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A structural model for the prostate disease marker, human prostate-specific antigen.

Prostate-specific antigen (PSA) provides an excellent serum marker for prostate cancer, the most frequent form of cancer in American males. PSA is a 237-residue protease based on sequence homology to kallikrein-like enzymes. To predict the 3-dimensional structure of PSA, homology modeling studies were performed based on sequence and structural alignments with tonin, pancreatic kallikrein, chymotrypsin, and trypsin. The structurally conserved regions of the 4 reference X-ray proteins provided the core structure of PSA, whereas the loop structures were modeled on the loops of tonin and kallikrein. The unique "kallikrein loop" insert, between Ser 95b and Pro 95k of kallikrein, was constructed using molecular mechanics, dynamics, and electrostatics calculations. In the resulting PSA structure, the catalytic triad, involving residues His 57, Asp 102, and Ser 195, and hydrophobic and electrostatic interactions typical of serine proteases were extremely well conserved. Similarly, the 5-disulfide bonds of kallikrein were also conserved in PSA. These results, together with the fact that no major steric clashes arose during the modeling process, provide strong evidence for the validity of the PSA model. Calculation of the electrostatic potential contours of kallikrein and PSA was carried out using the finite difference Poisson-Boltzmann method. The calculations revealed matching areas of negative potential near the catalytic triad, but differences in the positive potential surrounding the active site. The PSA glycosylation site, Asn 61, is fully accessible to the solvent and is enclosed in a positive region of the isopotential map. The bottom of the substrate specificity pocket, residue S1, is a serine (Ser 189) as in chymotrypsin, rather than aspartate (Asp 189) as in tonin, kallikrein, and trypsin. This fact, plus other features of the S1 binding-pocket region, suggest that PSA would prefer substrates with hydrophobic residues at the P1 position. The location of a potential zinc ion binding site involving the side chain of histidines 91, 101, and 233 is also suggested. This PSA model should facilitate the understanding and prediction of structural and functional properties of this important cancer marker.

Amino Acid Sequence↗

Novel approaches to the diagnostics and treatment of chronic prostatic diseases.

This article presents a modified technique for investigating the prostatic blood flow--rheoprostatography (impedance electroplethysmography of the prostate gland). It also gives some averaged rheographic parameters typical of most prevalent prostatic diseases (such as prostatitis, benign prostatic hyperplasia, and prostate cancer). These parameters were measured both under normal conditions and during functional tests. Furthermore, this article classifies prostatic blood-flow insufficiency into several stages. It is recommended that the combined therapy of chronic prostatic diseases should involve endorectal procedures of pulsed fluctuating stimulation (PFS), with rheographic monitoring being used as a feedback loop of such procedures.

Adult↗

CYR61, a cellular proliferation marker in dogs with prostatic disease.

The life expectancy of dogs is increasing and is associated with a greater frequency of age-related disease, including that of the prostate gland. A marker of cell proliferation, CYR61, may be detected in a number of conditions in humans, including hyperplasia and neoplasia. The objective of the present study was to investigate the degree of CYR61 expression in a number of different prostate diseases in dogs in order to understand the potential of this marker for diagnosis of prostatic disease. Immunohistochemistry with a CYR61 antibody was performed on prostatic tissue from 22 dogs with different diseases. Intense stromal staining was observed in cases of prostatic dysplasia and benign prostate hyperplasia. In contrast, CYR61 staining was very intense in alveolar epithelial cells in cases of epithelial benign prostate hyperplasia and one case of adenocarcinoma. An obvious CYR61 staining pattern was absent in cases of prostatitis. In conclusion, CYR61 may be a useful marker of cell proliferation in a number of prostatic pathologies, although further studies of normal tissue are warranted.

Angiogenesis Inducing Agents↗

The relationship between interleukin-6 and C-reactive protein in patients with benign and malignant prostate disease.

The relationship between interleukin-6 and C-reactive protein was evaluated in patients with benign (n=59) and malignant (n=86) prostate disease. The correlation coefficients for patients with benign prostatic disease and prostate cancer were rs=0.632, P<0.001 and rs=0.663, P<0.001, respectively. These results indicate that the relationship between interleukin-6 and C-reactive protein is similar in patients with benign and malignant prostate disease.

Aged↗

Biochemical profiles of prostatic fluid from normal and diseased prostate glands.

