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* Department of Internal Medicine 3 and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany;
Department of Rheumatology, Kaunas Medical University Hospital, Kaunus, Lithuania; and
Center of Experimental Rheumatology and Zurich Center of Integrative Human Physiology, University Hospital of Zurich, Zurich, Switzerland
1Correspondence: Department of Internal Medicine 3 and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Universitätsstr. 29, 91054 Erlangen, Germany. E-mail: joerg.distler{at}uk-erlangen.de
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Key Words: systemic sclerosis • scleroderma • fibroblasts • TGFβ • translational
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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. The resulting fibrosis disrupts the physiological structure of the involved tissues and leads to dysfunction of the affected organs. Tissue fibrosis causes not only significant morbidity in SSc patients but is also a major cause of death (2)
. The accumulation of ECM in SSc is caused by an increased synthesis of ECM by activated fibroblasts (3)
. Although the mechanisms for the pathological activation of fibroblasts in SSc are incompletely understood, much evidence suggests that transforming growth factor (TGF)β and platelet-derived growth factor (PDGF) play important roles for activation of fibroblasts (3)
. TGFβ and PDGF potently stimulate the synthesis of ECM in fibroblasts, and inhibition of TGFβ or PDGF signaling has been shown to reduce the development of fibrosis in various experimental models (4
, 5)
. Furthermore, overexpression of TGFβ in fibroblasts induces a scleroderma-like disease with tissue fibrosis (6)
. Despite the identification of TGFβ and PDGF as key players for the synthesis of ECM proteins in SSc, this knowledge has not yet been transferred from bench to bedside, and therapeutic strategies to selectively inhibit the pathological activation of fibroblasts in SSc are not available for daily care.
We recently demonstrated that the small molecule tyrosine kinase inhibitor imatinib (Gleevec®/Glivec®) prevented skin thickening in an experimental model of bleomycin-induced dermal fibrosis and reduced myofibroblast differentiation and collagen production (7)
. A potent antifibrotic effect of imatinib was also observed in animal models of pulmonary, renal, and liver fibrosis (8
9
10)
. Imatinib targets the TGFβ and PDGF signaling pathways by inhibiting the tyrosine kinase activity of abl and PDGF receptor. Apart from c-kit and c-fms, other tyrosine kinases are not affected at physiological concentrations (11)
. Thus, the combined inhibition of abl kinase and PDGF receptor signaling might be an effective therapeutic approach to selectively target the pathological activation of fibroblasts in fibrotic diseases. However, although life-treating events occur very rarely during the treatment with imatinib, up to 30% of patients discontinue therapy because of the development of drug resistance and adverse effects (12)
. Major adverse effects that occur in more than 10% of patients include edema, muscle cramps, diarrhea, anemia, neutropenia, and thrombocytopenia (12)
. Because a significant number of patients might have to discontinue treatment with imatinib, alternative inhibitors with a related mechanism of action but an improved profile of adverse effects will be needed.
Recently, dasatinib (Spyrcel®; Bristol-Myers Squibb, Princeton, NJ, USA) and nilotinib (Tasigna®; Novartis, Basel, Switzerland), 2 novel inhibitors of abl kinases and PDGF receptors, have been approved for the treatment of bcr-abl-positive chronic myelogenous leukemia (CML) with resistance or intolerance to imatinib. Dasatinib and nilotinib are highly potent small molecule tyrosine kinase inhibitors that can be administered orally (13
, 14)
. Nilotinib selectively inhibits the tyrosine kinase activity of abl kinases, PDGF receptor, and c-kit. In addition to these tyrosine kinases, dasatinib inhibits the structurally related family of src kinases (15)
. Src kinases might also be an interesting target for antifibrotic approaches in SSc as we demonstrated recently (16)
that inhibition of src signaling reduces the synthesis of ECM in vitro and prevents experimental fibrosis in vivo. As dasatinib and nilotinib inhibit simultaneously 2 major profibrotic pathways and are well tolerated, we evaluated the potential of dasatinib and nilotinib for the treatment of dermal fibrosis in SSc.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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. Biopsies from SSc patients (n=12) were taken from involved skin. Control fibroblasts (n=5) were obtained from skin biopsies of healthy volunteers, which were age- and sex-matched (Table 1
). Fibroblasts were prepared by outgrowth of skin biopsies and cultured as described (18)
. Fibroblasts from passages 4–8 were used for the experiments. All patients and controls signed a consent form approved by the local institutional review boards.
