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Cancer Therapy: Preclinical |
Authors' Affiliations: 1 Division of Clinical Immunology, Advanced Clinical Research Center, Institute of Medical Science, University of Tokyo and 2 Department of Pathology, Keio University, Tokyo, Japan; 3 Department of Medicine, Osaka Medical College, Osaka, Japan; and 4 Department of Hematologic Malignancies, Nevada Cancer Institute, Las Vegas, Nevada
Requests for reprints: Chikao Morimoto, Division of Clinical Immunology, Advanced Clinical Research Center, Institute of Medical Science, University of Tokyo, 4-6-1, Shirokanedai, Minato-ku, Tokyo 108-8639, Japan. E-mail: morimoto{at}ims.u-tokyo.ac.jp.
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Abstract |
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Experimental Design: Using immunohistochemistry, 12 patients' surgical specimens consisting of seven malignant mesothelioma, three reactive mesothelial cells, and two adenomatoid tumors were evaluated for expression of CD26. The effects of CD26 on malignant mesothelioma cells were assessed in the presence of transfection of CD26-expressing plasmid, humanized anti-CD26 mAb, or small interfering RNA against CD26. The in vivo growth inhibitory effect of humanized anti-CD26 mAb was assessed in human malignant mesothelioma cell mouse xenograft models.
Results: In surgical specimens, CD26 is highly expressed in malignant mesothelioma but not in benign mesothelial tissues. Depletion of CD26 by small interfering RNA results in the loss of adhesive property, suggesting that CD26 is a binding protein to the extracellular matrix. Moreover, our in vitro data indicate that humanized anti-CD26 mAb induces cell lysis of malignant mesothelioma cells via antibody-dependent cell-mediated cytotoxicity in addition to its direct anti-tumor effect via p27kip1 accumulation. In vivo experiments with mouse xenograft models involving human malignant mesothelioma cells show that humanized anti-CD26 mAb treatment drastically inhibits tumor growth in tumor-bearing mice, resulting in enhanced survival.
Conclusions: Our data strongly suggest that humanized anti-CD26 mAb treatment may have potential clinical use as a novel cancer therapeutic agent in CD26-positive malignant mesothelioma.
CD26 is a 110-kDa surface glycoprotein with dipeptidyl peptidase IV activity able to cleave selected biological factors to alter their functions (5). CD26/dipeptidyl peptidase IV is involved in T-lymphocyte costimulation and signal transduction processes (6, 7) and regulates topoisomerase II 
level in hematologic malignancies, affecting sensitivity to doxorubicin and etoposide (8). Expressed on various tissues (4, 9), CD26 is involved in the development of certain human cancers (9–12). CD26 is also known to serve as a binding motif for extracellular matrix (ECM) in human and rodents (13, 14). Previously, we reported that CD26 was collagen-binding protein using a CD26 positive JMN cell line, which is derived from malignant mesothelioma (15). Moreover, our previous works have shown that anti-CD26 monoclonal antibody (mAb) inhibits growth of CD26-positive T-cell malignancies (16, 17) and renal cell carcinoma (18).
Our previous report shows that the murine anti-CD26 mAb 14D10, which recognizes the cell membrane–proximal glycosylated region starting with a 20–amino acid flexible stalk region of human CD26, has direct antitumor effect by inducing G1-S arrest while concomitantly blocking the adhesion of cancer cells to the ECM. However, another murine anti-CD26 mAb, termed 5F8, which detects the cysteine-rich domain of CD26, lacks this biological activity (18).
Because human malignant mesothelioma is a highly malignant tumor resistant to apparent conventional treatment, the detection of novel target and development of new treatment strategies in malignant mesothelioma are urgently needed (4, 19). In this report, we analyzed the expression of CD26 in the tissues of patients with malignant mesothelioma and validated the antitumor effect of a novel humanized anti-CD26 mAb which was constructed from high-affinity Fab clone to the 14D10 variable region by targeting malignant mesothelioma, hence concomitantly showing the functional role of CD26 in this neoplasm.
