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Journal of Clinical Oncology, Vol = 26, No 17=20 (June 10), 2008: pp. 2795-2799
=A9 2008 American Society = of Clinical=20 Oncology.
DOI: 10.1200/JCO.2008.17.7436
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OVERVIEW

Cancer Stem Cells: A Step Toward the=20 Cure

Bruce M. Boman =

Helen F. Graham Cancer Center, Newark, DE; = Thomas=20 Jefferson University, Philadelphia, PA

Max S. Wicha

University of Michigan Comprehensive Cancer = Center, Ann=20 Arbor, MI

This special issue of Journal of Clinical Oncology is=20 devoted to the emerging field of cancer stem cells = (CSCs). The=20 goal of this article is to introduce general concepts = of CSC=20 biology to clinicians, and to provide a framework for = their=20 understanding the CSC-based approach to the development = of=20 novel diagnostics, therapeutics, and prevention = strategies in=20 oncology.

This new approach differs from the traditional one because = the=20 latter is based on the long-held concept that tumor = formation=20 and growth are due to increased proliferation of cells in=20 cancers compared with normal tissues. This traditional = view is=20 supported by molecular oncology research during the = last 50=20 years, which showed that tumors undergo a series of = genetic=20 events (mutations) that result in the activation or=20 overexpression of genes promoting proliferation (eg,=20 oncogenes), the silencing of genes involved in = inhibition of=20 proliferation (eg, tumor suppressor genes), and the = development=20 of the ability of cancer cells to elude apoptosis. The=20 consequence is the development and unchecked growth of = tumors=20 and their progression to metastases. Based on this = traditional=20 concept of tumor growth, it has been disappointing that = therapies designed to kill proliferating cells often fail = to=20 cure cancer patients.

Furthermore, during tumor development, tissues accumulate = a=20 series of mutations over years or even decades, but, = because=20 of tissue renewal, most cells in tissues are lost or = eliminated=20 in just a brief time, typically days or weeks, and with = their=20 loss, any mutations they have acquired would also be lost.=20 Thus, new mechanisms need to be considered to explain = human=20 tumorigenesis.

One explanation is that tumorigenic mutations occur in = cells=20 that are few in number but reside long term in = tissues. But that is not sufficient to explain = tumorigenesis.=20 To be truly tumorigenic, this population of rare, = mutated cells=20 would have to self-renew, clonally expand, and acquire=20 additional mutations. It is now widely believed that = these=20 long-lived, uncommon cells are tissue stem cells (SCs) = or cells=20 derived from them that acquire the ability to = self-renew. When=20 mutated, they can become CSCs. Both normal SCs and CSCs = may=20 account for only a small fraction of cells (3D~=201%) in any = given=20 tissue or tumor. By definition, SCs are self-renewing. = Mounting=20 evidence presented in the articles in this special = issue=20 suggests that CSCs initiate and drive tumor = growth.

This is nothing less than a paradigm shift.1=20 It is a shift to the view that, first, cancers = originate in=20 tissue stem or progenitor cells through dysregulation = of the=20 self-renewal process. Second, throughout tumorigenesis, = CSCs=20 drive tumor growth. Third, current chemotherapeutic = agents and=20 radiation therapy largely target proliferating and=20 differentiated cells that form the bulk of the tumor = but not=20 the relatively quiescent CSCs. Also, SCs are drug = resistant and=20 CSCs appear to be so too. Thus, this quiescence and = resistance=20 may account for many treatment failures. Fourth, if = this is the=20 case, then the only effective way to treat cancer is to = target=20 the CSC population.

Although this view may seem novel, the basic idea that SCs = are=20 the cells of clonal origin of malignancies has existed for = at=20 least several decades,2=20 if not longer,3=20 particularly for leukemias4-8=20 and teratomas.9-11=20 Early attempts=97beginning in the 1970s=97to directly = measure SCs=20 in tumors used several approaches.12=20 One was mouse-spleen colony assays (eg, injection of = lymphoma=20 cells into mice with the appearance of lymphoma = colonies in the=20 spleen). A second was the counting of metastatic lung = colonies=20 after intravenous inoculation of tumor cells into mice. = A third=20 was tumor colony formation in vitro. However, this = latter=20 method produced mixed results for human tumors.13=20 SCs have also been known for decades to radiation=20 biologists.14,<= A=20 = href=3D"http://jco.ascopubs.org/cgi/content/full/26/17/2795#R15">15=20 More recent evidence, as presented in the articles in = this=20 special issue, supports an SC origin for solid tumors = as well.=20 In the following paragraphs, we discuss the properties = of=20 normal SCs and CSCs, and their possible roles in = carcinogenesis=20 and in mediating tumor behavior.