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Incubation with dasatinib and nilotinib
Dasatinib and nilotinib were kindly provided by Bristol-Myers Squibb and Novartis, respectively. Stimulation experiments were performed in DMEM/1% fetal calf serum. Dermal fibroblasts were incubated with dasatinib or nilotinib at concentrations from 0.001 to 1.0 µg/ml for 24 h, which covered the mean plasma through and peak concentrations observed in humans after standard doses (15)
. For controls, fibroblasts were incubated with the solvent dimethyl sulfoxide in the same concentrations. In subsets of experiments, fibroblasts were stimulated with recombinant TGFβ at 10 ng/ml or PDGF-BB at 40 ng/ml (both R&D Systems, Abingdon, UK) 1 h after dasatinib or nilotinib. These concentrations of TGFβ and PDGF-BB represent standard concentrations used for the stimulation of dermal fibroblasts and are orientated on the serum levels in SSc patients (7)
.
Quantitative real-time polymerase chain reaction (PCR)
Total RNA was isolated with the NucleoSpin RNA II extraction system (Machery-Nagel, Düren, Germany) and reverse transcribed into cDNA with random hexamers as described (18)
. Gene expression was quantified by real-time PCR using the ABI Prism 7300 Sequence Detection System (Applied Biosystems, Rotkreuz, Switzerland). Specific primer pairs for each gene were designed with the Primer 3 software (7
, 13
). To normalize for the amounts of loaded cDNA, a predeveloped 18S assay (Applied Biosystems) was used. Genomic contamination and formation of primer dimers were excluded with samples without enzyme in the reverse transcription (nonreverse transcription controls), samples without cDNA (no template controls), and dissociation curve analysis. Differences were calculated with the threshold cycle (Ct) and the comparative Ct method for relative quantification.
Collagen measurements
Total soluble collagen in cell culture supernatants and skin samples was quantified using the SirCol collagen assay (Biocolor, Belfast, UK) (19)
. The amount of collagen protein in skin samples was adjusted to the amount of total protein as analyzed with the BCA Protein Assay kit (Pierce, Rockford, IL, USA).
Caspase 3 activity assay
SSc and healthy dermal fibroblasts were incubated with dasatinib or nilotinib in concentrations of 0.1 and 1.0 µg/ml for 7 days. Fresh medium containing the same concentrations of dasatinib and nilotinib was added every other day. The activities of caspase-3-like proteases were determined using the EnzChek caspase-3 assay kit (Invitrogen, Carlsbad, CA, USA).
Quantification of apoptotic and necrotic cells
SSc and healthy dermal fibroblasts were incubated with dastinib or nilotinib in concentrations of 1 µg/ml for 7 days with medium changes as described (7)
.
Bleomycin-induced dermal fibrosis
Skin fibrosis was induced in 6- to 8-wk-old C57/BL6 mice by local injections of bleomycin for 21 days (7)
. Briefly, 100 µl of bleomycin dissolved in 0.9% sodium chloride (NaCl) at a concentration of 0.5 mg/ml was administered every other day by subcutaneous injections in defined areas of the upper back in 5 groups. Subcutaneous injections of 100 µl 0.9% NaCl in a sixth group were used as controls for treatment with bleomycin. Four of the 5 bleomycin groups were additionally treated with different concentrations of either dasatinib or nilotinib. To analyze whether dasatinib and nilotinib can prevent dermal fibrosis, dasatinib and nilotinib were both started together with bleomycin. Dasatinib and nilotinib were given at final concentrations of 3 or 10 mg/kg (dasatinib) and 12.5 or 37.5 mg/kg (nilotinib) in a total volume of 100 µl twice a day (BID) by oral gavage. Mice in the control group and in the bleomycin group received 100 µl of the vehicle 1-methyl-2-pyrrolidone/PEG300 by oral gavage BID The doses used herein result in pharmacologically relevant serum levels in mice (20
21
22
23)
. After 21 days, animals were sacrificed by cervical dislocation. The bleomycin and the control groups consisted of 10 animals, the treatment groups of 8 animals each. The animal experiments were approved by the ethical committee of the University of Erlangen-Nuremberg.
