Publications by authors named "Milan Kral"

16 Publications

  • Page 1 of 1

Skp2 and Slug Are Coexpressed in Aggressive Prostate Cancer and Inhibited by Neddylation Blockade.

Int J Mol Sci 2021 Mar 11;22(6). Epub 2021 Mar 11.

Department of Clinical and Molecular Pathology, Faculty of Medicine and Dentistry, Palacky University and University Hospital, 779 00 Olomouc, Czech Republic.

Prostate cancer (PCa) is the second leading cause of cancer-related deaths in men in Western countries, and there is still an urgent need for a better understanding of PCa progression to inspire new treatment strategies. Skp2 is a substrate-recruiting component of the E3 ubiquitin ligase complex, whose activity is regulated through neddylation. Slug is a transcriptional repressor involved in the epithelial-to-mesenchymal transition, which may contribute to therapy resistance. Although Skp2 has previously been associated with a mesenchymal phenotype and prostate cancer progression, the relationship with Slug deserves further elucidation. We have previously shown that a high Gleason score (≥8) is associated with higher Skp2 and lower E-cadherin expression. In this study, significantly increased expression of Skp2, AR, and Slug, along with E-cadherin downregulation, was observed in primary prostate cancer in patients who already had lymph node metastases. Skp2 was slightly correlated with Slug and AR in the whole cohort (Rs 0.32 and 0.37, respectively), which was enhanced for both proteins in patients with high Gleason scores (Rs 0.56 and 0.53, respectively) and, in the case of Slug, also in patients with metastasis to lymph nodes (Rs 0.56). Coexpression of Skp2 and Slug was confirmed in prostate cancer tissues by multiplex immunohistochemistry and confocal microscopy. The same relationship between these two proteins was observed in three sets of prostate epithelial cell lines (PC3, DU145, and E2) and their mesenchymal counterparts. Chemical inhibition of Skp2, but not RNA interference, modestly decreased Slug protein in PC3 and its docetaxel-resistant subline PC3 DR12. Importantly, chemical inhibition of Skp2 by MLN4924 upregulated p27 and decreased Slug expression in PC3, PC3 DR12, and LAPC4 cells. Novel treatment strategies targeting Skp2 and Slug by the neddylation blockade may be promising in advanced prostate cancer, as recently documented for other aggressive solid tumors.
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http://dx.doi.org/10.3390/ijms22062844DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8000894PMC
March 2021

Do not underestimate anterior prostate cancer.

Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 2021 Jun 26;165(2):198-202. Epub 2020 Nov 26.

Department of Urology, Faculty of Medicine and Dentistry, Palacky University Olomouc and University Hospital Olomouc, Czech Republic.

Aims: With the introduction of magnetic resonance imaging in the diagnosis of prostate cancer and its use in targeted prostate biopsy, an increased incidence of anterior-predominant prostate cancer (APC) has been observed.

Methods: We enrolled 200 patients who underwent radical prostatectomy at our department between 12/2017 and 04/2019. We evaluated tumour location in the individual segments of the prostate, index tumour location and volume, and compared the postoperative stage, Gleason score, grade group (GG), and the presence of extraprostatic extension (EPE) in APC and posterior prostate cancer (PPC). We assessed the rate of MRI scans prior to prostate surgery as well as the influence of family history and PSA on the presence of APC.

Results: We found a significantly higher rate of anterior tumours than previously reported (37%) and confirmed that these tumours are diagnosed with a significantly larger index tumour volume (P=0.003). We also showed that a mere 6.76% of APCs were low-risk tumours not requiring radical treatment. Furthermore, anterior tumours were found significantly more often (P=0.001) in patients who underwent preoperative MRI. No differences were observed between PSA values, family history, presence of EPE, or locally advanced disease in APC vs. PPC.

