From: Subject: HEDGEHOG-GLI1 signaling regulates human glioma growth, cancer stem cell self-renewal and tumorigenicity Date: Thu, 21 Feb 2008 17:24:34 +0100 MIME-Version: 1.0 Content-Type: multipart/related; type="text/html"; boundary="----=_NextPart_000_0023_01C874AE.A06CDE40" X-MimeOLE: Produced By Microsoft MimeOLE V6.00.2900.3198 This is a multi-part message in MIME format. ------=_NextPart_000_0023_01C874AE.A06CDE40 Content-Type: text/html; charset="utf-8" Content-Transfer-Encoding: quoted-printable Content-Location: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1855204 =EF=BB=BF HEDGEHOG-GLI1 signaling regulates human glioma = growth, cancer stem cell self-renewal and tumorigenicity
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PubMed=20 articles by:
Clement, V. 
Sanchez, P. 
de Tribolet, N. 
Altaba, = A. 
Curr Biol. Author manuscript; = available in=20 PMC 2007 April 24.
Published in final edited form = as:
Curr = Biol.=20 2007 January = 23;=20 17(2):=20 165=E2=80=93172.
Published=20 online 2006 December 28. doi:=20 10.1016/j.cub.2006.11.033.
Copyright = notice and Disclaimer=
HEDGEHOG-GLI1 signaling regulates human = glioma growth,=20 cancer stem cell self-renewal and tumorigenicity
Virginie = Clement,1 Pilar=20 Sanchez,1,2 Nicolas de Tribolet,3 = Ivan=20 Radovanovic,3 and Ariel Ruiz i Altaba1
1 Department of Genetic Medicine = and=20 Development, University of Geneva Medical School, 8242 CMU, 1 rue = Michel=20 Servet, CH-1211 Geneva 4, Switzerland
3 Department of Neurosurgery, = Geneva=20 Cantonal Hospital, CH-1211 Geneva 4, Switzerland
Correspondence: Email: Ariel.RuizAltaba/at/medecine.unige.ch (ARA)
2Present address: = Departament de=20 Biologia Cel.lular, Universitat de Val=C3=A8ncia, 46100 Burjassot, = Val=C3=A8ncia,=20 Spain.
3D"Small=20 The publisher's final edited version of this article is available = at Curr Biol.
3D"Small=20 This article has been corrected. See the = correction in=20 volume 17 on page 192.
3D"Small=20 See other articles in PMC that cite=20 the published article.
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"=20 = src=3D"http://www.pubmedcentral.nih.gov/corehtml/pmc/pmcgifs/square.gif" = border=3D0>Summary 
Results and=20 discussion 
Supplementary=20 Material 
References 
Summary
Cancer stem = cells are rare=20 tumor cells characterized by their ability to self-renew and to = induce=20 tumorigenesis. They are present in gliomas and may be responsible = for the=20 lethality of these incurable brain tumors. In the most aggressive = and=20 invasive type, glioblastoma multiforme (GBM), an average of = =C2=B11 year spans=20 the period between detection and death (1).=20 The resistence of gliomas to current therapies may be related to = the=20 existence of cancer stem cells (2=E2=80=936).=20 We find that human gliomas display a stemness signature and = demonstrate=20 that HEDGEHOG (HH)-GLI signaling regulates the expression of = stemness=20 genes in and the self-renewal of CD133+ glioma cancer stem cells. = HH-GLI=20 signaling is also required for sustained glioma growth and = survival,=20 displaying additive and synergistic effects with temozolomide, the = current=20 chemotherapeutic agent of choice, which does not affect glioma = stem cell=20 self-renewal. Finally, interference of HH-GLI signaling with = cyclopamine=20 or through lentiviral-mediated silencing demonstrates that the=20 tumorigenicity of human gliomas in nude mice requires an active = pathway.=20 Our results reveal the essential role of HH-GLI signaling in = controlling=20 the behavior of human glioma cancer stem cells and offer new = therapeutic=20 possibilities.
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Summary 
"=20 = src=3D"http://www.pubmedcentral.nih.gov/corehtml/pmc/pmcgifs/square.gif" = border=3D0>Results and=20 discussion 
Supplementary=20 Material 
References 
Results and = discussion