The attempt to identify changes in the biochemical composition of prostatic fluid that might accompany and characterize disease states in the prostate was stimulated by two assumptions based on observations. First, the composition of prostatic fluid was judged to be likely to reflect the metabolic status of at least the epithelial cells accurately. Secondly, the metabolic changes preceding or associated with the development of carcinoma in the prostate seemed likely to be diffuse rather than limited to the histologically abnormal prostatic cells. As a consequence of these assumptions, prostatic fluid obtained from the urethra by digital massage of the prostate was evaluated microscopically and subjected to numerous analytical procedures. Differences in lactate dehydrogenase (LDH) isoenzymes, complement C3, and transferrin concentrations in the prostatic fluid of men with histologically identified carcinoma (Ca) and benign prostatic hyperplasia (BPH) have been observed. The ratio of LDH-5/ LDH-1 was found to have a mean value of 5.94 +/- 0.25(S.E.) in 98 determinations on 83 patients with Ca, and 1.84 +/- 0.14 in 212 determinations on 142 patients with BPH with 10 or less white blood cells per high power field (WBC/hpf) on microscopic examination of the prostatic fluid. Fluid from 52 patients with BPH with greater than 10 WBC/hpf (84 determinations) had a mean ratio of 5.85 +/- 0.88 and from 286 patients with greater than 10 WBC/hpf without an established histologic diagnosis (460 determinations) of 3.12 +/- 0.21. Two hundred twenty-two men under 45 years of age (255 determinations) judged to have a normal prostate clinically had a mean ratio of 0.67 +/- 0.05. The mean transferrin concentration in 44 patients (51 determinations) with Ca was 47.03 +/- 3.76mg/100 ml, in 59 patients with BPH (90 determinations) was 12.97 +/- 1.20, in 23 patients with BPH with > 10 WBC/hpf in the prostatic fluid (38 determinations) was 14.93 +/- 2.19, in 87 patients with > 10 WBC/hpf (92 determinations) was 13.42 +/- 1.41, and in 33 patients less than 45 years of age with clinically normal prostates (33 determinations) was 7.45 +/- 1.08. The mean complement C3 concentration in 46 patients with Ca (57 determinations) was 17.48 +/- 1.60, in 58 patients with BPH (85 determinations) was 3.83 +/- 0.55, in 24 patients with BPH with > 10 WBC/hpf (39 determinations) was 5.87 +/- 0.68, in 93 patients with > 10 WBC/hpf (98 determinations) was 4.47 +/- 0.53, and in 34 patients less than 45 years of age (34 determinations) was 2.06 +/- 0.43. The mean ratio of LDH-5/LDH-1 was significantly greater for Ca than BPH with 10 or less WBC/hpf in the prostatic fluid. The mean concentrations of transferrin and complement C3 were significantly greater in Ca than in all other groups studied. No obvious relationship between stage of disease and these findings was observed. These observations support the suggestion that determination of prostatic fluid composition assists in identifying men with a high risk of cancer of the prostate.

Acid Phosphatase↗

The response of seven prostatic fluid components to prostatic disease.

282 human prostatic fluid samples have been investigated for their pH value, zinc, and citrate concentration and their acid phosphatase, leucine aminopeptidase, diamine oxidase, and beta-glucuronidase activities. The results have been analysed in terms of the clinical status of the patients. Significant differences between patient categories were found with all but diamine oxidase and beta-glucuronidase. These differences were mainly found between men with apparently healthy prostates and prostatitis patients; the pH being raised and the acid phosphatase, leucine aminopeptidase, zinc and citrate being reduced. The diagnostic value of these parameters was evaluated, each could be used to classify correctly 90% of patients from these 2 groups. Zinc, citrate and leucine aminopeptidase showed no age relationship and were better than acid phosphatase and pH in discriminating between BPH and prostatitis. Evidence was also found for a return of normal secretory function sometime after an episode of prostatitis. Zinc and citrate are likely to be the most useful parameters for clinical evaluation.

Acid Phosphatase↗

Benign prostatic hyperplasia, prostate cancer and other prostate diseases diagnosed as a result of screening procedure among 1,004 men in the Lublin district.

