| 1. |
- Beshara, Soheir, et al.
(author)
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Anemia associated with advanced prostatic adenocarcinoma : Effects of recombinant human erythropoietin
- 1997
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In: The Prostate. - 0270-4137 .- 1097-0045. ; 31:3, s. 153-160
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Journal article (peer-reviewed)abstract
- BACKGROUND AND METHODS: Nine patients with hormone-refractory metastatic prostatic adenocarcinoma and anemia were treated with recombinant human erythropoietin (rHuEpo) at a median dose of 150 U/kg BW 3 times a week subcutaneously. Baseline hemoglobin (Hb) ranged from 70 to 116 g/L, and the study duration was 12 weeks (median patient participation period was 8 weeks). RESULTS: Four patients demonstrated a median Hb increase of 20 g/L and were considered responders. Three patients showed a median increase of 17 g/L but required blood transfusion once, and were therefore considered as partial responders. Baseline erythropoietic status showed a significant correlation between serum Epo and Hb. Inadequate Epo production, evaluated by the observed/predicted log Epo ratio, was found in two patients. Defective bone marrow activity, demonstrated by low transferrin receptor (TfR), and hypoferremia in spite of abundant iron stores were also shown. Hemorheological investigations showed elevated plasma viscosity. CONCLUSIONS: Our results indicate that suppression of erythropoiesis can be mainly explained by the depressed marrow activity. The altered hemorheology might contribute to the anemia. This anemia could possibly be corrected with rHuEpo.
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| 2. |
- Pandita, RK, et al.
(author)
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Testosterone-induced prostatic growth in the rat causes bladder overactivity unrelated to detrusor hypertrophy
- 1998
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In: The Prostate. - : John Wiley and Sons, Ltd. - 0270-4137 .- 1097-0045. ; 35:2, s. 102-108
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Journal article (peer-reviewed)abstract
- BACKGROUND: Testosterone treatment of rats produces prostatic hypertrophy and detrusor overactivity. Whether or not the detrusor overactivity can be related to an increase in the responsiveness of lower urinary tract smooth muscles is not known.METHODS: Male Sprague-Dawley rats were given daily injections of testosterone propionate for 2 weeks. Effects on cystometric parameters and on the responsiveness of isolated detrusor, urethral, and prostate smooth muscle preparations to drugs and electrical field stimulation were investigated.RESULTS: Testosterone treatment increased prostatic weight twofold (controls, 768 mg; testosterone-treated, 1,478 mg), but not bladder weight (103 mg vs. 116 mg). Micturition pressure (77%), bladder capacity (75%), residual volume (56%), and micturition volume (83%) increased significantly in treated animals, and bladder overactivity developed. No effect of intraarterial doxazosin on these changes was observed. The differences in urodynamic parameters between control and testosterone-treated rats could not be correlated with changes in bladder, urethral, or prostate excitatory innervation, as revealed by responses to electrical field stimulation, or by smooth muscle responses to different contractant drugs.CONCLUSIONS: Some of the urodynamic effects seen after testosterone treatment seem to be caused by the mechanical obstruction of the enlarged prostate. Since there were no changes in smooth muscle responsiveness, it is suggested that the bladder overactivity observed can partly be related to testosterone-induced changes of the micturition reflex at the lower urinary tract, spinal, and/or supraspinal levels.
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| 3. |
- Abrahamsson, P. ‐A, et al.