Previous work provided evidence for a role = of HH-GLI=20 signaling in gliomas (7).=20 SONIC HH (SHH) activates a signal transduction cascade that = includes the=20 action of the membrane proteins PATCHED1 (PTCH1) and SMOOTHENED = (SMOH),=20 leading to the action of GLI transcription factors (8).=20 Analyses of a panel of fresh brain tumors (Fig.=20 1A, Fig.=20 S1A) demonstrated the ubiquitous and varied expression of = HH-GLI=20 pathway components including GLI1, SHH and = PTCH1,=20 confirming the general presence of an active pathway (Fig.=20 1A, Figs.=20 S1B, C, S2), as GLI1 transcription is the only = reliable=20 marker of pathway activity. GLI1 was the only gene = overexpressed=20 on average in all tumor types as compared with the average = expression of=20 three separate cortical regions of normal brain tissue, = PTCH1=20 levels were lower in GBMs (9),=20 and SHH was high only in a subset of low grade gliomas. = Although=20 some gliomas express SHH in tumor cells (7),=20 a subset with low expression localized it in new vessels, whereas=20 PTCH1 was indeed expressed in tumor cells (7;=20 Fig.=20 1B).

Figure=20 1
Gene = expression in=20 human gliomas and requirement of HH-GLI=20 signaling

Gliomas showed a stemness signature (Fig.=20 1A, Fig.=20 S2) that included the expression of the stemness markers = NANOG,=20 OCT4, SOX and BMI1, centered over grade III gliomas = but=20 extending into neighboring grade IV (GBM) and grade II tumors (Fig.=20 1A). Tumors in transition may display a mixed character, such = as a=20 stemness signature and multiforme appearance in GBM-4 and GBM-6, = and low=20 grade pathology and a stemness signature in some grade II tumors = (Fig.=20 1A). In contrast, there was only a poor correlation between = grade and=20 a set of previously identified glioma prognostic markers (Fig.=20 S3). Two medulloblastomas used as control expressed = GLI1 but=20 did not overexpress the same stemness gene set (Fig.=20 1A). The stemness signature of grade III gliomas suggests the=20 abundance of cancer stem cells in these tumors.

All but one adherent primary cultures of = gliomas=20 tested decreased cell proliferation as measured by BrdU = incorporation=20 after 48h treatment with cyclopamine, a specific SMOH inhibitor = (10),=20 as compared with tomatidine as control (Fig.=20 1C). Inhibition was dose-dependent and cumulative over time = (Fig.=20 S4A). The GBM cell line U87 behaved similarly (Fig.=20 1C), decreased GLI1 expression upon cyclopamine = treatment (Fig.=20 S4B), and showed complete cell death after 10 days of = treatment (Fig.=20 S4C). Drug removal after 5 days allowed culture recovery, = indicating=20 temporally distinct cytostatic and cytotoxic effects.

GLI RNA interference (11)=20 demonstrated the general requirement of GLI1 and GLI2 in brain = tumor cell=20 proliferation, with GLI1 knock-down having the strongest effects, = as=20 compared with an unrelated siRNA control (Fig.=20 1D). As for prostate tumors (11),=20 most brain tumors tested had activation of the HH-GLI pathway at = the level=20 of SMOH in the membrane or above. However, since the one tumor = that was=20 insensitive to cyclopamine responded to GLI1 interference (Fig.=20 1D), activation here likely took place on or downstream of = SMOH. The=20 levels of inhibition reflected lipofection efficiencies and an = independent=20 set of siRNAs gave similar results (Fig.=20 S5A, B). Interference with GLI1 and GLI2 also increased = apoptosis (Fig.=20 1F). Long-term silencing in U87 cells increased in cell death = after=20 interference with GLI1 but not GLI2 (Fig.=20 S5C), indicating their differential requirement for survival = in these=20 cells. GLI3, in contrast, had positive effects in only a minority = of cases=20 (Fig.=20 1D), consistent with its rare role as a minor activator and = its more=20 common role as a major repressor of GLI targets (8).=20 GLI3 was found to mediate the effects of cyclopamine: cells = transfected=20 with GLI3 siRNA or a control siRNA and then treated with = this=20 drug showed that the anti-proliferative and pro-apoptotic effects = of=20 cyclopamine were reverted by inhibition of GLI3 (Fig.=20 1E, F).