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Materials and Methods |
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/Akt, CDK2, CDK4, CDK6, cyclin E, and ß-actin were from Cell Signaling Technology Inc., and mouse mAb to p27kip1, p21cip1/waf1, cyclin D1, and activated caspase-3 were from BD PharMingen. Antihuman IgG, Fc
fragment specific F(ab')2 fragment of goat and anti-mouse IgG, Fc fragment specific F(ab')2 fragment of goat were from Jackson ImmunoResearch. Cell culture and transfection. JMN cells were a kind gift from Dr. Brenda Gerwin (Laboratory of Human Carcinogenesis, NIH, Bethesda, MD). NCI-H2452 and 293T cells were obtained from the American Type Culture Collection. JMN and NCI-H2452 cell lines were derived from patients with malignant mesothelioma. All cells were grown in RPMI medium (Life Technologies Inc.) supplemented with 10% heat-inactivated fetal bovine serum, penicillin (100 units/mL), and streptomycin (100 µg/mL; Life Technologies) or G418 (500 µg/mL; Sigma-Aldrich). 293T cells were transfected with full-length CD26 subcloned into a pEB6 vector (22) using FuGENE6 reagent (Roche Diagnostics).
2-(2-methoxy-4-nitrophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfophenyl)-2H-tetrazolium assay. Cells were subjected to incubation in 96-well plates in media alone or in the presence of humanized anti-CD26 mAb (0.1, 1.0, or 10 µg/mL) or 2H4 (0.1, 1.0, or 10 µg/mL) for a total volume of 100 µL (5 x 103 cells per well). After 24 h of incubation in 37°C, 2-(2-methoxy-4-nitrophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfophenyl)-2H-tetrazolium (Seikagaku) was added to each well. After another 2 h of incubation, water soluble formazan dye upon bioreduction in the presence of an electron carrier, 1-methoxy-5-methylphenazinium, was measured at 450 nm using a microplate reader (Bio-Rad). All samples were tested in triplicate. Values reported represent the means of triplicated wells, and SE was within 15.
Immunohistochemistry. For immunohistochemistry, 12 patients' surgical specimens consisting of seven malignant mesothelioma, three reactive mesothelial cells, and two adenomatoid tumors were evaluated. For each, 10% formalin-fixed, paraffin-embedded specimens, containing both the carcinoma and its adjacent nonneoplastic tissue, were prepared. Paraffin-embedded tissues were dewaxed and rehydrated using xylene and ethanol, respectively. Slides were deparaffinized, then heated in a microwave processor for antigen retrieval in 10 mmol/L citrate buffer (pH 6.0) for 10 min. After blocking in 3% (v/v) bovine serum albumin, slides were incubated at 4°C overnight with the primary antibody (anti-CD26 mAb) and washed with PBS and the secondary antibody was labeled with biotin and applied for 30 min. Streptavidin-LSA amplification method was carried out for 30 min followed by peroxidase/diaminobenzidine substrate/chromagen. The slides were counterstained with hematoxylin. Two different pathologists checked the validity of the obtained results. All human specimens were obtained from Department of Pathology, Keio University (Tokyo, Japan), and informed consents were obtained from all patients according to the format of the institutional review board.
Depletion of endogenous CD26. To deplete endogenous CD26, small interfering RNA (siRNA) oligo-targeting CD26 cDNA (accession no. NM_001935) was made according to the design site of TAKARA BIO;5 sense: 5'-GAAAGGUGUCAGUACUAUU TT-3', antisense: 3'-TT CUUUCCACAGUCAUGAUAA-5', with scrambled control of small interfering RNA oligo-targeting human Cas-L; sense: 5'-UAAUUAGGGUCGGGUAAAC TT-3', antisense: 3'-TT AUUAAUCCCAGCCCAUUUG-5' being used as control. CD26 siRNA oligo (siCD26) was transfected using TransIT-TKO transfection reagent (Mirus Bio Corporation) according to the manufacturer's protocol.
SDS-PAGE and immuno-blotting. Preparation of whole-cell lysates, cell fractionations, and SDS-PAGE were done as described elsewhere (23).