(author)
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Immunohistochemical distribution of the three predominant secretory proteins in the parenchyma of hyperplastic and neoplastic prostate glands
- 1988
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In: The Prostate. - : Wiley. - 0270-4137 .- 1097-0045. ; 12:1, s. 39-46
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Journal article (peer-reviewed)abstract
- Prostatic acid phosphatase (PAP), prostate‐specific antigen (PSA), and β‐microseminoprotein (β‐MSP) were regularly localized immunohistochemically to the epithelium of the acini and that of the ducts in the nodules of 24 cases of benign prostatic hyperplasia. The immunohistochemical distribution of these three prostatic‐secreted proteins was also examined, with monoclonal antisera against PAP and PSA and with polyclonal antisera against PAP, PSA, and β‐MSP, in a series of 40 cases of prostatic adenocarcinomas graded according to the WHO classification. Highly differentiated (grade I) carcinomas showed a high incidence of PAP‐, PSA‐, and β‐MSP‐immunoreactive cells. As in the normal and hyperplastic prostate parenchyma, highly differentiated (grade I) carcinomas were found to contain an almost equal number of PAP‐, PSA‐, and β‐MSP‐immunoreactive cells. When semiquantitatively assessed, the incidence of PAP‐, PSA‐, and β‐MSP‐immunoreactive cells was found to be lower in the moderately and poorly differentiated (grades II and III) tumors than in the highly differentiated ones; they also showed greater staining variability. Tumor cells immunoreactive with a monoclonal antiserum raised against PAP in carcinomas of grades II and III were less frequent than tumor cells immunoreactive with antisera against PSA, β‐MSP, and a polyclonal antiserum against PAP. The almost identical distribution of PSA and β‐MSP in carcinomas of grades II and III suggests that PSA and β‐MSP are not less sensitive tumor markers than PAP for the monitoring of the course and the treatment of prostatic carcinomas.
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| 4. |
- Abrahamsson, P. ‐A, et al.
(author)
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Partial characterization of a thyroid‐stimulating hormone‐like peptide in neuroendocrine cells of the human prostate gland
- 1989
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In: The Prostate. - : Wiley. - 0270-4137 .- 1097-0045. ; 14:1, s. 71-81
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Journal article (peer-reviewed)abstract
- Immunohistochemical identification of the most prevalent type of neuroendocrine (NE) cells in the human prostate gland can be made with polyclonal antisera against human thyroid‐stimulating hormone (TSH). A TSH‐like peptide was characterized by analysis of prostatic tissue homogenates with sodium dodecyl sulfate‐polyacrylamide gel (SDS‐PAGE) electrophoresis followed by immunoblotting. A single protein band, with an apparent mass of about 32 kDa after reduction, was identified both with polyclonal antisera against human TSH and with a polyclonal antiserum raised against a synthetic peptide corresponding to the carboxyterminal part of the β‐subunit of human TSH. The TSH‐like prostatic peptide identified here is, on the basis of its molecular mass and absence of immunoreactivity with an antiserum raised against a synthetic peptide representing the mid‐portion of the β‐subunit of TSH, not identical with the pituitary β‐subunit of TSH. On the other hand, this 32 kDa prostatic peptide may have certain structural elements in common with the pituitary β‐subunit of TSH, since it is recognized both with polyclonal antisera against TSH and with an antiserum against the carboxyterminal part of the β‐subunit of TSH.
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| 5. |
- Adamo, Hanibal Hani, 1984-, et al.
(author)
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Prostate cancer induces C/EBPβ expression in surrounding epithelial cells which relates to tumor aggressiveness and patient outcome
- 2019
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In: The Prostate. - : John Wiley & Sons. - 0270-4137 .- 1097-0045. ; 79:5, s. 435-445
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Journal article (peer-reviewed)abstract
- Background: Implantation of rat prostate cancer cells into the normal rat prostate results in tumor-stimulating adaptations in the tumor-bearing organ. Similar changes are seen in prostate cancer patients and they are related to outcome. One gene previously found to be upregulated in the non-malignant part of tumor-bearing prostate lobe in rats was the transcription factor CCAAT/enhancer-binding protein- (C/EBP).Methods: To explore this further, we examined C/EBP expression by quantitative RT-PCR, immunohistochemistry, and Western blot in normal rat prostate tissue surrounding slow-growing non-metastatic Dunning G, rapidly growing poorly metastatic (AT-1), and rapidly growing highly metastatic (MatLyLu) rat prostate tumors?and also by immunohistochemistry in a tissue microarray (TMA) from prostate cancer patients managed by watchful waiting.Results: In rats, C/EBP mRNA expression was upregulated in the surrounding tumor-bearing prostate lobe. In tumors and in the surrounding non-malignant prostate tissue, C/EBP was detected by immunohistochemistry in some epithelial cells and in infiltrating macrophages. The magnitude of glandular epithelial C/EBP expression in the tumor-bearing prostates was associated with tumor size, distance to the tumor, and metastatic capacity. In prostate cancer patients, high expression of C/EBP in glandular epithelial cells in the surrounding tumor-bearing tissue was associated with accumulation of M1 macrophages (iNOS+) and favorable outcome. High expression of C/EBP in tumor epithelial cells was associated with high Gleason score, high tumor cell proliferation, metastases, and poor outcome.Conclusions: This study suggest that the expression of C/EBP-beta, a transcription factor mediating multiple biological effects, is differentially expressed both in the benign parts of the tumor-bearing prostate and in prostate tumors, and that alterations in this may be related to patient outcome.