To test for a possible role of HH-GLI = signaling in=20 cancer stem cells, we have used glioma stem cell cultures = (gliomaspheres)=20 (Fig.=20 2A, B), which self-renew and mimic the original tumor after=20 transplantation into the brains of immunocompromised mice (5).=20 Treatment with cyclopamine decreased their proliferation and = increased=20 apoptosis in a concentration-dependent manner (Fig.=20 2C, D). Inhibition of cell proliferation was recapitulated by=20 transduction with a recombinant lentiviral vector expressing an = shRNA=20 specific for SMOH (LV-shSMOH) as compared with a control = lentiviral vector=20 (LV-control) (Fig.=20 2E). Inhibition of SMOH mRNA by the LV-shSMOH was at = 67% in=20 U87 cells and at 66% in GBM-8 72h post-transduction.

Figure=20 2
Requirement of=20 HH-GLI function in glioma stem cell cultures and combined = effects=20 with = temozolomide

Long-term treatment and recovery assays = showed that=20 20, but not 10, days of treatment with cyclopamine were sufficient = to kill=20 all gliomasphere cells as the culture did not recover after an = additional=20 20 days without the drug (Fig.=20 S6E). In contrast, the DNA-damaging chemotherapeutic agent=20 temozolomide (TMZ; 1) also affected the proliferation and survival = of=20 glioma cells (Fig.=20 S6A-D) but was unable to prevent recovery (Fig.=20 S6F). Importantly, TMZ showed additive or synergistic effects = in=20 different glioma stem cell cultures with an intermediate dose = (5=CE=BCM) of=20 cyclopamine on the inhibition of cell proliferation and the = enhancement of=20 apoptosis (Fig.=20 2F, G).

Intracraneal xenografts of untransduced,=20 LacZ-lentiviral-transduced GBM gliomaspheres induced the = development of=20 massive infiltrative gliomas in nude mice after 2.5 months (Fig.=20 3A). These tumors expressed GLI1, SHH and=20 PTCH1 (Fig.=20 S7), consistent with the expression of these genes in gliomas = by in=20 situ (7).=20 Using a protocol with 104 GFP-lentiviral-transduced=20 gliomasphere cells injected into the striatum and left for 2 weeks = prior=20 to treatment for an additional 2 weeks we showed that cyclopamine = had a=20 beneficial effect. Systemic IP treatment with cyclopamine, but not = with=20 carrier alone, reduced glioma tumor volume (Fig.=20 3B) and cell proliferation (Fig.=20 3C). Similar effects were seen with subcutaneous xenografts of = U87=20 glioma cells: Delivery of cyclopamine in and around the tumor = inhibited=20 all growth and the tumors disappeared (Fig.=20 3I, J, L), showing a size differential with controls as soon = as the=20 second day of treatment.