Conclusions: The frequency of anterior tumours is higher than previously thought, and they include tumours requiring radical treatment. When these tumours are neglected, it may lead to patient undertreatment with impact on their life prognosis. Thus, we consider the use of MRI-targeted prostate biopsy to be a necessity both for ruling out APC in the case of repeatedly negative prostate biopsies and, in particular, before patient inclusion in active surveillance.
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http://dx.doi.org/10.5507/bp.2020.054DOI Listing
June 2021

The Percentage of Free PSA and Urinary Markers Distinguish Prostate Cancer from Benign Hyperplasia and Contribute to a More Accurate Indication for Prostate Biopsy.

Biomedicines 2020 Jun 25;8(6). Epub 2020 Jun 25.

Department of Clinical and Molecular Pathology, Faculty of Medicine and Dentistry, Palacky University and University Hospital, 779 00 Olomouc, Czech Republic.

The main advantage of urinary biomarkers is their noninvasive character and the ability to detect multifocal prostate cancer (CaP). We have previously implemented a quadruplex assay of urinary markers into clinical practice ( and with normalization). In this study, we aimed to validate it in a larger cohort with serum PSA 2.5-10 ng/mL and test other selected transcripts and clinical parameters, including the percentage of free prostate-specific antigen (PSA) (% free PSA) and inflammation. In the main cohort of 299 men, we tested the quadruplex transcripts. In a subset of 146 men, we analyzed additional transcripts ( and ). After a prostate massage, the urine was collected, RNA isolated from a cell sediment and qRT-PCR performed. Ct values of (i.e., PSA) were strongly correlated with Ct values of other genes which play a role in CaP (i.e., and ). and mRNA expression, as well as % free PSA, were significantly different for BPH and CaP. The best combined model (% free PSA plus and ) achieved an AUC of 0.728 in the main cohort. In the subset of patients, the best AUC 0.753 was achieved for the combination of , % free PSA, and . mRNA was increased in patients with inflammation, however, this did not affect the stratification of patients indicated for prostate biopsy. In conclusion, the percentage of free PSA and urinary markers contribute to a more accurate indication for prostate biopsy.
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http://dx.doi.org/10.3390/biomedicines8060173DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7344460PMC
June 2020

Aorto-caval Fistula Mimicking Clinical Signs of Renal Colic.

Urol J 2020 01 26;17(1):107-108. Epub 2020 Jan 26.

Department of Urology, Faculty of Medicine and Dentistry, Palacky University and University Hospital, Olomouc, Czech Republic.

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http://dx.doi.org/10.22037/uj.v0i0.5633DOI Listing
January 2020

High Skp2 expression is associated with a mesenchymal phenotype and increased tumorigenic potential of prostate cancer cells.

Sci Rep 2019 04 5;9(1):5695. Epub 2019 Apr 5.

Department of Cytokinetics, Institute of Biophysics of the Czech Academy of Sciences, Brno, Czech Republic.

Skp2 is a crucial component of SCF E3 ubiquitin ligase and is often overexpressed in various types of cancer, including prostate cancer (PCa). The epithelial-to-mesenchymal transition (EMT) is involved in PCa progression. The acquisition of a mesenchymal phenotype that results in a cancer stem cell (CSC) phenotype in PCa was described. Therefore, we aimed to investigate the expression and localization of Skp2 in clinical samples from patients with PCa, the association of Skp2 with EMT status, and the role of Skp2 in prostate CSC. We found that nuclear expression of Skp2 was increased in patients with PCa compared to those with benign hyperplasia, and correlated with high Gleason score in PCa patients. Increased Skp2 expression was observed in PCa cell lines with mesenchymal and CSC-like phenotype compared to their epithelial counterparts. Conversely, the CSC-like phenotype was diminished in cells in which SKP2 expression was silenced. Furthermore, we observed that Skp2 downregulation led to the decrease in subpopulation of CD44CD24 cancer stem-like cells. Finally, we showed that high expression levels of both CD24 and CD44 were associated with favorable recurrence-free survival for PCa patients. This study uncovered the Skp2-mediated CSC-like phenotype with oncogenic functions in PCa.
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http://dx.doi.org/10.1038/s41598-019-42131-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6451010PMC
April 2019

Role of early postoperative urethroscopy for urethral vitality assessment after penis replantation.