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| 6. |
- Adolfsson, Per, et al.
(author)
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Lysophosphatidic acid stimulates proliferation of cultured smooth muscle cells from human BPH tissue : Sildenafil and papaverin generate inhibition
- 2002
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In: The Prostate. - : Wiley. - 0270-4137 .- 1097-0045. ; 51:1, s. 50-58
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Journal article (peer-reviewed)abstract
- Background The endogenous substance lysophosphatidic acid (LPA) has been found to generate proliferation of cultured smooth muscle cells (SMC). Therefore, the effect of LPA on human benign prostate hyperplasia (BPH) could be of interest.Methods The proliferative effect of LPA on cultured human prostatic SMC from specimens obtained at trans-urethral resection of the prostate (TURP) because of BPH, was analyzed by [3H]-thymidine and [35S]-methionine incorporation. In addition, LPA stimulated BPH SMC were treated with papaverin, forskolin, sildenafil or zaprinast, well known to increase the intracellular level of cAMP or cGMP.Results LPA produced a dose-dependent increase in BPH SMC, both regarding DNA- and protein-synthesis with EC50 values of 3 and 10 μM, respectively. Furthermore, both papaverin, a general phosphodiesterase inhibitor regarding cAMP hydrolyzes, and forskolin, an adenylyl cyclase stimulating agent, inhibited the LPA-stimulated DNA replication in a dose dependent manner with IC50 = 2.5, and 0.35 μM, respectively. cGMP increasing agents, such as the NO-donors SIN-1 and SNAP, produced a weak anti-proliferative response. However, both phosphodiesterase 5 inhibitors sildenafil (Viagra®) and zaprinast efficiently blocked DNA replication. In addition, when the protein synthesis was examined, we found that the LPA response was significantly inhibited by forskolin and papaverin.Conclusions The major conclusion of this investigation is that the endogenous serum component LPA, is able to promote human BPH SMC growth. In addition, our study indicates that cyclic nucleotides can inhibit this effect. Future clinical studies will be needed to determine if different specific phosphodiesterase inhibitors per se or in combination could represent a new therapeutic possibility for the treatment of BPH.
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| 7. |
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| 8. |
- Assel, Melissa J., et al.
(author)
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Kallikrein markers performance in pretreatment blood to predict early prostate cancer recurrence and metastasis after radical prostatectomy among very high-risk men
- 2019
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In: Prostate. - : Wiley. - 0270-4137.
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Journal article (peer-reviewed)abstract
- Background: To assess whether a prespecified statistical model based on the four kallikrein markers measured in blood—total, free, and intact prostate-specific antigen (PSA), together with human kallikrein-related peptidase 2 (hK2)—or any individual marker measured in pretreatment serum were associated with biochemical recurrence-free (BCR) or metastasis-free survival after radical prostatectomy (RP) in a subgroup of men with very high-risk disease. Methods: We identified 106 men treated at Mayo Clinic from 2004 to 2008 with pathological Gleason grade group 4 to 5 or seminal vesicle invasion at RP. Univariable and multivariable Cox models were used to test the association between standard predictors (Kattan nomogram and GPSM [Gleason, PSA, seminal vesicle and margin status] score), kallikrein panel, and individual kallikrein markers with the outcomes. Results: BCR and metastasis occurred in 67 and 30 patients, respectively. The median follow-up for patients who did not develop a BCR was 10.3 years (interquartile range = 8.2-11.8). In this high-risk group, neither Kattan risk, GPSM score, or the kallikrein panel model was associated with either outcome. However, after adjusting for Kattan risk and GPSM score, separately, preoperative intact PSA was associated with both outcomes while hK2 was associated with metastasis-free survival. Conclusions: Conventional risk prediction tools were poor discriminators for risk of adverse outcomes after RP (Kattan risk and GPSM risk) in patients with very high-risk disease. Further studies are needed to define the role of individual kallikrein marker forms in the blood to predict adverse prostate cancer outcomes after RP in this high-risk setting.
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| 9. |
- Aumüller, G., et al.