Figure=20 3
Inhibition of human=20 glioma xenograft growth in vivo by interference with HH-GLI=20 signaling

Similar results were obtained after the=20 cell-autonomous knock-down of SMOH. LV-shRNA-SMOH reduced = SMOH=20 mRNA levels by 65=E2=80=9385% in U87 and GBM-8 cells, reduced = GLI1 levels=20 by =C2=B145% in both, markedly reduced tumor volume, and reduced = BrdU=20 incorporation 2=E2=80=933-fold (Fig.=20 3D, F, G, J, K, M and not shown). To further control any = differences=20 between the experimental and control injected cells, we rendered = LV-shSMOH=20 silent and conditionally inducible by treatment with doxycycline = (DOX)=20 through co-transduction with LV-tTR-KRAB (14).=20 Two weeks after intracranial injection of 104 = co-transduced=20 GBM-8 cells, one half of the mice were treated with DOX for an = additional=20 2 weeks while the other half were left untreated. DOX-treatment, = inducing=20 the silencing of SMOH, reduced tumor volume by =C2=B180% as = compared with mice=20 that did not receive DOX (Fig.=20 3E). Long-term analysis of straight LV-shSMOH and LV-control=20 transduced GBM-8 cells demonstrated the greater survival of = LV-shSMOH=20 harboring mice versus LV-control mice (Fig.=20 3H).

The stemness signature of grade III = gliomas but not=20 of most GBMs contrasts with the ability of both to form = gliomaspheres. If=20 GBM cancer stem cells are simply less abundant than those in grade = III=20 tumors, the selection of cancer stem cells in gliomasphere = cultures could=20 yield a similar enrichment. The expression patterns of 25 selected = genes=20 in 7 gliomasphere cultures (Figs.=20 1A, 4A,=20 S8)=20 identified a subgroup of genes displaying expression within a = 2-fold=20 variation from the mean, or over-expression, in all spheres. This = included=20 GLI1, PTCH1, NANOG, OCT4, SOX2, BMI1 and PCNA. = The=20 latter indicated similar proliferation of all sphere cultures. = Different=20 gliomaspheres therefore have active GLI1 function and might have = similar=20 numbers of cancer stem cells assuming similar expression per = cell.

Figure=20 4
Effects = of HH-GLI=20 signaling on self-renewal and on CD133+ glioma cancer stem=20 cells

To test for a link between HH-GLI = signaling and=20 stemness we quantified the ability of dissociated, single = gliomasphere=20 cells to generate secondary spheres as a measure of self-renewal = (Fig.=20 4B, E). Treatment of dissociated gliomasphere cells with = cyclopamine=20 for 7 days, prior to renewed dissociation and cloning without the = drug,=20 resulted in a =C2=B123=E2=80=9365% reduction in clones as compared = to tomatidine=20 treatment (Fig.=20 4C). Because 7 days allows for =C2=B15 cell divisions = (calculated from BrdU=20 incorporation data), giving rise to a 32-cell gliomasphere derived = from a=20 single cell (assuming constant division rates), and the cloning = rate was=20 at 6=E2=80=937%, there are on average 2 stem cells per 32-cell = sphere. Since=20 cyclopamine treatment for 7d also decreased sphere volume by = =C2=B150% (Fig.=20 4B), as it also affected growth, we deduced that cyclopamine = treatment=20 reduced the number of cancer stem cells to 0.25 per sphere on = average,=20 thus rendering most of them non-viable, consistent with the lack = of=20 recovery after long-term cyclopamine treatment (Fig.=20 S6E). Transient inhibition of SMOH (with DOX) for 7 days prior = to=20 cloning mimicked the results obtained with cyclopamine (Fig.=20 4D). Similar treatment with recombinant SHH, in contrast, = increased=20 the number of clones by =C2=B1145=E2=80=93240% (Fig.=20 S9A). As SHH treatment increased sphere volume = =C2=B13=E2=80=934-fold on average=20 (Fig.=20 4B), it induced an increased in the number of glioma stem = cells to=20 =C2=B112=E2=80=9315 per sphere. Similar experiments with TMZ = showed that it does not=20 significantly affect cancer stem cell self-renewal (p=3D0.3, = 50=CE=BCM TMZ versus=20 DMSO-treatment).