BIOLOGIC PROPERTIES OF = SCs

The most well-known property of SC populations is their = ability=20 to self-renew. Self-renewal is particularly important in=20 tissues with high turnover, such as the GI tract and = bone=20 marrow, as well as in tissue repair after injury. = Self-renewal=20 involves the ability of normal SC populations to = precisely=20 maintain their numbers through a combination of = symmetric and=20 asymmetric SC division.16,<= A=20 = href=3D"http://jco.ascopubs.org/cgi/content/full/26/17/2795#R17">17=20 The property of self-renewal is also a hallmark of = populations=20 of CSCs. However, in this case, mechanisms involved in=20 self-renewal are dysregulated and seem to lead to CSC = overpopulation.=20 The underlying mechanisms for replacing lost SCs (eg, = during=20 tissue repair) or in generating excess SC numbers (eg, in = tumor=20 development) are believed to relate to increases in = symmetric=20 SC division (which produces two SC daughters) relative to=20 asymmetric SC division (which produces one SC daughter = and one=20 non-SC daughter). Indeed, we documented this concept=20 quantitatively for colon cancer development using = mathematical=20 modeling.17=20 We showed that only increased symmetric division of = cancer SCs=20 could account for the biologic observation that there = is an=20 exponential increase in SCs, non-SC proliferative = cells, and=20 nonproliferative cell populations in the development of = colorectal cancer. Our modeling also showed that only = increased=20 symmetric SC division could account for the known long = lag=20 phase in colon cancer development, which is typical in = the=20 development of many cancers.

Although SCs have the capacity for self-renewal, in fact = they=20 are relatively quiescent; that is, they have proliferative=20 capacity but are often not cycling. Indeed, they have = been=20 shown to have significantly longer cell cycle times = than=20 proliferating non-SCs.18=20 This is presumably due to the arrest of SCs at a = G0-like=20 cell cycle phase or checkpoint.

Another property of SCs is their potential for = multilineage=20 differentiation. This is consistent with the CSC = hypothesis=20 because cancers typically contain multiple differentiated = cell=20 types that correspond to cells in the tissue from which = the=20 cancer arose. This suggests a SC origin for these tumors=20 because only multipotent SCs (or perhaps SC-like = progenitor=20 cells) could have given rise to these different cell = types.=20 Indeed, it has been known for more than a century that = tumors=20 are composed of heterogeneous populations of partially=20 differentiated cell types that resemble those in the = normal=20 organ.19=20 This observation gave rise to the idea that tumors are=20 functioning as aberrantly developed complex = organs.20=20 This is consistent with the concept that CSCs, like = normal SCs,=20 give rise to a hierarchical organization of cell = populations=20 that underlie organogenesis.21=20 This hierarchy includes CSCs that produce committed = progenitor=20 cells that, in turn, produce rapidly proliferating = cells,=20 finally resulting in the generation of fully = differentiated=20 cells (Table=20 1). This is discussed further in this issue in the = articles=20 by Sell and Leffert22=20 on liver CSCs and by Lee et al23=20 on pancreatic CSCs.


View this=20 table:
[in=20 this window]
[in a new window]

  = 		Table = 1.=20 Hierarchal Organization and Properties of Stem, = Proliferating,=20 and Non-Proliferative Cell Populations =

 = ;
The=20 development of various organs during embryogenesis is known = to=20 involve specific signaling pathways. Key pathways include = sonic=20 hedgehog, Notch, PTEN, BMI-1, WNT, and p53. Indeed, there = is=20 growing evidence that these signaling pathways regulate = self-renewal=20 of normal SC populations.16=20 These pathways are known to become dysregulated during=20 development of tumors, which is believed to lead to=20 dysregulation of SC self-renewal and contribute to = neoplastic=20 proliferation.21=20

METHODS TO IDENTIFY AND ISOLATE=20 SCs

Progress in the field of SC biology, including CSC = biology,=20 has been long hampered by difficulties in identifying,=20 isolating, and characterizing SCs. However, = considerable=20 progress has been made recently. At first, SC = populations could=20 only be identified functionally using their ability to = undergo=20 self-renewal and differentiation into multiple = lineages. More=20 recently, CSCs and even normal SCs from certain tissues = have=20 been identified and isolated. This became possible in = large=20 part due to the identification of SC markers (Table=20 2), their use in combination with = fluorescence-activated=20 cell sorting, and the ability to show that specific = cell=20 subpopulations form tumors in xenograft assays in=20 immunocompromised mice.4=20 The CSCs and the tumors they form demonstrate the = capacity for=20 serial passage (transplantability) in immunocompromised = mice=20 and for generation of multiple cell lineages in a=20 histopathologic pattern resembling the original tumor. = This=20 approach has been used to isolate CSCs from various = cancer=20 types (Table=20 2), as discussed in the corresponding articles in = this=20 issue. Interestingly, many CSC markers are shared across=20 multiple tumor types. They also may be expressed on normal=20 tissue SCs in organs from which these tumors = originated.=20


View this=20 table:
[in=20 this window]
[in a new window]

  = 		Table = 2.=20 Markers to Identify and Isolate Stem Cells From = Various=20 Malignancies =

 = ;
CSCs=20 have also been identified by in vitro sphere-forming = assays.24=20 It has been demonstrated that the ability of cells to form=20 colonies in multicellular spheroids or spherical cell=20 aggregates under nonadherent culture conditions is a=20 characteristic of many cells having self-renewal = capacity.=20 These spheroids can be disaggregated and passaged = multiple=20 times with retention of sphere-forming ability. = Spheroid=20 formation in vitro was used to study CSCs in breast = (see=20 article in this issue by Kakarala and Wicha25)=20 and brain (see article in this issue by Dirks26).=20 The practicality, ease, and low cost of this assay = makes it=20 adaptable for performing high-throughput screens for=20 identifying drugs that target CSCs and for measuring = the=20 effects of radiation on CSCs. Targets can be validated = using=20 more labor-intensive xenograft models.