(author)
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Species‐ and organ‐specificity of secretory proteins derived from human prostate and seminal vesicles
- 1990
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In: The Prostate. - : Wiley. - 0270-4137 .- 1097-0045. ; 17:1, s. 31-40
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Journal article (peer-reviewed)abstract
- Polyclonal antibodies against semenogelin (SG) isolated from human seminal vesicle secretion and acid phosphatase (PAP), β‐microseminoprotein (β‐MSP), and Prostate‐Specific Antigen (PSA) derived from human prostatic fluid, as well as a monoclonal antibody against β‐MSP were used for immunocytochemical detection of the respective antigens in different organs from different species. SG immunoreactivity was detected in the epithelium of the pubertal and adult human and in monkey seminal vesicle, ampulla of the vas deferens, and ejaculatory duct. PAP, β‐MSP, and PSA immunoreactivities were detected in the pubertal and adult human prostate and the cranial and caudal monkey prostate. With the exception of a weak PSA immunoreactivity in the proximal portions of the ejaculatory duct, none of the latter antisera reacted with seminal vesicle, ampullary, and ejaculatory duct epithelium. Among the non‐primate species studied (dog, bull, rat, guinea pig) only the canine prostatic epithelium displayed a definite immunoreactivity with the PAP antibody and a moderate reaction with the PSA antibody. No immunoreaction was seen in bull and rat seminal vesicle and canine ampulla of the vas deferens with the SG antibody. The same was true for the (ventral) prostate of rat, bull, and dog for β‐MSP. The epithelium of the rat dorsal prostate showed a slight cross‐reactivity with the monoclonal antibody against β‐MSP and one polyclonal antibody against PSA. The findings indicate a rather strict species‐dependent expression of human seminal proteins which show some similarities in primates, but only marginal relationship to species with different physiology of seminal fluid.
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| 10. |
- Aydogdu, Özgu, 1978, et al.
(author)
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Prostate-to-bladder cross-sensitization in a model of zymosan-induced chronic pelvic pain syndrome in rats.
- 2021
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In: The Prostate. - : Wiley. - 1097-0045 .- 0270-4137. ; 81:4, s. 252-260
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Journal article (peer-reviewed)abstract
- The aim of the present study was to investigate the effects of chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) on bladder function and pathophysiology.To create a model for CPPS, rats were intraprostatically injected with zymosan or saline, serving as control. Metabolic cage experiments were performed 7, 14, or 21 days after zymosan injection and after 14 days in the control group. Thereafter, cystometry was performed in which simulated micturition cycles were induced by saline infusion and contractile responses to the cholinergic agonist methacholine and the purinergic agonist ATP were measured. Following cystometry, the prostate and urinary bladder were excised and assessed histopathologically for possible inflammatory changes.Metabolic cage data revealed a significantly increased urinary frequency in zymosan treated rats. Likewise, the volume per micturition was significantly lower in all CPPS groups compared to controls. Cystometry showed a significant increase in the number of nonvoiding contractions, longer voiding time, and a trend towards lower compliance in CPPS rats compared to controls. Induction of CPPS led to significantly reduced cholinergic and purinergic contractile responses. Histopathological analysis demonstrated prostatic inflammation in all CPPS groups, in particular in later stage groups. Both the extent and grade of bladder inflammation were significantly higher in CPPS groups compared to controls.The current findings demonstrate a potential prostate-to-bladder cross-sensitization leading to symptoms of bladder overactivity and signs of bladder inflammation. Future clinical studies are required to verify the outcomes of the current study and enable advancement of patient care.
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| 11. |
- Babiker, Adil A., et al.
