From: Subject: =?Windows-1252?Q?Human_Neural_Stem_Cells_Target_Experimental_Intracranial?= =?Windows-1252?Q?_Medulloblastoma_and_Deliver_a_Therapeutic_Gene_Leading_?= =?Windows-1252?Q?to_Tumor_Regression_=97_Clinical_Cancer_Research?= Date: Thu, 1 Jul 2010 22:51:04 +0200 MIME-Version: 1.0 Content-Type: multipart/related; type="text/html"; boundary="----=_NextPart_000_0000_01CB196F.E2DD9DB0" X-MimeOLE: Produced By Microsoft MimeOLE V6.00.2900.5931 This is a multi-part message in MIME format. ------=_NextPart_000_0000_01CB196F.E2DD9DB0 Content-Type: text/html; charset="utf-8" Content-Transfer-Encoding: quoted-printable Content-Location: http://clincancerres.aacrjournals.org/content/12/18/5550.full =EF=BB=BF Human Neural Stem = Cells Target Experimental Intracranial Medulloblastoma and Deliver a = Therapeutic Gene Leading to Tumor Regression =E2=80=94 Clinical Cancer = Research
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Human Neural Stem Cells Target Experimental = Intracranial=20 Medulloblastoma and Deliver a Therapeutic Gene Leading to Tumor = Regression

  1. Seung-Ki=20 Kim1,=20
  2. Seung=20 U. Kim2,3,=20
  3. In=20 Ho Park2,=20
  4. Jung=20 Hee Bang2,=20
  5. Karen=20 S. Aboody4,=20
  6. Kyu-Chang=20 Wang5,=20
  7. Byung-Kyu=20 Cho5,=20
  8. Manho=20 Kim6,=20
  9. Lata=20 G. Menon1,=20
  10. Peter=20 M. Black1=20 and=20
  11. Rona=20 S. Carroll1=20
  1. Authors' Affiliations:1Department of Neurosurgery, Brigham and = Women's=20 Hospital and Children's Hospital, Harvard Medical School, Boston,=20 Massachusetts; 2Brain Disease Research = Center, Ajou=20 University, Suwon, Korea; 3Division of = Neurology,=20 UBC Hospital, University of British Columbia, Vancouver, Canada; 4Divisions of Hematology and Hematopoietic = Cell=20 Transplantation and Neurosciences, City of Hope National Medical = Center and=20 Beckman Research Institute, Duarte, California; and Departments of 5Neurosurgery and 6Neurology,=20 Seoul National University Hospital, Seoul, Korea
  1. Requests for = reprints:
    Rona S.=20 Carroll, Department of Neurosurgery, Brigham and Women's Hospital, 221 = Longwood Avenue, Boston, MA 02115. Phone: 617-278-0177; Fax: = 617-232-9029;=20 E-mail: rcarroll{at}rics.bwh.harvard.edu. =
Next=20 Section

Abstract

Purpose: Medulloblastoma, a malignant = pediatric brain=20 tumor, is incurable in about one third of patients despite multimodal=20 treatments. In addition, current therapies can lead to long-term = disabilities.=20 Based on studies of the extensive tropism of neural stem cells (NSC) = toward=20 malignant gliomas and the secretion of growth factors common to glioma = and=20 medulloblastoma, we hypothesized that NSCs could target medulloblastoma = and be=20 used as a cellular therapeutic delivery system.

Experimental Design: The migratory ability = of HB1.F3=20 cells (an immortalized, clonal human NSC line) to medulloblastoma was = studied=20 both in vitro and in vivo. As proof-of-concept, we = used HB1.F3=20 cells engineered to secrete the prodrug activating enzyme cytosine = deaminase. We=20 investigated the potential of human NSCs to deliver a therapeutic gene = and=20 reduce tumor growth.

Results: The migratory capacity of HB1.F3 = cells was=20 confirmed by an in vitro migration assay, and corroborated = in=20 vivo by injecting chloromethylbenzamido-Dil=E2=80=93labeled HB1.F3 = cells into the=20 hemisphere contralateral to established medulloblastoma in nude mice. = In=20 vitro studies showed the therapeutic efficacy of HB1.F3-CD on Daoy = cells in=20 coculture experiments. In vitro therapeutic studies were = conducted in=20 which animals bearing intracranial medulloblastoma were injected = ipsilaterally=20 with HB1.F3-CD cells followed by systemic 5-flourocytosine treatment. = Histologic=20 analyses showed that human NSCs migrate to the tumor bed and its = boundary,=20 resulting in a 76% reduction of tumor volume in the treatment group = (P=20 < 0.01).

Conclusion: These studies show for the = first time the=20 potential of human NSCs as an effective delivery system to target and=20 disseminate therapeutic agents to medulloblastoma.

Medulloblastoma is the most common childhood malignant brain = tumor.=20 Although multimodal treatments, including radical surgical resection = followed by=20 radiation and chemotherapy, have substantially improved the survival = rate for=20 this disease, it remains incurable in about one third of patients. These = treatments are also toxic and can lead to long-term disabilities (1,=20 2).=20 The main cause of death is recurrence associated with tumor = dissemination, at=20 which point current therapeutic options have little efficacy (3,=20 4).=20 Consequently, there is substantial need for novel, effective, = low-toxicity=20 therapies for children with medulloblastoma.

The discovery of the inherent tumor-tropic properties of = neural stem=20 cells (NSC) could serve as a novel adjuvant strategy to current = medulloblastoma=20 treatments. Recent studies have shown that NSCs have the capacity to = target=20 therapeutic genes to brain tumors, such as malignant glioma (5=E2=80=9313)=20 and melanoma brain metastasis (14).=20 We have expanded these investigations to determine whether NSCs are = capable of=20 targeting medulloblastoma in an orthotopic xenograft animal model. = Therapeutic=20 proof-of-concept studies were done using cytosine deaminase = (CD)=E2=80=93producing NSCs=20 and systemic 5-fluorocytosine (5-FC) prodrug administration. Our results = show=20 for the first time the potential of NSCs as an effective delivery system = to=20 target and disseminate therapeutic agents to medulloblastoma. This = provides a=20 rationale for further evaluation of the NSC-based cellular delivery = system for=20 human medulloblastoma.

Previous=20 SectionNext=20 Section

Materials and Methods

Cell culture. HB1.F3 is an = immortalized=20 human NSC (hNSC) line derived from the human fetal brain (ventricular = zone) at=20 15 weeks of gestation by an amphotropic, replication-incompetent = retroviral=20 vector containing v-myc (15=E2=80=9318).=20 This is a well-established and well-characterized NSC line that is = multipotent,=20 migratory, and nontumorigenic in vivo (12,=20 15=E2=80=9322).=20 HB1.F3 cells were maintained as adherent cultures in DMEM supplemented = with 10%=20 fetal bovine serum, 2 mmol/L l-glutamine, and = 100 units/mL=20 penicillin, 100 =CE=BCg/mL streptomycin, 0.25 =CE=BCg/mL amphotericin B = (Invitrogen, Grand=20 Island, NY).

The human medulloblastoma cell line Daoy was obtained from = S.L.=20 Pomeroy (Children's Hospital, Boston, MA). The human glioblastoma cell = lines=20 U87MG and U251MG and the fibroblast line NIH 3T3 were obtained from the = American=20 Type Culture Collection (Manassas, VA). Daoy, U251MG, and NIH 3T3 cells = were=20 cultured in DMEM supplemented with 10% fetal bovine serum, 2 mmol/L = l-glutamine, 2 mmol/L sodium pyruvate, and 100 = units/mL=20 penicillin, 100 =CE=BCg/mL streptomycin, 0.25 =CE=BCg/mL amphotericin B. = U87MG cells were=20 cultured in MEM=CE=B1 (Invitrogen) supplemented with 10% fetal bovine = serum, 2 mmol/L=20 l-glutamine, 2 mmol/L nonessential amino acids, = 2 mmol/L=20 sodium pyruvate, and 100 units/mL penicillin, 100 =CE=BCg/mL = streptomycin, 0.25 =CE=BCg/mL=20 amphotericin B. All cells were maintained in humidified atmosphere = containing 5%=20 CO2 at 37=C2=B0C.

In vitro migration assay. The = directed=20 migration ability of HB1.F3 to Daoy cells was determined using a = modified=20 transwell migration assay. Daoy cells were incubated in serum-free = medium for 24=20 hours, and the resulting conditioned medium was collected and placed in = the=20 lower well of fibronectin-coated (Chemicon, Temecula, CA) 10-mm tissue = culture=20 Transwell plates (8 =CE=BCm; Nunc International, Rochester, NY). HB1.F3 = cells in=20 serum-free medium (50,000/0.5 mL) were seeded in the upper well of the = transwell=20 plates. NIH 3T3 cells were plated as a negative control. Following = incubation=20 for 6 hours at 37=C2=B0C, nonmigrated cells were scraped off the upper = side of the=20 filter and the filters were then stained with Three-Step Stain Set=20 (Richard-Allan Scientific, Kalamazoo, MI). All experiments were = conducted in=20 quadruplicate. Nuclei of migrated cells were counted in five high-power = fields=20 (=C3=97200) and the values expressed as the mean =C2=B1 SE.

In vivo migration assay. To = assess the=20 migratory ability of HB1.F3 cells in vivo, the cells were = injected=20 intracranially, contralateral to the experimental tumor. Briefly, Swiss = nude=20 male mice (n =3D 8; 6-8 weeks old; Charles River, Wilmington, = MA) were=20 anesthetized (100 mg/kg ketamine and 5 mg/kg xylazine) and = stereotactically=20 implanted with 120,000 Daoy cells in 3 =CE=BCL of PBS via a 30-gauge = Hamilton syringe=20 into the left forebrain (2.5 mm lateral and 1 mm anterior to bregma, at = a 2.5 mm=20 depth from the skull surface). Four weeks after tumor cell implantation, = HB1.F3=20 cells (240,000 in 6 =CE=BCL PBS) were injected into the right forebrain = (2.5 mm=20 lateral and 1 mm anterior to bregma, at a 2.5 mm depth from the skull = surface;=20 n =3D 4). As a control, a group of medulloblastoma-bearing = animals=20 (n =3D 4) were injected with NIH 3T3 cells in the right = forebrain using=20 the same stereotactic coordinates. For this study, the ratio of cells = tested for=20 their migratory ability (HB1.F3 or NIH 3T3) to tumor cells was 2:1. = HB1.F3 or=20 NIH 3T3 cells were labeled with the chloromethylbenzamido-DiI (CM-DiI, = Molecular=20 Probes, Eugene, OR) before injection for 30 minutes according to the = protocol of=20 the manufacturer. CM-DiI is nondiffusible by virtue of its covalent = binding to=20 cellular thiols and has been shown to be particularly suitable for = labeling and=20 in vivo tracking of cells for a minimum of 10 weeks (23,=20 24).=20 Fourteen days after intracranial, contralateral injection of HB1.F3 or = NIH 3T3=20 cells, animals were perfused with 4% paraformaldehyde under deep = anesthesia. The=20 brains were harvested, placed in sucrose gradient solution, embedded in = optimum=20 cutting temperature compound (Sakura Finetek USA, Torrance, CA), and = stored at=20 =E2=88=9280=C2=B0C. Brains were cryosectioned coronally (10 =CE=BCm), = mounted on slides, and=20 stained with 4=E2=80=B2,6-diamidino-2-phenylindole per standard = protocol. Intracranial=20 distribution of CM-DiI-labeled NSCs was assessed with fluorescent = microscopy.=20 All animal studies were carried out in the animal facility at Brigham = and=20 Women's Hospital in accordance with federal, local, and institutional=20 guidelines.

Confirmation of chemoattractant ligands and=20 receptors. Recent studies suggest that the brain = tumor=E2=80=93targeting=20 behavior of NSCs is mediated by chemoattractant molecules and their = respective=20 receptors including stem cell factor (SCF)/c-Kit (25),=20 stromal cell=E2=80=93derived factor 1 (SDF-1)/CXC chemokine receptor 4 = (CXCR4; ref. 26)=20 and vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR)-1 = and VEGFR2=20 (22).=20 Therefore, the expression of these chemoattractant ligands and their = associated=20 receptors was examined in Daoy and HB1.F3 cells by reverse = transcription-PCR.=20

Total cellular RNA was prepared using the RNeasy Mini Kit = protocol=20 (Qiagen, Valencia, CA). Single-stranded cDNA was prepared from 1 =CE=BCg = of total RNA=20 using oligo-p(dT)15 primer following the First Strand cDNA = Synthesis=20 Kit for reverse transcription-PCR (avian myeloblastosis virus) protocol = (Roche,=20 Indianapolis, IN). cDNA from the reverse transcription reaction was used = in the=20 subsequent PCR reactions in the presence of 0.2 =CE=BCmol/L each of = 5=E2=80=B2 and 3=E2=80=B2=20 primers, 2.5 units of Taq polymerase, 1.5 mmol/L MgCl2, 0.2 = mmol/L=20 deoxynucleotide mix, and 1=C3=97 PCR buffer. Touchdown PCR for these = chemoattractant=20 factors (ligands and receptors) and =CE=B2-actin, a positive = control, was=20 carried out for 25 cycles. The reaction products were analyzed on a 2.5% = agarose=20 gel stained with ethidium bromide. The sense and antisense primers and = the=20 predicted sizes of the reverse transcription-PCR reaction products were = as=20 follows: SCF, 5=E2=80=B2-ACTTGGATTCTCACTTGCATTT-3=E2=80=B2 (sense) and=20 5=E2=80=B2-CTTTCTCAGGACTTAATGTTGAAG-3=E2=80=B2 (antisense; 505 bp); = c-Kit,=20 5=E2=80=B2-GCCCACAATAGATTGGTATTT-3=E2=80=B2 (sense) and = 5=E2=80=B2-AGCATCTTTACAGCGACAGTC-3=E2=80=B2 (antisense;=20 570 bp); SDF-1, 5=E2=80=B2-ATGAACGCCAAGGTCGTGGTC-3=E2=80=B2 (sense) and=20 5=E2=80=B2-GGCTGTTGTGCTTACTTGTTT-3=E2=80=B2 (antisense; 281 bp); CXCR4,=20 5=E2=80=B2-CTCTCCAAAGGAAAGCGAGGTGGACAT-3=E2=80=B2 (sense) and = 5=E2=80=B2-AGACTGTACACTGTAGGTGCTGAAATCA-3=E2=80=B2=20 (antisense; 558 bp); VEGF, = 5=E2=80=B2-AAGCCATCCTGTGTGCCCCTGATG-3=E2=80=B2 (sense) and=20 5=E2=80=B2-GCTCCTTCCTCCTGCCCGGCTCAC-3=E2=80=B2 (antisense; 377 bp); = VEGFR1,=20 5=E2=80=B2-GCAAGGTGTGACTTTTGTTC-3=E2=80=B2 (sense) and = 5=E2=80=B2-AGGATTTCTTCCCCTGTGTA-3=E2=80=B2 (antisense;=20 512 bp); VEGFR2, 5=E2=80=B2-ACGCTGACATGTACGGTCTAT-3=E2=80=B2 (sense) and = 5=E2=80=B2-GCCAAGCTTGTACCATGTGAG-3=E2=80=B2 (antisense; 438 bp); and = =CE=B2-actin,=20 5=E2=80=B2-GCCCAGAGCAAGAGAGGCAT-3=E2=80=B2 (sense) and = 5=E2=80=B2-GGCCATCTCTTGCTCGAAGT-3=E2=80=B2 (antisense;=20 513 bp).

Engineering of HB1.F3-CD. The = clonal=20 HB1.F3-CD line was derived from parental HB1.F3 cells. An expression = plasmid was=20 constructed with the retroviral pBabePuro backbone to include the E. = coli CD cDNA (1.5-kb fragment) transcribed from the long terminal = repeat.=20 Vectors were packaged by cotransduction of the CD puro plasmid with the = MV12=20 envelope coding plasmid cDNA into pA317 cells. CD puro retroviral = supernatant=20 was used for multiple infections of the HB1.F3 cells. Transduced HB1.F3 = cells=20 (HB1.F3-CD) were selected with 3 =CE=BCg/mL puromycin for 4 weeks.

Successful transduction of HB1.F3-CD cells was confirmed by = reverse=20 transcription-PCR. The CD transcript (559 bp) was amplified by touchdown = PCR=20 with the following primers: sense, = 5=E2=80=B2-GCGCGAGTCACCGCCAGCCACACCACGGC-3=E2=80=B2;=20 antisense, 5=E2=80=B2-GTTTGTAATCGATGGCTTCTGGCTGC-3=E2=80=B2. = =CE=B2-Actin controls confirmed equal=20 RNA loading.

