Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0376358 (prostate cancer)
 59,338 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Since its identification in seminal fluid in 1971, much new information has been obtained about the biology and expression of prostate-specific antigen (PSA). PSA is a glycoprotein composed of 93% amino acids and 7% carbohydrates, with a molecular weight of about 30,000 Da. Functionally and structurally PSA is a kallikrein-like serine protease, and its physiologic role is degradation of the major proteins of seminal coagulum (semenogelin I and II, fibronectin), which leads to semen liquefaction. The PSA gene is located on the 13q region of chromosome 19, and it has a high degree of homology (more than 80%) with genes of the human glandular kallikrein (hKGK1). PSA production and expression are preferentially but not exclusively associated to the normal, benign hyperplastic and cancerous tissues of the prostate. In fact, it has been demonstrated that PSA is also present in accessory male sex glands and breast cancer. It was recently reported that PSA was also present in milk of lactating women. Many factors may influence PSA synthesis and production, and among them the most important are androgen, retinoic acid and growth factor stimulation. Significant advances have been recently made as regards the molecular isoforms of PSA. In the seminal fluid PSA seems partially bound to a serpine (protein C inhibitor), whereas in serum it is predominantly associated to alpha-1-antichymotrypsin and in a small quantity to alpha-2-macroglobulin. These new findings will have implications for the clinical application of PSA as a tumor marker for prostate cancer.
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PMID:Biochemical characteristics and recent biological knowledge on prostate-specific antigen. 862 11

Prostate-specific antigen (PSA), produced by prostate cells, provides an excellent serum marker for prostate cancer. It belongs to the human kallikrein family of enzymes, a second prostate-derived member of which is human glandular kallikrein-1 (hK2). Active PSA and hK2 are both 237-residue kallikrein-like proteases, based on sequence homology. An hK2 model structure based on the serine protease fold is presented and compared to PSA and six other serine proteases in order to analyze in depth the role of the surface-accessible loops surrounding the active site. The results show that PSA and hK2 share extensive structural similarity and that most amino acid replacements are centered on the loops surrounding the active site. Furthermore, the electrostatic potential surfaces are very similar for PSA and hK2. PSA interacts with at least two serine protease inhibitors (serpins): alpha-1-antichymotrypsin (ACT) and protein C inhibitor (PCI). Three-dimensional model structures of the uncleaved ACT molecule were developed based upon the recent X-ray structure of uncleaved antithrombin. The serpin was docked both to PSA and hK2. Amino acid replacements and electrostatic complementarities indicate that the overall orientation of the proteins in these complexes is reasonable. In order to investigate PSA's heparin interaction sites, electrostatic computations were carried out on PSA, hK2, protein C, ACT, and PCI. Two heparin binding sites are suggested on the PSA surface and could explain the enhanced complex formation between PSA and PCI, while inhibiting the formation of the ACT-PSA complex, PSA, hK2, and their preliminary complexes with ACT should facilitate the understanding and prediction of structural and functional properties for these important proteins also with respect to prostate diseases.
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PMID:Structural investigation of the alpha-1-antichymotrypsin: prostate-specific antigen complex by comparative model building. 873 55

Human glandular kallikrein (hK2) is a possible new marker for prostate cancer that is homologous to prostate specific antigen. Purified hK2 added to serum or plasma reacted with endogenous protease inhibitors to form complexes of >350, 135, and 80 kDa, and some hK2 remained free, as judged by immunoblotting. The former two complexes could be removed by specific antibodies to alpha2-macroglobulin and to C1- inactivator, respectively, and they comigrated on SDS-PAGE with complexes formed between hK2 and purified alpha2-macroglobulin or C1-inactivator. hK2 complexes of 80 kDa could not be completely removed with any anti-serpin antibody used. Thus, these may consist of more than one type of hK2 complex. In contrast, essentially all hK2 complexes were removed from seminal plasma by antibody to protein C inhibitor, demonstrating that protein C inhibitor is the only significant inhibitor of hK2 in semen. hK2 reacted more rapidly with alpha2-macroglobulin than with any other inhibitor in plasma or serum. Divalent metal ions and heparin did not appreciably affect the rate of formation of any of the hK2 complexes in serum or plasma or with purified alpha2-macroglobulin or C1-inactivator. Measurement of one or more of the hK2 forms identified here may have diagnostic or prognostic potential for prostate cancer.
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PMID:alpha2-macroglobulin and C1-inactivator are plasma inhibitors of human glandular kallikrein. 985 94