(author)
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Mapping pro- and antiangiogenic factors on the surface of prostasomes of normal and malignant cell origin
- 2010
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In: The Prostate. - : Wiley. - 0270-4137 .- 1097-0045. ; 70:8, s. 834-847
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Journal article (peer-reviewed)abstract
- BACKGROUND: Angiogenesis is the formation of new blood vessels by capillary sprouting from pre-existing vessels. Tumor growth is angiogenesis-dependent and the formation of new blood vessels is associated with the increased expression of angiogenic factors. Prostasomes are secretory granules produced, stored and released by the glandular epithelial cells of the prostate. We investigated the expression of selected angiogenic and anti-angiogenic factors on the surface of prostasomes of different origins as well as the direct effect of prostasomes on angiogenesis. METHODS: VEGF, endothelin-1, endostatin, and thrombospondin-1 were determined on prostasomes from seminal fluid and human prostate cancer cell lines (DU145,PC-3,LNCaP) using different immunochemical techniques. Human dermal microvascular endothelial cells were incubated with seminal and DU145 cell-prostasomes and with radioactive thymidine. The effect of prostasomes on angiogenesis was judged by measuring the uptake of labeled thymidine. The presence of any deleterious effects of prostasomes on the endothelial cells was investigated using thymidine assay and confocal laser microscopy. RESULTS: VEGF and endothelin-1 were determined on malignant cell-prostasomes (no difference between cell lines) but not determined on seminal prostasomes. The same applies for the expression of endostatin but with much higher expression on malignant cell-prostasomes with obvious differences between them. Seminal and DU145 cell-prostasomes were found to have anti-angiogenic effect which was more expressed by DU145 cell-prostasomes. No deleterious effect of prostasomes on endothelial function was detected using either thymidine assay or microscopy. CONCLUSIONS: Prostasomes contain pro- and anti-angiogenic factors that function to counteract each other unless the impact from one side exceeds the other to bring about dysequilibrium.
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| 12. |
- Babiker, Adil A., et al.
(author)
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Overexpression of ecto-protein kinases in prostasomes of metastatic cell origin
- 2006
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In: The Prostate. - : Wiley. - 0270-4137 .- 1097-0045. ; 66:7, s. 675-686
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Journal article (peer-reviewed)abstract
- BACKGROUND:Prostasomes are secretory granules produced, stored, and released by the glandular epithelial cells of the prostate. They express numerous enzymes whose physiological roles have so far not been fully evaluated. In this study, we investigated the expression and function of prostasomal protein kinases and ATPase.METHODS:The protein kinase activities of prostasomes isolated from seminal fluid and malignant prostate cell lines (PC-3, DU145, and LNCaP) were investigated using the model phosphorylation substrates histone and casein, as well as the plasma proteins C3 and fibrinogen, in combination with specific protein kinase inhibitors. The prostasomal ATPase activity was also evaluated. The expression of protein kinases and ATPase on prostasomes was verified by flow cytometry.RESULTS:Prostasomes (intact or solubilized with octylglucoside or saponin) from prostate cancer cells had higher expression of protein kinases A, C, and casein kinase II compared to prostasomes isolated from seminal plasma, resulting in higher phosphorylation of both exogenous and endogenous substrates. Using intact prostasomes, it was found that prostasomes of metastatic origin had lower ATPase activity, resulting in higher residual ATP available for the phosphorylation reaction. Finally, complement component C3 and fibrinogen (two proteins whose activities are modulated by phosphorylation) were identified as physiologically relevant phosphorylation substrates.CONCLUSIONS:These results indicate that prostasomes are capable of modifying proteins possibly involved in the innate response by extracellular phosphorylation mediated by ecto-kinases. This is a novel mechanism by which prostatic malignant cells may interact with their environment.
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| 13. |
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| 14. |
- Babiker, Adil A., et al.
(author)
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Prothrombotic effect of prostasomes of metastatic cell and seminal origin
- 2007
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In: The Prostate. - : Wiley. - 0270-4137 .- 1097-0045. ; 67:4, s. 378-388
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Journal article (peer-reviewed)abstract
- BACKGROUND. Prostasomes are secretory granules produced by the glandular epithelial cells of the prostate. Seminal prostasomes contain high amounts of Tissue Factor (TF) but no studies of TF on malignant cell prostasomes have been made. Here we compare the expression, phosphorylation, and function of TF on prostasomes of different origin. METHODS. TF was detected on prostasomes isolated from seminal fluid and human prostate cancer cell lines (PC-3, DU145, and LNCaP) using FACS and enzyme immunoassay (EIA). Incubation of prostasomes with radioactive ATP under conditions favoring protein kinase A activity led to phosphorylation of TF as detected by immunoprecipitation and SDS-PAGE. The prothrombotic effect of prostasomes was investigated in whole blood and recalcified plasma. Blocking experiments were performed using anti-TF antibodies and corn trypsin inhibitor. RESULTS. TF was expressed on all tested prostasome preparations with lowest values found for seminal ones. Prostasomal TF was the main endogenous substrate for prostasomal protein kinase A. All tested prostasome preparations greatly enhanced the rate of clot formation in a dose-dependent fashion, that is, the clotting capability of prostasomes seemed to be related to the extent of their expression of TF. In addition, the density of the clot varied between different prostasome preparations. When incubated in whole blood, prostasomes were found to associate to WBC thereby inducing them to express and release TF. CONCLUSIONS. These data show that TF is overexpressed and also subjected to phosphorylation by malignant cell prostasomes. This suggests major roles for prostasomes in thrombotic events that occur in some advanced cases of prostate cancer.