Antibody-dependent cell-mediated cytotoxicity. The capacity of mAb to induce effector cell–dependent lysis of tumor cells was evaluated in Calcein-AM–release assay. Healthy donor natural killer cells were isolated from peripheral blood mononuclear cells by NK Cell Isolation kit II Miltenyi Biotec (Bergisch Gladbach) and used as effector cells. Target cells (1 x 106) were labeled with 10 µmol/L Calcein-AM (Dojindo) under shaking conditions at 37°C for 1 h. Cells were washed thrice with PBS and were resuspended in culture medium (1 x 105 cells/mL). Labeled cells were dispensed in 96-well U-bottomed plates (5 x 103 in 50 µL/well) and preincubated (37°C, 30 min) with 50 µL of 7-fold serial dilutions of humanized anti-CD26 mAb or 14D10 in culture medium, ranging from 0.1 pg/mL to 0.1 mg/mL (final concentrations). Culture medium was added instead of mAb to determine the spontaneous Calcein-AM release, with Triton X-100 (1% final concentration) being added to determine the maximal Calcein-AM release. Thereafter, human effector cells (HuEC) were added to the wells (5 x 105 cells per well) and cells were incubated at 37°C overnight. Supernatants were then collected for measurement of the Calcein-AM release. Percentage of specific lysis was calculated using the following formula: % specific lysis = (experimental release – spontaneous release)/(maximal release – spontaneous release) x 100; where maximal release was determined by adding Triton X-100 to target cells and spontaneous release was measured in the absence of sensitizing Abs and effector cells.
Complement-dependent cytotoxicity. Complement-dependent cytotoxicity (CDC) assay was done as described previously (24). Target cells were dispensed in 96-well U-bottomed plates (1 x 105 cells per well) incubated with various concentrations of mAbs at 4°C for 30 min. Subsequently, human serum was added and cells were incubated at 37°C for 2 h. Evaluation of CDC-specific cell death along with antibody-dependent cell-mediated cytotoxicity (ADCC)–specific cell death was assessed by Annexin V–FITC Apoptosis Detection kit (BioVision) and detection of activated caspase-3.
Assessment of antitumor activity of humanized anti-CD26 mAb in effector-depleted SCID mice. All in vivo studies were approved by the Institute Animal Care and Use Committee. Six-week-old female NOD-SCID mice were purchased from Charles River (Kanagawa, Japan) and were pretreated with anti–asialo-GM1 polyclonal antisera 25% (v/v; WAKO) i.p. 1 day before mAb treatment.
To assess the effect of humanized anti-CD26 mAb against tumorigenicity, JMN cells (1 x 106) were inoculated s.c. into the left flank of mice. Mice were treated with intratumoral injection of isotype-matched control mAb and 5F8, 14D10, or humanized anti-CD26 mAb (10 µg per each injection) on the 14th day after cancer cell inoculation when the tumor mass became visible (5 mm in size). Each mAb was given thrice per week. Tumor-bearing mice were then monitored for tumor development and progression. Tumor size was determined by caliper measurement of the largest (x) and smallest (y) perpendicular diameters and was calculated according to the formula V = 
/6 x xy2.
To assess the effect of humanized anti-CD26 mAb against tumor dissemination, JMN cells (1 x 105) were injected i.v. via tail vein. Thereafter, mice were treated with i.v. injection of isotype-matched control mAb and 5F8, 14D10, or humanized anti-CD26 mAb (10 µg per each injection), starting on the day of cancer cell injection. Each mAb was given thrice per week. Cumulative proportion survival was assessed by Kaplan-Meier.
Assessment of antitumor activity of humanized anti-CD26 mAb in effector-present Balb mice. Six-week-old female Balb mice were purchased from Charles River, and treatment with anti–asialo-GM1 polyclonal antisera was not introduced to preserve the binding of the mouse effector system.
To assess the effect of humanized anti-CD26 mAb against tumorigenicity, JMN cells (1 x 106) were inoculated s.c. into the left flank of mice. Mice were treated with intratumoral injection of isotype-matched control mAb and 5F8, 14D10, or humanized anti-CD26 mAb (10 µg per each injection) on the 14th day after cancer cell inoculation when the tumor mass became visible (5 mm in size). Each mAb was given thrice per week. Tumor-bearing mice were then monitored for tumor development and progression. Tumor size was determined by caliper measurement of the largest (x) and smallest (y) perpendicular diameters and was calculated according to the formula V = /6 x xy2. On the 35th day after the first mAb treatment, all mice were euthanized to assess the microscopic feature of resected specimens in s.c. tumorigenicity model.