Histological analysis
The injected skin areas were fixed in 4% formalin and embedded in paraffin. Two micrometer sections were stained with hematoxylin and eosin. The dermal thickness was analyzed with a Nikon Eclipse 80i microscope (Nikon, Badhoevedorp, Netherlands) at x200 by measuring the distance between the epidermal-dermal junction and the dermal-subcutaneous fat junction at sites of induration at 3 consecutive skin sections of each animal.
Detection of myofibroblasts
Myofibroblasts were identified by staining for 
-SMA using monoclonal antiactin -smooth muscle antibodies (Sigma-Aldrich, Steinheim, Germany) as described previously (7)
. In each section, -SMA-positive myofibroblasts were counted in 3 randomly chosen high-power fields.
Statistics
Data are expressed as means ± SE. The Wilcoxon signed-rank tests for related samples and the Mann-Whitney U test for nonrelated samples were used for statistical analyses. A value of P < 0.05 was considered statistically significant. The inhibitory concentration 50 (IC50) was calculated using GraphPad Prism software (GraphPad, San Diego, CA, USA) and a nonlinear regression curve-fit model.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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A). Treatment with dasatinib reduced the TGFβ-induced synthesis of col 1a1 mRNA in a dose-dependent manner. Dasatinib decreased significantly the mRNA for col 1a1 from 195 ± 10 to 126 ± 12% vs. controls at a concentration of 0.001 µg/ml, to 80 ± 6% at 0.01 µg/ml, and to 62 ± 7% at 0.1 µg/ml (P=0.016). The greatest decrease, to 39 ± 3% of controls, was measured at a concentration of 1.0 µg/ml (P=0.009). Dasatinib also dose-dependently down-regulated the induction of mRNA for col 1a2 and fibronectin-1 by TGFβ in SSc fibroblasts (Fig. 1B, C
). At concentrations of 1.0 µg/ml, dasatinib reduced the mRNA levels of col 1a2 to 34 ± 7% and of fibronectin-1 to 51 ± 1% vs. controls (P=0.009 for both). The IC50 for these effects was 0.0005–0.002 µg/ml.
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Because dasatinib inhibits the tyrosine kinase activity of PDGF receptors, we next investigated the potential of dasatinib to block the profibrotic effects of PDGF. PDGF stimulated the synthesis of col 1a1 by 194 ± 40% in SSc fibroblasts (Fig. 1D
). Dasatinib reduced the induction of col 1a1 by PDGF in a dose-dependent manner with a maximal inhibition to 33 ± 2% vs. controls at concentrations of 1.0 µg/ml (P=0.004; Fig. 1D
). Dasatinib also blocked the induction of mRNA for col 1a2 and fibronectin-1 with maximal reductions to 36 ± 4 and 44 ± 1%, respectively (P=0.004 and P=0.012; Fig. 1E, F
). No significant differences in the responsiveness to dasatinib were observed between dermal fibroblasts derived from SSc patients and healthy controls (Fig. 1)
. The IC50 values of these effects were 0.0002–0.002 µg/ml.
Nilotinib decreases the production of ECM proteins
Like dasatinib, nilotinib potently decreased the expression of col 1a1, col 1a2, and fibronectin-1 in dermal fibroblasts stimulated with TGFβ or PDGF in a dose-dependent manner (Fig. 2
), with IC50 values of 0.0008–0025 µg/ml. Nilotinib decreased the expression of mRNA for col 1a1 to 35 ± 5%, of col 1a2 to 38 ± 5%, and of fibronectin-1 to 35 ± 4% at concentrations of 1.0 µg/ml in fibroblasts stimulated with TGFβ (P=0.009, P=0.012, and P=0.004, respectively; Fig. 2A-C
). Nilotinib also affected the expression of mRNAs for col 1a1, col 1a2, and fibronectin-1 on stimulation with PDGF with reductions of 38 ± 3, 35 ± 5, and 37 ± 4% vs. controls (P=0.012, P=0.009, and P=0.009, respectively; Fig. 2D-F
). Similar results were also obtained with healthy dermal fibroblasts.