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| 15. |
- Babiker, Adil A., et al.
(author)
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Transfer of functional prostasomal CD59 of metastatic prostatic cancer cell origin protects cells against complement attck
- 2005
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In: The Prostate. - : Wiley. - 0270-4137 .- 1097-0045. ; 62:2, s. 105-114
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Journal article (peer-reviewed)abstract
- BACKGROUND: Prostasomes are secretory granules produced, stored, and released, by the glandular epithelial cells of the prostate. They express the glycosylphosphatidylinositol (GPI)-anchored complement regulatory protein CD59, which has been shown to be transferred to spermatozoa and erythrocytes.METHODS: The CD59 content of prostasomes isolated from seminal fluid and malignant prostate cells (PC-3, DU145, and LNCaP) and the transfer of prostasomal CD59 to rabbit erythrocytes (RE) and to PIPLC-treated and unmanipulated cancer cells were investigated using FACS. All prostasomes were also incubated with RE and tested in a hemolytic assay.RESULTS: Prostasomes from cancer cells had higher expression of CD59 than those of normal cells. Prostasomal CD59 of different origin could be transferred to RE, malignant cell lines stripped of CD59 by PIPLC, or unmanipulated LNCaP cells. Malignant cell prostasomes had an increased ability to inhibit complement-mediated lysis compared to those from non-malignant cells.CONCLUSIONS: These results point to a novel mechanism by which prostasomes can protect prostatic malignant cells from complement attack.
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| 16. |
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| 17. |
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| 18. |
- Bjartell, Anders, et al.
(author)
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Immunohistochemical detection of cysteine-rich secretory protein 3 in tissue and in serum from men with cancer or benign enlargement of the prostate gland.
- 2006
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In: The Prostate. - : Wiley. - 0270-4137 .- 1097-0045. ; 66:Dec 30, s. 591-603
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Journal article (peer-reviewed)abstract
- BACKGROUND. Recently, the gene for cysteine-rich secretory protein 3 (CRISP-3) was reported to be highly upregulated in prostate cancer (PCa) compared to benign prostatic tissue. The current aims were to investigate diagnostic use of tissue expression and immunodetection in serum of CRISP-3 for detection or monitoring of PCa. METHODS. Radical prostatectomy specimens and tissue microarrays from transurethral resections and metastases were analyzed for CRISP-3 and PSA by immunohistochemistry. CRISP-3 in tissue homogenates and in serum was measured by an in-house ELISA and PSA by a commercially available immunoassay. RESULTS. Immunostaining for CRISP-3 in benign prostatic epithelium was generally weak or not detectable. Specific and strong immunostaining was found in a major proportion of cells in high-grade prostatic-intraepithelial-neoplasia (HG-PIN,12/17 patients), in most primary tumors (111/115), and in lymph node (11/15) and bone (12/15) metastases. CRISP-3 immunostaining intensity was regularly strong in areas of Gleason grades 4/5, where PSA-immunoreaction was less intense. Serum levels of CRISP-3 were not different in patients with PCa (n = 152) compared to men with BPH (n = 81). There was a very weak co-variation between levels of CRISP-3 versus PSA in serum from PCa patients (P < 0.05). After orchiectomy, levels of CRISP-3 in serum decreased in median with 11% compared to a 97% median decrease of PSA in serum from 15/20 patients with advanced PCa. CONCLUSIONS. Strong immunostaining for CRISP-3 is common in HG-PIN and preserved in most PCa specimens, which warrant further immunohistochemical studies of CRISP-3 in PCa. Serum levels of CRISP-3 do not primarily reflect PCa.
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| 19. |
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| 20. |
- Bovinder Ylitalo, Erik, et al.