To confirm the bioactivity of CD produced from HB1.F3-CD, = the=20 cytotoxic effect of 5-FC and 5-flurouracil (5-FU) on HB1.F3-CD was = analyzed by=20 cell viability assay. Sensitivity to 5-FC or 5-FU was also assessed for = HB1.F3,=20 Daoy, U87MG, and U251MG cells. For all studies, cells (4 =C3=97 = 103 per=20 well) were plated in 96-well plates (Corning, Inc., Acton, MA). After 24 = hours,=20 cells were treated with 5-FC (Sigma-Aldrich, St. Louis, MO) or 5-FU=20 (Sigma-Aldrich) with final concentrations in the range of 0 to 100 = =CE=BCg/mL. Cells=20 were incubated at 37=C2=B0C for 4 days and quantification of cell = viability was done=20 with a colorimetric assay using Cell Counting Kit-8 (Dojindo Molecular=20 Technologies, Gaithersburg, MD). All experiments were conducted in=20 quadruplicate. Viability determination was based on the bioconversion of = the=20 tetrazolium compound,=20 2-(2-methoxy-4-nitrophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfophenyl)-2= H-tetrazolium,=20 into formazan, as determined by absorbance at 450 nm using a multiwell = scanning=20 spectrophotometer. Cell viability was expressed as the mean =C2=B1 SE in = percentage=20 of the control viability (=3D100%).

In addition, the migratory capacity of HB1.F3-CD cells was = assessed=20 in vitro and in vivo as described above.

In vitro therapeutic efficacy of = HB1.F3-CD.=20 Therapeutic efficacy of HB1.F3-CD cells after 5-FC treatment was = analyzed by=20 coculture experiments. Daoy cells (4 =C3=97 103 per well) = were plated in=20 96-well plates and experiments were done as follows: on day 1, = increasing=20 amounts of HB1.F3 or HB1.F3-CD cells (0, 2 =C3=97 103, 4 = =C3=97 103,=20 8 =C3=97 103, and 16 =C3=97 103 per well) were = added to the tumor=20 cell cultures; day 2, 5-FC (100 =CE=BCg/mL) was added to the mixed cell = cultures; day=20 6, quantification of cell viability was done as described above. All = experiments=20 were conducted in quadruplicate. Cell viability was expressed as the = mean =C2=B1 SE=20 in percentage of the control viability (=3D100%).

In vivo therapeutic efficacy of = HB1.F3-CD.=20 Animals received stereotactic implantation of Daoy cells (120,000 in 3 = =CE=BCL PBS)=20 into the left forebrain as described above. Two weeks after tumor cell=20 implantation, the animals were randomized into five groups: group 1, = treated=20 with ipsilateral intratumoral injection of PBS (8 =CE=BCL; n = =3D 6); groups 2=20 and 3, treated with ipsilateral intratumoral injection of 480,000 HB1.F3 = cells=20 in 8 =CE=BCL of PBS (n =3D 6 for each group); groups 4 and 5, = treated with=20 ipsilateral intratumoral injection of 480,000 HB1.F3-CD cells in PBS = (n=20 =3D 6 for each group). In this study, the ratio of stem cells/tumor = cells was 4:1.=20 HB1.F3 and HB1.F3-CD were labeled with the CM-DiI cell tracker before = injection.=20 One week after hNSC injection, groups 3 and 5 received i.p. injections = of 5-FC=20 (500 mg/kg) twice a day for 14 days. Three weeks after the last 5-FC = treatment,=20 animals were perfused and the brains harvested and processed as = described above.=20 Tissue was stained with 4=E2=80=B2,6-diamidino-2-phenylindole or H&E = per standard=20 protocol. Intracranial distribution of CM-DiI-labeled hNSCs was assessed = by=20 fluorescent microscopy. Tumor volumes were estimated using the formula = for=20 ellipsoid and expressed as mean =C2=B1 SE as previously described (27).=20

Immunohistochemistry was carried out with the Vectastain = Elite ABC=20 kit (Vector Laboratories, Burlingame, CA). Brain sections were fixed in = cold=20 acetone. Primary antibody included anti-Ki67 nuclear antigen (1:100; = DAKO,=20 Carpinteria, CA) for proliferating cells. Sections were counterstained = with=20 hematoxylin, and negative control slides were obtained by omitting the = primary=20 antibody. The proliferative index was defined as the percentage of = positively=20 stained cells of 100 nuclei from five randomly chosen high-power fields. =

Statistics. All of the values = were=20 calculated as mean =C2=B1 SE or were expressed as percentage of control = =C2=B1 SE.=20 Significant differences between assessment of in vitro = migration, cell=20 viability, and tumor volume were determined using the Mann-Whitney = U=20 test. P < 0.05 was considered significant.

Previous=20 SectionNext=20 Section

Results

Migratory capacity of hNSCs in = vitro. To=20 determine the migratory capacity of hNSCs to medulloblastoma cells, an = in=20 vitro transwell migration assay was done. Daoy conditioned medium=20 significantly stimulated the directional migration of HB1.F3 cells (36.8 = =C2=B1 7.93=20 cells per high-power field) compared with that of NIH 3T3 cells (4.2 = =C2=B1 1.30=20 cells per high-power field; P < 0.05; Fig.=20 1 ).

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Fig. = 1.=20

In vitro migration assay. The = migratory=20 ability of HB1.F3 or NIH 3T3 cells to Daoy cells was determined using a = modified=20 transwell migration assay. Daoy conditioned medium significantly = stimulates the=20 directional migration of HB1.F3 cells compared with NIH 3T3 fibroblast = cells=20 (36.8 =C2=B1 7.93 cells per high-power field for HB1.F3 cells versus 4.2 = =C2=B1 1.30 cells=20 per high-power field for NIH 3T3 cells; P < 0.05, = Mann-Whitney=20 U test). Magnification, =C3=97100.

Migratory capacity of hNSCs in = vivo. To=20 confirm the migratory ability of hNSCs to medulloblastoma in = vivo, Daoy=20 cells were implanted into the left hemisphere. Four weeks later, = CM-DiI-labeled=20 HB1.F3 cells were injected into the contralateral hemisphere. = CM-DiI-labeled=20 HB1.F3 cells were seen migrating across the corpus callosum (Fig.=20 2A ) and populating medulloblastoma tumor in the opposite hemisphere = (Fig.=20 2B). It should be noted that at the time of HB1.F3 injection (4 = weeks after=20 Daoy implantation), the established Daoy tumors were small, but the NSCs = were=20 still able to migrate to the tumor site. Very few hNSCs were seen beyond = the=20 tumor edge, showing the remarkable migratory capacity of NSCs to the=20 infiltrating tumor cell in the peritumoral normal brain. In contrast, = the NIH=20 3T3 fibroblast cells did not migrate and remained localized at the area = of the=20 injection site.

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Fig. = 2.=20

In vivo migration assay. To = assess=20 migratory ability of HB1.F3 cells in vivo, CM-DiI-labeled = HB1.F3 cells=20 were injected into the hemisphere contralateral to the tumor cell = implantation=20 (Daoy cells). CM-DiI-labeled HB1.F3 cells (red) are seen = migrating=20 across the corpus callosum (arrow; = 4=E2=80=B2,6-diamidino-2-phenylindole=20 staining; =C3=9740 magnification) in the HB1.F3 injected hemisphere = (A) and=20 populating the tumor bed (arrowhead) in the tumor implanted = hemisphere=20 (B; =C3=97100 magnification).

Confirmation of chemoattractant ligands and=20 receptors. The brain tumor=E2=80=93targeting behavior of = hNSCs has been=20 reported to be mediated by a multitude of factors, including the = SCF/c-Kit (25),=20 SDF-1/CXCR4 (26),=20 and the VEGF/VEGFR1 and VEGFR2 (22)=20 signaling pathways. Using reverse transcription-PCR, the presence of the = ligands=20 SCF, SDF-1, and VEGF in Daoy cells, and of their associated receptors = c-Kit,=20 CXCR4, VEGFR1, and VEGFR2 in HB1.F3 cells (Fig.=20 3A ), was confirmed. A =CE=B2-actin control confirmed RNA = quality.

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Fig. = 3.=20

The analysis of expression of = chemoattractant=20 factors (ligands and receptors) and CD using reverse transcription-PCR.=20 A, the presence of the ligands SCF, SDF-1, and VEGF in Daoy = cells, and=20 of their corresponding receptors c-Kit, CXCR4, VEGFR1, and VEGFR2 in = HB1.F3=20 cells, was confirmed and visualized on 2.5% agarose gel. B, the = HB1.F3-CD line was derived from HB1.F3 cells by retroviral transduction = with=20 E. coli CD. The CD transcript was expressed only in HB1.F3-CD = cells,=20 but not in HB1.F3 cells.

CD-producing HB1.F3 cells. = Expression of=20 the CD transcript in HB1.F3-CD was confirmed by reverse = transcription-PCR. The=20 CD transcript was found to be only expressed in HB1.F3-CD cells, but not = in the=20 parental HB1.F3 cells (Fig.=20 3B).

Sensitivity of HB1.F3-CD to 5-FC or 5-FU was assessed and = compared=20 with that of HB1.F3, Daoy, U87MG, and U251MG cells. Only HB1.F3-CD cells = were=20 sensitive to 5-FC treatment at a concentration of 10 =CE=BCg/mL = (P <=20 0.05, Fig.=20 4A ), confirming the enzymatic conversion of prodrug 5-FC to the = toxic 5-FU.=20 The growth of the other cell lines was not affected by 5-FC even at a=20 concentration of 100 =CE=BCg/mL, indicating the lack of expression of CD = in these=20 cells. In contrast, all cells lines were sensitive to 5-FU. The highest=20 sensitivity was observed in hNSCs with or without CD transduction, = followed by=20 medulloblastoma cells, and lastly in glioblastoma cells in decreasing = order (Fig.=20 4B). A notable and highly significant finding is that = medulloblastoma cells=20 are more sensitive to 5-FU than glioblastoma cells such as U87MG and = U251MG. For=20 example, Daoy cells (52.7 =C2=B1 4.01%) showed a significant decrease in = cell=20 viability compared with U87MG (88.8 =C2=B1 9.54%) or U251MG (89.2 =C2=B1 = 2.56%) cells at=20 the 0.5 =CE=BCg/mL 5-FU treatment (P < 0.05).

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Fig. = 4.=20

The bioactivity of 5-FC and 5-FU was = determined by=20 cell viability assay. HB1.F3-CD, HB1.F3, Daoy, U87MG, and U251MG cells = (4 =C3=97=20 103 per well each) were plated in 96-well cell plates and = sensitivity=20 to 5-FC/5-FU was measured by colorimetric assays with Cell Counting = Kit-8.=20 Columns, mean cell viability (percentage of the control viability); = bars, SE.=20 A, only HB1.F3-CD cells are sensitive to 5-FC treatment at a=20 concentration of 10 =CE=BCg/mL 5-FC (P < 0.05, Mann-Whitney = U=20 test), confirming the enzymatic conversion of prodrug 5-FC to the toxic = 5-FU.=20 The growth of other cells is not affected by 5-FC up to a concentration = of 100=20 =CE=BCg/mL, indicating the lack of expression of cytosine deaminase in = these cells.=20 B, after 5-FU treatment, sensitivity is the highest in human = neural=20 stem cells, followed by medulloblastoma cells and glioblastoma cells in=20 decreasing order.

The potential for migration of NSCs was not affected by = transduction=20 with CD. The migratory pattern of HB1.F3-CD in vitro and in = vivo was indistinguishable from that of HB1.F3 cells (Fig.=20 6A).

In vitro therapeutic efficacy of = HB1.F3-CD.=20 To confirm the =E2=80=9Cbystander effect=E2=80=9D of the CD released = from the HB1.F3-CD cells,=20 cell viability studies were done in a coculture system. After 5-FC = treatment,=20 Daoy cells cultured in the presence of HB1.F3-CD cells, but not the = parental=20 HB1.F3 cells, showed significant growth inhibition even when the ratio = of=20 HB1.F3-CD cells/tumor cells was as low as 1:2 (P < 0.05; Fig.=20 5 ). Without 5-FC treatment, Daoy cells cultured with HB1.F3-CD = cells showed=20 no growth inhibition. This indicates that HB1.F3-CD cells can convert = sufficient=20 amounts of 5-FC to 5-FU to effectively kill Daoy cells in = vitro.

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Fig. = 5.=20

In vitro therapeutic efficacy = of=20 HB1.F3-CD. Therapeutic efficacy of HB1.F3-CD cells after 5-FC treatment = was=20 analyzed by coculture experiments. Daoy cells (4 =C3=97 103 = per well) were=20 plated in 96-well plates. After 24 hours, increasing amounts of HB1.F3 = or=20 HB1.F3-CD cells (0, 2 =C3=97 103, 4 =C3=97 103, 8 = =C3=97 103,=20 and 16 =C3=97 103 per well) were added to the tumor cell = cultures. After=20 5-FC (100 =CE=BCg/mL) treatment, cell viability was measured by = colorimetric assays=20 with Cell Counting Kit-8. Columns, mean percentage of the control = viability;=20 bars, SE. Daoy cells cultured in the presence of HB1.F3-CD cells, but = not HB1.F3=20 cells, show significant growth inhibition after 5-FC treatment, even = when the=20 ratio of HB1.F3-CD cells/tumor cells is as low as 1:2 (P < = 0.05,=20 Mann-Whitney U test). Without 5-FC treatment, Daoy cells = cultured with=20 HB1.F3-CD cells show no growth inhibition.

In vivo therapeutic efficacy of = HB1.F3-CD.=20 To assess the therapeutic efficacy of HB1.F3-CD in medulloblastoma = animal=20 models, we injected CM-DiI-labeled HB1.F3-CD cells into tumor-bearing = animals.=20 The distribution of HB1.F3-CD cells and tumor volumes were determined on = harvested brain tissue 3 weeks after the last 5-FC treatment. In = vivo=20 studies showed that the majority of intracranially injected = CM-DiI-labeled=20 HB1.F3-CD cells localized to the tumor bed and the tumor-normal = parenchyma=20 interface (Fig.=20 6B ).

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Fig. = 6.=20

Intracranial distribution and in = vivo=20 therapeutic efficacy of HB1.F3-CD. A, HB1.F3-CD were labeled = with=20 CM-DiI and injected into the hemisphere contralateral to the tumor cell=20 implantation. HB1.F3-CD cells (red) are observed migrating = towards=20 intracranial medulloblastoma (arrowhead) through normal brain=20 parenchyma in a similar pattern as parental cells = (4=E2=80=B2,6-diamidino-2-phenylindole=20 staining; merged image; =C3=97100 magnification). B, the = majority of=20 CM-DiI-labeled HB1.F3-CD cells, injected intracranially, are located at = the=20 border between tumor (arrowhead) and normal parenchyma=20 (4=E2=80=B2,6-diamidino-2-phenylindole staining; merged image; =C3=97100 = magnification).=20 Cavity formation (arrow) is more dramatic in areas where the = labeled=20 HB1.F3-CD cells are found, suggesting a bystander effect. C, = tumor=20 volumes were estimated from histologic analysis. Columns, mean; bars, = SE. After=20 systemic treatment with 5-FC, 76% reduction of tumor volume is shown in=20 HB1.F3-CD-treated animals (2.6 =C2=B1 1.49 mm3) compared with = PBS-treated=20 animals (10.7 =C2=B1 6.80 mm3; * P < 0.01, = Mann-Whitney=20 U test). D, representative histologic photographs = (H&E=20 staining; =C3=971 magnification).

Histologic analysis showed a 76% reduction of tumor volume = in the=20 brains of 5-FC-treated HB1.F3-CD animals (2.6 =C2=B1 1.49 = mm3) compared=20 with PBS-treated control animals (10.7 =C2=B1 6.80 mm3; = P <=20 0.01; Fig. 6C=20 and D) and all other control groups. We could not detect any = abnormalities=20 in the parenchyma surrounding the tumor in treated animals. The = proliferative=20 index revealed no significant differences among the groups.

Previous=20 SectionNext=20 Section

Discussion

The focus of this study is to explore the migratory = capacity and=20 therapeutic potential of hNSCs in experimental medulloblastoma. We have=20 previously reported the inherent migratory, tumor-tropic, and = therapeutic=20 properties of NSCs (C17.2 and HB1.F3) to intracranial glioblastomas (5,=20 12).=20 In this study, we have chosen to use human HB1.F3 NSCs as it is a=20 well-established and well-characterized human stem cell line (12,=20 15=E2=80=9322).=20 No signs of local or systemic toxicity in HB1.F3 and HB1.F3-CD treated = groups=20 were observed although the therapeutic effects were assessed 6 weeks = after hNSC=20 injection.

