRNA expression in BPH-1, LNCaP and MDAPCa2b cell lines with or without 5-aza-2'-deoxycytidine (5-aza-dC) and trichostatin-A (TSA) treatment were investigated by qRT-PCR. Complete or partial methylation of 15-LO-1 promoter was observed in all PCa patients but the normal donor prostates showed significantly less or no methylation. Exposure of LNCAP and MDAPCa2b cell lines to 5-aza-dC and TSA resulted in the downregulation of 15-LO-1 gene expression. Our results demonstrate that 15-LO-1 promoter methylation is frequently present in PCa patients and identify a new role for epigenetic phenomenon in PCa wherein hypermethylation of the 15-LO-1 promoter leads to the upregulation of 15-LO-1 expression and enzyme activity contributes to PCa initiation and progression.

Detection of human herpesvirus 8 (HHV-8) in normal prostates.

BACKGROUND: Human herpesvirus 8 (HHV-8) DNA has been detected in semen and prostatic tissues in some, but not all reports. We have analyzed prostate tissues from HHV-8 seropositive men for the expression of viral proteins and determined if expression of these proteins are associated with increased inflammation. METHODS: Paraffin sections of non-cancerous prostates from HHV-8 seropositive (n = 16) and seronegative (n = 2) men who died with AIDS were screened for expression of three viral proteins by immunohistochemistry. Levels of inflammation were determined by expression of CD68 and CD20. Cellular proliferation was determined by expression of Ki67. RESULTS: Among the 16 HHV-8 seropositive cases, 68.9% (11/16) (95% C.I. = 0.41-0.89) were positive for HHV-8 protein expression, while the 2 seronegative patients showed no HHV-8 protein expression. There was increased inflammation among HHV-8 positive prostates. CONCLUSIONS: These results demonstrate that HHV-8 is present in normal prostates of HIV-infected men and the expression of viral proteins is associated with increased localized inflammation.

Limited survival of adult human testicular tissue as ectopic xenograft.

BACKGROUND: Grafting of testicular tissue into immunodeficient mice has become an interesting and promising scientific tool for the generation of gametes and the study of testicular function. This technique might potentially be used to generate sperm from patients whose testes need to be removed or are destroyed due to therapeutic intervention or as a consequence of disease. Here we explore whether adult human testicular tissue from patients with different testicular pathologies survives as xenograft. METHODS AND RESULTS: Testis tissue from adult patients with varying degrees of spermatogenesis was grafted into two strains of immunodeficient mice (severe combined immunodeficiency, Nu/Nu). Tissue with active spermatogenesis prior to grafting largely regressed. However, testicular tissue survival was better in cases where spermatogenesis was suppressed prior to grafting and occasionally spermatogonial stem cells survived. Cases with spermatogenic disruption were not corrected by the xenografting. CONCLUSION: Superior survival of the germinal epithelium and spermatogonia when spermatogenesis was suppressed prior to grafting could provide a novel strategy for germline preservation in pre-pubertal cancer patients. This approach could also be valuable to study the early stages of human spermatogenesis.

Molecular dynamics of the compensatory response to myocardial infarct.

Myocardial infarct via occlusion of the left anterior descending coronary in rats caused overriding depression in transcription, signal transduction, inflammation and extracellular matrix pathways in the infarct zone within 24 h. In contrast, remote zone gene expression was reciprocally activated during the immediate post-infarct period. Infarct zone signal transduction occurred primarily through TGFbeta1 induction while the remote zone exhibited elevated WNT, NOTCH, GPCR and transmembrane signaling. A minimal day 1 acute phase, inflammatory response was detected in the infarct zone while interleukins (IL1alpha, IL1beta, IL6, IL12alpha, IL18) and the TNFalpha superfamily were activated in the remote zone. Different cytochrome subsets were activated in each left ventricular region on day 1 while anti-oxidant genes were elevated only in the remote zone. The infarct zone exhibited mixed early transcription factor activation across all binding domains with a balance favoring constitutive gene activation and differentiation pathways as opposed to cell proliferation. In contrast, the remote zone exhibited activation of extensive developmental transcription factors involved in specification of cell phenotype, tissue-specific interactions and position-specific cell proliferation on day 1. The day 28 infarct zone response mirrored the day 1 remote zone response including activation of genes associated with matrix remodeling (metallothionein and metalloproteinase 9, 12, 23), as well as genes associated with cell proliferation and phenotype specification (MYC, EGR2, ATF3, HOXA1) recapitulating developmental histogenesis programs.

Cutaneous wound analysis using hyperspectral imaging.

A correlative bright-field and hyperspectral analysis of full-thickness, cutaneous wounds in a porcine model was undertaken to investigate the efficacy of hyperspectral imaging as an alternate method for wound identification. Analysis of a randomly selected specimen yielded distinct spectral signatures for cutaneous regions of interest including the epidermis, injured dermis, and normal dermis. The scanning of the entire specimen group using these hyperspectral signatures revealed an exclusionary, pseudo-color pattern whereby a central wound region was consistently defined by a unique spectral signature. An algorithm was derived as an objective tool for the comparison of the wound regions defined by the hyperspectral classification versus the pathologists' manual tracings. The dimensions of the wound identified in the hyperspectral assay did not differ significantly from the wound region identified by the pathologists using standard bright-field microscopy. These data indicate that hyperspectral analysis may provide a high-throughput alternative for wound estimation that approximates standard bright-field imaging and pathologist evaluation.