Human kallikrein 2 (hK2) is a serine protease expressed predominantly in the prostate which has 80% homology to prostate-specific antigen (PSA). hK2 is an active trypsin-like protease which has been shown by immuno-histochemical staining to be more highly expressed in prostate carcinoma than in benign prostate tissue. Unlike PSA, hK2 activates pro-PSA , pro-hK2 and the zymogen form of urokinase-type plasminogen activator (uPA), an extracellular protease correlated with prostate cancer and metastasis. We show here that hK2 rapidly forms a complex with plasminogen activator inhibitor-1 (PAI-1), the primary inhibitor of uPA in tissues. In addition, hK2 inactivated 6 to 7 mol of PAI-1 by cleavage at Arg346-Met347 for every mole of hK2-PAI-1 complex formed. In contrast with hK2, PSA neither complexed with nor inactivated PAI-1. PAI-1 inhibited hK2 comparably with protein C inhibitor (PCI) and at least 20 times more rapidly than alpha1-anti-chymotrypsin (ACT). N-Terminal sequencing shows that hK2 forms a covalent complex with PAI-1, PCI and ACT after cleavage at Arg346-Met347, Arg354-Ser355 and Leu358-Ser359, respectively. During complex formation, hK2 inactivated PAI-1 but did not inactivate ACT or PCI. Our current results suggest that the increased hK2 expression in prostate cancer tissues could influence cancer biology not only by activation of uPA but also by inactivation of its primary inhibitor, PAI-1.
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PMID:Prostatic human kallikrein 2 inactivates and complexes with plasminogen activator inhibitor-1. 1020 59

Human glandular kallikrein 2 (hK2) is a trypsin-like serine protease expressed predominantly in the prostate epithelium. Recently, hK2 has proven to be a useful marker that can be used in combination with prostate specific antigen for screening and diagnosis of prostate cancer. The cleavage by hK2 of certain substrates in the proteolytic cascade suggest that the kallikrein may be involved in prostate cancer development; however, there has been very little other progress toward its biochemical characterization or elucidation of its true physiological role. In the present work, we adapt phage substrate technology to study the substrate specificity of hK2. A phage-displayed random pentapeptide library with exhaustive diversity was generated and then screened with purified hK2. Phages displaying peptides susceptible to hK2 cleavage were amplified in eight rounds of selection and genes encoding substrates were transferred from the phage to a fluorescent system using cyan fluorescent protein (derived from green fluorescent protein) that enables rapid determination of specificity constants. This study shows that hK2 has a strict preference for Arg in the P1 position, which is further enhanced by a Ser in P'1 position. The scissile bonds identified by phage display substrate selection correspond to those of the natural biological substrates of hK2, which include protein C inhibitor, semenogelins, and fibronectin. Moreover, three new putative hK2 protein substrates, shown elsewhere to be involved in the biology of the cancer, have been identified thus reinforcing the importance of hK2 in prostate cancer development.
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PMID:Substrate specificity of human kallikrein 2 (hK2) as determined by phage display technology. 1204 84

Although with earlier detection of prostate cancer more men face the long-term consequences of primary treatment, studies on the impact of treatment on long-term health-related quality of life (HRQoL) are scarce. We followed 314 men with newly diagnosed localized prostate cancer from 1 month before until 5 years after radical prostatectomy (n = 127) or external beam radiotherapy (n = 187; median follow-up = 52 months). Questionnaires addressing disease-specific (UCLA PCI) and generic (SF-36, EQ-5D) HRQoL were sent 1 month before and 6, 12 and 52 months after treatment. Repeated-measures modeling was used to study HRQoL over time. Regular urinary leakage was reported by 12% of prostatectomy patients before treatment and by 31% at the 52-month assessment. Erectile dysfunction before treatment was reported by 31% of prostatectomy patients and by 40% of radiotherapy patients; at the 52-month assessment, these percentages were 88% and 64%, respectively. Erectile dysfunction present at 1 year posttreatment can be considered permanent. Prostatectomy patients reported better generic functioning both before and after treatment than radiotherapy patients, who were on average 5.9 years older and had more comorbid conditions. General physical functioning of prostatectomy patients slightly improved over time, but declined in radiotherapy patients. The relation between age and physical scores was found to be nonlinear. The long-term physical decline in radiotherapy patients partly resulted from aging and its nonlinear impact on health, although treatment effects cannot be excluded. Scores of both patient groups remained above those of norm populations. Innovative graphs describing disease-specific and generic functions after treatment can help patients and physicians in their treatment choices.
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PMID:Five-year follow-up of health-related quality of life after primary treatment of localized prostate cancer. 1580 Sep 19