Microsurgery 2019 May 25;39(4):371-372. Epub 2019 Jan 25.

Department of Urology, Faculty of Medicine and Dentistry, Palacky University and University Hospital Olomouc, Olomouc, Czech Republic.

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http://dx.doi.org/10.1002/micr.30430DOI Listing
May 2019

Trop-2 plasticity is controlled by epithelial-to-mesenchymal transition.

Carcinogenesis 2018 12;39(11):1411-1418

Department of Cytokinetics, Institute of Biophysics of the Czech Academy of Sciences, Brno, Czech Republic.

The cell surface glycoprotein Trop-2 is commonly overexpressed in carcinomas and represents an exceptional antigen for targeted therapy. Here, we provide evidence that surface Trop-2 expression is functionally connected with an epithelial phenotype in breast and prostate cell lines and in patient tumor samples. We further show that Trop-2 expression is suppressed epigenetically or through the action of epithelial-to-mesenchymal transition transcription factors and that deregulation of Trop-2 expression is linked with cancer progression and poor patient prognosis. Moreover, our data suggest that the cancer plasticity-driven intratumoral heterogeneity in Trop-2 expression may significantly contribute to response and resistance to therapies targeting Trop-2-expressing cells.
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http://dx.doi.org/10.1093/carcin/bgy095DOI Listing
December 2018

Cisplatin or LA-12 enhance killing effects of TRAIL in prostate cancer cells through Bid-dependent stimulation of mitochondrial apoptotic pathway but not caspase-10.

PLoS One 2017 28;12(11):e0188584. Epub 2017 Nov 28.

Department of Cytokinetics, Institute of Biophysics, Czech Academy of Sciences, v.v.i., Brno, Czech Republic.

Searching for new strategies for effective elimination of human prostate cancer cells, we investigated the cooperative cytotoxic action of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and two platinum-based complexes, cisplatin or LA-12, and related molecular mechanisms. We demonstrated a notable ability of cisplatin or LA-12 to enhance the sensitivity of several human prostate cancer cell lines to TRAIL-induced cell death via an engagement of mitochondrial apoptotic pathway. This was accompanied by augmented Bid cleavage, Bak activation, loss of mitochondrial membrane potential, activation of caspase-8, -10, -9, and -3, and XIAP cleavage. RNAi-mediated silencing of Bid or Bak in Bax-deficient DU 145 cells suppressed the drug combination-induced cytotoxicity, further underscoring the involvement of mitochondrial signaling. The caspase-10 was dispensable for enhancement of cisplatin/LA-12 and TRAIL combination-induced cell death and stimulation of Bid cleavage. Importantly, we newly demonstrated LA-12-mediated enhancement of TRAIL-induced cell death in cancer cells derived from human patient prostate tumor specimens. Our results provide convincing evidence that employing TRAIL combined with cisplatin/LA-12 could contribute to more effective killing of prostate cancer cells compared to the individual action of the drugs, and offer new mechanistic insights into their cooperative anticancer action.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0188584PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5705153PMC
December 2017

Cranberry intervention in patients with prostate cancer prior to radical prostatectomy. Clinical, pathological and laboratory findings.

Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 2016 Dec 10;160(4):559-565. Epub 2016 Nov 10.

Department of Medical Chemistry and Biochemistry, Faculty of Medicine and Dentistry, Palacky University Olomouc, Czech Republic.

Background And Objectives: Recently, we described an inverse association between cranberry supplementation and serum prostate specific antigen (PSA) in patients with negative biopsy for prostate cancer (PCa) and chronic nonbacterial prostatitis. This double blind placebo controlled study evaluates the effects of cranberry consumption on PSA values and other markers in men with PCa before radical prostatectomy.