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Dasatinib and nilotinib reduce the production of collagen protein
The inhibition of the synthesis of ECM proteins in dermal fibroblasts by dasatinib and nilotinib was confirmed on the protein level using the SirCol collagen assay. Dose-dependent reductions of the collagen synthesis were detected in SSc and healthy fibroblasts treated with dasatinib and nilotinib (Fig. 3
). At concentrations of 1.0 µg/ml, dasatinib decreased the TGFβ-stimulated collagen production in SSc fibroblasts to 52 ± 15% and the PDGF-stimulated collagen production by 49 ± 6% (P=0.016; Fig. 3A
). Nilotinib reduced the production of collagen in SSc fibroblasts stimulated with TGFβ or PDGF to 50 ± 7 and 51 ± 9%, respectively (P=0.009 for both; Fig. 3B
). Similar results were obtained with healthy dermal fibroblasts (data not shown).
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Dasatinib and nilotinib do not change the balance between matrix-degrading enzymes and their inhibitors
To exclude the possibility that the inhibitory effects on the production of ECM proteins is counterbalanced by a reduced activity of matrix-degrading enzymes, we investigated the effects of dasatinib and nilotinib on the expression of major matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs). Neither dasatinib nor nilotinib altered the expression of MMP-1, MMP-2, or MMP-3 in dermal fibroblasts in concentrations up to 1.0 µg/ml. Dasatinib and nilotinib also did not stimulate the expression of TIMP-1, TIMP-2, and TIMP-3 in SSc or healthy dermal fibroblasts.
Dasatinib and nilotinib do not induce cell death in fibroblasts
Activation of caspase 3 is a central step in the initiation of apoptosis. After incubation of SSc and healthy dermal fibroblasts with dasatinib and nilotinib at concentrations ranging from 0.1 to 1.0 µg/ml, no increase in the activity of caspase 3 was detected.
Apoptotic cells cannot maintain the membrane lipid asymmetry, and phospatidylserine translocates to the outer leaflet of the cell membrane, where it can be detected with annexin V. No difference in the numbers of annexin V-positive cells was observed between controls and SSc and healthy dermal fibroblasts treated with dasatinib and nilotinib in concentrations of 1.0 µg/ml for 7 days.
In necrotic cells, the structural integrity of the cellular membrane is lost and propidiumiodide (PI) can enter the cells. Long-term treatment of SSc dermal fibroblasts with dasatinib and nilotinib did not increase the percentage of PI-positive cells vs. controls. Comparable results were also obtained with healthy dermal fibroblasts.
Dasatinib and nilotinib reduce bleomycin-induced dermal fibrosis in vivo
The potential of dasatinib and nilotinib as potential antifibrotic therapeutic approaches was evaluated in the mouse model of bleomycin-induced dermal fibrosis. The lower doses of 3 mg/kg for dasatinib and 12.5 mg/kg for nilotinib and the higher doses of 10 mg/kg for dasatinib and 37.5 mg/kg for nilotinib BID mark the dose range that yields therapeutically relevant concentrations, which can also be achieved in humans, using current dosage regimens (13
14
15
, 20
21
22
23)
. No differences in body weight or behavior were detected between the bleomycin group and the groups treated with dasatinib or nilotinib, suggesting that dasatinib and nilotinib were well tolerated.
Skin from bleomycin-injected mice without dasatinib or nilotinib treatment showed typical features of skin fibrosis with dense accumulation of collagen bundles in the dermis (Fig. 4
B). In mice treated in parallel with dasatinib or nilotinib, these morphological changes were greatly reduced (Fig. 4C-F
). To quantify the degree of the skin fibrosis, dermal thickness was measured. An increase of the dermal thickness of 146 ± 10% was determined in mice injected with bleomycin vs. controls (P<0.001; Fig. 4G
). Dasatinib and nilotinib dose-dependently prevented dermal thickening. At a dose of 3 mg/kg BID, dasatinib reduced the increase in dermal thickness by 37 ± 7% (P=0.06 vs. bleomycin). The dermal thickness was further reduced by 64 ± 6% at a dose of 10 mg/kg dasatinib BID (P<0.003 vs. bleomycin). Similar to dasatinib, nilotinib dose-dependently reduced the increase of the dermal thickness by 68 ± 6 and 87 ± 6% at doses of 12.5 and 37.5 mg/kg BID, respectively (P<0.003 and P<0.001). Of note, the dermal thickness in mice treated with bleomycin and nilotinib at concentrations of 37.5 mg/kg BID did not differ significantly from that of control animals (P=0.20; Fig. 4F, G
).