The in vitro and in vivo studies clearly = show for=20 the first time the ability of NSCs to target medulloblastoma, indicating = that=20 the tumor tropism of NSCs is not limited to gliomas (14).=20 Furthermore, migration of HB1.F3 was not affected by the CD = transduction. To=20 better define the crosstalk between medulloblastoma and hNSCs, we = investigated=20 the signals that have been shown to modulate the brain tumor tropism of = NSCs,=20 such as SCF/c-Kit (25),=20 SDF-1/CXCR4 (26),=20 and VEGF/VEGFR1 and VEGFR2 (22).=20 Our study documented the presence of chemoattractant factors (ligands in = medulloblastoma and receptors in hNSCs), which may allow them to = communicate=20 with each other and facilitate the migration we observed.

After confirmation of the tropism of hNSCs for = medulloblastoma, we=20 tested their therapeutic potential using the CD enzyme/5-FC prodrug = system. CD=20 is a bacterial enzyme that converts the nontoxic prodrug 5-FC to the = cytotoxic=20 drug 5-FU, a nucleotide analogue that disrupts DNA synthesis in = proliferating=20 cells (28).=20 Because mammalian cells do not express significant amounts of CD, as = shown in=20 the present study, 5-FC is nontoxic at concentrations that result in = strong=20 antimicrobial activity. Tumor cells transfected with the E. = coli CD=20 gene become selectively sensitive to the toxic effects of 5-FC; e.g., = expression=20 of this enzyme in glioma cells confers their lethal sensitivity to = systemically=20 administration of 5-FC (29).=20 In addition, this enzyme/prodrug system has a bystander effect (30,=20 31),=20 shown by the death of unmodified tumor cells adjacent to genetically = modified=20 cells. NSCs engineered to express a suicide gene such as CD are a = particularly=20 good choice because they can generate agents that kill tumor cells as = well as=20 result in self-elimination if the NSCs start dividing in vivo. = Although=20 HB1.F3 cells have proved to be a non-tumor-producing line in = vivo model=20 (12,=20 15=E2=80=9322),=20 there is possibility of integration of NSCs into the stroma of brain = tumors.=20 Recently, more studies of neurogenesis have focused on modulation of = endogenous=20 precursors, rather than in vitro propagation of cell lines (32).=20

Our group and others have shown that NSCs transduced with = the CD gene=20 retain their tumor tracking properties and are therapeutically effective = for=20 malignant gliomas in animal models (5,=20 6).=20 To our knowledge, these data are the first to show therapeutic efficacy = of this=20 hNSC-CD/5-FC system in a medulloblastoma model; the systemic = administration of=20 5-FC in combination with CD-expressing hNSCs resulted in a 76% reduction = in=20 intracranial medulloblastoma tumor volume in nude mice.

Although there was a significant tumor volume reduction = induced by=20 this therapy, the proliferative index of the remaining tumor was still = high. As=20 the therapeutic benefit from one-time drug delivery may be short-lived = as the=20 tumor regrows, additional cycles of HB1.F3-CD and 5-FC therapy can be = given to=20 eradicate the cancer cells not removed by the first wave of therapy.=20 Alternatively, NSCs can be engineered with other potentially beneficial=20 therapeutic genes (differentiating agents, immune-enhancing agents,=20 apoptosis-promoting agents, antiangiogenic agents, etc.), which can be = given in=20 combination with HB1.F3-CDs or sequentially.

Although systemic 5-FU is not routinely used in the = clinical=20 management of brain tumors, as it does not cross the blood-brain = barrier, we=20 clearly show that medulloblastoma is sensitive to 5-FU, even more so = than=20 glioblastoma. The selective activation of prodrug in tumor tissues by = exogenous=20 enzyme for cancer therapy has been accomplished by several ways, = including=20 gene-directed enzyme prodrug therapy, virus-directed enzyme prodrug = therapy, and=20 antibody-directed enzyme prodrug therapy (33).=20 Our cell-directed enzyme prodrug therapy with NSCs is potentially more = flexible=20 than previous methods because of the tumor-tropic capacity of NSCs. = Because of=20 an impressive bystander effect, as little as 2% of the tumor mass = containing=20 CD-expressing cells may generate significant oncolysis (31).=20 This unique property increases the likelihood of achieving therapeutic = efficacy.=20 When cell-directed enzyme prodrug therapy is applied clinically, the = interval=20 between enzyme and prodrug administrations should be optimized so that = CD/5-FC=20 system could work after NSCs localize to tumor site to avoid systemic = toxicity.=20

In the clinical setting, NSC therapy could be used in = conjunction=20 with standard therapies. Especially in the case of recurrence with tumor = dissemination in the subarachnoid space, NSCs can be grafted into tumor=20 resection cavity to target residual invading and disseminating tumor = cells.=20 Furthermore, based on our study, the same approach can be exploited = using other=20 sources of stem cells and engineered to deliver other antitumor agents = for=20 medulloblastoma therapies.

In conclusion, this study indicates that hNSCs have = migratory=20 capacity and tropism for medulloblastoma. Furthermore, they can be = genetically=20 modified ex vivo to express genes that have therapeutic = efficacy=20 against human medulloblastoma. These results suggest a potential role of = hNSCs=20 as a targeted, therapeutic delivery vehicle for human medulloblastoma.=20

Previous=20 SectionNext=20 Section

Footnotes

  • Grant support: NIH and Seoul National = University=20 Hospital Research Fund no. 03-2002-092 (B-K. Cho), Korea Science and=20 Engineering Foundation-Science Research Center, Ajou University Brain = Disease=20 Center (S.U. Kim), Hagerty Fund (P.M. Black), and Korea Research = Foundation=20 Grant no. KRF-2006-312-E00117 (S-K. Kim).

  • The costs of publication of this article were defrayed in = part by=20 the payment of page charges. This article must therefore be hereby = marked=20 advertisement in accordance with 18 U.S.C. Section 1734 = solely to=20 indicate this fact.

    • Accepted June 8, 2006.
    • Received November 15, 2005.
    • Revision received May 9, 2006.=20
Previous=20 Section