Methods: Prior to surgery, 64 patients with prostate cancer were randomized to a cranberry or placebo group. The cranberry group (n=32) received a mean 30 days of 1500 mg cranberry fruit powder. The control group (n=32) took a similar amount of placebo. Selected blood/urine markers as well as free and total phenolics in urine were measured at baseline and on the day of surgery in both groups. Prostate tissue markers were evaluated after surgery.

Results: The serum PSA significantly decreased by 22.5% in the cranberry arm (n=31, P<0.05). A trend to down-regulation of urinary beta-microseminoprotein (MSMB) and serum gamma-glutamyltranspeptidase, as well as upregulation of IGF-1 was found after cranberry supplementation. There were no changes in prostate tissue markers or, composition and concentration of phenolics in urine.

Conclusions: Daily consumption of a powdered cranberry fruit lowered serum PSA in patients with prostate cancer. The whole fruit contains constituents that may regulate the expression of androgen-responsive genes.
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http://dx.doi.org/10.5507/bp.2016.056DOI Listing
December 2016

High-grade urothelial bladder cancer in children: A case report and critical analysis of the literature.

Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 2016 Dec 3;160(4):578-582. Epub 2016 Oct 3.

Department of Urology, Faculty of Medicine and Dentistry, Palacky University Olomouc and University Hospital Olomouc, Czech Republic.

Background: Bladder cancer is relatively common in adults. In children, it is extremely rare and in the majority of cases, low grade, low stage urothelial cancers are found.

Case Report: We describe the diagnostic, therapeutic, and follow-up management of bladder cancer in a 3-year-old boy examined for painless hematuria. Transurethral resection of the tumor was performed and T1 high grade urothelial cancer with osseous metaplasia was found in definitive specimens. During the 2-year follow-up, there has been no recurrence. Typical characteristics of the most prevalent bladder tumors are presented.

Conclusion: Despite its low incidence and low prevalence bladder cancer in children is a very serious condition which must not be missed in the differential diagnosis of hematuria or urinary tract infection. It is vital to differentiate urothelial cancer from hamartoma and nephrogenic adenoma and, particularly in osseous metaplasia, from sarcomatoid carcinoma. Especially in high-grade cancers, precise TUR of the tumor with a careful follow-up is essential to detect cancer recurrence and reduce progression.
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http://dx.doi.org/10.5507/bp.2016.045DOI Listing
December 2016

Wooden Foreign Body in the Renal Pelvis.

Urology 2016 Aug 12;94:e7-8. Epub 2016 May 12.

Department of Urology, Faculty of Medicine and Dentistry, Palacký University and University Hospital, Olomouc, Czech Republic.

Migration of foreign bodies into the renal collecting system is very rare and usually concerns iatrogenically implanted objects. Migration of a foreign body from the gastrointestinal tract to the kidneys is even more rare. We present a case of migration of a wooden toothpick from the duodenum into the pelvis of the right kidney. The patient was not aware that he swallowed a toothpick; the foreign body resulted in hematuria and flank pain. The toothpick was missed during the initial computed tomography urography. Correct diagnosis was revealed by follow-up computed tomography. The toothpick was extracted endoscopically.
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http://dx.doi.org/10.1016/j.urology.2016.05.004DOI Listing
August 2016

DNA damage signalling barrier, oxidative stress and treatment-relevant DNA repair factor alterations during progression of human prostate cancer.

Mol Oncol 2016 06 3;10(6):879-94. Epub 2016 Mar 3.