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Dasatinib and nilotinib prevent myofibroblast differentiation in vivo
Treatment with dasatinib and nilotinib also strongly decreased the number of myofibroblasts in lesional skin. In bleomycin-treated animals, the number of myofibroblasts per high-power field increased by 373 ± 9% in bleomycin-treated animals vs. controls (P<0.001 vs. controls; Fig. 5
). In the groups treated with dasatinib, myofibroblasts were decreased by 77 ± 7% at a dose of 3 mg/kg BID (P<0.004 vs. bleomycin group) and 96 ± 12% in mice treated with 10 mg/kg BID (P<0.001 vs. bleomycin group; Fig. 5
). Treatment with nilotinib at doses of 12.5 and 37.5 mg/kg BID reduced the numbers by 76 ± 11 and 103 ± 7%, respectively (P<0.003 and P<0.001 vs. bleomycin group). Thus, dasatinib at a concentration of 10 mg/kg BID and nilotinib at a concentration of 37.5 mg/kg BID completely prevented the differentiation of resting fibroblasts into myofibroblasts induced by bleomycin (P=0.61 and P=0.83 vs. controls, respectively; Fig. 5
).
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Dasatinib and nilotinib reduce accumulation of collagen protein in experimental dermal fibrosis
Besides a significantly reduced dermal thickness and a decreased number of myofibroblasts, treatment with dasatinib and nilotinib dose-dependently reduced the accumulation of collagen protein (Fig. 6
). In bleomycin-treated mice, the amount of collagen protein was increased by 245 ± 15% vs. controls (P<0.001). In animals treated concomitantly with dasatinib at a dose of 3 mg/kg BID, the increase of collagen protein was decreased by 60 ± 9% vs. animals treated only with bleomycin (P=0.06). At a dose of 10 mg/kg BID, dasatinib reduced the accumulation of collagen by 89 ± 12% (P<0.019). Nilotinib reduced the increased concentration of collagen in the skin on treatment with bleomycin by 73 ± 12% at a concentration of 12.5 mg/kg BID (P<0.021) and by 99 ± 16% at a concentration of 37.5 mg/kg BID (P<0.005). No significant difference was observed in the collagen content in lesional skin of mice treated with dasatinib at a concentration of 10 mg/kg BID or nilotinib at a concentration of 37.5 mg/kg BID and controls (P=0.19 for dasatinib and P=0.41 for nilotinib; Fig. 6
).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The concentrations of dasatinib and nilotinib used to evaluate their antifibrotic potential were adapted to the plasma concentration of dasatinib and nilotinib measured in clinical trials (13
, 14)
. The concentrations of dasatinib and nilotinib used for the in vitro experiments, ranging from 0.01 to 1.0 µg/ml, cover the mean plasma through and peak concentrations obtained in humans after standard doses of dasatinib and nilotinib used for the treatment of CML in humans (13
, 14)
. Within these concentrations, dasatinib and nilotinib suppressed the expression of major ECM proteins by more than 80% in vitro. Similarly, the doses of dasatinib and nilotinib that almost completely prevented the development of skin fibrosis in bleomycin-treated mice resulted in therapeutically relevant serum concentrations of dasatinib and nilotinib (20
21
22
23)
.