We used CD133 expression to purify=20 glioma-initiating cancer stem cells by FACS (5=E2=80=936)=20 (Fig.=20 4E). The percentage of secondary clones from CD133+ = FACS-sorted GBM-8 cells was 40-fold higher as compared with=20 CD133=E2=88=92 cells. The percentage of secondary = spheres from CD133+=20 FACS-sorted cell from 4 gliomasphere cultures was lower than the=20 percentage of CD133+ cells (Fig.=20 4F), raising the possibility that not all CD133+ = cells are=20 cancer stem cells as determined by clonogenic behavior. Analysis = of a=20 subset of genes in CD133+ versus = CD133=E2=88=92 cells showed=20 that SHH was enriched in all samples whereas = NOTCH1 was=20 enriched in all efficient cultures (Fig.=20 4F; Fig.=20 S10), revealing a correlation between efficiency of sphere = formation=20 (quality) and stemness marker expression (Fig.=20 S10).

Cyclopamine treatment of = CD133+ cells=20 for 7 days prior to cloning without the drug (see Fig.=20 4E) reduced the number of clones by =C2=B120=E2=80=9345% (Fig=20 4F). This result was observed in sphere cultures after several = passages as well as in CD133+ cells freshly purified from a = patient=E2=80=99s GBM=20 (Fig.=20 4F). Conversely, SHH treatment increased secondary sphere = formation by=20 120=E2=80=93140% (Fig.=20 S9B). The decrease in clonogenicity resulting from inhibition = of=20 endogenous HH-GLI signaling was correlated with a coordinated = decrease in=20 GLI1, PTCH1 and SHH expression at the = time of=20 cloning and with the specific and coordinated downregulation of = stemness=20 genes (Fig.=20 4G). Treatment of freshly FACS-sorted CD133+ cells with = cyclopamine=20 for only 4h resulted in a decrease in GLI1, PTCH1, = NANOG,=20 SOX2 and OCT4 expression by 50%, 40%, 10%, 57% and = 20% for=20 GBM-8 (and in GMB-6, not shown), respectively, as compared with=20 cyclopamine-treated CD133- cells, strongly suggesting the direct=20 inhibition of HH-GLI signaling and stemness in CD133+ cells.

Here we demonstrate that human gliomas = and their=20 cancer stem cells require HH-GLI pathway activity for = proliferation,=20 survival, self-renewal and tumorigenicity. The widespread = expression of=20 GLI1 in gliomas is consistent with its isolation from a = glioma=20 cell line (15)=20 and its expression in brain tumors in situ (7).=20 The discrepancy with previous work, suggesting that GLI1 = was not=20 overexpressed in gliomas (16),=20 can be partly explained by the fact that the cerebellum was used = as the=20 baseline, which we now know expresses GLI1 at the highest = levels=20 (17).=20 We have also uncovered a stemness signature that we interpret to = denote=20 the abundance of cancer stem cells in grade III gliomas. Cancer = stem cells=20 in GBMs may become diluted by the increased number of more = differentiated=20 tumor-derived cells, which gives them their multiforme character, = and by=20 the enhanced participation of non-tumor cells in GBMs, for = instance=20 through increased angiogenesis. Interestingly, angiogenesis in = GBMs could=20 not only provide required nutrients to the tumor but also enhance = its=20 growth and cancer stem cell self-renewal in cases when new vessels = express=20 SHH. Whereas glioma cancer stem cells express markers of = endogenous stem=20 cells (4,18,19),=20 the origin of the former is unclear. They could arise through a=20 dedifferentiation process or derive from precursors or endogenous = brain=20 stem cells (18,20=E2=80=9322).=20 Paralleling the derivation of medulloblastomas from SHH-dependent = cortical=20 cerebellar cells (7,17,23),=20 glioma stem cells could derive from endogenous GLI1+ = cells,=20 including those found in stem cell niches (7,17,24=E2=80=9327).