To assess the effect of humanized anti-CD26 mAb against tumor dissemination, JMN cells (1 x 105) were i.v. injected via tail vein. Thereafter, mice were treated with i.v. injection of isotype-matched control mAb or humanized anti-CD26 mAb (10 µg per each injection) starting on the day of cancer cell injection. Each mAb was given thrice per week. Cumulative proportion of survival was assessed by Kaplan-Meier. To further assess the effect of humanized anti-CD26 mAb on distant metastasis formation, treated mice were euthanized and multiple metastasis formation in the lung and liver was calculated in another tumor dissemination model. JMN cells (1 x 105) were injected i.v. into mice in each group. Mice were treated with i.v. injection of isotype-matched control mAb (lane 1, n = 4), 5F8 (lane 2, n = 4), 14D10 (lane 3, n = 4), or humanized anti-CD26 mAb (lane 4, n = 4) on the day of cancer cell injection. Each mAb was given thrice per week. On the 35th day after cancer cell injection, mice were euthanized and multiple metastasis formation in the lung and liver was calculated.
Construction of HuEC–engrafted mice and assessment of antitumor activity in NOD/Shi-scid. IL-Rnull mice. NOD/Shi-scid. IL-Rnull (NOG mice) were obtained from Central Institute for Experimental Animals. Human peripheral blood mononuclear cells were isolated from the peripheral blood of a healthy donor using Lymphoprep (AXIS-SHIELD) and were used as HuEC. Thereafter, HuEC (5 x 106 cells) were injected i.p. in a volume of 0.2 mL suspended in PBS into NOG-SCID mice under sterile conditions. The mice were pretreated with a 0.2 mL anti–asialo-GM1 polyclonal antisera 25% (v/v; WAKO) given i.p. 1 day before HuEC injection. NCI-H2452 cells (5 x 104) were injected i.p. into SCID mice engrafted with human HuEC 1 day after HuEC injection. One, three, and five days later, humanized anti-CD26 mAb were injected i.p. Mice were observed daily to monitor for death due to ascites tumor development. Cumulative proportion of survival was assessed by Kaplan-Meier.
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Results |
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Because CD26 has been described previously to play a role in cell adhesion to the ECM proteins (13, 25), we examined whether CD26 plays a role in cellular interaction with the ECM. As seen in Fig. 1C, NCI-H2452 that were depleted of endogenous CD26 using siRNA oligo showed significant loss of CD26 binding to ECM proteins, including fibronectin and collagen I. In contrast to these results, depletion of CD26 did not alter binding to laminin (an ECM protein lacking binding ability to CD26) or hyaluronan (a ligand for CD44; Fig. 1C). In further support of these findings, 293T cells transfected with full-length CD26 cDNA subcloned into pEB6 vector showed higher binding ability to fibronectin and collagen I than control pEB6–transfected 293T cells (Fig. 1C). Moreover, depletion of CD26 was associated with the up-regulation of p27kip1 (Fig. 1D). These findings thus suggested that CD26 serves as a binding molecule to distinct ECM proteins and that contact inhibition may play a contributing role to the observed CD26 depletion–mediated up-regulation of p27kip1 associated with CD26 depletion (26, 27).
Anti-CD26 mAb perturbs cellular binding to ECM. Because CD26 proved to be an ECM-binding protein, we further evaluated whether anti-CD26 mAbs disrupt cellular adhesion to ECM. For this purpose, isotype-matched control mAb and 5F8, 14D10, and humanized anti-CD26 mAb were evaluated for potential disruption to cellular adhesion to ECM. As seen in Fig. 2A , JMN cells treated with 14D10 and humanized anti-CD26 mAb had decreased binding to fibronectin and collagen I, whereas control mAb and 5F8 (anti-CD26 mAb without biological function) did not influence binding to fibronectin and collagen I. Moreover, 14D10 and humanized anti-CD26 mAb transmitted direct growth inhibition to JMN cells by in vitro proliferation assay in a dose-dependent manner, with humanized anti-CD26 mAb having a stronger antiproliferative effect than 14D10 (Fig. 2B). Importantly, 14D10 and humanized anti-CD26 mAb induced up-regulation of p27kip1 and down-regulation of CDK2. These results suggested that both 14D10 and humanized anti-CD26 mAb dynamically transmit contact inhibition–related growth inhibition via up-regulation of p27kip1 and down-regulation of CDK2.