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PADDING-TOP: 0px; FONT-FAMILY: = inherit; BORDER-RIGHT-WIDTH: 0px; outline-style: none } H4 { BORDER-TOP-WIDTH: 0px; PADDING-RIGHT: 0px; PADDING-LEFT: 0px; = BORDER-LEFT-WIDTH: 0px; BORDER-BOTTOM-WIDTH: 0px; PADDING-BOTTOM: 0px; = MARGIN: 0px; VERTICAL-ALIGN: baseline; PADDING-TOP: 0px; FONT-FAMILY: = inherit; BORDER-RIGHT-WIDTH: 0px; outline-style: none } H5 { BORDER-TOP-WIDTH: 0px; PADDING-RIGHT: 0px; PADDING-LEFT: 0px; = BORDER-LEFT-WIDTH: 0px; BORDER-BOTTOM-WIDTH: 0px; PADDING-BOTTOM: 0px; = MARGIN: 0px; VERTICAL-ALIGN: baseline; PADDING-TOP: 0px; FONT-FAMILY: = inherit; BORDER-RIGHT-WIDTH: 0px; outline-style: none } H6 { BORDER-TOP-WIDTH: 0px; PADDING-RIGHT: 0px; PADDING-LEFT: 0px; = BORDER-LEFT-WIDTH: 0px; BORDER-BOTTOM-WIDTH: 0px; PADDING-BOTTOM: 0px; = MARGIN: 0px; VERTICAL-ALIGN: baseline; PADDING-TOP: 0px; FONT-FAMILY: = inherit; BORDER-RIGHT-WIDTH: 0px; outline-style: none } P { BORDER-TOP-WIDTH: 0px; PADDING-RIGHT: 0px; PADDING-LEFT: 0px; = BORDER-LEFT-WIDTH: 0px; BORDER-BOTTOM-WIDTH: 0px; PADDING-BOTTOM: 0px; = MARGIN: 0px; VERTICAL-ALIGN: baseline; PADDING-TOP: 0px; FONT-FAMILY: = inherit; BORDER-RIGHT-WIDTH: 0px; outline-style: none } BLOCKQUOTE { BORDER-TOP-WIDTH: 0px; PADDING-RIGHT: 0px; PADDING-LEFT: 0px; = BORDER-LEFT-WIDTH: 0px; BORDER-BOTTOM-WIDTH: 0px; PADDING-BOTTOM: 0px; = MARGIN: 0px; VERTICAL-ALIGN: baseline; PADDING-TOP: 0px; FONT-FAMILY: = inherit; BORDER-RIGHT-WIDTH: 0px; outline-style: none } PRE { BORDER-TOP-WIDTH: 0px; PADDING-RIGHT: 0px; PADDING-LEFT: 0px; = BORDER-LEFT-WIDTH: 0px; BORDER-BOTTOM-WIDTH: 0px; PADDING-BOTTOM: 0px; = MARGIN: 0px; VERTICAL-ALIGN: baseline; PADDING-TOP: 0px; FONT-FAMILY: = inherit; BORDER-RIGHT-WIDTH: 0px; outline-style: none } A { BORDER-TOP-WIDTH: 0px; PADDING-RIGHT: 0px; PADDING-LEFT: 0px; = BORDER-LEFT-WIDTH: 0px; BORDER-BOTTOM-WIDTH: 0px; PADDING-BOTTOM: 0px; = MARGIN: 0px; VERTICAL-ALIGN: baseline; PADDING-TOP: 0px; FONT-FAMILY: = inherit; BORDER-RIGHT-WIDTH: 0px; outline-style: none } ABBR { BORDER-TOP-WIDTH: 0px; PADDING-RIGHT: 0px; PADDING-LEFT: 0px; = BORDER-LEFT-WIDTH: 0px; BORDER-BOTTOM-WIDTH: 0px; PADDING-BOTTOM: 0px; = MARGIN: 0px; VERTICAL-ALIGN: baseline; PADDING-TOP: 0px; FONT-FAMILY: = inherit; BORDER-RIGHT-WIDTH: 0px; outline-style: none } ACRONYM { BORDER-TOP-WIDTH: 0px; PADDING-RIGHT: 0px; PADDING-LEFT: 0px; = BORDER-LEFT-WIDTH: 0px; BORDER-BOTTOM-WIDTH: 0px; PADDING-BOTTOM: 0px; = MARGIN: 0px; VERTICAL-ALIGN: baseline; PADDING-TOP: 0px; FONT-FAMILY: = inherit; BORDER-RIGHT-WIDTH: 0px; outline-style: none } ADDRESS { BORDER-TOP-WIDTH: 0px; PADDING-RIGHT: 0px; PADDING-LEFT: 0px; = BORDER-LEFT-WIDTH: 0px; BORDER-BOTTOM-WIDTH: 0px; PADDING-BOTTOM: 0px; = MARGIN: 0px; VERTICAL-ALIGN: baseline; PADDING-TOP: 0px; FONT-FAMILY: = inherit; BORDER-RIGHT-WIDTH: 0px; outline-style: none } BIG { BORDER-TOP-WIDTH: 0px; PADDING-RIGHT: 0px; PADDING-LEFT: 0px; = BORDER-LEFT-WIDTH: 0px; BORDER-BOTTOM-WIDTH: 0px; PADDING-BOTTOM: 0px; = MARGIN: 0px; VERTICAL-ALIGN: baseline; PADDING-TOP: 0px; FONT-FAMILY: = inherit; BORDER-RIGHT-WIDTH: 0px; outline-style: none } CITE { BORDER-TOP-WIDTH: 0px; PADDING-RIGHT: 0px; PADDING-LEFT: 0px; = BORDER-LEFT-WIDTH: 0px; BORDER-BOTTOM-WIDTH: 0px; PADDING-BOTTOM: 0px; = MARGIN: 0px; VERTICAL-ALIGN: baseline; PADDING-TOP: 0px; FONT-FAMILY: = inherit; BORDER-RIGHT-WIDTH: 0px; outline-style: none } CODE { BORDER-TOP-WIDTH: 0px; PADDING-RIGHT: 0px; PADDING-LEFT: 0px; = BORDER-LEFT-WIDTH: 0px; BORDER-BOTTOM-WIDTH: 0px; PADDING-BOTTOM: 0px; = MARGIN: 0px; VERTICAL-ALIGN: baseline; PADDING-TOP: 0px; FONT-FAMILY: = inherit; BORDER-RIGHT-WIDTH: 0px; outline-style: none } DEL { BORDER-TOP-WIDTH: 0px; PADDING-RIGHT: 0px; PADDING-LEFT: 0px; = BORDER-LEFT-WIDTH: 0px; BORDER-BOTTOM-WIDTH: 0px; PADDING-BOTTOM: 0px; = MARGIN: 0px; VERTICAL-ALIGN: baseline; PADDING-TOP: 0px; FONT-FAMILY: = inherit; BORDER-RIGHT-WIDTH: 0px; outline-style: none } DFN { BORDER-TOP-WIDTH: 0px; PADDING-RIGHT: 0px; PADDING-LEFT: 0px; = BORDER-LEFT-WIDTH: 0px; BORDER-BOTTOM-WIDTH: 0px; PADDING-BOTTOM: 0px; = MARGIN: 0px; VERTICAL-ALIGN: baseline; PADDING-TOP: 0px; FONT-FAMILY: = inherit; BORDER-RIGHT-WIDTH: 0px; outline-style: none } EM { BORDER-TOP-WIDTH: 0px; PADDING-RIGHT: 0px; PADDING-LEFT: 0px; = BORDER-LEFT-WIDTH: 0px; BORDER-BOTTOM-WIDTH: 0px; PADDING-BOTTOM: 0px; = MARGIN: 0px; VERTICAL-ALIGN: baseline; PADDING-TOP: 0px; FONT-FAMILY: = inherit; BORDER-RIGHT-WIDTH: 0px; outline-style: none } FONT { BORDER-TOP-WIDTH: 0px; PADDING-RIGHT: 0px; PADDING-LEFT: 0px; = BORDER-LEFT-WIDTH: 0px; BORDER-BOTTOM-WIDTH: 0px; PADDING-BOTTOM: 0px; = MARGIN: 0px; VERTICAL-ALIGN: baseline; PADDING-TOP: 0px; FONT-FAMILY: = inherit; BORDER-RIGHT-WIDTH: 0px; outline-style: none } IMG { BORDER-TOP-WIDTH: 0px; PADDING-RIGHT: 0px; PADDING-LEFT: 0px; = BORDER-LEFT-WIDTH: 0px; BORDER-BOTTOM-WIDTH: 0px; PADDING-BOTTOM: 0px; = MARGIN: 0px; VERTICAL-ALIGN: baseline; PADDING-TOP: 0px; FONT-FAMILY: = inherit; BORDER-RIGHT-WIDTH: 0px; outline-style: none } INS { BORDER-TOP-WIDTH: 0px; PADDING-RIGHT: 0px; PADDING-LEFT: 0px; = BORDER-LEFT-WIDTH: 0px; BORDER-BOTTOM-WIDTH: 0px; PADDING-BOTTOM: 0px; = MARGIN: 0px; VERTICAL-ALIGN: baseline; PADDING-TOP: 0px; FONT-FAMILY: = inherit; BORDER-RIGHT-WIDTH: 0px; outline-style: none } KBD { BORDER-TOP-WIDTH: 0px; PADDING-RIGHT: 0px; PADDING-LEFT: 0px; = BORDER-LEFT-WIDTH: 0px; BORDER-BOTTOM-WIDTH: 0px; PADDING-BOTTOM: 0px; = MARGIN: 0px; VERTICAL-ALIGN: baseline; PADDING-TOP: 0px; FONT-FAMILY: = inherit; BORDER-RIGHT-WIDTH: 0px; outline-style: none } Q { BORDER-TOP-WIDTH: 0px; PADDING-RIGHT: 0px; PADDING-LEFT: 0px; = BORDER-LEFT-WIDTH: 0px; BORDER-BOTTOM-WIDTH: 0px; PADDING-BOTTOM: 0px; = MARGIN: 0px; VERTICAL-ALIGN: baseline; PADDING-TOP: 0px; FONT-FAMILY: = inherit; BORDER-RIGHT-WIDTH: 0px; outline-style: none } S { BORDER-TOP-WIDTH: 0px; PADDING-RIGHT: 0px; PADDING-LEFT: 0px; = BORDER-LEFT-WIDTH: 0px; BORDER-BOTTOM-WIDTH: 0px; PADDING-BOTTOM: 0px; = MARGIN: 0px; VERTICAL-ALIGN: baseline; PADDING-TOP: 0px; FONT-FAMILY: = inherit; BORDER-RIGHT-WIDTH: 0px; outline-style: none } SAMP { BORDER-TOP-WIDTH: 0px; PADDING-RIGHT: 0px; PADDING-LEFT: 0px; = BORDER-LEFT-WIDTH: 0px; BORDER-BOTTOM-WIDTH: 0px; PADDING-BOTTOM: 0px; = MARGIN: 0px; VERTICAL-ALIGN: baseline; PADDING-TOP: 0px; FONT-FAMILY: = inherit; BORDER-RIGHT-WIDTH: 0px; outline-style: none } SMALL { BORDER-TOP-WIDTH: 0px; PADDING-RIGHT: 0px; PADDING-LEFT: 0px; = BORDER-LEFT-WIDTH: 0px; BORDER-BOTTOM-WIDTH: 0px; PADDING-BOTTOM: 0px; = MARGIN: 0px; VERTICAL-ALIGN: baseline; PADDING-TOP: 0px; FONT-FAMILY: = inherit; BORDER-RIGHT-WIDTH: 0px; outline-style: none } STRIKE { BORDER-TOP-WIDTH: 0px; PADDING-RIGHT: 0px; PADDING-LEFT: 0px; = BORDER-LEFT-WIDTH: 0px; BORDER-BOTTOM-WIDTH: 0px; PADDING-BOTTOM: 0px; = MARGIN: 0px; VERTICAL-ALIGN: baseline; PADDING-TOP: 0px; FONT-FAMILY: = inherit; BORDER-RIGHT-WIDTH: 0px; outline-style: none } STRONG { BORDER-TOP-WIDTH: 0px; PADDING-RIGHT: 0px; PADDING-LEFT: 0px; = BORDER-LEFT-WIDTH: 0px; BORDER-BOTTOM-WIDTH: 0px; PADDING-BOTTOM: 0px; = MARGIN: 0px; VERTICAL-ALIGN: baseline; PADDING-TOP: 0px; FONT-FAMILY: = inherit; BORDER-RIGHT-WIDTH: 0px; outline-style: none } SUB { BORDER-TOP-WIDTH: 0px; PADDING-RIGHT: 0px; PADDING-LEFT: 0px; = BORDER-LEFT-WIDTH: 0px; BORDER-BOTTOM-WIDTH: 0px; PADDING-BOTTOM: 0px; = MARGIN: 0px; VERTICAL-ALIGN: baseline; PADDING-TOP: 0px; FONT-FAMILY: = inherit; BORDER-RIGHT-WIDTH: 0px; outline-style: none } SUP { BORDER-TOP-WIDTH: 0px; PADDING-RIGHT: 0px; PADDING-LEFT: 0px; = BORDER-LEFT-WIDTH: 0px; BORDER-BOTTOM-WIDTH: 0px; PADDING-BOTTOM: 0px; = MARGIN: 0px; VERTICAL-ALIGN: baseline; PADDING-TOP: 0px; FONT-FAMILY: = inherit; BORDER-RIGHT-WIDTH: 0px; outline-style: none } TT { BORDER-TOP-WIDTH: 0px; PADDING-RIGHT: 0px; PADDING-LEFT: 0px; = BORDER-LEFT-WIDTH: 0px; BORDER-BOTTOM-WIDTH: 0px; PADDING-BOTTOM: 0px; = MARGIN: 0px; VERTICAL-ALIGN: baseline; PADDING-TOP: 0px; FONT-FAMILY: = inherit; BORDER-RIGHT-WIDTH: 0px; outline-style: none } VAR { BORDER-TOP-WIDTH: 0px; PADDING-RIGHT: 0px; PADDING-LEFT: 0px; = BORDER-LEFT-WIDTH: 0px; BORDER-BOTTOM-WIDTH: 0px; PADDING-BOTTOM: 0px; = MARGIN: 0px; VERTICAL-ALIGN: baseline; PADDING-TOP: 0px; FONT-FAMILY: = inherit; BORDER-RIGHT-WIDTH: 0px; outline-style: none } DL { BORDER-TOP-WIDTH: 0px; PADDING-RIGHT: 0px; PADDING-LEFT: 0px; = BORDER-LEFT-WIDTH: 0px; BORDER-BOTTOM-WIDTH: 0px; PADDING-BOTTOM: 0px; = MARGIN: 0px; VERTICAL-ALIGN: baseline; PADDING-TOP: 0px; FONT-FAMILY: = inherit; BORDER-RIGHT-WIDTH: 0px; outline-style: none } DT { BORDER-TOP-WIDTH: 0px; PADDING-RIGHT: 0px; PADDING-LEFT: 0px; = BORDER-LEFT-WIDTH: 0px; BORDER-BOTTOM-WIDTH: 0px; PADDING-BOTTOM: 0px; = MARGIN: 0px; VERTICAL-ALIGN: baseline; PADDING-TOP: 0px; FONT-FAMILY: = inherit; BORDER-RIGHT-WIDTH: 0px; outline-style: none } DD { BORDER-TOP-WIDTH: 0px; PADDING-RIGHT: 0px; PADDING-LEFT: 0px; = BORDER-LEFT-WIDTH: 0px; BORDER-BOTTOM-WIDTH: 0px; PADDING-BOTTOM: 0px; = MARGIN: 0px; VERTICAL-ALIGN: baseline; PADDING-TOP: 0px; FONT-FAMILY: = inherit; BORDER-RIGHT-WIDTH: 0px; outline-style: none } OL { BORDER-TOP-WIDTH: 0px; PADDING-RIGHT: 0px; PADDING-LEFT: 0px; = BORDER-LEFT-WIDTH: 0px; BORDER-BOTTOM-WIDTH: 0px; PADDING-BOTTOM: 0px; = MARGIN: 0px; VERTICAL-ALIGN: baseline; PADDING-TOP: 0px; FONT-FAMILY: = inherit; BORDER-RIGHT-WIDTH: 0px; outline-style: none } UL { BORDER-TOP-WIDTH: 0px; PADDING-RIGHT: 0px; PADDING-LEFT: 0px; = BORDER-LEFT-WIDTH: 0px; BORDER-BOTTOM-WIDTH: 0px; PADDING-BOTTOM: 0px; = MARGIN: 0px; VERTICAL-ALIGN: baseline; PADDING-TOP: 0px; FONT-FAMILY: = inherit; BORDER-RIGHT-WIDTH: 0px; outline-style: none } LI { BORDER-TOP-WIDTH: 0px; PADDING-RIGHT: 0px; PADDING-LEFT: 0px; = BORDER-LEFT-WIDTH: 0px; BORDER-BOTTOM-WIDTH: 0px; PADDING-BOTTOM: 0px; = MARGIN: 0px; VERTICAL-ALIGN: baseline; PADDING-TOP: 0px; FONT-FAMILY: = inherit; BORDER-RIGHT-WIDTH: 0px; outline-style: none } FIELDSET { BORDER-TOP-WIDTH: 0px; PADDING-RIGHT: 0px; PADDING-LEFT: 0px; = BORDER-LEFT-WIDTH: 0px; BORDER-BOTTOM-WIDTH: 0px; PADDING-BOTTOM: 0px; = MARGIN: 0px; VERTICAL-ALIGN: baseline; PADDING-TOP: 0px; FONT-FAMILY: = inherit; BORDER-RIGHT-WIDTH: 0px; outline-style: none } FORM { BORDER-TOP-WIDTH: 0px; PADDING-RIGHT: 0px; PADDING-LEFT: 0px; = BORDER-LEFT-WIDTH: 0px; BORDER-BOTTOM-WIDTH: 0px; PADDING-BOTTOM: 0px; = MARGIN: 0px; VERTICAL-ALIGN: baseline; PADDING-TOP: 0px; FONT-FAMILY: = inherit; BORDER-RIGHT-WIDTH: 0px; outline-style: none } LABEL { BORDER-TOP-WIDTH: 0px; PADDING-RIGHT: 0px; PADDING-LEFT: 0px; = BORDER-LEFT-WIDTH: 0px; BORDER-BOTTOM-WIDTH: 0px; PADDING-BOTTOM: 0px; = MARGIN: 0px; VERTICAL-ALIGN: baseline; PADDING-TOP: 0px; FONT-FAMILY: = inherit; BORDER-RIGHT-WIDTH: 0px; outline-style: none } LEGEND { BORDER-TOP-WIDTH: 0px; PADDING-RIGHT: 0px; PADDING-LEFT: 0px; = BORDER-LEFT-WIDTH: 0px; BORDER-BOTTOM-WIDTH: 0px; PADDING-BOTTOM: 0px; = MARGIN: 0px; VERTICAL-ALIGN: baseline; PADDING-TOP: 0px; FONT-FAMILY: = inherit; BORDER-RIGHT-WIDTH: 0px; outline-style: none } TABLE { BORDER-TOP-WIDTH: 0px; PADDING-RIGHT: 0px; PADDING-LEFT: 0px; = BORDER-LEFT-WIDTH: 0px; BORDER-BOTTOM-WIDTH: 0px; PADDING-BOTTOM: 0px; = MARGIN: 0px; VERTICAL-ALIGN: baseline; PADDING-TOP: 0px; FONT-FAMILY: = inherit; BORDER-RIGHT-WIDTH: 0px; outline-style: none } CAPTION { BORDER-TOP-WIDTH: 0px; PADDING-RIGHT: 0px; PADDING-LEFT: 0px; = BORDER-LEFT-WIDTH: 0px; BORDER-BOTTOM-WIDTH: 0px; PADDING-BOTTOM: 0px; = MARGIN: 0px; VERTICAL-ALIGN: baseline; PADDING-TOP: 0px; FONT-FAMILY: = inherit; BORDER-RIGHT-WIDTH: 0px; outline-style: none } TBODY { BORDER-TOP-WIDTH: 0px; PADDING-RIGHT: 0px; PADDING-LEFT: 0px; = BORDER-LEFT-WIDTH: 0px; BORDER-BOTTOM-WIDTH: 0px; PADDING-BOTTOM: 0px; = MARGIN: 0px; VERTICAL-ALIGN: baseline; PADDING-TOP: 0px; FONT-FAMILY: = inherit; BORDER-RIGHT-WIDTH: 0px; outline-style: none } TFOOT { BORDER-TOP-WIDTH: 0px; PADDING-RIGHT: 0px; PADDING-LEFT: 0px; = BORDER-LEFT-WIDTH: 0px; BORDER-BOTTOM-WIDTH: 0px; PADDING-BOTTOM: 0px; = MARGIN: 0px; VERTICAL-ALIGN: baseline; PADDING-TOP: 0px; FONT-FAMILY: = inherit; BORDER-RIGHT-WIDTH: 0px; outline-style: none } THEAD { BORDER-TOP-WIDTH: 0px; PADDING-RIGHT: 0px; PADDING-LEFT: 0px; = BORDER-LEFT-WIDTH: 0px; BORDER-BOTTOM-WIDTH: 0px; PADDING-BOTTOM: 0px; = MARGIN: 