Danish Cancer Society Research Center, Copenhagen, Denmark; Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden; Laboratory of Genome Integrity, Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University, Olomouc, Czech Republic. Electronic address:

The DNA damage checkpoints provide an anti-cancer barrier in diverse tumour types, however this concept has remained unexplored in prostate cancer (CaP). Furthermore, targeting DNA repair defects by PARP1 inhibitors (PARPi) as a cancer treatment strategy is emerging yet requires suitable predictive biomarkers. To address these issues, we performed immunohistochemical analysis of multiple markers of DNA damage signalling, oxidative stress, DNA repair and cell cycle control pathways during progression of human prostate disease from benign hyperplasia, through intraepithelial neoplasia to CaP, complemented by genetic analyses of TMPRSS2-ERG rearrangement and NQO1, an anti-oxidant factor and p53 protector. The DNA damage checkpoint barrier (γH2AX, pATM, p53) mechanism was activated during CaP tumorigenesis, albeit less and with delayed culmination compared to other cancers, possibly reflecting lower replication stress (slow proliferation despite cases of Rb loss and cyclin D1 overexpression) and progressive loss of ATM activator NKX3.1. Oxidative stress (8-oxoguanine lesions) and NQO1 increased during disease progression. NQO1 genotypes of 390 men did not indicate predisposition to CaP, yet loss of NQO1 in CaP suggested potential progression-opposing tumour suppressor role. TMPRSS2-ERG rearrangement and PTEN loss, events sensitizing to PARPi, occurred frequently along with heterogeneous loss of DNA repair factors 53BP1, JMJD1C and Rev7 (all studied here for the first time in CaP) whose defects may cause resistance to PARPi. Overall, our results reveal an unorthodox DNA damage checkpoint barrier scenario in CaP tumorigenesis, and provide novel insights into oxidative stress and DNA repair, with implications for biomarker guidance of future targeted therapy of CaP.
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http://dx.doi.org/10.1016/j.molonc.2016.02.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5423169PMC
June 2016

Opposite regulation of MDM2 and MDMX expression in acquisition of mesenchymal phenotype in benign and cancer cells.

Oncotarget 2015 Nov;6(34):36156-71

Department of Cytokinetics, Institute of Biophysics, Academy of Sciences of The Czech Republic, v.v.i., Brno, Czech Republic.

Plasticity of cancer cells, manifested by transitions between epithelial and mesenchymal phenotypes, represents a challenging issue in the treatment of neoplasias. Both epithelial-mesenchymal transition (EMT) and mesenchymal-epithelial transition (MET) are implicated in the processes of metastasis formation and acquisition of stem cell-like properties. Mouse double minute (MDM) 2 and MDMX are important players in cancer progression, as they act as regulators of p53, but their function in EMT and metastasis may be contradictory. Here, we show that the EMT phenotype in multiple cellular models and in clinical prostate and breast cancer samples is associated with a decrease in MDM2 and increase in MDMX expression. Modulation of EMT-accompanying changes in MDM2 expression in benign and transformed prostate epithelial cells influences their migration capacity and sensitivity to docetaxel. Analysis of putative mechanisms of MDM2 expression control demonstrates that in the context of defective p53 function, MDM2 expression is regulated by EMT-inducing transcription factors Slug and Twist. These results provide an alternative context-specific role of MDM2 in EMT, cell migration, metastasis, and therapy resistance.
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http://dx.doi.org/10.18632/oncotarget.5392DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4742168PMC
November 2015

The role of high cell density in the promotion of neuroendocrine transdifferentiation of prostate cancer cells.

Mol Cancer 2014 May 20;13:113. Epub 2014 May 20.

Department of Cytokinetics, Institute of Biophysics, Academy of Sciences of the Czech Republic, v,v,i, Královopolská 135, CZ-612 65 Brno, Czech Republic.

Background: Tumor heterogeneity and the plasticity of cancer cells present challenges for effective clinical diagnosis and therapy. Such challenges are epitomized by neuroendocrine transdifferentiation (NED) and the emergence of neuroendocrine-like cancer cells in prostate tumors. This phenomenon frequently arises from androgen-depleted prostate adenocarcinoma and is associated with the development of castration-resistant prostate cancer and poor prognosis.