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fragment specific F(ab')2 fragment of goat, and anti-mouse IgG, Fc fragment specific F(ab')2 fragment of goat were used as mimicry of human effectors to humanized anti-CD26 mAb and 14D10, respectively. As seen in Fig. 3B (top three panels), cross-linked humanized anti-CD26 mAb induced late apoptosis, whereas cross-linked 14D10 did not induce late and early apoptosis. Importantly, neither humanized anti-CD26 mAb nor 14D10-induced CDC using human complement (Fig. 3B). To further support these binding, only cross-linked humanized anti-CD26 mAb induced activation of caspase-3 in JMN cells, whereas neither cross-linked 14D10, humanized anti-CD26 mAb plus human complement, and 14D10 plus human complement induced activation of caspase-3 (Fig. 3C). These results therefore indicated that humanized anti-CD26 mAb elicits ADCC-specific lysis but not CDC-specific lysis.
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Discussion |
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Immunohistologic analysis indicates that human malignant mesothelioma cells express high level of surface CD26 than nonmalignant tissue, suggesting that CD26 may play a role in cancer growth and progression. It should be noted that depletion of endogenous CD26 in NCI-H2452 using siRNA oligo results in significant loss of binding to ECM, including fibronectin and collagen I. Moreover, 293T cells transfected with full-length CD26 cDNA exhibit higher binding affinity to fibronectin and collagen I than control mock-transfected 293T cells. Moreover, depletion of CD26 leads to the up-regulation of p27kip1. These findings thus suggest that CD26 is involved in cancer cell adhesion to ECM and that contact inhibition may play a contributing role to the observed CD26 depletion–mediated up-regulation of p27kip1. Of note is the fact that it has been previously reported that p27kip1 is up-regulated during contact inhibition (26).
Both humanized anti-CD26 mAb and 14D10 display direct inhibition of malignant mesothelioma growth via p27kip1 up-regulation and disruption of binding to ECM. Hence, our results with these anti-CD26 monoclonal antibodies are consistent with those obtained from above small interfering RNA study, showing that both humanized anti-CD26 mAb and 14D10 have an antagonistic effect on the adhesive property of malignant mesothelioma.
Further examination of their effector functions associated with anti-CD26 mAb–mediated antitumor effect indicates that humanized anti-CD26 mAb, but 14D10, elicits ADCC-induced cell lysis. Cross-linking of humanized anti-CD26 mAb results in an accumulation of annexin V–positive and propidium iodide–positive population and cleavage of activated caspase-3. These data suggest that humanization of anti-CD26 mAb elicits greater contribution from ADCC in addition to a direct antitumor effect. Meanwhile, the precious reason why humanized anti-CD26 mAb does not induce CDC activity is not clear at the moment. One of the reasons is the high-surface expression of DAF and CD59, which are antagonistic to human complement proteins (data not shown). Or, our in vitro system may not be appropriate for the induction of CDC activation.
In vivo study with NOD-SCID mice shows that humanized anti-CD26 mAb and 14D10 reduce the tumorigenicity of s.c.-inoculated JMN cells, suggesting that humanized anti-CD26 mAb possesses direct antitumor effect as well. Our results also suggest that humanized anti-CD26 mAb is more potent in reducing tumor formation, possibly due to its higher binding affinity to CD26 than 14D10.
Meanwhile, in vivo study with Balb mice show that humanized anti-CD26 mAb and 14D10 are equally effective in reducing the tumorigenicity of s.c.-inoculated JMN cells. These data suggest that the mouse effector system may potentiate the antitumor effect of 14D10 more than humanized anti-CD26 mAb. In fact, not only humanized anti-CD26 mAb but also 14D10-treated tumor specimens from these mice exhibit a reduction of viable cells in tumor mass. It is also noteworthy that both humanized anti-CD26 mAb and 14D10 reduce the formation of distant metastasis, findings which may be partly explained from our in vitro results that CD26 serves as a binding protein to distinct ECM proteins.
In vivo study with NOG-SCID mice which lack functional mice effectors show that dual-xenograft of HuEC plus target cells results in greater mouse survival than single xenograft of target cells when combined with humanized anti-CD26 mAb. These data clearly corroborate the in vitro data, suggesting that humanized anti-CD26 mAb induces a biphasic antitumor action with a human effector system.