Our results argue for the development of=20 antagonists of GLI1,2 and agonists of GLI3R as anti-cancer agents. = Since=20 cyclopamine induces both of these changes simultaneously and shows = additive and synergistic effects with TMZ, a combinatorial = approach with=20 these agents may be advantageous to treat the tumor bulk and its = cancer=20 stem cells. The findings that HH-GLI signaling is involved in = regulating=20 the proliferation of both endogenous brain stem cells (24=E2=80=9327)=20 and glioma cancer stem cells (this work), and due to the lack of = obvious=20 secondary effects in cyclopamine-treated adult mice (25,28,=20 this work), we suggest that such treatments may spare normal = quiescent=20 stem cells in their niches, likely allowing regeneration of any = damage to=20 normal adult tissues after cessation of = treatment.

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Supplementary Material
 
Acknowledgments

We thank lab members for discussion, H. Weiner for initial = brain tumor=20 samples and D. Trono for lentivectors. This work was supported by = a=20 private donation from the Lombard-Odier-Darier-Hentsch bank to NdT = and=20 grants from the Louis-Jeantet Foundation, the Leenaards = Foundation, the=20 Swiss National Foundation, the Swiss Cancer League and the NIH to = ARA.

 
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Publisher's Disclaimer: This is a = PDF file=20 of an unedited manuscript that has been accepted for publication. = As a=20 service to our customers we are providing this early version of = the=20 manuscript. The manuscript will undergo copyediting, typesetting, = and=20 review of the resulting proof before it is published in its final = citable=20 form. Please note that during the production process errors may be = discovered which could affect the content, and all legal = disclaimers that=20 apply to the journal pertain.
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"=20 = src=3D"http://www.pubmedcentral.nih.gov/corehtml/pmc/pmcgifs/square.gif" = border=3D0>References 
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i < len; i++)=0A= {=0A= if (elmnts.item(i).className.indexOf(className, " ") = !=3D -1)=0A= {=0A= elmnts.item(i).innerHTML =3D innerHTML;=0A= unObscuredEmails[className] =3D true=0A= =0A= }=0A= }=0A= }=0A= }=0A= catch(e){=0A= }=0A= }=0A= =0A= //=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D= =3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D= =3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D= =3D=3D=3D=3D=3D=0A= function pubMedDbLinkSubmit(control) {=0A= try{=0A= if (control.pubmedOption) =0A= control =3D control.pubmedOption=0A= if (control.options)=0A= location.href =3D = control.options[control.options.selectedIndex].value;=0A= }=0A= catch(e){}=0A= return false;=0A= }=0A= ------=_NextPart_000_0023_01C874AE.A06CDE40 Content-Type: application/octet-stream Content-Transfer-Encoding: quoted-printable Content-Location: http://www.ncbi.nlm.nih.gov/corehtml/jsutils/utils.1.js // $Id: utils.1.js,v 1.12 2008/01/14 14:44:06 sponomar Exp $=0A= var