0px; VERTICAL-ALIGN: baseline; PADDING-TOP: 0px; FONT-FAMILY: = inherit; BORDER-RIGHT-WIDTH: 0px; outline-style: none } TR { BORDER-TOP-WIDTH: 0px; PADDING-RIGHT: 0px; PADDING-LEFT: 0px; = BORDER-LEFT-WIDTH: 0px; BORDER-BOTTOM-WIDTH: 0px; PADDING-BOTTOM: 0px; = MARGIN: 0px; VERTICAL-ALIGN: baseline; PADDING-TOP: 0px; FONT-FAMILY: = inherit; BORDER-RIGHT-WIDTH: 0px; outline-style: none } TH { BORDER-TOP-WIDTH: 0px; PADDING-RIGHT: 0px; PADDING-LEFT: 0px; = BORDER-LEFT-WIDTH: 0px; BORDER-BOTTOM-WIDTH: 0px; PADDING-BOTTOM: 0px; = MARGIN: 0px; VERTICAL-ALIGN: baseline; PADDING-TOP: 0px; FONT-FAMILY: = inherit; BORDER-RIGHT-WIDTH: 0px; outline-style: none } TD { BORDER-TOP-WIDTH: 0px; PADDING-RIGHT: 0px; PADDING-LEFT: 0px; = BORDER-LEFT-WIDTH: 0px; BORDER-BOTTOM-WIDTH: 0px; PADDING-BOTTOM: 0px; = MARGIN: 0px; VERTICAL-ALIGN: baseline; PADDING-TOP: 0px; FONT-FAMILY: = inherit; BORDER-RIGHT-WIDTH: 0px; outline-style: none } A IMG { BORDER-TOP-WIDTH: 0px; BORDER-LEFT-WIDTH: 0px; BORDER-BOTTOM-WIDTH: = 0px; BORDER-RIGHT-WIDTH: 0px } :link IMG { BORDER-TOP-WIDTH: 0px; BORDER-LEFT-WIDTH: 0px; BORDER-BOTTOM-WIDTH: = 0px; BORDER-RIGHT-WIDTH: 0px } :visited IMG { BORDER-TOP-WIDTH: 0px; BORDER-LEFT-WIDTH: 0px; BORDER-BOTTOM-WIDTH: = 0px; BORDER-RIGHT-WIDTH: 0px } :focus { outline: none } BODY { BACKGROUND: white; COLOR: black; LINE-HEIGHT: 1.25 } TABLE { BORDER-COLLAPSE: collapse; border-spacing: 0px } CAPTION { FONT-WEIGHT: normal; TEXT-ALIGN: left } TH { FONT-WEIGHT: normal; TEXT-ALIGN: left } TD { FONT-WEIGHT: normal; TEXT-ALIGN: left } BLOCKQUOTE:unknown { content: "" } BLOCKQUOTE:unknown { content: "" } Q:unknown { content: "" } Q:unknown { content: "" } BLOCKQUOTE { quotes: "" "" } Q { quotes: "" "" } BODY { FONT-SIZE: 100%; BACKGROUND: white fixed no-repeat; COLOR: black; = LINE-HEIGHT: 1; FONT-FAMILY: "Lucida Grande", "Lucida Sans Unicode", = Tahoma, Verdana, Arial, Helvetica, sans-serif } P { MARGIN: 1em 5% } PRE { MARGIN: 1em 5% } LABEL { MARGIN: 1em 5% } UL { MARGIN: 1em 5% } OL { MARGIN: 1em 5% } DL { MARGIN: 1em 5% } FIELDSET { MARGIN: 1em 5% } ADDRESS { MARGIN: 1em 5% } H1 { MARGIN: 0px 0px 0.4em } H2 { MARGIN: 0px 0px 0.4em } H3 { MARGIN: 0px 0px 0.4em } H4 { MARGIN: 0px 0px 0.4em } H5 { MARGIN: 0px 0px 0.4em } H6 { MARGIN: 0px 0px 0.4em } H1 { FONT-WEIGHT: bold; TEXT-ALIGN: left } H2 { FONT-WEIGHT: bold; TEXT-ALIGN: left } H3 { FONT-WEIGHT: bold; TEXT-ALIGN: left } H4 { FONT-WEIGHT: bold; TEXT-ALIGN: left } H1 { FONT-SIZE: 1.8em } H2 { FONT-SIZE: 1.5em } H3 { FONT-SIZE: 1.2em } BLOCKQUOTE { MARGIN: 1em 7% } LI { MARGIN-LEFT: 5% } DD { MARGIN-LEFT: 5% } FIELDSET { PADDING-RIGHT: 0.5em; PADDING-LEFT: 0.5em; PADDING-BOTTOM: 0.5em; = PADDING-TOP: 0.5em } EM { FONT-STYLE: italic } STRONG { FONT-WEIGHT: 700 } CODE { FONT-FAMILY: Courier New, Courier, monospace } VAR { FONT-FAMILY: Courier New, Courier, monospace } KBD { FONT-FAMILY: Courier New, Courier, monospace } SAMP { FONT-FAMILY: Courier New, Courier, monospace } PRE { FONT-FAMILY: Courier New, Courier, monospace } SUP { FONT-SIZE: 0.85em; VERTICAL-ALIGN: super; LINE-HEIGHT: 0 } SUB { FONT-SIZE: 0.85em; VERTICAL-ALIGN: sub; LINE-HEIGHT: 0 } DIV.hw-gen-page { PADDING-RIGHT: 4em; PADDING-LEFT: 2em; FONT-SIZE: 0.8em; = PADDING-BOTTOM: 2em; PADDING-TOP: 0.5em } .hw-gen-page #skip-link { LEFT: -9999px; POSITION: absolute } #content-block { BORDER-TOP-WIDTH: 0px; PADDING-RIGHT: 0px; PADDING-LEFT: 0px; = BORDER-LEFT-WIDTH: 0px; BORDER-BOTTOM-WIDTH: 0px; PADDING-BOTTOM: 0px; = MARGIN: 0px; OVERFLOW: hidden; LINE-HEIGHT: 1.3; PADDING-TOP: 0px; = BORDER-RIGHT-WIDTH: 0px } #content-block P { BORDER-TOP-WIDTH: 0px; PADDING-RIGHT: 0px; PADDING-LEFT: 0px; = BORDER-LEFT-WIDTH: 0px; BORDER-BOTTOM-WIDTH: 0px; PADDING-BOTTOM: 0px; = MARGIN: 15px 0px; LINE-HEIGHT: 1.5; PADDING-TOP: 0px; = BORDER-RIGHT-WIDTH: 0px } #content-block { PADDING-RIGHT: 20px; PADDING-LEFT: 5px; FLOAT: right; PADDING-BOTTOM: = 0px; WIDTH: 518px; PADDING-TOP: 0px } #col-2 { OVERFLOW: hidden; WIDTH: 210px } #col-3 { OVERFLOW: hidden; WIDTH: 210px } #col-2 { FLOAT: left } #proxied-contents #col-2 { FLOAT: left } #proxied-contents #col-main { PADDING-RIGHT: 10px; FLOAT: left; OVERFLOW: hidden; WIDTH: 533px } #footer { CLEAR: both } .banner-ads UL { LIST-STYLE-TYPE: none } DIV.hw-gen-page IMG.adborder0 { BORDER-RIGHT: black 0px solid; BORDER-TOP: black 0px solid; = BORDER-LEFT: black 0px solid; BORDER-BOTTOM: black 0px solid } DIV.hw-gen-page IMG.adborder1 { BORDER-RIGHT: black 1px solid; BORDER-TOP: black 1px solid; = BORDER-LEFT: black 1px solid; BORDER-BOTTOM: black 1px solid } DIV.hw-gen-page IMG.adborder2 { BORDER-RIGHT: black 2px solid; BORDER-TOP: black 2px solid; = BORDER-LEFT: black 2px solid; BORDER-BOTTOM: black 2px solid } 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BORDER-TOP-STYLE: none; BORDER-RIGHT-STYLE: none; = BORDER-LEFT-STYLE: none; BORDER-BOTTOM-STYLE: none } #col-2 A { COLOR: #404040 } #col-2 A:link { COLOR: #404040 } #col-3 A { COLOR: #404040 } #col-3 A:link { COLOR: #404040 } #col-2 A:visited { COLOR: #581858 } #col-3 A:visited { COLOR: #581858 } #col-2 A:hover { COLOR: #404040; BORDER-BOTTOM: #404040 1px dotted; TEXT-DECORATION: = none } #col-3 A:hover { COLOR: #404040; BORDER-BOTTOM: #404040 1px dotted; TEXT-DECORATION: = none } #col-2 A:active { COLOR: #404040 } #col-3 A:active { COLOR: #404040 } #col-3 UL.cover-announce A { COLOR: #2f5085 } #col-3 UL.cover-announce A:link { COLOR: #2f5085 } #col-3 UL.cover-announce A:visited { COLOR: #2f5085 } #col-3 UL.cover-announce A:hover { COLOR: #2f5085; BORDER-BOTTOM: #2f5085 1px dotted; TEXT-DECORATION: = none } #col-3 UL.cover-announce A:active { COLOR: #2f5085 } DIV.sidebar A:hover { TEXT-DECORATION: none } DIV#header { BACKGROUND-POSITION: right top; MARGIN-TOP: 0px; BACKGROUND-IMAGE: = url(/shared/img/standard-design/design2/corner.gif); WIDTH: 960px; = BACKGROUND-REPEAT: no-repeat; BORDER-BOTTOM-STYLE: none } #header #main-logo { MARGIN: 15px 0px 0px 24px; BORDER-TOP-STYLE: none; BORDER-RIGHT-STYLE: = none; BORDER-LEFT-STYLE: none; BORDER-BOTTOM-STYLE: none } #header UL.home-page-ads { PADDING-RIGHT: 10px; PADDING-LEFT: 10px; LEFT: 450px; PADDING-BOTTOM: = 5px; MARGIN: 1.5em 0px 35px; WIDTH: 250px; PADDING-TOP: 5px; = LIST-STYLE-TYPE: none; POSITION: absolute; TOP: 0px } #header UL.home-page-ads LI { PADDING-RIGHT: 0px; PADDING-LEFT: 0px; PADDING-BOTTOM: 0px; MARGIN: = 0px; WIDTH: 250px; PADDING-TOP: 0px; HEIGHT: 40px; TEXT-ALIGN: center } #header UL.home-page-ads LI IMG { BORDER-RIGHT: #aaaaaa 1px solid; BORDER-TOP: #aaaaaa 1px solid; = DISPLAY: block; BORDER-LEFT: #aaaaaa 1px solid; WIDTH: 250px; = BORDER-BOTTOM: #aaaaaa 1px solid; HEIGHT: 40px; BACKGROUND-COLOR: = #e0e0e0 } #header .banner-ads { PADDING-RIGHT: 10px; PADDING-LEFT: 10px; LEFT: 450px; PADDING-BOTTOM: = 5px; MARGIN: 1.5em 0px 35px; WIDTH: 250px; PADDING-TOP: 5px; = LIST-STYLE-TYPE: none; POSITION: absolute; TOP: 0px } .banner-ads#header UL { LIST-STYLE-TYPE: none } #header .banner-ads LI { PADDING-RIGHT: 0px; PADDING-LEFT: 0px; PADDING-BOTTOM: 0px; MARGIN: = 0px; PADDING-TOP: 0px; TEXT-ALIGN: center } #header .banner-ads LI IMG { BORDER-RIGHT: #aaaaaa 1px solid; BORDER-TOP: #aaaaaa 1px solid; = DISPLAY: block; BORDER-LEFT: #aaaaaa 1px solid; BORDER-BOTTOM: #aaaaaa = 1px solid; BACKGROUND-COLOR: #e0e0e0 } #header .header-buttons { PADDING-RIGHT: 0px; PADDING-LEFT: 0px; PADDING-BOTTOM: 0px; MARGIN: 5px = 0px 8px 24px; PADDING-TOP: 0px; LIST-STYLE-TYPE: none } #header .header-buttons { COLOR: #0083a8 } #header .header-buttons A { COLOR: #0083a8 } #header .header-buttons LI { PADDING-RIGHT: 0.4em; DISPLAY: inline; PADDING-LEFT: 0.4em; = PADDING-BOTTOM: 0px; MARGIN: 0px; BORDER-LEFT: #666666 1px solid; = PADDING-TOP: 0px } #header .header-buttons LI SPAN { FONT-WEIGHT: bold; FONT-SIZE: 87.5% } #header .header-buttons LI.first { PADDING-LEFT: 0px; BORDER-LEFT-STYLE: none } #header .corner { RIGHT: 0px; POSITION: absolute; TOP: 0px } #header .inst-branding { BORDER-LEFT: #c8c8c8 1px dashed } #header #hdr-login { BORDER-LEFT: #c8c8c8 1px dashed } #header .header-qs { BORDER-LEFT: #c8c8c8 1px dashed } #header .inst-branding { PADDING-LEFT: 5px; LEFT: 756px; POSITION: absolute; TOP: 0px; HEIGHT: = 30px } #header #authstring { DISPLAY: block; LEFT: 0%; WIDTH: 756px; LINE-HEIGHT: 100%; PADDING-TOP: = 5px; POSITION: absolute; TEXT-ALIGN: center } #header #authstring { COLOR: white } #header #authstring LI { PADDING-RIGHT: 2px; PADDING-LEFT: 2px; FONT-SIZE: 87.5%; = PADDING-BOTTOM: 2px; BORDER-TOP-STYLE: none; PADDING-TOP: 2px; = BORDER-RIGHT-STYLE: none; BORDER-LEFT-STYLE: none; LIST-STYLE-TYPE: = none; BORDER-BOTTOM-STYLE: none } #header #authstring A { COLOR: white } #header #hdr-login { PADDING-RIGHT: 0px; PADDING-LEFT: 10px; LEFT: 756px; PADDING-BOTTOM: = 5px; PADDING-TOP: 0px; POSITION: absolute; TOP: 30px } #header #hdr-login FORM LABEL { FONT-SIZE: 87.5%; WHITE-SPACE: nowrap } #header #hdr-login INPUT { FONT-SIZE: 87.5%; WHITE-SPACE: nowrap } #header #hdr-login { COLOR: #0083a8 } #header #hdr-login LABEL { PADDING-RIGHT: 0px; DISPLAY: block; PADDING-LEFT: 0px; FONT-SIZE: = 87.5%; PADDING-BOTTOM: 2px; MARGIN: 0px; WIDTH: 80px; PADDING-TOP: 5px } #header #hdr-login INPUT { PADDING-RIGHT: 0px; PADDING-LEFT: 0px; FONT-SIZE: 87.5%; = PADDING-BOTTOM: 0px; WIDTH: 110px; PADDING-TOP: 0px; HEIGHT: 15px } #header .header-qs INPUT { PADDING-RIGHT: 0px; PADDING-LEFT: 0px; FONT-SIZE: 87.5%; = PADDING-BOTTOM: 0px; WIDTH: 110px; PADDING-TOP: 0px; HEIGHT: 15px } #header #hdr-login INPUT#hdr-login-signin { PADDING-RIGHT: 0px; PADDING-LEFT: 5px; PADDING-BOTTOM: 0px; = VERTICAL-ALIGN: bottom; WIDTH: auto; PADDING-TOP: 0px; HEIGHT: auto } #header .bar { PADDING-LEFT: 20px; MARGIN-LEFT: -20px; WIDTH: 980px; HEIGHT: 60px } #footer .bar { PADDING-LEFT: 20px; MARGIN-LEFT: -20px; WIDTH: 980px; HEIGHT: 60px } #header .bar { BACKGROUND-COLOR: #0083a8 } #footer .bar { BACKGROUND-COLOR: #0083a8 } #header .bar-inner { WIDTH: 960px; COLOR: white; HEIGHT: 60px } #header .bar-inner { BACKGROUND-COLOR: #00a0cc } #footer .footer-group { BACKGROUND-COLOR: #00a0cc } #header .header-qs { PADDING-RIGHT: 5px; DISPLAY: block; PADDING-LEFT: 10px; Z-INDEX: 1; = LEFT: 756px; PADDING-BOTTOM: 7px; MARGIN: 0px; WIDTH: 195px; = PADDING-TOP: 10px; POSITION: absolute; TOP: 112px; HEIGHT: 40px } #header .header-qs LABEL { LEFT: -9999px; POSITION: absolute } #header #hdr-login-signin-label { LEFT: -9999px; POSITION: absolute } #header #header-qs-search-label { LEFT: -9999px; POSITION: absolute } #header .header-qs A { FONT-SIZE: 87.5%; COLOR: white; LINE-HEIGHT: 1.5; WHITE-SPACE: nowrap } #header DIV.adv-search-link A:hover { COLOR: white; BORDER-BOTTOM: white 1px dotted } #header DIV.adv-search-link A:visited { COLOR: white } #header DIV.adv-search-link A:active { COLOR: white } #header DIV.adv-search-link A:link { COLOR: white } #header .header-qs INPUT#header-qs-search-go { MARGIN-LEFT: 0.5em; VERTICAL-ALIGN: bottom; WIDTH: 27px; HEIGHT: auto } #content-block { PADDING-RIGHT: 20px; PADDING-LEFT: 5px; FLOAT: left; PADDING-BOTTOM: = 0px; WIDTH: 518px; PADDING-TOP: 0px } #col-2 { PADDING-RIGHT: 0px; PADDING-LEFT: 0px; PADDING-BOTTOM: 0px; MARGIN: = 0px; PADDING-TOP: 0px } #col-3 { PADDING-RIGHT: 0px; PADDING-LEFT: 0px; PADDING-BOTTOM: 0px; MARGIN: = 0px; PADDING-TOP: 0px } #col-2 { BORDER-RIGHT: #aaaaaa 1px dashed; PADDING-RIGHT: 13px; FLOAT: left; = MARGIN: 0px; OVERFLOW: hidden; WIDTH: 200px } #content-block { COLOR: #403838; BACKGROUND-COLOR: white } .pagetype-proxied #content-block { BORDER-RIGHT: #aaaaaa 1px dashed; PADDING-RIGHT: 0px; PADDING-LEFT: = 0px; PADDING-BOTTOM: 0px; WIDTH: 756px; PADDING-TOP: 0px } .proxied-column-display#proxied-contents #col-main { PADDING-RIGHT: 10px; FLOAT: left; OVERFLOW: hidden; WIDTH: 518px } .proxied-column-display#proxied-contents #col-2 { BORDER-RIGHT: 0px solid; FLOAT: left } #proxied-contents { PADDING-RIGHT: 10px; PADDING-LEFT: 15px } .proxied-column-display#proxied-contents { PADDING-RIGHT: 0px } .proxied-column-display#proxied-contents .search-nav A { FONT-WEIGHT: normal; COLOR: black } .pagetype-proxied #header .banner-ads UL { MARGIN: 1em 5% } .pagetype-proxied #col-3 .content-box H3 { PADDING-RIGHT: 0px; PADDING-LEFT: 0px; FONT-SIZE: 1.2em; = PADDING-BOTTOM: 