ROLE OF CSCs IN CANCER INITIATION, = PRIMARY TUMOR=20 GROWTH, AND METASTASES

Our current understanding of human carcinogenesis involves = two=20 central ideas. One is that most, if not all, cancers = result=20 from the accumulation of specific genetic mutations. The = other=20 is that tumorigenesis involves aberrant tissue = organization=20 and cell proliferation. The CSC paradigm begins to suggest = how=20 these two events are linked. That is, it provides a = cellular=20 mechanism that can explain how the genetic and epigenetic=20 changes give rise to the tissue changes. Moreover, = evidence=20 suggests that these mechanisms may be operational in = all phases=20 of tumorigenesis: initiation, progression, invasion, = and=20 metastasis. The idea that cancer initiation involves=20 development of CSC overpopulation was supported by an = analysis=20 of tissues from hereditary cancer patients.27,<= A=20 = href=3D"http://jco.ascopubs.org/cgi/content/full/26/17/2795#R28">28=20 For fully developed cancers, support comes from recent = reports=20 that many cancers contain a small but significant = proportion=20 (3D~1%) of=20 CSCs.29-<= A=20 = href=3D"http://jco.ascopubs.org/cgi/content/full/26/17/2795#R35">35=20 Given that the total number of cells is exponentially = increased=20 (up to 108 to 1013 cells) in = fully=20 developed cancers, it can be deduced that the size of = the SC=20 subpopulation in those tumors is also exponentially = increased.=20 Indeed, this must have occurred during all phases of=20 tumorigenesis.17=20 The progressive increase in the CSC population throughout=20 tumorigenesis in the colon will be discussed in this = issue in=20 the article by Boman and Huang36=20 on colon cancer SCs. Regarding metastases, there is a = growing=20 body of evidence that suggests that metastases develop = when=20 distant organs are seeded with CSCs that arise from a = primary=20 tumor.37=20 This implicates CSCs in the seeding and growth of = metastatic=20 lesions. This mechanism is discussed, in this issue, in = the=20 article on breast CSCs by Kakarala and Wicha.25=20

CSCs IN CANCER DIAGNOSIS, TREATMENT, = AND=20 PREVENTION

As noted, current systemic cancer therapies frequently = fail=20 to eradicate advanced tumors. Failure of these therapies = to=20 effectively target cancer SCs may account for this = failure.38=20 First, most current agents destroy rapidly proliferating=20 cells=97cells that represent the bulk of tumor cell = populations.=20 If cancer SCs drive tumorigenesis, current = chemotherapeutic=20 approaches may be ineffective because cancer SCs, like = all SCs,=20 are relatively quiescent; that is, they proliferate = only=20 infrequently. Second, SCs tend to be more resistant to=20 chemotherapeutic agents and radiation than are more = mature cell=20 types from the same tissue. This is believed to be due = to the=20 presence of multidrug resistance, antiapoptotic = proteins, and=20 enhanced DNA repair mechanisms. Since this appears to = hold true=20 for cancer SCs, we would predict that they would also = display=20 resistance to therapeutics. This is discussed, in this = issue,=20 in the article by Eyler and Rich.39=20 Third, most current therapies do not target the signaling=20 pathways that regulate self-renewal, which appear to be = either=20 mutated or epigenetically dysregulated. These pathways, = including sonic hedgehog, Notch, PTEN, BMI-1, WNT, and = p53, are=20 discussed in this issue in the article by Fan and=20 Eberhart.40=20 There is evidence that these pathways are involved in=20 regulation of self-renewal, and effective therapies = will need=20 to target symmetric SC division.17=20 Targeting these pathways, it should be noted, will = probably=20 not be enough=97an ideal agent would have to = selectively=20 target cancer SCs over normal SCs. Without this = selectivity,=20 the effectiveness of treatment might be limited by = systemic=20 toxicity.