utils=3D{=0A= KeyCode_TAB:9,=0A= KeyCode_DELETE:46,=0A= KeyCode_BACKSPACE:8,=0A= KeyCode_LEFT_ARROW:37,=0A= KeyCode_RIGHT_ARROW:39,=0A= KeyCode_HOME:36,=0A= KeyCode_END:35,=0A= KeyCode_PAGE_UP:33,=0A= KeyCode_PAGE_DOWN:34,=0A= KeyCode_UP_ARROW:38,=0A= KeyCode_DOWN_ARROW:40,=0A= KeyCode_ESC:27,=0A= KeyCode_ENTER:13,=0A= KeyCode_SPACE:32,=0A= KeyCode_SHIFT_KEY:16,=0A= KeyCode_CTRL_KEY:17,=0A= KeyCode_ALT_KEY:18,=0A= KeyCode_LEFT_MS_WINDOWS_KEY:91,=0A= KeyCode_RIGHT_MS_WINDOWS_KEY:92,=0A= KeyCode_MS_MENU_KEY:93,=0A= isObject: function(a) { return (a && typeof a =3D=3D 'object'); 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" + sText;=0A= else=0A= obj.innerHTML+=3DsText;=0A= }=0A= },=0A= selectRange:function (oObj,iStart,iLength ) {=0A= if (!(oObj && oObj.value)) return;=0A= if (oObj.createTextRange) {=0A= var oRange=3DoObj.createTextRange();=0A= oRange.moveStart("character", iStart);=0A= oRange.moveEnd("character", iLength - oObj.value.length);=0A= oRange.select();=0A= } else if (oObj.setSelectionRange) {=0A= oObj.setSelectionRange(iStart,iLength);=0A= }=0A= oObj.focus();=0A= },=0A= getSelection:function() {=0A= var text =3D "";=0A= if (window.getSelection) {=0A= text+=3Dwindow.getSelection();=0A= } else if (document.getSelection) {=0A= text+=3Ddocument.getSelection();=0A= } else if (document.selection){=0A= text+=3Ddocument.selection.createRange().text;=0A= }=0A= return text;=0A= },=0A= getPlural:function x_Plural(iN,sSuffix) {=0A= if (undefined=3D=3DsSuffix) {=0A= return (iN > 1 ? "s" : "");=0A= } else if ("y" =3D=3D sSuffix) {=0A= return (iN > 1 ? "ies" : "");=0A= } else {=0A= return (iN > 1 ? sSuffix + "s" : sSuffix);=0A= }=0A= },=0A= getPeriodToString:function(iDelta) {=0A= var x =3D "Error, cannot convert '" + iDelta + "'";=0A= var sDir;=0A= iDelta=3DparseInt(iDelta);=0A= if (iDelta<0) {=0A= sDir =3D " before";=0A= iDelta=3D-iDelta;=0A= } else=0A= sDir =3D " ago";=0A= var iS=3DparseInt(iDelta/1000);=0A= var iM,iH,iD;=0A= if (iS<60) {=0A= x =3D iS + " second" + this.getPlural(iS);=0A= } else {=0A= iM=3DparseInt(iS/60);=0A= if (iM<60) {=0A= x =3D iM + " minute" + this.getPlural(iM);=0A= } else {=0A= iH=3DparseInt(iM/60);=0A= if (iH<24) {=0A= iM=3DiM-iH *60;=0A= x =3D iH + " hour" + this.getPlural(iH) + " and " + iM + " minute" + = this.getPlural(iM);=0A= } else {=0A= iD=3DparseInt(iH/24);=0A= iH-=3DiD *24;=0A= x =3D iD + " day" + this.getPlural(iD) + " and " + iH + " hour" + = this.getPlural(iH);=0A= }=0A= }=0A= }=0A= return x+sDir;=0A= },=0A= addEvent_guid:1,=0A= addEvent:function (element,type,handler) {=0A= if (!handler.$$guid) handler.$$guid=3Dthis.addEvent_guid++;=0A= if (!element.events) element.events=3D{};=0A= var handlers=3Delement.events[type];=0A= if (!handlers) {=0A= handlers=3Delement.events[type]=3D{};=0A= if (element["on" + type]) {=0A= handlers[0] =3D element["on" + type];=0A= }=0A= }=0A= handlers[handler.$$guid]=3Dhandler;=0A= element["on" + type] =3D handleEvent;=0A= function handleEvent(event) {=0A= var returnValue=3Dtrue;=0A= event=3Devent || fixEvent(window.event);=0A= var handlers=3Dthis.events[event.type];=0A= for (var i in handlers) {=0A= this.$$handleEvent=3Dhandlers[i];=0A= if (this.