0.3em; MARGIN: 0px; PADDING-TOP: 0.3em } #proxied-contents TH { FONT-WEIGHT: bold } #proxied-contents TABLE { LINE-HEIGHT: 110% } #proxied-contents TD { PADDING-RIGHT: 0px; PADDING-LEFT: 0px; PADDING-BOTTOM: 0px; MARGIN: = 0px; PADDING-TOP: 0px } TR { PADDING-RIGHT: 0px; PADDING-LEFT: 0px; PADDING-BOTTOM: 0px; MARGIN: = 0px; PADDING-TOP: 0px } TH { PADDING-RIGHT: 0px; PADDING-LEFT: 0px; PADDING-BOTTOM: 0px; MARGIN: = 0px; PADDING-TOP: 0px } P { PADDING-RIGHT: 0px; PADDING-LEFT: 0px; PADDING-BOTTOM: 0px; MARGIN: = 0px; PADDING-TOP: 0px } OL { PADDING-RIGHT: 0px; PADDING-LEFT: 0px; PADDING-BOTTOM: 0px; MARGIN: = 0px; PADDING-TOP: 0px } UL { PADDING-RIGHT: 0px; PADDING-LEFT: 0px; PADDING-BOTTOM: 0px; MARGIN: = 0px; PADDING-TOP: 0px } #proxied-contents H1 { LINE-HEIGHT: 120%; TEXT-ALIGN: left } H3 { LINE-HEIGHT: 120%; TEXT-ALIGN: left } DL { LINE-HEIGHT: 120%; TEXT-ALIGN: left } DT { LINE-HEIGHT: 120%; TEXT-ALIGN: left } DD { LINE-HEIGHT: 120%; TEXT-ALIGN: left } #proxied-contents .proxied-collections H1 { MARGIN-TOP: 0.5em } #col-3 H1 { LINE-HEIGHT: 100%; TEXT-ALIGN: left } H3 { LINE-HEIGHT: 100%; TEXT-ALIGN: left } DL { LINE-HEIGHT: 100%; TEXT-ALIGN: left } DT { LINE-HEIGHT: 100%; TEXT-ALIGN: left } DD { LINE-HEIGHT: 100%; TEXT-ALIGN: left } #proxied-contents #col-3 P { MARGIN: 1em 5% } PRE { MARGIN: 1em 5% } LABEL { MARGIN: 1em 5% } UL { MARGIN: 1em 5% } OL { MARGIN: 1em 5% } DL { MARGIN: 1em 5% } FIELDSET { MARGIN: 1em 5% } ADDRESS { MARGIN: 1em 5% } #col-2 #cb-art-nav LI { MARGIN-TOP: 0.4em } #col-2 DIV.sidebar-issue-nav { MARGIN: 5px 0px 0px 5px } #col-2 DIV.article-nav { MARGIN: 5px 0px 0px 5px } #col-2 DIV.search-nav { MARGIN: 5px 0px 0px 5px } #col-3 { PADDING-RIGHT: 0px; PADDING-LEFT: 0px; FLOAT: left; PADDING-BOTTOM: = 0px; MARGIN: 0px; OVERFLOW: visible; WIDTH: 203px; PADDING-TOP: 0px; = TEXT-ALIGN: left } #col-3 { BACKGROUND-COLOR: white } #col-3 * { POSITION: static } #col-3 DIV { PADDING-RIGHT: 0px; PADDING-LEFT: 0px; PADDING-BOTTOM: 0px; MARGIN: = 0px; PADDING-TOP: 0px } DIV.content-box A:link { COLOR: #404040; TEXT-DECORATION: none } DIV.content-box A:visited { COLOR: #404040; TEXT-DECORATION: none } DIV.content-box A:hover { COLOR: #404040; TEXT-DECORATION: none } DIV.content-box A:active { COLOR: #404040; TEXT-DECORATION: none } #col-3 UL.pub-links LI A:link { BORDER-BOTTOM-WIDTH: 0px; TEXT-DECORATION: none } #col-3 UL.pub-links LI A:visited { BORDER-BOTTOM-WIDTH: 0px; TEXT-DECORATION: none } #col-3 UL.pub-links LI A:hover { BORDER-BOTTOM-WIDTH: 0px; TEXT-DECORATION: none } #col-3 UL.pub-links LI A:active { BORDER-BOTTOM-WIDTH: 0px; TEXT-DECORATION: none } #col-3 UL.ex-pub-links LI A:link { BORDER-BOTTOM-WIDTH: 0px; TEXT-DECORATION: none } #col-3 UL.ex-pub-links LI A:visited { BORDER-BOTTOM-WIDTH: 0px; TEXT-DECORATION: none } #col-3 UL.ex-pub-links LI A:hover { BORDER-BOTTOM-WIDTH: 0px; TEXT-DECORATION: none } #col-3 UL.ex-pub-links LI A:active { BORDER-BOTTOM-WIDTH: 0px; TEXT-DECORATION: none } #col-3 UL.pub-links { PADDING-RIGHT: 0px; PADDING-LEFT: 0px; LEFT: -7px; PADDING-BOTTOM: 0px; = MARGIN: 10px 0px; OVERFLOW: hidden; PADDING-TOP: 0px; POSITION: relative } #col-3 UL.pub-links { LIST-STYLE-TYPE: none } #col-3 UL.pub-links { COLOR: #0083a8 } #col-3 UL.pub-links LI A { COLOR: #0083a8 } #col-3 UL.pub-links LI { BORDER-RIGHT: #aaaaaa 1px dashed; PADDING-RIGHT: 5px; BORDER-TOP: = #aaaaaa 1px dashed; PADDING-LEFT: 4px; FONT-WEIGHT: bold; FONT-SIZE: = 0.85em; PADDING-BOTTOM: 10px; MARGIN: 0px; BORDER-LEFT: #aaaaaa 1px = dashed; PADDING-TOP: 10px; BORDER-BOTTOM: #aaaaaa 1px; POSITION: static; = BACKGROUND-COLOR: white } #col-3 UL.pub-links LI A { BACKGROUND-POSITION: left top; DISPLAY: block; PADDING-LEFT: 1em; = BACKGROUND-IMAGE: = url(/shared/img/standard-design/design2/jnl-link-bullet.gif); = LINE-HEIGHT: 1.2; BACKGROUND-REPEAT: no-repeat } #col-3 UL.pub-links LI.last { BORDER-BOTTOM: #aaaaaa 1px dashed } #col-3 .sidebar-icon-group { PADDING-RIGHT: 20px; PADDING-LEFT: 20px; PADDING-BOTTOM: 20px; = PADDING-TOP: 20px } #col-3 .sidebar-icon-group A:hover { BORDER-BOTTOM: 0px solid } #col-3 UL.ex-pub-links { PADDING-RIGHT: 0px; PADDING-LEFT: 0px; LEFT: -7px; PADDING-BOTTOM: 0px; = MARGIN: 10px 0px; OVERFLOW: hidden; PADDING-TOP: 0px; POSITION: relative } #col-3 UL.ex-pub-links { LIST-STYLE-TYPE: none } #col-3 UL.ex-pub-links { COLOR: #0083a8 } #col-3 UL.ex-pub-links LI A { COLOR: #0083a8 } #col-3 UL.ex-pub-links LI { BORDER-RIGHT: #aaaaaa 1px dashed; PADDING-RIGHT: 5px; BORDER-TOP: = #aaaaaa 1px dashed; PADDING-LEFT: 4px; FONT-WEIGHT: bold; FONT-SIZE: = 75%; PADDING-BOTTOM: 10px; MARGIN: 0px; BORDER-LEFT: #aaaaaa 1px dashed; = PADDING-TOP: 10px; BORDER-BOTTOM: #aaaaaa 1px; POSITION: static; = BACKGROUND-COLOR: white } #col-3 UL.ex-pub-links LI A { BACKGROUND-POSITION: left top; DISPLAY: block; PADDING-LEFT: 1em; = BACKGROUND-IMAGE: = url(/shared/img/standard-design/design2/jnl-link-bullet.gif); = LINE-HEIGHT: 1.2; BACKGROUND-REPEAT: no-repeat } #col-3 UL.ex-pub-links LI.last { BORDER-BOTTOM: #aaaaaa 1px dashed } #col-3 UL.tower-ads { PADDING-RIGHT: 0em; PADDING-LEFT: 0em; LIST-STYLE-IMAGE: none; = PADDING-BOTTOM: 0em; MARGIN: 0em; PADDING-TOP: 0em; LIST-STYLE-TYPE: = none } #col-3 UL.tower-ads LI IMG { PADDING-RIGHT: 0px; DISPLAY: block; PADDING-LEFT: 0px; PADDING-BOTTOM: = 0px; MARGIN: 0em auto 0.5em; PADDING-TOP: 0px } #col-3 .publisher-icon { =09 } #footer { WIDTH: 960px; TEXT-ALIGN: left } #footer { CLEAR: both; BACKGROUND-POSITION: 756px 0px; BACKGROUND-IMAGE: = url(/shared/img/standard-design/design2/dash.gif); PADDING-BOTTOM: 20px; = BACKGROUND-REPEAT: repeat-y; BACKGROUND-COLOR: white } #footer UL { FONT-SIZE: 80%; LIST-STYLE-TYPE: none } #footer .bar { CLEAR: both; POSITION: static } #footer .footer-group { FONT-WEIGHT: bold; COLOR: white; HEIGHT: 60px } #footer .footer-group P { PADDING-RIGHT: 10px; PADDING-LEFT: 10px; PADDING-BOTTOM: 10px; = PADDING-TOP: 10px } #footer .footer-col-left { BORDER-RIGHT: #c8c8c8 1px dashed; FLOAT: left; WIDTH: 756px } #footer .footer-col-right { FLOAT: left; WIDTH: 203px } #footer .footer-col-right UL { PADDING-RIGHT: 0px; DISPLAY: block; PADDING-LEFT: 0px; PADDING-BOTTOM: = 0px; MARGIN: 0px; PADDING-TOP: 8px; LIST-STYLE-TYPE: none } #footer .footer-col-right LI { PADDING-RIGHT: 10px; DISPLAY: block; PADDING-LEFT: 10px; = PADDING-BOTTOM: 4px; BORDER-TOP-STYLE: none; PADDING-TOP: 4px; = BORDER-RIGHT-STYLE: none; BORDER-LEFT-STYLE: none; TEXT-ALIGN: left; = BORDER-BOTTOM-STYLE: none } #footer .copyright { FONT-SIZE: 80%; MARGIN: 1em auto } #footer A:hover { COLOR: white; BORDER-BOTTOM: white 1px dotted } #skip-link { LEFT: -9999px; POSITION: absolute } #header #hdr-login { HEIGHT: 75px } DIV.hw-gen-page .view-more { BORDER-RIGHT: gray 1px solid; BORDER-TOP: gray 1px solid; BORDER-LEFT: = gray 1px solid; BORDER-BOTTOM: gray 1px solid } #header #hdr-login LABEL#hdr-login-signin-label { DISPLAY: inline } ------=_NextPart_000_0000_01CB196F.E2DD9DB0 Content-Type: text/css; charset="iso-8859-1" Content-Transfer-Encoding: quoted-printable Content-Location: http://clincancerres.aacrjournals.org/content/12/18/home-page.css #pageid-home #content-block DIV.main-block { FLOAT: left; MARGIN-BOTTOM: 10px; WIDTH: 350px } #pageid-home #content-block .main-block LI { MARGIN: 0px } #pageid-home #content-block .main-block UL { MARGIN: 0px } #pageid-home #content-block H2 { FONT-SIZE: 1.2em; FONT-FAMILY: Arial, "Lucida Grande", "Lucida Sans = Unicode", Tahoma, Verdana, Helvetica, sans-serif } #pageid-home #content-block H3 { FONT-SIZE: 1.2em; FONT-FAMILY: Arial, "Lucida Grande", "Lucida Sans = Unicode", Tahoma, Verdana, Helvetica, sans-serif } #pageid-home #content-block H2 { COLOR: #0083a8 } #pageid-home #content-block H3 { COLOR: #0083a8 } #pageid-home #content-block H2 A { COLOR: #0083a8 } #pageid-home #content-block DIV.home-announce A { COLOR: #0083a8 } #content-block DIV.home-announce A:hover { BORDER-TOP-WIDTH: 0px; BORDER-LEFT-WIDTH: 0px; BORDER-BOTTOM-WIDTH: = 0px; BORDER-RIGHT-WIDTH: 0px; TEXT-DECORATION: underline } #pageid-home #content-block H2.current-issue { PADDING-RIGHT: 0px; PADDING-LEFT: 0px; PADDING-BOTTOM: 20px; MARGIN: = 0px; PADDING-TOP: 20px } #pageid-home #content-block A.current-issue-link { BORDER-BOTTOM: #0083a8 1px dotted } #pageid-home #content-block .cover-img-wrap { LEFT: 20px; BACKGROUND-IMAGE: = url(/shared/img/standard-design/design2/cover_shadow.png); = BACKGROUND-REPEAT: no-repeat; POSITION: relative; TOP: -25px } #pageid-home #cover-image { LEFT: 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targetName =3D overrideTarget;=0A= }=0A= if ((overrideConfig !=3D undefined) && overrideConfig && = (overrideConfig.length > 0)) {=0A= config =3D overrideConfig;=0A= }=0A= }=0A= }=0A= var origTitle =3D $(this).attr("title");=0A= var newTitle =3D '';=0A= if ((origTitle =3D=3D undefined) || (!origTitle)) {=0A= origTitle =3D '';=0A= }=0A= else {=0A= newTitle =3D origTitle + ' ';=0A= }=0A= newTitle +=3D '[opens in a new window]';=0A= $(this).attr("target", targetName).attr("title", newTitle);=0A= if (config !=3D null) {=0A= $(this).click(function() {=0A= window.open(this.href, targetName, config);=0A= return false;=0A= });=0A= }=0A= }=0A= );=0A= =0A= /* attach onFocus handlers to quick-search fields, to clear the=0A= field when it receives focus IF it contains the default=0A= value (such as "Search the site") */=0A= updateFormInput("#header-qs-search-label", "#header-qs-input", '', '');=0A= =0A= /* handle collapsing content-box areas, with user prefs */=0A= setupCollapsibles();=0A= =0A= /* 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{=0A= contractStr =3D gSiteOptions.contractString;=0A= }=0A= else { contractStr =3D '-'; }=0A= }=0A= $(parentJQueryEl).each(=0A= function(i) {=0A= var $this =3D $(this);=0A= var id =3D $this.attr("id");=0A= if (id !=3D null) {=0A= var $labelElement, $label;=0A= for (var i =3D 0; i < gSiteOptions.collapsibleLabels.length; i++) {=0A= $labelElement =3D gSiteOptions.collapsibleLabels[i];=0A= $label =3D $this.find($labelElement);=0A= if ($label.length) {=0A= // get first one=0A= if ($label.length > 1) {=0A= $label =3D $label.eq(0);=0A= }=0A= break;=0A= }=0A= }=0A= =0A= // if there's already a toggle leave this as is=0A= var alreadyHasToggle =3D ($label.length && = $label.find("a.collapse-toggle").length);=0A= if ($label.length) {=0A= if (!(alreadyHasToggle)) {=0A= var labelText =3D $label.html();=0A= $label.empty().append('' + contractStr + = ' ' + labelText + '');=0A= }=0A= }=0A= =0A= var isOpen =3D true;=0A= if (setPrefs) {=0A= var statePref =3D getPrefValue(id + "-state");=0A= if (statePref && ((statePref =3D=3D 'open') || (statePref =3D=3D = 'closed'))) {=0A= if (statePref =3D=3D 'closed') {=0A= isOpen =3D false;=0A= }=0A= }=0A= else {=0A= // no pref, or unknown value=0A= if ($this.hasClass('default-closed')) {=0A= isOpen =3D false;=0A= }=0A= }=0A= }=0A= var childListType;=0A= if ($this.children("ol").length) {=0A= childListType =3D "ol";=0A= }=0A= else {=0A= childListType =3D "ul";=0A= }=0A= if (!isOpen && !(alreadyHasToggle)) {=0A= toggleCollapse($this, childListType, ($labelElement + " a = span.view-more"), expandStr, contractStr);=0A= }=0A= $this.find("a.collapse-toggle").click(=0A= function(e) {=0A= // need to find first parent that is in either state...=0A= // $(this).parents(".collapsible, .collapsed").each(=0A= $(this).parents().each(=0A= function(i) {=0A= if ($(this).hasClass('collapsible') || = $(this).hasClass('collapsed')) {=0A= var isCollapsed =3D $this.hasClass('collapsed');=0A= if (setPrefs) {=0A= var prefName =3D id + "-state";=0A= if (isCollapsed) {=0A= setPref(prefName, "open");=0A= }=0A= else {=0A= setPref(prefName, "closed");=0A= }=0A= }=0A= toggleCollapse($(this), childListType, ($labelElement + " a = span.view-more"), expandStr, contractStr);=0A= fixColHeights(-1);=0A= return false;=0A= }=0A= }=0A= );=0A= e.preventDefault();=0A= }=0A= );=0A= }=0A= }=0A= );=0A= }=0A= =0A= function handleMostBoxes() {=0A= var hadMostBoxes =3D false;=0A= $("div.most-links-box").each(=0A= function(i) {=0A= var $this =3D $(this);=0A= modClass($this, '', 'js-marker');=0A= hadMostBoxes =3D true;=0A= // 1) get the
    child=0A= var $mostlist =3D $this.children("ul");=0A= // 2) build a new
      for the header, from