(author)
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Marked response to cabazitaxel in prostate cancer xenografts expressing androgen receptor variant 7 and reversion of acquired resistance by anti-androgens
- 2020
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In: Prostate. - : Wiley. - 0270-4137 .- 1097-0045. ; 80:1, s. 214-224
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Journal article (peer-reviewed)abstract
- Background Taxane treatment may be a suitable therapeutic option for patients with castration-resistant prostate cancer and high expression of constitutively active androgen receptor variants (AR-Vs). The aim of the study was to compare the effects of cabazitaxel and androgen deprivation treatments in a prostate tumor xenograft model expressing high levels of constitutively active AR-V7. Furthermore, mechanisms behind acquired cabazitaxel resistance were explored. Methods Mice were subcutaneously inoculated with 22Rv1 cells and treated with surgical castration (n = 7), abiraterone (n = 9), cabazitaxel (n = 6), castration plus abiraterone (n = 8), castration plus cabazitaxel (n = 11), or vehicle and/or sham operation (n = 23). Tumor growth was followed for about 2 months or to a volume of approximately 1000 mm(3). Two cabazitaxel resistant cell lines; 22Rv1-CabR1 and 22Rv1-CabR2, were established from xenografts relapsing during cabazitaxel treatment. Differential gene expression between the cabazitaxel resistant and control 22Rv1 cells was examined by whole-genome expression array analysis followed by immunoblotting, immunohistochemistry, and functional pathway analysis. Results Abiraterone treatment alone or in combination with surgical castration had no major effect on 22Rv1 tumor growth, while cabazitaxel significantly delayed and in some cases totally abolished 22Rv1 tumor growth on its own and in combination with surgical castration. The cabazitaxel resistant cell lines; 22Rv1-CabR1 and 22Rv1-CabR2, both showed upregulation of the ATP-binding cassette sub-family B member 1 (ABCB1) efflux pump. Treatment with ABCB1 inhibitor elacridar completely restored susceptibility to cabazitaxel, while treatment with AR-antagonists bicalutamide and enzalutamide partly restored susceptibility to cabazitaxel in both cell lines. The cholesterol biosynthesis pathway was induced in the 22Rv1-CabR2 cell line, which was confirmed by reduced sensitivity to simvastatin treatment. Conclusions Cabazitaxel efficiently inhibits prostate cancer growth despite the high expression of constitutively active AR-V7. Acquired cabazitaxel resistance involving overexpression of efflux transporter ABCB1 can be reverted by bicalutamide or enzalutamide treatment, indicating the great clinical potential for combined treatment with cabazitaxel and anti-androgens.
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| 21. |
- Bruun, Laila, et al.
(author)
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Assessment of intra-individual variation in prostate-specific antigen levels in a biennial randomized prostate cancer screening program in Sweden.
- 2005
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In: Prostate. - : Wiley. - 0270-4137 .- 1097-0045. ; 65:3, s. 216-221
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Journal article (peer-reviewed)abstract
- Abstract BACKGROUND The degree of variability in prostate-specific antigen (PSA) measurements is important for interpreting test results in screening programs, and particularly for interpreting the significance of changes between repeated tests. This study aimed to determine the long-term intra-individual variation for PSA in healthy men. METHODS A randomly selected cohort of men in a biennial prostate cancer screening program (ERSPC) conducted in Sweden from 1995-1996 to 2001-2002. We studied men who had total PSA (tPSA) levels < 2.0 ng/ml in 2001-2002. This included 791 men with tPSA 0.61 ng/ml (group A), 1,542 men with tPSA 0.99 ng/ml (group B), and 1,029 men with tPSA 1.00-1.99 ng/ml (group C). The intra-individual variability of free PSA (fPSA) and tPSA was assessed by calculating coefficients of variation (CV) for each individual's PSA measurements from the first and second round of screening (1995-1996 and 1997-1998). RESULTS Intra-individual CV (geometric means) for tPSA were 13.7%, 12.7%, and 11.5% in groups A, B, and C, respectively. Corresponding CVs for fPSA were significantly lower, ranging from 12.1% to 10.4%. The estimated biological variation of tPSA and fPSA in groups A to C were 12.5%, 11.4%, 10.0% and 9.7%, 7.8%, 7.5%, respectively. CONCLUSIONS In healthy men with PSA levels less than 2 ng/ml, the natural long-term variability for tPSA was less than 14%, and with 95% probability, a change in tPSA greater than 30% indicates a change beyond normal random variation. © 2005 Wiley-Liss, Inc.