Urological problems especially connected with prostate diseases appear in older men: prostatitis, benign prostatic hyperplasia, prostate cancer and others. Prostate cancer is the most common cancer in men and the second leading cause of deaths in male population. Therefore, it seems important to early detect prostate cancer in general practice setting due to screening procedures such as digital rectal exam and prostate-specific-antigen test. The aim of the study was to examine the character of diagnoses of a prostate disease among 1,004 men of the Lublin district who reported to a doctor during screening procedure carried out in urology outpatient clinic at Clinical Hospital in Lublin in the year 2000. After physical examination urologists initially diagnosed a prostate disease and sent men suspected to have a prostate cancer to further investigations. There was studied age and place of living. Benign prostate hyperplasia was the most common diagnosis made in 77.1% of subjects. It occurred most often in men aged 51-70 years. Prostate cancer was suspected in 3.5% of subjects. Frequency of benign prostate hyperplasia and prostate cancer suspicion increased with age. On the basis of studies screening procedures seem beneficial in the early detection of prostate cancer in men over 50.

Adult↗

[Screening for prostatic diseases in one-day total health check-up by using prostate specific antigen, international prostate symptom score and QOL index].

We preliminarily studied screening for prostatic diseases in one-day total health check-up by employing prostate specific antigen (PSA), international prostate symptom score (IPSS) and quality of life (QOL) index. From January 6 to March 31, 1998, a total of 390 men were included in this study, whose age ranged from 50 to 78 years with the mean of 57.5 years. The questionnaires, IPSS and QOL index, were mailed to the participants in advance. PSA (IMx: Dainapack) was measured at the end of the health check-up and the results of tests were explained on the same day. Participants who showed more than 8 points in IPSS, more than 4 points in QOL index and/or more than 4.1 ng/ml in PSA were given a referral to urologists of corresponding hospitals for further examination. A total of 116 men (29.7%) were judged to need thorough examination. Among 106 men who were referred to urologists, only 34 (32.1%) had visited the urologists by the end of July 1998. Two men (0.51% in all participants) were diagnosed with prostate cancer, 10 received some pharmacotherapy, and 2 underwent transurethral resection of prostate. The results indicate that screening for prostatic diseases in total health check-up is useful, even in an institute without staff urologists, in close association with urologists.

Aged↗

[A study on the mass screening system for prostatic diseases].

Between 1984 and 1990, a mass screening for prostatic diseases was carried out on men over 55 years old in cities, towns and villages in Toyama Prefecture, Japan. The total number of subjects examined in the primary study was 1,232, which was 17.7% of the males over 55 years old in these areas. The primary study consisted of inquiry concerning urination, digital examination of the prostate, transabdominal ultrasonography, and determination of tumor markers. A secondary study was indicated for 100 subjects (8.9%) suspected to have prostatic cancer and 169 (15%) suspected to have benign prostatic hypertrophy, but only 92 (35%) of them were actually examined. Prostatic cancer was histologically diagnosed in 3 subjects (0.3%), and benign prostatic hypertrophy was established in 56 subjects (4.5%), who were referred to urologists. Though a high percentage of the population was covered by the primary study the percentage of subjects who received the secondary study among those in whom it was indicated was low. This probably was a reason for the low detection rate of prostatic cancer. An improved system is considered to be needed to increase the efficiency of mass screening for prostatic diseases.

Humans↗

Effect of age on biochemical disease-free outcome in patients with T1-T3 prostate cancer treated with definitive radiotherapy in an equal-access health care system: a radiation oncology report of the Department of Defense Center for Prostate Disease Research.

PURPOSE: It has traditionally been a common perception that young age is a negative prognostic factor in prostate cancer (CaP). Furthermore, many urologists believe that younger patients are better suited to surgery rather than radiotherapy (RT) because of this perception. However, the data on the effect of age on outcome in patients with CaP are unclear. The records of the Department of Defense Center for Prostate Disease Research were queried for the biochemical disease-free results of patients after definitive RT and analyzed by age. MATERIALS AND METHODS: The records of 1018 patients with T1-T3 CaP treated with definitive RT between 1988 and 2000 were reviewed. The records of patients receiving adjuvant hormonal therapy or adjuvant or salvage RT postoperatively were excluded. Biochemical failure was calculated by the American Society for Therapeutic Radiology and Oncology criteria. The median potential follow-up was 85.3 months as of December 31, 2001. RESULTS: Age did not affect biochemical disease-free survival significantly when considered as <60 vs. >/=60 years (p = 0.646), by decade (p = 0.329), or as a continuous variable (correlation coefficient r = 0.017, regression slope = 0.007, with p = 0.588 and R(2) < 0.001). Using multiple regression analysis, age was still not significant (p = 0.408). Other variables analyzed were pretreatment prostate-specific antigen level (p < 0.001), Gleason sum (p = 0.023), stage (p = 0.828), and RT dose (p = 0.033). CONCLUSIONS: Age and biochemical disease-free survival after RT for CaP are not related. Age may not be a valid factor in choosing between primary treatment options for CaP.