The c-abl and Src kinases are intracellular tyrosine kinases that have recently been shown to be important regulators of the synthesis of ECM. c-Abl is activated by TGFβ and PDGF and mediates the profibrotic effects of TGFβ independently of Smad3 (8)
. The importance of c-abl for the production of ECM proteins is underlined by the observations that the induction of ECM proteins by TGFβ is strongly decreased in cells lacking c-abl (8)
and that inhibitors of c-abl reduce the collagen production potently in vitro and in vivo (7
8
9
, 24)
. We recently demonstrated (16)
that Src kinases are activated by TGFβ and PDGF in SSc fibroblasts and that overexpression of a dominant negative mutant of Src or overexpression of the endogenous inhibitor C-terminal Src kinase decreases the release of collagen in vitro. Furthermore, treatment with SU6656, a specific inhibitor of Src kinases, prevented the development of experimental dermal fibrosis (16)
. Despite the potent antifibrotic effects of selective inhibitors of Src, the combined inhibition of Src in addition to c-abl and PDGF receptor by dasatinib was not superior to inhibition of c-abl and PDGF receptor alone by nilotinib in the present study. This finding might be explained by the fact that Src kinases mediate their profibrotic effects indirectly via c-abl. Src kinases have been shown to regulate the activity of c-abl via phosphorylation of c-abl on Y412 in the activation loop (25
, 26)
. Phosphorylation of the activation loop stabilizes a conformation of c-abl that is compatible with substrate binding and catalysis. Mutation of Y412 prevents phosphorylation of c-abl by Src kinases and heavily impairs tyrosine kinase activity of c-abl, suggesting that Src kinases are major regulators of c-abl. Thus, the profibrotic effects of Src kinases might be mediated via c-abl, and inhibition of Src might not exert additional antifibrotic effects when its downstream target c-abl is simultaneously inhibited, as with dasatinib in our study.
The data from this study are supported by studies with the c-abl kinase inhibitor imatinib in different fibrotic conditions (7
8
9
10
, 24)
, indicating that targeting intracellular signaling pathways of major profibrotic cytokines is indeed a valuable approach. Dasatinib and nilotinib have been shown to inhibit the activity of bcr-abl 300-1300x and 20–50x more potently than imatinib (27)
. Compared with imatinib, the more potent inhibition of abl kinases by dasatinib and nilotinib was not reflected by stronger antifibrotic effects. Although a direct head-to-head comparison was not performed, the observed antifibrotic effects of dasatinib and nilotinib were within the range observed with imatinib (7)
. The inhibitory effects on col 1a1, col 1a2, and fibronectin-1 in dermal fibroblasts is comparable among all 3 tyrosine kinase inhibitors, achieving an 80% reduction in vitro, and imatinib, dasatinib, and nilotinib all completely prevented the development of experimental skin fibrosis. The lack of differences in the antifibrotic effects despite the stronger inhibition of bcr-abl is most likely explained by the fact that treatments with imatinib already result in a maximal biological effect and almost complete inhibition of abl and PDGF receptor signaling in vitro and in vivo. Imatinib inhibits abl kinases and PDGF receptor signaling with IC50 values of 0.04 and 0.3 µM, respectively. Thus, the activity of c-abl in vivo is almost completely inhibited by imatinib at a concentration of 1.0 µM, which reflects the mean plasma through concentration of imatinib in humans.
In addition to prevention, treatment of established fibrosis is a major therapeutic aim. Although it was beyond the scope of the present study to study treatment of established fibrosis, clinical observations on CML patients treated with imatinib suggest that abl kinase inhibitors might also be effective for treatment of established fibrosis because repeated biopsies of the bone marrow of patients with CML and secondary myelofibrosis demonstrated a regression of fibrosis within the bone marrow on treatment (28
, 29)
.
Therapies that selectively target the pathological activation of fibroblasts and the increased production of ECM in fibrotic diseases are lacking. Given the unmet medical need for drugs controlling fibrosis in humans, dasatinib and nilotinib could step into this vacancy. Dasatinib and nilotinib strongly inhibit the production of ECM proteins on TGFβ and PDGF challenge and prevent the development of experimental skin fibrosis in vivo. These results suggest that dasatinib and nilotinib, which are both approved for the treatment of CML, augment the arsenal of molecular-targeted therapies for future clinical trials in fibrotic diseases.
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ACKNOWLEDGMENTS |
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Received for publication January 7, 2008. Accepted for publication February 7, 2008.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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