Control of SC numbers would also be important in cancer=20 chemoprevention. The ideal cancer chemopreventive agent = would=20 also selectively target CSCs over normal SCs. This = suggests=20 that the development of agents that eliminate or = control CSC=20 populations may be an effective strategy for cancer = prevention=20 as well as the development of more effective cancer = therapies.=20 Indeed, experiments using antibodies against an CSC = marker,=20 CD44, eliminated human acute myeloid leukemic SCs in=20 immunodeficient mice transplanted with human acute = myeloid=20 leukemia.41=20

It is also likely that treatment of patients with = CSC-targeted=20 therapeutics will require new clinical end points for=20 monitoring therapeutic efficacy. This is the case = because one=20 is targeting only a small fraction of cells within the = tumor,=20 not the bulk of the tumor. In addition, responses may = take a=20 much longer time than is typically seen with agents = that are=20 cytotoxic to the rapidly dividing cells that constitute = the=20 bulk of the tumor. Rational approaches might also = include using=20 cytotoxic chemotherapies to target the proliferating = bulk of=20 the tumor in addition to a CSC-directed therapy = directed at=20 eliminating this critical cell population. An important = end=20 point will likely involve assessing changes in the size = of the=20 CSC population in response to treatment. One way to do = this=20 might be by monitoring the burden of CSCs in the = circulation.=20 Of course patient survival remains the ultimate = clinical end=20 point, which will involve appropriate clinical = trials.=20

Markers for CSCs could be used for predicting treatment = responses=20 by identifying the presence of specific CSC subtypes that = are=20 selectively sensitive to specific agents, particularly = biologic=20 agents such as antibodies against specific CSC targets.=20 Microarray and proteomic profiling of CSCs will likely = lead to=20 identification of new markers, as well as potential = therapeutic=20 targets. Indeed, a recent microarray study identified a = genetic=20 signature associated with the BMI-1 driven SC = self-renewal=20 pathway.42=20 Other gene expression studies have identified genes = associated=20 with prognosis in breast cancer, and these signatures = contained=20 the aldehyde dehydrogenase 1 (ALDH1) SC marker.43,<= A=20 = href=3D"http://jco.ascopubs.org/cgi/content/full/26/17/2795#R44">44=20 This approach to identify new markers is discussed, in = this=20 issue, in the article by Glinsky.45=20 CSC markers may have prognostic value by allowing = assessment=20 of the size of the CSC population within any given tumor. = Early=20 evidence suggests that the greater the size of the CSC=20 population, the poorer the prognosis, as reflected by = tumor=20 aggressiveness and/or patient survival. This is = discussed, in=20 this issue, in the article by Kakarala and = Wicha.25=20

MATHEMATICAL MODELING OF CSC DYNAMICS = AND=20 THERAPEUTIC APPROACHES

Mathematical modeling will be especially useful in = understanding=20 the role of CSCs in cancer development and growth, as well = as=20 response to therapy. For example, modeling provided a=20 quantitative basis for the ideas that CSCs drive tumor = growth,=20 curative anticancer therapy must eradicate or control = CSC=20 populations,28,<= A=20 = href=3D"http://jco.ascopubs.org/cgi/content/full/26/17/2795#R46">46=20 and that future therapeutic approaches need to target=20 symmetric division of CSCs.17=20

Future modeling studies will be important because SCs are = involved=20 in homeostasis of normal tissues, which are complex in = their=20 structure and in their dynamics, and which involve many=20 interacting cellular pathways. Moreover, the = development of=20 tumors is a complicated biologic process, and this will = add to=20 the overall complexity. Indeed, a recent article = advocates the=20 use of mathematical studies on SCs as a requisite to = advance=20 the field.47=20

Mathematical modeling will also be required to understand=20 responses to treatment when using anti-CSC therapies,=20 especially in predicting how treatments might affect = the=20 dynamics of tumor growth and overall tumor responses to = treatment. This is exemplified by recent modeling = studies that=20 have provided explanations for the role of CSCs in = development=20 of resistance to imatinib therapy in patients with = chronic=20 myeloid leukemia.48-<= A=20 = href=3D"http://jco.ascopubs.org/cgi/content/full/26/17/2795#R51">51=20 Such modeling will also likely be useful in developing=20 treatment and dose schedules, as well as criteria for=20 monitoring therapeutic responses. The use of = mathematical=20 modeling is discussed further throughout this issue, = especially=20 in the article by Michor.52=20

OVERTURE TO THIS SPECIAL = ISSUE

To fully appreciate the CSC-based approach to cancer = treatment,=20 diagnosis, and prevention requires a discussion of = different=20 cancer types and the CSCs that drive tumor growth in each = type.=20 The rest of this JCO special issue is devoted to that = end.=20 This includes 13 articles that focus on the roles SCs = may play=20 in each type of malignancy. Together, these articles=20 illustrate the commonality of CSCs in multiple tumor = types.=20 This suggests that approaches involving similar = techniques and=20 molecular markers may be applicable across tumor types. = Furthermore, because pathways of CSC self-renewal and = cellular=20 survival also seem to be preserved across different = tumor=20 types, strategies designed to target CSCs may also have = broad=20 clinical utility. This suggests the need to develop=20 pathway-based rather than tumor type-based approaches = to=20 CSC-based therapy. This issue also includes five articles=20 covering select research and clinical topics related to = CSCs=20 and clinical oncology, including molecular profiling and=20 biomarkers, mathematical models, chemotherapy = resistance,=20 radiation resistance, and imaging approaches. All of = these=20 articles provide evidence that SCs or their = self-renewing=20 progeny may be the cells of origin of specific cancer = types,=20 and demonstrate that significant progress has been made = in=20 identifying and characterizing each of those CSC = populations.=20 The goal of this issue is to inform clinicians and = clinical=20 investigators about progress in the field of CSCs. If = the=20 hypotheses central to this emerging field prove to be = correct,=20 then they represent an important paradigm shift in our=20 understanding of carcinogenesis. The great promise of = this work=20 is that it may lead to more effective strategies for = cancer=20 prevention and treatment. Given that CSC-targeting = agents are=20 now entering clinical trials, we will soon have an = indication=20 as to whether this is the case.