Adult↗

A mobile mass screening unit for prostatic disease.

A mobile unit for mass screening of prostatic disease using transrectal ultrasonotomography was developed in December 1980. In the following years we screened 1,396 males over 55 years of age. We have detected 463 cases [33.2%] of benign prostatic hypertrophy [BPH] and eight cases [0.6%] of prostatic cancer. The detection rate of BPH and malignancy of the prostate was shown to be very high. Thus, the unit promises to be of value in preventative medicine projects for prostatic disease in Japan.

Humans↗

Isoflavones and the prevention and treatment of prostate disease: is there a role?

Epidemiologic and experimental data suggest that isoflavones have benefits for preventing and treating some prostate disease. Isoflavone supplements may therefore be an important tool for men concerned about prostate disease, such as those with benign prostatic hypertrophy undergoing watchful waiting or those concerned about the potential for prostate cancer. Conclusive proof of a relationship between isoflavones and the prevention and treatment of prostate disease can only come from prospective, randomized, controlled clinical trials.

Aged↗

Histochemistry of steroid receptors in prostatic diseases.

Tissue obtained from 55 men with prostatic disease was assayed for estrogen and androgen receptors by a newly developed histochemical technique. The material studied consisted of 45 specimens of benign nodular prostatic hyperplasia and 10 specimens of prostatic adenocarcinoma. The results obtained were compared to those of parallel biochemical assays in 17 cases and successfully correlated in 85 percent. The new procedure is rapid, inexpensive and accurate, allowing for the detection of receptor in cytoplasm and/or nucleus and evaluation of receptor heterogeneity. The histochemical method may offer an alternate to biochemical assay of prostatic tissue as contamination with steroid binding globulins does not appear to be a problem at this time.

Fluorescent Antibody Technique↗

Reproducibility of transrectal ultrasound of prostatic disease.

One hundred patients with suspicion of prostatic disease were examined by transrectal ultrasound. Two urologists with experience in this technique performed the examination separately for each patient. In the present study the differential diagnosis between normal prostate, benign hypertrophy and prostate cancer was almost perfectly reproducible. However, prostatitis was a difficult diagnosis by transrectal ultrasound. Prostatic cysts and stones were readily recognised. Although not perfectly reproducible, the transverse dimensions of the prostatic adenomas were reasonably comparable. Measurement of the longitudinal diameter of prostatic adenomas was difficult and poorly reproducible in our hands.

Humans↗

Regulation of apoptosis in prostatic disease.

BACKGROUND: Recent studies suggest that aberrant regulation of apoptosis, including acquired apoptosis resistance, contributes to perturbations in cell growth that, in part, underlie the development of benign prostatic hyperplasia (BPH) and prostate cancer. Importantly, apoptosis resistance can enhance the malignant properties of prostate cancer cells, contributing to their widespread metastatic activities. Since apoptosis resistance likely contributes to benign and malignant prostate disease, the promotion of apoptosis represents a reasonable therapeutic objective. METHODS: This brief review focuses on the role of apoptosis in prostatic disease and discusses potential intervention points for novel therapeutics. CONCLUSIONS: Novel therapies for prostatic disease, including gene therapy and biological therapy that involve apoptosis as a mechanism of action, are being developed and tested. Ultimately, the identification of proapoptotic and antiapoptotic genes and the pathways through which they operate will serve to provide more rational approaches for further development of more efficacious therapeutic strategies for benign and malignant prostatic disease.

Apoptosis↗

Mass screening program for prostatic diseases with transrectal ultrasonotomography.

A special chair-type apparatus for transrectal ultrasonotomography was developed in our laboratory 3 years ago. We did a mass screening program for prostatic disease, using this equipment as the primary study in the system. The 132 apparently normal men evaluated ranged in age from 40 to 76 years (mean 55.0). The 48 patients suspected of having prostatic disease underwent secondary studies, consisting of the usual urological examinations. Prostatic disease was detected in 24 cases, including 18 cases of benign prostatic hyperplasia. Thus, the model program revealed an extraordinarily high prevalence of latent prostatic disease among apparently normal older men.

Adult↗