      child:=0A= var hasSelected =3D false;=0A= var mostHdrList =3D null;=0A= if ($mostlist.length) {=0A= var hasItems =3D false;=0A= var hdrList =3D '
        ';=0A= var $mostli =3D $mostlist.children("li");=0A= if ($mostli.length) {=0A= hasItems =3D true;=0A= $mostli.each(=0A= function(i) {=0A= var $hdr =3D $(this).children("h4").html();=0A= if ($(this).hasClass("most-cur-sel")) {=0A= hasSelected =3D true;=0A= hdrList +=3D '
      • ' + $hdr + '
        • ';=0A= }=0A= else {=0A= hdrList +=3D '
      • ' + $hdr + '
        • ';=0A= }=0A= }=0A= );=0A= }=0A= hdrList +=3D '
      ';=0A= if (hasItems) {=0A= var header =3D $this.find("div.most-header h3");=0A= if (header.length) {=0A= header.after(hdrList);=0A= }=0A= }=0A= mostHdrList =3D $this.find("div.most-header ul");=0A= }=0A= // 3) if none of the items are selected, make the first one be=0A= if (((mostHdrList !=3D null) && mostHdrList.length) && = (!hasSelected)) {=0A= modClass(mostHdrList.find("li:first"), "most-cur-sel", "");=0A= modClass($this.children("ul").children("li:first"), "most-cur-sel", = "");=0A= }=0A= // 4) bind a handler to each heading li a to toggle = class=3D"most-cur-sel" for =0A= // that item and its corresponding item in the list below=0A= if (((mostHdrList !=3D null) && mostHdrList.length)) {=0A= mostHdrList.find("li a").click(=0A= function(e) {=0A= var curA =3D $(this);=0A= toggleMostSelection(e, $this, curA.text());=0A= }=0A= );=0A= }=0A= }=0A= );=0A= if (hadMostBoxes) {=0A= fixColHeights(-1);=0A= }=0A= }=0A= =0A= function toggleMostSelection(e, mostItemDiv, groupName) {=0A= if (mostItemDiv.length) {=0A= var hdrItems =3D mostItemDiv.find("div.most-header ul li");=0A= if (hdrItems.length) {=0A= hdrItems.each(=0A= function() {=0A= var hdrName =3D $(this).text();=0A= var isChoice =3D (hdrName =3D=3D groupName);=0A= if (isChoice) {=0A= modClass($(this), 'most-cur-sel', '');=0A= }=0A= else {=0A= modClass($(this), '', 'most-cur-sel');=0A= }=0A= }=0A= );=0A= }=0A= var listItems =3D mostItemDiv.children("ul").find("li");=0A= if (listItems.length) {=0A= listItems.each(=0A= function() {=0A= var itemName =3D $(this).children("h4").text();=0A= var isChoice =3D (itemName =3D=3D groupName);=0A= if (isChoice) {=0A= modClass($(this), 'most-cur-sel', '');=0A= }=0A= else {=0A= modClass($(this), '', 'most-cur-sel');=0A= }=0A= }=0A= );=0A= }=0A= }=0A= fixColHeights(-1);=0A= e.preventDefault();=0A= }=0A= =0A= function toggleCollapse(collapsibleEl, hideTagExpr, modTextTagExpr, = expandStr, contractStr) {=0A= if (typeof(expandStr) =3D=3D "undefined") {=0A= expandStr =3D getSiteOption('expandString','+');=0A= }=0A= if (typeof(contractStr) =3D=3D "undefined") {=0A= contractStr =3D getSiteOption('contractString','-');=0A= }=0A= =0A= var $this =3D collapsibleEl;=0A= if ($this.hasClass('collapsed')) {=0A= modClass($this, 'collapsible', 'collapsed');=0A= }=0A= else if ($this.hasClass('collapsible')) {=0A= modClass($this, 'collapsed', 'collapsible');=0A= }=0A= var $toToggle =3D $this.find(hideTagExpr);=0A= if ($toToggle.length) {=0A= $toToggle.toggle();=0A= }=0A= var $rewrite =3D $this.find(modTextTagExpr);=0A= if ($rewrite.length) {=0A= $rewrite.each(=0A= function(i, e) {=0A= var txt =3D $(e).text();=0A= if (txt =3D=3D expandStr) {=0A= $(e).empty().append(contractStr);=0A= }=0A= else if (txt =3D=3D contractStr) {=0A= $(e).empty().append(expandStr);=0A= }=0A= }=0A= );=0A= }=0A= }=0A= =0A= function setupDockBlock(col, dockId, dockClass, contentRules) {=0A= if ((col =3D=3D 2) || (col =3D=3D 3)) {=0A= var navOrigHeight =3D ((col =3D=3D 2) ? gColOrigHeights.col2 : = gColOrigHeights.col3);=0A= var gColNum =3D col;=0A= var gNav =3D ((col =3D=3D 2) ? gCol2 : gCol3);=0A= var gNavHeight =3D ((gNav.length) ? navOrigHeight : 0);=0A= var gNavTopOffset =3D (gNavHeight > 0 ? gNav.offset().top : 0);=0A= var gScrollPos =3D 0;=0A= var gNavDocked =3D false;=0A= /* this won't work in IE 6, so skip it */=0A= /* article navigation docking block */=0A= $(window).scroll(function () {=0A= if (gNavHeight > 0 && !isIE6) {=0A= var offsets =3D getPageOffset();=0A= var origHeight =3D ((gColNum =3D=3D 2) ? gColOrigHeights.col2 : = gColOrigHeights.col3);=0A= var navBottom =3D (gNavTopOffset + origHeight) - offsets.y;=0A= if (gScrollPos !=3D offsets.y) {=0A= gScrollPos =3D offsets.y;=0A= if ((navBottom <=3D 0) && !gNavDocked) {=0A= /* dock the nav */=0A= gNavDocked =3D true;=0A= addDockBlock(col, dockId, dockClass, contentRules);=0A= }=0A= else if (gNavDocked && (navBottom > 0)) {=0A= /* undock the nav */=0A= gNavDocked =3D false;=0A= removeDockBlock(col, dockId);=0A= }=0A= }=0A= }=0A= });=0A= }=0A= }=0A= function addDockBlock(col, dockId, dockClass, contentRules) {=0A= // get direct children li elements only=0A= var colId =3D ("col-" + col);=0A= var newDiv =3D ' 1) {=0A= for (var i =3D 0; i < (contentRules.length - 1); i =3D i + 2) {=0A= var addTo =3D processDockingRule(contentRules[i]);=0A= var add =3D processDockingRule(contentRules[i + 1]);=0A= var addTarget, addVal;=0A= if (addTo.ruleType =3D=3D 'empty') {=0A= addTarget =3D newDivJQuery;=0A= }=0A= else if (addTo.ruleType =3D=3D 'jQuery') {=0A= addTarget =3D $(addTo.rule);=0A= }=0A= if (add.ruleType =3D 'jQuery') {=0A= var addJQEl =3D $(add.rule);=0A= if (addJQEl.length) {=0A= addVal =3D addJQEl.clone();=0A= }=0A= else {=0A= addVal =3D '';=0A= }=0A= }=0A= else if (add.ruleType =3D 'html') {=0A= addVal =3D add.rule;=0A= }=0A= if (addTarget.length && !(addVal =3D=3D '')) {=0A= addTarget.append(addVal);=0A= }=0A= else {=0A= }=0A= }=0A= }=0A= var newDockJQrule =3D "#" + colId + " #" + dockId;=0A= var newDock =3D $(newDockJQrule);=0A= if (newDock.length) {=0A= prepCollapsibles(newDockJQrule + " div.collapsible, " + newDockJQrule = + " div.collapsed", false);=0A= newDock.fadeIn(250);=0A= }=0A= }=0A= =0A= function processDockingRule(rule) {=0A= var retObj =3D new Object();=0A= retObj.empty =3D (((rule !=3D undefined) && (!(rule =3D=3D ''))) ? = false : true);=0A= if (rule =3D=3D '') {=0A= retObj.ruleType =3D 'empty';=0A= }=0A= else if (/^\$\(.+\)$/.test(rule)) {=0A= retObj.ruleType =3D 'jQuery';=0A= retObj.rule =3D rule.replace(/^\$\((.+)\)$/,"$1");=0A= }=0A= else {=0A= retObj.ruleType =3D 'html';=0A= retObj.rule =3D rule;=0A= }=0A= return retObj;=0A= }=0A= =0A= function removeDockBlock(col, dockId) {=0A= var dockedNav =3D $("div#" + dockId);=0A= if(dockedNav.length) {=0A= dockedNav.fadeOut(250, function() { dockedNav.remove(); });=0A= }=0A= }=0A= =0A= =0A= function updateFormInput(labelMatchString, inputMatchString, = defaultColorString, textColorString) {=0A= if ((defaultColorString =3D=3D null) || (defaultColorString =3D=3D '')) = {=0A= defaultColorString =3D "#A0A0A0";=0A= }=0A= if ((textColorString =3D=3D null) || (textColorString =3D=3D '')) {=0A= textColorString =3D "black";=0A= }=0A= var label =3D $(labelMatchString);=0A= var input =3D $(inputMatchString);=0A= if (input.length) {=0A= if ((label.length) && (input.val() =3D=3D '')) {=0A= input.val(label.text()).css("color",defaultColorString);=0A= }=0A= input.focus(=0A= function(e) {=0A= if ((label.length) && ($(this).val() =3D=3D label.text())) {=0A= $(this).val('').css("color",textColorString);=0A= }=0A= }=0A= );=0A= input.blur(=0A= function(e) {=0A= if ((label.length) && ($(this).val() =3D=3D '')) {=0A= $(this).val(label.text()).css("color",defaultColorString);=0A= }=0A= }=0A= );=0A= }=0A= var parentForm =3D label.parents("form").eq(0);=0A= if (parentForm.length) {=0A= parentForm.submit(=0A= function() {=0A= if ((label.length) && (input.length) && (input.val() =3D=3D = label.text())) {=0A= input.val('');=0A= }=0A= return true;=0A= }=0A= );=0A= }=0A= }=0A= =0A= function checkUnloadedImgs(lookupRule) {=0A= if (lookupRule =3D=3D null) {=0A= lookupRule =3D "img";=0A= }=0A= var imageNum =3D -1;=0A= var images =3D $(lookupRule);=0A= if (images.length) {=0A= imageNum =3D 0;=0A= images.each(=0A= function() {=0A= //if ($(this).height() =3D=3D 0) {=0A= if (this.offsetHeight =3D=3D 0) {=0A= imageNum++;=0A= }=0A= }=0A= );=0A= }=0A= return imageNum;=0A= }=0A= =0A= function fixHeightForImages(iter, numImagesToLoad, lookupRule) {=0A= if (lookupRule =3D=3D null) {=0A= lookupRule =3D "img";=0A= }=0A= if (numImagesToLoad > 0) {=0A= var lastNumImagesToLoad =3D numImagesToLoad;=0A= var newNumImagesToLoad =3D checkUnloadedImgs(lookupRule);=0A= if (newNumImagesToLoad < lastNumImagesToLoad) {=0A= fixColHeights(1);=0A= if ((newNumImagesToLoad > 0) && (iter < 10)) {=0A= setTimeout("fixHeightForImages(" + (iter+1) + "," + = newNumImagesToLoad + ",'" + lookupRule + "')", 1000);=0A= }=0A= }=0A= }=0A= }=0A= function getColInfo(colJQEl) {=0A= var colInfo =3D { valid: false, height: 0, bottom: 0, lastElBottom: 0, = extra: 0, fix: false };=0A= if (colJQEl.length) {=0A= var c =3D colJQEl.children();=0A= if (c.length) {=0A= colInfo.height =3D getObjHeight(colJQEl);=0A= colInfo.bottom =3D colJQEl.offset().top + colInfo.height;=0A= var last =3D c.eq(c.length - 1);=0A= colInfo.lastElBottom =3D last.offset().top + getObjHeight(last);=0A= colInfo.extra =3D colInfo.bottom - colInfo.lastElBottom;=0A= colInfo.valid =3D true;=0A= }=0A= }=0A= return colInfo;=0A= }=0A= function checkColHeights() {=0A= var colToFix =3D 0;=0A= if ((gIsMultiCol || gColTempResize) && ((gColOrigHeights.main + = gColOrigHeights.col2 + gColOrigHeights.col3) > 0)) {=0A= var colMainInfo =3D getColInfo(gColMain);=0A= var col2Info =3D getColInfo(gCol2);=0A= var col3Info =3D getColInfo(gCol3);=0A= if (colMainInfo.valid && (gColLows.main =3D=3D 0)) { gColLows.main =3D = colMainInfo.lastElBottom; }=0A= if (col2Info.valid && (gColLows.col2 =3D=3D 0)) { gColLows.col2 =3D = col2Info.lastElBottom; }=0A= if (col3Info.valid && (gColLows.col3 =3D=3D 0)) { gColLows.col3 =3D = col3Info.lastElBottom; }=0A= // check if low point in any column has changed=0A= if ((colMainInfo.valid) && (colMainInfo.lastElBottom !=3D = gColLows.main)) {=0A= colMainInfo.fix =3D true;=0A= }=0A= if ((col2Info.valid) && (col2Info.lastElBottom !=3D gColLows.col2)) {=0A= col2Info.fix =3D true;=0A= }=0A= if ((col3Info.valid) && (col3Info.lastElBottom !=3D gColLows.col3)) {=0A= col3Info.fix =3D true;=0A= }=0A= // check for columns not having same bottom points=0A= if ((colMainInfo.valid) &&=0A= (((col2Info.valid) && (colMainInfo.height < col2Info.height)) ||=0A= ((col3Info.valid) && (colMainInfo.height < col3Info.height)))) {=0A= colMainInfo.fix =3D true;=0A= }=0A= if ((col2Info.valid) &&=0A= (((colMainInfo.valid) && (col2Info.height < colMainInfo.height)) ||=0A= ((col3Info.valid) && (col2Info.height < col3Info.height)))) {=0A= col2Info.fix =3D true;=0A= }=0A= if ((col3Info.valid) &&=0A= (((colMainInfo.valid) && (col3Info.height < colMainInfo.height)) ||=0A= ((col2Info.valid) && (col3Info.height < col2Info.height)))) {=0A= col3Info.fix =3D true;=0A= }=0A= =0A= if (colToFix > -1) {=0A= if (colMainInfo.valid && colMainInfo.fix) {=0A= if ((col2Info.valid && col2Info.fix) || (col3Info.valid && = col3Info.fix)) {=0A= colToFix =3D -1;=0A= }=0A= else { colToFix =3D 1; }=0A= }=0A= else if (col2Info.valid && col2Info.fix) {=0A= if (col3Info.valid && col3Info.fix) {=0A= colToFix =3D -1;=0A= }=0A= else { colToFix =3D 2; }=0A= }=0A= else if (col3Info.valid && col3Info.fix) {=0A= colToFix =3D 3;=0A= }=0A= }=0A= =0A= if (colToFix !=3D 0) {=0A= fixColHeights(colToFix);=0A= }=0A= if (colMainInfo.valid) { gColLows.main =3D colMainInfo.lastElBottom; }=0A= if (col2Info.valid) { gColLows.col2 =3D col2Info.lastElBottom; }=0A= if (col3Info.valid) { gColLows.col3 =3D col3Info.lastElBottom; }=0A= }=0A= setTimeout("checkColHeights()", 5000);=0A= }=0A= function fixColHeights(colChanged) {=0A= if ((gIsMultiCol || gColTempResize) && getSiteOption('setColSizes', = true)) {=0A= var setAll =3D false;=0A= if (colChanged =3D=3D 1) {=0A= if (gColMain.length) {=0A= setObjHeight(gColMain,'auto');=0A= gColOrigHeights.main =3D getObjHeight(gColMain);=0A= }=0A= }=0A= else if (colChanged =3D=3D 2) {=0A= if (gCol2.length) {=0A= setObjHeight(gCol2,'auto');=0A= gColOrigHeights.col2 =3D getObjHeight(gCol2);=0A= }=0A= }=0A= else if (colChanged =3D=3D 3) {=0A= if (gCol3.length) {=0A= setObjHeight(gCol3,'auto');=0A= gColOrigHeights.col3 =3D getObjHeight(gCol3);=0A= }=0A= }=0A= else {=0A= if (colChanged =3D=3D -1) {=0A= // force resize all 3=0A= if (gColMain.length) { setObjHeight(gColMain,'auto'); }=0A= if (gCol2.length) { setObjHeight(gCol2,'auto'); }=0A= if (gCol3.length) { setObjHeight(gCol3,'auto'); }=0A= }=0A= gColOrigHeights.main =3D ((gColMain.length) ? = (getObjHeight(gColMain)) : 0);=0A= gColOrigHeights.col2 =3D ((gCol2.length) ? (getObjHeight(gCol2)) : 0);=0A= gColOrigHeights.col3 =3D ((gCol3.length) ? 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'&' : '?') = + 'baseURI=3D' + ((baseAjaxUrl.indexOf('?') > 0) ? = baseAjaxUrl.substring(0, baseAjaxUrl.indexOf('?')): baseAjaxUrl);=0A= //var ajaxUrl =3D baseAjaxUrl + ((href.indexOf('?') >=3D 0) ? '&' : = '?') + 'baseURI=3D' + baseAjaxUrl;=0A= $.ajax({=0A= url: ajaxUrl,=0A= dataType: "html",=0A= type: "GET",=0A= error: ajaxErr,=0A= beforeSend: addFigHeaders,=0A= success: function(xhtml) {=0A= addFig(xhtml, figWrapperEl);=0A= },=0A= complete: ajaxComplete=0A= });=0A= e.preventDefault();=0A= }=0A= function addFigHeaders(req) {=0A= addCommonHeaders(req);=0A= addPartHeaders(req);=0A= }=0A= =0A= function addFig(xhtmlData, figWrapperEl) {=0A= if (xhtmlData && !(xhtmlData.indexOf('=3D 0)) {=0A= figWrapperEl.replaceWith(xhtmlData);=0A= newWindowTargets();=0A= var lookupRule =3D "div.article div.fig img";=0A= var numImagesToLoad =3D checkUnloadedImgs(lookupRule);=0A= setTimeout("fixHeightForImages(1" + "," + numImagesToLoad + ",'" + = lookupRule + "')", 1000);=0A= fixColHeights(1);=0A= }=0A= }=0A= =0A= function refLinksNewWindowTarget() {=0A= $("div.ref-list div.cit-extra a").each(=0A= function(i) {=0A= var origTitle =3D $(this).attr("title");=0A= var newTitle =3D '';=0A= if ((origTitle =3D=3D undefined) || (!origTitle)) {=0A= origTitle =3D '';=0A= }=0A= else {=0A= newTitle =3D origTitle + ' ';=0A= }=0A= newTitle +=3D '[opens in a new window]';=0A= $(this).attr("target", "_blank").attr("title", newTitle);=0A= }=0A= );=0A= }=0A= =0A= function addRefPops() {=0A= var numMissed =3D 0;=0A= var maxToSkip =3D getSiteOption('refPopsMaxToSkip', 10);=0A= var i =3D 1;=0A= var idroot =3D "#xref-ref-";=0A= var el =3D $(idroot + i + '-1');=0A= /* not all refs appear in text; compensate */=0A= while (numMissed < maxToSkip) {=0A= if (el.length) {=0A= numMissed =3D 0;=0A= el.hover(dispRef, hideRef);=0A= var j =3D 2;=0A= var el2 =3D $(idroot + i + "-" + j);=0A= while (el2.length) {=0A= el2.hover(dispRef, hideRef);=0A= j++;=0A= el2 =3D $(idroot + i + "-" + j);=0A= }=0A= }=0A= else {=0A= numMissed++;=0A= }=0A= i++;=0A= el =3D $(idroot + i + "-1");=0A= }=0A= }=0A= =0A= function dispRef(e) {=0A= var link =3D $(this).attr("href");=0A= if($("div#hovering-ref").length) {=0A= $("div#hovering-ref").remove();=0A= //alert("hovering-ref div removed on new hover!");=0A= }=0A= var linkEl =3D $(link);=0A= if (linkEl.length) {=0A= var citHtml =3D linkEl.next("div").children("div.cit-metadata");=0A= if (!(citHtml.length)) {=0A= citHtml =3D linkEl.parent().next("div").children("div.cit-metadata");=0A= }=0A= if (citHtml.length) {=0A= var newDiv =3D '