The serine protease inhibitor (serpin) protein C inhibitor (PCI) has been found in the prostate and possibly is a marker to distinguish normal prostate, benign prostatic hyperplasia, and prostate cancer. In this study, we assessed PCI expression in normal, hyperplastic, and malignant prostatic tissues, prostate cancer cell lines, and the CWR22 prostate cancer xenograft model that allowed us to study PCI expression and its regulation in response to androgens. By Northern blot, immunohistochemistry, and in situ hybridization, we found that PCI was expressed in both benign and malignant prostate tissues. Protein C inhibitor was expressed in both androgen-independent (PC-3) and androgen-dependent (LNCaP) prostate cancer cell lines. Furthermore, PCI was detected in all CWR22 tumor samples (androgen dependent, 6 days post-castration, 12 days post-castration followed by 72 h of testosterone treatment, and recurrent CWR22 tumor), although expression of the mature forms of both prostate-specific antigen (PSA) and its homolog, kallikrein 2 (hK2), was clearly androgen-dependent. These results suggest that PCI expression is not regulated by androgens and that PCI is unlikely to be a tumor suppressor gene, but also that PCI may be involved in regulating key serine proteases involved in metastatic prostate disease.
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PMID:Protein C inhibitor (plasminogen activator inhibitor-3) expression in the CWR22 prostate cancer xenograft. 1587 12

Prostate cancer screening, diagnosis, and treatment have changed dramatically in the last 20 years. Patients with newly diagnosed prostate cancer have many treatment options available. We attempted to determine how patient demographics and quality of life (QOL) have changed, and we describe the average patient with newly diagnosed prostate cancer in the early 21st century. From the Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE) we identified 3003 men with prostate cancer diagnosed between 1997 and 2003 for whom pretreatment demographic and QOL data were available. All patients completed both the University of California-Los Angeles Prostate Cancer Index (UCLA-PCI) and the Rand Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36) as self-administered questionnaires at the time of diagnosis. We compared demographic variables (age at diagnosis, race/ethnicity, education, number of comorbidities, body mass index [BMI], and insurance type), treatment choice, and pretreatment QOL scores on the SF-36 and UCLA-PCI scales for the periods 1997 to 1999 or 2000 to 2003. Stratified analysis by risk category was performed for demographic and QOL data for the 2 periods. Race/ethnicity and insurance demographics were statistically different for the 2 periods. Low-risk patients also showed a statistically increased BMI in the 2000 to 2003 period. Risk category predicted performance on both inventories, with low-risk patients having better function than intermediate-risk patients and high-risk patients in the areas of urinary bother, bowel function and bother, and sexual function and bother, as well as in many general well-being and emotional health scales on the SF-36. We conclude that the "average" prostate cancer patient is white, 65 years of age, overweight, educated at a college level, and has 1 to 2 comorbidities. Patients report average or above-average pretreatment health-related QOL for all scales based on 2 validated instruments. In this cohort, more patients chose radical prostatectomy than any other form of treatment.
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PMID:Who is the average patient presenting with prostate cancer? 1619 11

We compared health-related quality-of-life (HRQL) after intensity-modulated radiotherapy (IMRT) with statuses obtained after old and new protocols of three-dimensional conformal radiation therapy (3DCRT) for localized prostate cancer. We measured the general and disease specific HRQL using the MOS 36-Item Health Survey (SF-36), and the University of California, Los Angeles Prostate Cancer Index (UCLA PCI), respectively. IMRT resulted in similar profiles of general and disease-specific HRQL to two other methods within the first year after treatment. Moreover, IMRT gave rise to comparable urinary, intestinal and sexual side effects despite the high dose of radiation applied.
Prostate Cancer Prostatic Dis 2007
PMID:Health-related quality-of-life after external beam radiation therapy for localized prostate cancer: intensity-modulated radiation therapy versus conformal radiation therapy. 1716 68

Prostate cancer is detected today at earlier stages and in younger men than ever before. A lot of men are asymptomatic and also physically and sexually active at diagnosis, and most of them are being treated by curative procedures. These trends have led to increasing numbers of patients undergoing disease management for longer periods of time. For many patients quality of life (QoL) may be just as important as survival. Thus, QoL considerations may well be the critical factor in medical decision-making for most of them. Widespread interest in studying patient-centred outcomes has led to the development of methods for health-related QoL measurements. In fact, many questionnaires have been introduced in clinical practice to assess the impact of QoL in patients (SF-36, CARES, FACT, EORTC QLQ-C30, GRISS, UCLA PCI, PCOS). Herein we evaluate the impact of QoL on patients affected by prostate cancer and treated with watchful waiting, radical prostatectomy, radiotherapy and hormonal therapy; we have also considered the role of supportive care, including the administration of analgesics, antidepressants, corticosteroids, bisphosphonates, antiemetics and stool softeners, together with psychological support. The ultimate goal of QoL research should strongly improve medical care and concretely assist patients and physicians in treatment decision-making.
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PMID:Prostate cancer treatment and quality of life. 1743 64


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