CD26 status may be altered in cancer and may have an effect on the growth and metastatic potential of various tumors. Absence of CD26 is associated with the development of some cancers, whereas presence of CD26 is associated with a more aggressive phenotype in other neoplasms. For example, in non–small cell lung cancer cell lines, cells transfected with CD26 develop morphologic changes, altered contact inhibition, and reduced ability for anchorage-independent growth (29). CD26 reexpression also correlates with increased p21cip2/waf1 expression, leading to induction of apoptosis and cell cycle arrest in G1 stage. Wesley et al. reported that CD26/dipeptidyl peptidase IV up-regulates the expression of CDKI p27kip1 by 4-fold to 6-fold in CD26-transfected DU-145 metastatic prostate cancer cells compared with the parent and vector-transfected DU-145 cells (30). It is also reported that overexpression of CD26 in ovarian cancer leads to increased E-cadherin and tissue inhibitors of matrix metalloproteinases, resulting in decreased invasive potential (31). CD26/dipeptidyl peptidase IV thus functions as a tumor suppressor in the cases described above, and its down-regulation may contribute to the loss of growth control. In contrast, CD26 expression is associated with a more aggressive clinical course in T-cell large granular lymphocyte leukemia (32).
An earlier report indicated that CD26 and CD40L expression is mutually exclusive, with CD40L expressed on cells from more indolent diseases. Of note is that CD26 expression on T-cell LBL/ALL is associated with a worse survival (33). We now show that CD26 is highly expressed in malignant mesothelioma tissues and anti-CD26 mAb treatment and CD26 down-regulation by siRNA in CD26-positive malignant mesothelioma cell lines lead to contact inhibition and p27kip1 up-regulation. Therefore in case of malignant tumors, such as T-cell lymphoma, and malignant mesothelioma, CD26 plays a role in tumor growth and may be involved in invasion and metastasis.
Malignant mesothelioma is an aggressive neoplasm with a dismal prognosis and is relatively unresponsive to chemotherapy. One study systematically reviewed evidence for chemotherapy effect from 1965 through June 2001 and found 83 studies with 88 treatment arms (34). Cisplatin was the most active single drug, and cisplatin with doxorubicin had the highest response rate (28.5% response rate; confidence interval, 21.3% to 35.7%). Since this report, results of a phase III randomized trial (using 448 chemotherapy naive patients with unresectable mesothelioma) involving the combination cisplatis/pemetrexed (an antimetabolite) or cisplatin alone have shown that medium survival is extended from 9.3 months in patients treated with cisplatin to 12.1 months in patients treated with both agents (35). However, standard treatments for malignant mesothelioma are still not satisfactory in terms of survival; hence, there is an urgent need for novel therapeutic approaches for malignant mesothelioma.
Our data therefore indicate that the novel humanized anti-CD26 mAb is an effective therapeutic tool for cancer treatment including malignant mesothelioma, as it can use the human effector system to target cancer cells in addition to its direct antitumor effect.
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Footnotes |
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The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Conflict of interest: Dr. Morimoto is a board member of Y's Therapeutics, and Dr. Dang is a scientific adviser in Y's Therapeutics. The other authors have no competing financial interests.
5 http://www.takara-bio.co.jp/RNAi.htm 
Received 1/16/07; revised 3/14/07; accepted 3/22/07.
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expression in the B-cell lymphoma line Jiyoye by CD26/dipeptidyl peptidase IV is associated with enhanced in vitro and in vivo sensitivity to doxorubicin. Cancer Res 2005;65:1973–83. and sensitivity to apoptosis induced by topoisomerase II inhibitors. Br J Cancer 2003;89:1366–74.[CrossRef][Medline]This article has been cited by other articles:
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  N. Kawasaki, C.-W. Lin, R. Inoue, K.-H. Khoo, N. Kawasaki, B. Y. Ma, S. Oka, M. Ishiguro, T. Sawada, H. Ishida, et al. Highly fucosylated N-glycan ligands for mannan-binding protein expressed specifically on CD26 (DPPVI) isolated from a human colorectal carcinoma cell line, SW1116 Glycobiology, April 1, 2009; 19(4): 437 - 450. [Abstract] [Full Text] [PDF]
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