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        ';=0A= $("body").append(newDiv);=0A= var elH =3D getObjHeight($("div#hovering-ref"));=0A= $("div#hovering-ref").css("left", e.pageX+10).css("top", = e.pageY-elH).css("position", "absolute");=0A= }=0A= }=0A= }=0A= =0A= function hideRef(e) {=0A= if($("div#hovering-ref").length) {=0A= $("div#hovering-ref").remove();=0A= }=0A= }=0A= =0A= function getHWCiting() {=0A= var citingA =3D $("#cb-hw-citing-articles");=0A= if (citingA.length) {=0A= var newA =3D 'Loading citing = article data...';=0A= citingA.replaceWith(newA);=0A= var href =3D citingA.attr("href");=0A= var id =3D '';=0A= if (href && (href.indexOf('?') > 0)) {=0A= var args =3D href.substring(href.indexOf('?') + 1).split('&');=0A= for (var i =3D 0; i < args.length; i++) {=0A= if (args[i].toLowerCase().indexOf('legid=3D') =3D=3D 0) {=0A= id =3D args[i].substring(args[i].indexOf('=3D') + 1);=0A= if (id.indexOf('#') > 0) {=0A= id =3D id.substring(0, id.indexOf('#'));=0A= }=0A= }=0A= }=0A= if (!(id =3D=3D '')) {=0A= var host =3D document.location.protocol + "//" + = document.location.host;=0A= var ajaxUrl =3D host + '/cited-by/' + id.replace(/;/,'/');=0A= $.ajax({=0A= url: ajaxUrl,=0A= dataType: "html",=0A= type: "GET",=0A= error: ajaxErr,=0A= success: addHWCiting,=0A= complete: ajaxComplete=0A= });=0A= =0A= }=0A= }=0A= }=0A= }=0A= function getHWRelatedURLs() {=0A= var relatedURLsA =3D $("#cb-related-urls");=0A= var relatedURLsMsg =3D = getSiteOption('relatedWebPageLoadingText','Loading related web page = data...'); =0A= if (relatedURLsA.length) {=0A= var newA =3D '' + = relatedURLsMsg + '';=0A= relatedURLsA.replaceWith(newA);=0A= var href =3D relatedURLsA.attr("href");=0A= var id =3D '';=0A= if (href && (href.indexOf('?') > 0)) {=0A= var args =3D href.substring(href.indexOf('?') + 1).split('&');=0A= for (var i =3D 0; i < args.length; i++) {=0A= if (args[i].toLowerCase().indexOf('legid=3D') =3D=3D 0) {=0A= id =3D args[i].substring(args[i].indexOf('=3D') + 1);=0A= if (id.indexOf('#') > 0) {=0A= id =3D id.substring(0, id.indexOf('#'));=0A= }=0A= }=0A= }=0A= if (!(id =3D=3D '')) {=0A= var host =3D document.location.protocol + "//" + = document.location.host;=0A= var ajaxUrl =3D host + '/related-web-pages/' + id.replace(/;/,'/');=0A= $.ajax({=0A= url: ajaxUrl,=0A= dataType: "html",=0A= type: "GET",=0A= error: ajaxErr,=0A= success: addRelatedURLs,=0A= complete: ajaxComplete=0A= });=0A= =0A= }=0A= }=0A= }=0A= }=0A= function getPatientInformData() {=0A= var pInformA =3D $("#cb-patientinform");=0A= if (pInformA.length) {=0A= var newA =3D 'Loading = patientINFORMation...';=0A= pInformA.replaceWith(newA);=0A= var href =3D pInformA.attr("href");=0A= var id =3D '';=0A= if (href && (href.indexOf('?') > 0)) {=0A= var args =3D href.substring(href.indexOf('?') + 1).split('&');=0A= for (var i =3D 0; i < args.length; i++) {=0A= if (args[i].toLowerCase().indexOf('legid=3D') =3D=3D 0) {=0A= id =3D args[i].substring(args[i].indexOf('=3D') + 1);=0A= if (id.indexOf('#') > 0) {=0A= id =3D id.substring(0, id.indexOf('#'));=0A= }=0A= }=0A= }=0A= if (!(id =3D=3D '')) {=0A= var host =3D document.location.protocol + "//" + = document.location.host;=0A= var ajaxUrl =3D host + '/related-web-pages/patientinform/' + = id.replace(/;/,'/');=0A= $.ajax({=0A= url: ajaxUrl,=0A= dataType: "html",=0A= type: "GET",=0A= error: ajaxErr,=0A= success: addPatientInform,=0A= complete: ajaxComplete=0A= });=0A= =0A= }=0A= }=0A= }=0A= }=0A= function getISIRelated() {=0A= var relatedA =3D $("#cb-isi-similar-articles");=0A= if (relatedA.length) {=0A= var newA =3D 'Loading Web = of Science article data...';=0A= relatedA.replaceWith(newA);=0A= var href =3D relatedA.attr("href");=0A= var id =3D '';=0A= if (href) {=0A= var hrefDec =3D decodeURI(href);=0A= if ((hrefDec.indexOf('?') > 0)) {=0A= var args =3D hrefDec.substring(hrefDec.indexOf('?') + 1).split('&');=0A= for (var i =3D 0; i < args.length; i++) {=0A= var argDec =3D decodeURIComponent(args[i]);=0A= if (argDec.toLowerCase().indexOf('access_num=3D') =3D=3D 0) {=0A= id =3D argDec.substring(argDec.indexOf('=3D') + 1);=0A= if (id.indexOf('#') > 0) {=0A= id =3D id.substring(0, id.indexOf('#'));=0A= }=0A= }=0A= }=0A= if (!(id =3D=3D '')) {=0A= var host =3D document.location.protocol + "//" + = document.location.host;=0A= var ajaxUrl =3D host + '/isi-links/has-related/' + = id.replace(/;/,'/');=0A= $.ajax({=0A= url: ajaxUrl,=0A= dataType: "html",=0A= type: "GET",=0A= error: ajaxErr,=0A= success: addISIRelated,=0A= complete: ajaxComplete=0A= });=0A= }=0A= }=0A= }=0A= }=0A= }=0A= function getCiting(service, msg, pathseg, successFn) {=0A= var citingA =3D $("#cb-" + service + "-citing-articles");=0A= if (citingA.length) {=0A= var newA =3D '' = + msg + '';=0A= citingA.replaceWith(newA);=0A= var href =3D citingA.attr("href");=0A= var id =3D '';=0A= if (href) {=0A= var hrefDec =3D decodeURI(href);=0A= if ((hrefDec.indexOf('?') > 0)) {=0A= var args =3D hrefDec.substring(hrefDec.indexOf('?') + 1).split('&');=0A= for (var i =3D 0; i < args.length; i++) {=0A= var argDec =3D decodeURIComponent(args[i]);=0A= if (argDec.toLowerCase().indexOf('access_num=3D') =3D=3D 0) {=0A= id =3D argDec.substring(argDec.indexOf('=3D') + 1);=0A= if (id.indexOf('#') > 0) {=0A= id =3D id.substring(0, id.indexOf('#'));=0A= }=0A= }=0A= }=0A= if (!(id =3D=3D '')) {=0A= var host =3D document.location.protocol + "//" + = document.location.host;=0A= var ajaxUrl =3D host + '/' + service + '-links/' + pathseg + = id.replace(/;/,'/');=0A= $.ajax({=0A= url: ajaxUrl,=0A= dataType: "html",=0A= type: "GET",=0A= error: ajaxErr,=0A= success: successFn,=0A= complete: ajaxComplete=0A= });=0A= }=0A= }=0A= }=0A= }=0A= }=0A= =0A= function getISICiting() {=0A= var citingA =3D $("#cb-isi-citing-articles");=0A= if (citingA.length) {=0A= var newA =3D 'Loading Web of = Science citing article data...';=0A= citingA.replaceWith(newA);=0A= var href =3D citingA.attr("href");=0A= var id =3D '';=0A= if (href) {=0A= var hrefDec =3D decodeURI(href);=0A= if ((hrefDec.indexOf('?') > 0)) {=0A= var args =3D hrefDec.substring(hrefDec.indexOf('?') + 1).split('&');=0A= for (var i =3D 0; i < args.length; i++) {=0A= var argDec =3D decodeURIComponent(args[i]);=0A= if (argDec.toLowerCase().indexOf('access_num=3D') =3D=3D 0) {=0A= id =3D argDec.substring(argDec.indexOf('=3D') + 1);=0A= if (id.indexOf('#') > 0) {=0A= id =3D id.substring(0, id.indexOf('#'));=0A= }=0A= }=0A= }=0A= if (!(id =3D=3D '')) {=0A= var host =3D document.location.protocol + "//" + = document.location.host;=0A= var ajaxUrl =3D host + '/isi-links/' + id.replace(/;/,'/');=0A= $.ajax({=0A= url: ajaxUrl,=0A= dataType: "html",=0A= type: "GET",=0A= error: ajaxErr,=0A= success: addISICiting,=0A= complete: ajaxComplete=0A= });=0A= }=0A= }=0A= }=0A= }=0A= }=0A= function getEntrezLinks() {=0A= var entrezDiv =3D $("#cb-entrez-links-placeholder");=0A= if (entrezDiv.length) {=0A= var entrezA =3D entrezDiv.children("a");=0A= if (entrezA) {=0A= var host =3D document.location.protocol + "//" + = document.location.host;=0A= var ajaxUrl =3D host + entrezA.attr("href");=0A= $.ajax({=0A= url: ajaxUrl,=0A= dataType: "html",=0A= type: "GET",=0A= error: ajaxErr,=0A= success: addEntrezLinks,=0A= complete: ajaxComplete=0A= });=0A= }=0A= }=0A= }=0A= =0A= function ajaxErr(req, msg, e) {=0A= }=0A= function ajaxComplete(req, msg) {=0A= }=0A= function updateCBItem(cbItem, newHTML, hasData) {=0A= var parentItem =3D cbItem.parents("li").eq(0);=0A= cbItem.replaceWith(newHTML);=0A= if (!hasData) {=0A= // hide the parent li=0A= if (parentItem.length) {=0A= modClass(parentItem,"nodata","");=0A= // check if there are any siblings still being displayed=0A= var otherItems =3D parentItem.siblings();=0A= var allItemsEmpty;=0A= if (otherItems.length) {=0A= if (otherItems.length =3D=3D otherItems.filter(".nodata").length) {=0A= allItemsEmpty =3D true=0A= }=0A= else {=0A= allItemsEmpty =3D false;=0A= }=0A= }=0A= else {=0A= allItemsEmpty =3D true;=0A= }=0A= if (allItemsEmpty) {=0A= var cbsection =3D parentItem.parents("div.cb-section").eq(0);=0A= if (cbsection.length) {=0A= modClass(cbsection,"nodata","");=0A= }=0A= }=0A= }=0A= }=0A= // in frameset fix targets on child links, forms=0A= fixFrameLinks(parentItem.find("a,form"));=0A= fixColHeights(2);=0A= }=0A= function fixFrameLinks(jqItems) {=0A= if ((gIsFrameset !=3D null) && gIsFrameset) {=0A= jqItems.each(=0A= function(i) {=0A= var href =3D $(this).attr("href");=0A= var action =3D $(this).attr("action"); // if form=0A= if ((href !=3D null) || (action !=3D null)) {=0A= var inFrameAnchor =3D ((href !=3D null) && = (((/frameset=3D/.test(href)) && (/#/.test(href))) || = (href.substring(0,1) =3D=3D '#')));=0A= if ((!inFrameAnchor) || (action !=3D null)) {=0A= $(this).attr("target", "_top");=0A= }=0A= }=0A= }=0A= );=0A= }=0A= }=0A= function addRelatedURLs(xhtmlData) {=0A= var cbA =3D $("#cb-loading-related-urls");=0A= if (gIsFrameset) {=0A= if (cbA.length) {=0A= updateCBItem(cbA, '', false);=0A= }=0A= }=0A= else if (xhtmlData && !(xhtmlData.indexOf('=3D 0)) {=0A= $("#related-urls").replaceWith(xhtmlData);=0A= var relatedWebPagesLabel =3D getSiteOption('relatedWebPagesLabel', = 'Related Web Pages');=0A= fixColHeights(1);=0A= if (cbA.length) {=0A= updateCBItem(cbA, '' + relatedWebPagesLabel = + '', true);=0A= }=0A= }=0A= else {=0A= if (cbA.length) {=0A= updateCBItem(cbA, '', false);=0A= }=0A= }=0A= }=0A= function addPatientInform(xhtmlData) {=0A= var cbA =3D $("#cb-loading-patientinform");=0A= if (gIsFrameset) {=0A= if (cbA.length) {=0A= updateCBItem(cbA, '
        Not = available in this view
        ', false);=0A= }=0A= }=0A= else if (xhtmlData && !(xhtmlData.indexOf('=3D 0)) {=0A= $("#patientinform-links").replaceWith(xhtmlData);=0A= fixColHeights(1);=0A= if (cbA.length) {=0A= updateCBItem(cbA, 'patientINFORMation', true);=0A= }=0A= }=0A= else {=0A= if (cbA.length) {=0A= updateCBItem(cbA, '
        No = patientINFORMation available for this article
        ', false);=0A= }=0A= }=0A= }=0A= function addHWCiting(xhtmlData) {=0A= var cbA =3D $("#cb-loading-hw-cited");=0A= if (gIsFrameset) {=0A= if (cbA.length) {=0A= updateCBItem(cbA, '
        Not available = in this view
        ', false);=0A= }=0A= }=0A= else if (xhtmlData) {=0A= $("#content-block").append(xhtmlData);=0A= var hwCitingLabel =3D getSiteOption('hwCitingLabel', 'View citing = article information');=0A= fixColHeights(1);=0A= if (cbA.length) {=0A= updateCBItem(cbA, '' + hwCitingLabel + '', = true);=0A= }=0A= }=0A= else {=0A= if (cbA.length) {=0A= updateCBItem(cbA, '
        No citing = articles
        ', false);=0A= }=0A= }=0A= }=0A= function addISIRelated(xhtmlData) {=0A= var cbA =3D $("#cb-isi-similar-articles");=0A= if (xhtmlData && !(xhtmlData.indexOf('=3D 0)) {=0A= if (cbA.length) {=0A= updateCBItem(cbA, xhtmlData, true);=0A= }=0A= }=0A= else {=0A= if (cbA.length) {=0A= updateCBItem(cbA, '', false);=0A= }=0A= }=0A= }=0A= function addISICiting(xhtmlData) {=0A= var cbA =3D $("#cb-loading-isi-cited");=0A= if (xhtmlData && !(xhtmlData.indexOf('=3D 0)) {=0A= if (cbA.length) {=0A= updateCBItem(cbA, xhtmlData, true);=0A= }=0A= }=0A= else {=0A= if (cbA.length) {=0A= updateCBItem(cbA, '
        No Web of = Science citing articles
        ', false);=0A= }=0A= }=0A= }=0A= function addScopusCiting(xhtmlData) {=0A= var cbA =3D $("#cb-loading-scopus-cited");=0A= if (xhtmlData && (xhtmlData.indexOf('=3D 0)) {=0A= if (cbA.length) {=0A= updateCBItem(cbA, xhtmlData, true);=0A= }=0A= }=0A= else {=0A= if (cbA.length) {=0A= updateCBItem(cbA, '
        No Scopus = citing articles
        ', false);=0A= }=0A= }=0A= }=0A= function addEntrezLinks(xhtmlData) {=0A= var entrezDiv =3D $("#cb-entrez-links-placeholder");=0A= =0A= if (xhtmlData && (xhtmlData.indexOf('        =3D 0)) {=0A= if (entrezDiv.length) {=0A= updateCBItem(entrezDiv, xhtmlData, true);=0A= }=0A= }=0A= else {=0A= if (entrezDiv.length) {=0A= updateCBItem(entrezDiv, '', false);=0A= }=0A= }=0A= }=0A= =0A= function updateSBLinks() {=0A= var fbLink =3D $("a.sb-facebook");=0A= if (fbLink.length) {=0A= fbLink.click(=0A= function(e) {=0A= window.open(this.href, 'sharer', = 'toolbar=3D0,status=3D0,width=3D626,height=3D436');=0A= e.preventDefault();=0A= }=0A= );=0A= }=0A= }=0A= =0A= function addDockedNav() {=0A= var slugEl =3D $("#col-2 #slugline");=0A= // get direct children li elements only=0A= var artViews =3D $("#article-cb-main .cb-section ol:has(li = a[rel^=3D'view-']) > li").clone();=0A= var newDiv =3D '
        ';=0A= $("#col-2").append(newDiv);=0A= $("#col-2 #docked-nav").hide();=0A= var newDivJQuery =3D $("#docked-nav");=0A= newDivJQuery.append('

        This Article

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