Myopodin, a synaptopodin homologue, is frequently deleted in invasive prostate cancers.

Prostate cancer is one of the leading causes of cancer-related deaths for men in the United States. Like other malignancies, prostate cancer is underscored by a variety of aberrant genetic alterations during its development. Although loss of heterozygosity or allelic loss is frequently identified among prostate cancers, few genes have been identified thus far as critical to the development of invasive prostate cancers. In this report, we used the recently developed technology, the "differential subtraction chain," to perform a genome-wide search for sequences that are deleted in an aggressive prostate cancer. Among the deleted sequences, we found that one sequence was deleted in >50% of prostate cancers we tested. We mapped this sequence to chromosome 4q25 by screening the Genebridge 4 hamster radiation panel with primers specific to this probe, and subsequently identify a 54-kb minimal common deletion region that contains the sequence encoding myopodin. Sequence analysis indicates that myopodin shares significant homology with synaptopodin, a protein closely associated with podocyte and neuron differentiation. Further study shows that frequent complete or partial deletions of the myopodin gene occurred among invasive prostate cancer cases (25 of 31 cases, or 80%). Statistical analysis indicates that deletion of myopodin is highly correlated with the invasiveness of prostate cancers, and thus may hold promise as an important prognostic marker for prostate cancers.

E-cadherin expression and PSA secretion in human prostate epithelial cells.

Prostate-specific antigen (PSA) is the most widely used marker for the diagnosis of prostate cancer and is an independent predictor of prostatic capsular invasion. A number of studies have identified E-cadherin, a cell adhesion protein, as a potential invasion suppressor which is decreased in prostate adenocarcinoma. Our goal in the present study was to evaluate E-cadherin expression in primary cultures and determine the relationship between E-cadherin expression and PSA secretion in both primary cultures and the prostate tumor cell line, LNCaP. Immunohistochemical studies and Western blot analysis confirmed greater expression of E-cadherin in normal epithelial cells than tumor-derived prostate cells. This is the first report that the incubation of normal prostate epithelial cells with E-cadherin antibody increases the amount of PSA detected in the media of normal cells as well as in LNCaP. Since E-cadherin may function as an invasion suppressor, an understanding of the decreased expression of this adhesion factor and the impact on PSA secretion may aid in understanding epithelial tumorigenesis.

Expression patterns of vitamin D receptor in human prostate.

UV exposure and serum levels of vitamin D have been linked in several studies with prostate cancer risk. At the cellular level, the principal action of vitamin D is mediated though vitamin D receptors (VDR). Since prostate cancer is a disease strongly associated with age, we examined the presence of VDR in normal prostate from donors of various ages to determine if the VDR expression pattern changed with age. We also compared the VDR expression in the peripheral and central zones of the prostate to determine if the expression pattern varied by location. Immunohistochemical studies were performed on paraffin-embedded tissue from cases selected by the following age decades; 10-19, 20-29, 30-39, 40-49, 50-59, and 60-69. Both the central and peripheral zones were examined for VDR expression. The intensity of VDR expression in prostate was compared with expression in different types of human tissues. Mean VDR expression was lowest in the 10-19 years of age group. The intensity of the nuclear VDR was higher though the fifth decade, and then declined in cases of ages 60-70. When multiple sections of the same donor prostate were compared, VDR expression was greater in the peripheral zone compared to the central zone.

Efficacy of a synthetic lytic peptide in the treatment of prostate cancer.

In the last several years, significant effort has been applied to identifying novel agents with effectiveness against prostate cancer. These studies were designed to determine the efficacy of one of these novel compounds, D2A21, in the treatment of an animal model of prostate cancer. Using the Mat-Ly-Lu(MLL) line of the Dunning R-3327 rat prostate adenocarcinoma model, the optimal dose, schedule and route of administration of D2A21 were established. A study involving the G line was used to further support these findings. In addition, hemotoxylin and eosin stained tissue samples were examined to investigate the extent of inhibition of lung metastases in animals injected with MLL cells. When D2A21 was injected intraperitoneally or subcutaneously, MLL and G cell tumor growth was inhibited 50-72% as demonstrated by both tumor volumes and weights. The optimal dosage of 0.179 mg/injection was established and it was determined to be most efficacious when administered five times per week. At this concentration, D2A21 appears to have no significant toxicity. Additionally, D2A21 increased the survival rate from only 25% to 70-75% in animals that were challenged with a large number of tumor cells. The peptide D2A21 is able to significantly inhibit tumor growth in rat models of prostate cancer. In addition, it can inhibit metastases and decrease deaths resulting from metastases in these animals.