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| 22. |
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| 23. |
- Cantarutti, Anna, et al.
(author)
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Body mass index and mortality in men with prostate cancer
- 2015
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In: The Prostate. - : WILEY-BLACKWELL. - 0270-4137 .- 1097-0045. ; 75:11, s. 1129-1136
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Journal article (peer-reviewed)abstract
- BACKGROUNDBody Mass index (BMI) has been shown to affect risk and mortality of several cancers. Prostate cancer and obesity are major public health concerns for middle-aged and older men. Previous studies of pre-diagnostic BMI have found an increased risk of prostate cancer mortality in obese patients. OBJECTIVETo study the associations between BMI at time of prostate cancer diagnosis and prostate cancer specific and overall mortality. METHODSBMI was analyzed both as a continuous variable and categorized into four groups based on the observed distribution in the cohort (BMI<22.5, 22.5<25, 25<27.5 and 27.5kg/m(2)). The association between BMI and mortality was assessed using stratified Cox proportional hazards models and by fitting regression splines for dose response analysis in 3,161 men diagnosed with prostate cancer. After 11 years of follow up via linkage to the population-based cause of death registry, we identified 1,161 (37%) deaths off which 690 (59%) were due to prostate cancer. RESULTSHigh BMI (BMI27.5kg/m(2)) was associated with a statistically significant increased risk of prostate cancer specific mortality (HR:1.44, 95%CI: 1.09-1.90) and overall mortality (HR:1.33, 95%CI: 1.09-1.63) compared to the reference group (BMI 22.5<25kg/m(2)). Additionally, men with a low BMI (<22.5kg/m(2)), had a statistically significant increased risk of prostate cancer specific mortality (HR:1.33, 95%CI: 1.02-1.74) and overall mortality (HR:1.36, 95%CI: 1.11-1.67) compared to the reference. However, this effect disappeared when men who died within the first two years of follow-up were excluded from the analyses while the increased risk of prostate cancer specific mortality and overall mortality remained statistically significant for men with a BMI27.5kg/m(2) (HR:1.44, 95%CI: 1.09-1.90 and HR: 1.33, 95%CI: 1.09-1.63, respectively). CONCLUSIONThis study showed that a high BMI at time of prostate cancer diagnosis was associated with increased overall mortality. Prostate 75: 1129-1136, 2015. (c) 2015 Wiley Periodicals, Inc.
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- Carlsson, Björn, et al.
(author)
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Characterization of human prostate and breast cancer cell lines for experimental T cell-based immunotherapy
- 2007
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In: The Prostate. - : Wiley. - 0270-4137 .- 1097-0045. ; 67:4, s. 389-395
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Journal article (peer-reviewed)abstract
- BACKGROUND. In order to develop experimental immunotherapy for prostate and breast cancer it is of outmost importance to have representative target cell lines that through human leukocyte antigen (HLA) class I molecules present relevant levels of peptides from tumor-associated antigens for cytotoxic T lymphocyte (CTL) recognition. METHODS. We sequenced the HLA-A and HLA-B loci of eight commonly used prostate and breast cancer cell lines and analyzed the surface expression of HLA-ABC, HLA-DR, CD40, CD80, CD86, and CD54 by flow cytometry. We also analyzed the cell lines for mRNA expression from 25 genes reported to be specifically or preferentially expressed by prostate cells. RESULTS. Among the analyzed cell lines we found that LNCaP, PC-346C and MCF-7 are HLA-A*0201 positive. However, the HLA-A2 expression level is low and only MCF-7 upregulates HLA-A2 in response to IFN-γ stimulation. MCF-7 also expresses high levels of CD54, which further improve its value as a CTL target cell line. On the other hand, LNCaP and PC-346C express 25 and 23 out of 25 prostate-related genes, respectively, while MCF-7 expresses 16 out of 25 genes. CONCLUSIONS. None of the analyzed prostate cancer cell lines are optimal CTL target cells. However, MCF-7 could in many cases be used as a complement to HLA-A*0201 positive prostate cancer cells. The LNCaP and PC-346C cell lines are rich sources of prostate-related antigens that may be valuable for cancer vaccine development.
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