Results: In this study, we showed that NED was evoked in both androgen receptor (AR)-positive and AR-negative prostate epithelial cell lines by growing the cells to a high density. Androgen depletion and high-density cultivation were both associated with cell cycle arrest and deregulated expression of several cell cycle regulators, such as p27Kip1, members of the cyclin D protein family, and Cdk2. Dual inhibition of Cdk1 and Cdk2 using pharmacological inhibitor or RNAi led to modulation of the cell cycle and promotion of NED. We further demonstrated that the cyclic adenosine 3', 5'-monophosphate (cAMP)-mediated pathway is activated in the high-density conditions. Importantly, inhibition of cAMP signaling using a specific inhibitor of adenylate cyclase, MDL-12330A, abolished the promotion of NED by high cell density.

Conclusions: Taken together, our results imply a new relationship between cell cycle attenuation and promotion of NED and suggest high cell density as a trigger for cAMP signaling that can mediate reversible NED in prostate cancer cells.
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http://dx.doi.org/10.1186/1476-4598-13-113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4229954PMC
May 2014

Androgen depletion induces senescence in prostate cancer cells through down-regulation of Skp2.

Neoplasia 2011 Jun;13(6):526-36

Department of Cytokinetics, Institute of Biophysics, AS CR, Brno, Czech Republic.

Although the induction of senescence in cancer cells is a potent mechanism of tumor suppression, senescent cells remain metabolically active and may secrete a broad spectrum of factors that promote tumorigenicity in neighboring malignant cells. Here we show that androgen deprivation therapy (ADT), a widely used treatment for advanced prostate cancer, induces a senescence-associated secretory phenotype in prostate cancer epithelial cells, indicated by increases in senescence-associated β-galactosidase activity, heterochromatin protein 1β foci, and expression of cathepsin B and insulin-like growth factor binding protein 3. Interestingly, ADT also induced high levels of vimentin expression in prostate cancer cell lines in vitro and in human prostate tumors in vivo. The induction of the senescence-associated secretory phenotype by androgen depletion was mediated, at least in part, by down-regulation of S-phase kinase-associated protein 2, whereas the neuroendocrine differentiation of prostate cancer cells was under separate control. These data demonstrate a previously unrecognized link between inhibition of androgen receptor signaling, down-regulation of S-phase kinase-associated protein 2, and the appearance of secretory, tumor-promoting senescent cells in prostate tumors. We propose that ADT may contribute to the development of androgen-independent prostate cancer through modulation of the tissue microenvironment by senescent cells.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3114246PMC
http://dx.doi.org/10.1593/neo.11182DOI Listing
June 2011

Genetic determinants of prostate cancer: a review.

Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 2011 Mar;155(1):3-9

Department of Urology, University Hospital Olomouc, Faculty of Medicine and Dentistry, Palacky University Olomouc, Czech Republic.

Background: In prostate cancer, early detection and appropriate treatment remain key approaches. But given the constantly increasing incidence, prostate cancer ethiopathogenetic determinants are a current focus of attention. Although the development of this cancer is influenced by both environmental and genetic factors which are as yet ill-defined, genetic studies have revealed gene abnormalities which may be specifically associated with the risk of prostate cancer: changes in genes for the androgen receptor, RNAseL, ELAC2, MSR1, BRCA 1 and 2, HPCX, KLF6, HPC20 and fusion genes, e.g. TMPRSS2-ERG). Despite differing research results from molecular biological studies, these techniques can assist in earlier diagnosis enabling timely initiation of treatment.

Methods: Methods and literature: MEDLINE search was performed to collect both original and review articles addressing prostate cancer and genetic risk factors using key words genetics, prostate cancer and risk.

Conclusions: A number of potential genetic risk factors/markers has been identified which may in near future contribute to earlier diagnosis of prostate cancer so that earlier treatment can be started. Despite many promising data we have found differing results and therefore we suppose further research should be conducted to achieve more precise conclusion. This review focuses on current knowledge of the genetic factors affecting the development of prostate cancer.
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http://dx.doi.org/10.5507/bp.155.2011.001DOI Listing
March 2011