$$handleEvent(event)=3D=3D=3Dfalse) {=0A= returnValue=3Dfalse;=0A= }=0A= }=0A= return returnValue;=0A= };=0A= function fixEvent(event) {=0A= event.preventDefault=3DfixEvent.preventDefault;=0A= event.stopPropagation=3DfixEvent.stopPropagation;=0A= return event;=0A= };=0A= fixEvent.preventDefault=3Dfunction() {=0A= this.returnValue=3Dfalse;=0A= };=0A= fixEvent.stopPropagation=3Dfunction() {=0A= this.cancelBubble=3Dtrue;=0A= };=0A= return handler.$$guid;=0A= },=0A= removeEvent:function (element,type,handler) {=0A= if (element.events && element.events[type]) {=0A= delete element.events[type][handler.$$guid];=0A= return handler.$$guid;=0A= }=0A= return null;=0A= },=0A= preventDefault:function(e) {=0A= if (e.preventDefault) e.preventDefault();=0A= else window.event.returnValue=3Dfalse;=0A= },=0A= getRelatedTarget:function(e) {=0A= if (!e) var e=3Dwindow.event;=0A= if (e.relatedTarget) return e.relatedTarget;=0A= else if (e.toElement) return e.toElement;=0A= else if (e.fromElement) return e.fromElement;=0A= },=0A= getTargetObj:function(eEvent) {=0A= var oTarget;=0A= var e=3DeEvent || window.event;=0A= if (e=3D=3Dnull) return null;=0A= if (e.srcElement=3D=3Dnull) oTarget=3De.target;=0A= else oTarget=3De.srcElement;=0A= while (oTarget && oTarget.nodeType !=3D1) oTarget=3DoTarget.parentNode;=0A= return oTarget;=0A= },=0A= printObj:function (oObj,iLevel) {=0A= var s =3D "";=0A= var sIdent =3D "";=0A= if (!iLevel) iLevel=3D0;=0A= for (var i=3D0;i";=0A= }=0A= return s;=0A= },=0A= jsLoader:{=0A= oLoaded:[],=0A= sBase:"",=0A= load:function (aScripts) {=0A= var oS =3D document.getElementsByTagName("script");=0A= for (var j=3D0;j");=0A= this.oLoaded.push(sNewSrc);=0A= }=0A= }=0A= }=0A= },=0A= insertInHtml:function(text,obj) {=0A= if (document.all) {=0A= obj.innerHTML+=3Dtext;=0A= } else {=0A= var range=3Ddocument.createRange();=0A= range.setStartAfter(obj);=0A= var docFrag=3Drange.createContextualFragment(text);=0A= obj.appendChild(docFrag);=0A= }=0A= },=0A= replaceInHtml:function(text,obj) {=0A= if (document.all) {=0A= obj.innerHTML=3Dtext;=0A= } else {=0A= while (obj.hasChildNodes()) obj.removeChild(obj.firstChild);=0A= var range=3Ddocument.createRange();=0A= range.setStartAfter(obj);=0A= var docFrag=3Drange.createContextualFragment(text);=0A= obj.appendChild(docFrag);=0A= }=0A= }=0A= };=0A= String.prototype.trimSpaces=3Dfunction(trimMode) {=0A= var targetString=3Dthis;=0A= var iPos=3D0;=0A= if (!trimMode) trimMode=3D0;=0A= if (trimMode=3D=3D0|| trimMode=3D=3D1) {=0A= if (targetString.charAt(iPos)=3D=3D" ") {=0A= while(targetString.charAt(iPos)=3D=3D" ") iPos++;=0A= targetString=3DtargetString.substr(iPos);=0A= }=0A= }=0A= iPos=3DtargetString.length-1;=0A= if (trimMode=3D=3D0|| trimMode=3D=3D2) {=0A= if (targetString.charAt(iPos) =3D=3D " ") {=0A= while(targetString.charAt(iPos) =3D=3D " ") iPos--;=0A= targetString=3DtargetString.substr(0,iPos+1);=0A= }=0A= }=0A= return targetString;=0A= }=0A= function $() {=0A= var elements=3Dnew Array();=0A= for (var i=3D0;i0) {=0A= var W=3DoMetadata.aView[0].W * oThis.fScale;=0A= for = (oThis.iScaleIndex=3D0;oThis.iScaleIndex