AUTHORS=92 DISCLOSURES OF POTENTIAL = CONFLICTS OF=20 INTEREST

Although all authors completed the disclosure declaration, = the=20 following author(s) indicated a financial or other = interest=20 that is relevant to the subject matter under consideration = in=20 this article. Certain relationships marked with a "U" are = those=20 for which no compensation was received; those = relationships=20 marked with a "C" were compensated. For a detailed = description=20 of the disclosure categories, or for more information = about=20 ASCO's conflict of interest policy, please refer to the = Author=20 Disclosure Declaration and the Disclosures of Potential=20 Conflicts of Interest section in Information for=20 Contributors.

Employment or Leadership Position: Bruce M. Boman, CA*TX = Inc (C) Consultant or Advisory Role: None = Stock=20 Ownership: Max C. Wicha, Oncomed Honoraria: = None=20 Research Funding: None Expert Testimony: = None=20 Other Remuneration: None

AUTHOR CONTRIBUTIONS

Manuscript writing: Bruce M. Boman, Max S. Wicha =

ACKNOWLEDGMENTS

We acknowledge the valuable discussions regarding the = manuscript=20 of Jeremy Z. Fields, PhD, Director of Scientific Research,=20 CA*TX Inc, Gladwyne, PA.

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To = view a=0A= copy of this license, visit = http://creativecommons.org/licenses/by-sa/2.5/ or=0A= send a letter to Creative Commons, 559 Nathan Abbott Way, Stanford, = California=0A= 94305, USA.=0A= =0A= Attribution: Leave my name and web address in this script intact.=0A= =0A= Not Supported in Opera=0A= ----------------------=0A= * user/password authentication=0A= * responseXML data member=0A= =0A= Not Fully Supported in Opera=0A= ----------------------------=0A= * async requests=0A= * abort()=0A= * getAllResponseHeaders(), getAllResponseHeader(header)=0A= =0A= */=0A= // IE support=0A= if (window.ActiveXObject && !window.XMLHttpRequest) {=0A= window.XMLHttpRequest =3D function() {=0A= var msxmls =3D new Array(=0A= 'Msxml2.XMLHTTP.5.0',=0A= 'Msxml2.XMLHTTP.4.0',=0A= 'Msxml2.XMLHTTP.3.0',=0A= 'Msxml2.XMLHTTP',=0A= 'Microsoft.XMLHTTP');=0A= for (var i =3D 0; i < msxmls.length; i++) {=0A= try {=0A= return new ActiveXObject(msxmls[i]);=0A= } catch (e) {=0A= }=0A= }=0A= return null;=0A= };=0A= }=0A= // Gecko support=0A= /* ;-) */=0A= // Opera support=0A= if (window.opera && !window.XMLHttpRequest) {=0A= window.XMLHttpRequest =3D function() {=0A= this.readyState =3D 0; 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i < this._headers.length; i++) {=0A= if (header =3D=3D '*' || this._headers[i].h =3D=3D header) {=0A= ret +=3D this._headers[i].h + ': ' + this._headers[i].v + '\n';=0A= }=0A= }=0A= return ret;=0A= };=0A= this.getResponseHeader =3D function(header) {=0A= var ret =3D getAllResponseHeader(header);=0A= var i =3D ret.indexOf('\n');=0A= if (i !=3D -1) {=0A= ret =3D ret.substring(0, i);=0A= }=0A= return ret;=0A= };=0A= this.setRequestHeader =3D function(header, value) {=0A= this._headers[this._headers.length] =3D {h:header, v:value};=0A= };=0A= this.open =3D function(method, url, async, user, password) {=0A= this.method =3D method;=0A= this.url =3D url;=0A= this._async =3D true;=0A= this._aborted =3D false;=0A= this._headers =3D [];=0A= if (arguments.length >=3D 3) {=0A= this._async =3D async;=0A= }=0A= if (arguments.length > 3) {=0A= opera.postError('XMLHttpRequest.open() - user/password not = supported');=0A= }=0A= this.readyState =3D 1;=0A= if (this.onreadystatechange) {=0A= this.onreadystatechange();=0A= }=0A= };=0A= this.send =3D function(data) {=0A= if (!navigator.javaEnabled()) {=0A= alert("XMLHttpRequest.send() - Java must be installed and = enabled.");=0A= return;=0A= }=0A= if (this._async) {=0A= setTimeout(this._sendasync, 0, this, data);=0A= // this is not really asynchronous and won't execute until the = current=0A= // execution context ends=0A= } else {=0A= this._sendsync(data);=0A= }=0A= }=0A= this._sendasync =3D function(req, data) {=0A= if (!req._aborted) {=0A= req._sendsync(data);=0A= }=0A= };=0A= this._sendsync =3D function(data) {=0A= this.readyState =3D 2;=0A= if (this.onreadystatechange) {=0A= this.onreadystatechange();=0A= }=0A= // open connection=0A= var url =3D new java.net.URL(new = java.net.URL(window.location.href), this.url);=0A= var conn =3D url.openConnection();=0A= for (var i =3D 0; i < this._headers.length; i++) {=0A= conn.setRequestProperty(this._headers[i].h, this._headers[i].v);=0A= }=0A= this._headers =3D [];=0A= if (this.method =3D=3D 'POST') {=0A= // POST data=0A= conn.setDoOutput(true);=0A= var wr =3D new = java.io.OutputStreamWriter(conn.getOutputStream(), this._getCharset());=0A= wr.write(data);=0A= wr.flush();=0A= wr.close();=0A= }=0A= // read response headers=0A= // NOTE: the getHeaderField() methods always return nulls for me :(=0A= var gotContentEncoding =3D false;=0A= var gotContentLength =3D false;=0A= var gotContentType =3D false;=0A= var gotDate =3D false;=0A= var gotExpiration =3D false;=0A= var gotLastModified =3D false;=0A= for (var i =3D 0; ; i++) {=0A= var hdrName =3D conn.getHeaderFieldKey(i);=0A= var hdrValue =3D conn.getHeaderField(i);=0A= if (hdrName =3D=3D null && hdrValue =3D=3D null) {=0A= break;=0A= }=0A= if (hdrName !=3D null) {=0A= this._headers[this._headers.length] =3D {h:hdrName, = v:hdrValue};=0A= switch (hdrName.toLowerCase()) {=0A= case 'content-encoding': gotContentEncoding =3D true; break;=0A= case 'content-length' : gotContentLength =3D true; break;=0A= case 'content-type' : gotContentType =3D true; break;=0A= case 'date' : gotDate =3D true; break;=0A= case 'expires' : gotExpiration =3D true; break;=0A= case 'last-modified' : gotLastModified =3D true; break;=0A= }=0A= }=0A= }=0A= // try to fill in any missing header information=0A= var val;=0A= val =3D conn.getContentEncoding();=0A= if (val !=3D null && !gotContentEncoding) = this._headers[this._headers.length] =3D {h:'Content-encoding', v:val};=0A= val =3D conn.getContentLength();=0A= if (val !=3D -1 && !gotContentLength) = this._headers[this._headers.length] =3D {h:'Content-length', v:val};=0A= val =3D conn.getContentType();=0A= if (val !=3D null && !gotContentType) = this._headers[this._headers.length] =3D {h:'Content-type', v:val};=0A= val =3D conn.getDate();=0A= if (val !=3D 0 && !gotDate) this._headers[this._headers.length] = =3D {h:'Date', v:(new Date(val)).toUTCString()};=0A= val =3D conn.getExpiration();=0A= if (val !=3D 0 && !gotExpiration) = this._headers[this._headers.length] =3D {h:'Expires', v:(new = Date(val)).toUTCString()};=0A= val =3D conn.getLastModified();=0A= if (val !=3D 0 && !gotLastModified) = this._headers[this._headers.length] =3D {h:'Last-modified', v:(new = Date(val)).toUTCString()};=0A= // read response data=0A= var reqdata =3D '';=0A= var stream =3D conn.getInputStream();=0A= if (stream) {=0A= var reader =3D new java.io.BufferedReader(new = java.io.InputStreamReader(stream, this._getCharset()));=0A= var line;=0A= while ((line =3D reader.readLine()) !=3D null) {=0A= if (this.readyState =3D=3D 2) {=0A= this.readyState =3D 3;=0A= if (this.onreadystatechange) {=0A= this.onreadystatechange();=0A= }=0A= }=0A= reqdata +=3D line + '\n';=0A= }=0A= reader.close();=0A= this.status =3D 200;=0A= this.statusText =3D 'OK';=0A= this.responseText =3D reqdata;=0A= this.readyState =3D 4;=0A= if (this.onreadystatechange) {=0A= this.onreadystatechange();=0A= }=0A= if (this.onload) {=0A= this.onload();=0A= }=0A= } else {=0A= // error=0A= this.status =3D 404;=0A= this.statusText =3D 'Not Found';=0A= this.responseText =3D '';=0A= this.readyState =3D 4;=0A= if (this.onreadystatechange) {=0A= this.onreadystatechange();=0A= }=0A= if (this.onerror) {=0A= this.onerror();=0A= }=0A= }=0A= };=0A= };=0A= }=0A= // ActiveXObject emulation=0A= if (!window.ActiveXObject && window.XMLHttpRequest) {=0A= window.ActiveXObject =3D function(type) {=0A= switch (type.toLowerCase()) {=0A= case 'microsoft.xmlhttp':=0A= case 'msxml2.xmlhttp':=0A= case 'msxml2.xmlhttp.3.0':=0A= case 'msxml2.xmlhttp.4.0':=0A= case 'msxml2.xmlhttp.5.0':=0A= return new XMLHttpRequest();=0A= }=0A= return null;=0A= };=0A= }=0A= ------=_NextPart_000_00AC_01CAD4D7.C8F8B4C0 Content-Type: application/octet-stream Content-Transfer-Encoding: quoted-printable Content-Location: http://jco.ascopubs.org/javascript/ajax/utility.js /************************************************************************= *****=0A= * javascript/ajax/utility.js=0A= *=0A= * Utility functions for working with XMLHttpRequest data.=0A= *=0A= * Copyright 2006 Board of Trustees of the Leland Stanford Junior = University.=0A= = *************************************************************************= ***/=0A= =0A= /*=0A= * Copy XML nodes into an HTMLElement. This effectively=0A= * clones XML markup which uses XHTML naming conventions=0A= * into an HTML DOM.=0A= */=0A= function copy_xml_to_html(src, dst) {=0A= if (src.nodeType =3D=3D 1) { /* Node.ELEMENT_NODE */=0A= var e =3D document.createElement(src.nodeName);=0A= for (var i =3D 0; i < src.childNodes.length; i++) {=0A= copy_xml_to_html(src.childNodes[i], e);=0A= }=0A= for (var i =3D 0; i < src.attributes.length; i++) {=0A= var n =3D src.attributes[i].name;=0A= var v =3D unescape_xml_string(src.attributes[i].value); =0A= e.setAttribute(n, v);=0A= if (n =3D=3D "class") {=0A= e.className =3D v;=0A= }=0A= else if (n =3D=3D "style") {=0A= set_css_style(v, e, "");=0A= }=0A= }=0A= dst.appendChild(e);=0A= }=0A= else if (src.nodeType =3D=3D 3) { /* Node.TEXT_NODE */=0A= dst.appendChild(document.createTextNode(src.nodeValue));=0A= }=0A= }=0A= =0A= /* =0A= * It is unclear that this is the right thing to be calling=0A= * from copy_xml_to_html, but it appears that Safari decides=0A= * to convert & to the NCR #, and then encodes that=0A= * NCR to &%26%2338;. So, I'm going to treat the DOM Attr=0A= * value as a plain string, and run our XML string input=0A= * through the decoding routine below.=0A= */=0A= function unescape_xml_string(s) {=0A= return s.replace(/'/g, "'")=0A= .replace(/'/g, "'")=0A= .replace(/"/g, "\"")=0A= .replace(/"/g, "\"")=0A= .replace(/>/g, ">")=0A= .replace(/>/g, ">")=0A= .replace(/</g, "<")=0A= .replace(/</g, "<")=0A= .replace(/&/g, "&")=0A= .replace(/&/g, "&");=0A= }=0A= =0A= /*=0A= * Parse set of CSS rules and apply them to an element.=0A= * This is quite horrifying, but I'm unable to determine=0A= * how else to handle this with IE 6. FireFox and other=0A= * sane browsers let you simply set the style attribute=0A= * or use e.style.setProperty(rule, value, priority),=0A= * IE 6 appears to have neither of these capabilities..=0A= */=0A= function set_css_style(css, e, priority) {=0A= var rules =3D css.split(";");=0A= for (var i =3D 0; i < rules.length; i++) {=0A= var nvpair =3D rules[i].split(":");=0A= if (nvpair.length =3D=3D 2) {=0A= try {=0A= var name =3D nvpair[0]; /* style attribute */=0A= var value =3D nvpair[1]; /* attribute value */=0A= =0A= /*=0A= * For each possible style attribute, set the=0A= * appropriate style property in the element.=0A= */=0A= if (name =3D=3D "background") {=0A= e.style.background =3D value;=0A= }=0A= else if (name =3D=3D "background-attachment") {=0A= e.style.backgroundAttachment =3D value;=0A= }=0A= else if (name =3D=3D "background-color") {=0A= e.style.backgroundColor =3D value;=0A= }=0A= else if (name =3D=3D "background-image") {=0A= e.style.backgroundImage =3D value;=0A= }=0A= else if (name =3D=3D "background-position") {=0A= e.style.backgroundPosition =3D value;=0A= }=0A= else if (name =3D=3D "background-position-x") {=0A= e.style.backgroundPositionX =3D value;=0A= }=0A= else if (name =3D=3D "background-position-y") {=0A= e.style.backgroundPositionY =3D value;=0A= }=0A= else if (name =3D=3D "background-repeat") {=0A= e.style.backgroundRepeat =3D value;=0A= }=0A= else if (name =3D=3D "behavior") {=0A= e.style.behavior =3D value;=0A= }=0A= else if (name =3D=3D "border") {=0A= e.style.border =3D value;=0A= }=0A= else if (name =3D=3D "border-bottom") {=0A= e.style.borderBottom =3D value;=0A= }=0A= else if (name =3D=3D "border-bottom-color") {=0A= e.style.borderBottomColor =3D value;=0A= }=0A= else if (name =3D=3D "border-bottom-style") {=0A= e.style.borderBottomStyle =3D value;=0A= }=0A= else if (name =3D=3D "border-bottom-width") {=0A= e.style.borderBottomWidth =3D value;=0A= }=0A= else if (name =3D=3D "border-collapse") {=0A= e.style.borderCollapse =3D value;=0A= }=0A= else if (name =3D=3D "border-color") {=0A= e.style.borderColor =3D value;=0A= }=0A= else if (name =3D=3D "border-left") {=0A= e.style.borderLeft =3D value;=0A= }=0A= else if (name =3D=3D "border-left-color") {=0A= e.style.borderLeftColor =3D value;=0A= }=0A= else if (name =3D=3D "border-left-style") {=0A= e.style.borderLeftStyle =3D value;=0A= }=0A= else if (name =3D=3D "border-left-width") {=0A= e.style.borderLeftWidth =3D value;=0A= }=0A= else if (name =3D=3D "border-right") {=0A= e.style.borderRight =3D value;=0A= }=0A= else if (name =3D=3D "border-right-color") {=0A= e.style.borderRightColor =3D value;=0A= }=0A= else if (name =3D=3D "border-right-style") {=0A= e.style.borderRightStyle =3D value;=0A= }=0A= else if (name =3D=3D "border-right-width") {=0A= e.style.borderRightWidth =3D value;=0A= }=0A= else if (name =3D=3D "border-style") {=0A= e.style.borderStyle =3D value;=0A= }=0A= else if (name =3D=3D "border-top") {=0A= e.style.borderTop =3D value;=0A= }=0A= else if (name =3D=3D "border-top-color") {=0A= e.style.borderTopColor =3D value;=0A= }=0A= else if (name =3D=3D "border-top-style") {=0A= e.style.borderTopStyle =3D value;=0A= }=0A= else if (name =3D=3D "border-top-width") {=0A= e.style.borderTopWidth =3D value;=0A= }=0A= else if (name =3D=3D "border-width") {=0A= e.style.borderWidth =3D value;=0A= }=0A= else if (name =3D=3D "bottom") {=0A= e.style.bottom =3D value;=0A= }=0A= else if (name =3D=3D "clear") {=0A= e.style.clear =3D value;=0A= }=0A= else if (name =3D=3D "clip") {=0A= e.style.clip =3D value;=0A= }=0A= else if (name =3D=3D "color") {=0A= e.style.color =3D value;=0A= }=0A= else if (name =3D=3D "cssText") {=0A= e.style.Sets =3D value;=0A= }=0A= else if (name =3D=3D "cursor") {=0A= e.style.cursor =3D value;=0A= }=0A= else if (name =3D=3D "direction") {=0A= e.style.direction =3D value;=0A= }=0A= else if (name =3D=3D "display") {=0A= e.style.display =3D value;=0A= }=0A= else if (name =3D=3D "font") {=0A= e.style.font =3D value;=0A= }=0A= else if (name =3D=3D "font-family") {=0A= e.style.fontFamily =3D value;=0A= }=0A= else if (name =3D=3D "font-size") {=0A= e.style.fontSize =3D value;=0A= }=0A= else if (name =3D=3D "font-style") {=0A= e.style.fontStyle =3D value;=0A= }=0A= else if (name =3D=3D "font-variant") {=0A= e.style.fontVariant =3D value;=0A= }=0A= else if (name =3D=3D "font-weight") {=0A= e.style.fontWeight =3D value;=0A= }=0A= else if (name =3D=3D "height") {=0A= e.style.height =3D value;=0A= }=0A= else if (name =3D=3D "ime-mode") {=0A= e.style.imeMode =3D value;=0A= }=0A= else if (name =3D=3D "layout-flow") {=0A= e.style.layoutFlow =3D value;=0A= }=0A= else if (name =3D=3D "layout-grid") {=0A= e.style.layoutGrid =3D value;=0A= }=0A= else if (name =3D=3D "layout-grid-char") {=0A= e.style.layoutGridChar =3D value;=0A= }=0A= else if (name =3D=3D "layout-grid-line") {=0A= e.style.layoutGridLine =3D value;=0A= }=0A= else if (name =3D=3D "layout-grid-mode") {=0A= e.style.layoutGridMode =3D value;=0A= }=0A= else if (name =3D=3D "layout-grid-type") {=0A= e.style.layoutGridType =3D value;=0A= }=0A= else if (name =3D=3D "left") {=0A= e.style.left =3D value;=0A= }=0A= else if (name =3D=3D "letter-spacing") {=0A= e.style.letterSpacing =3D value;=0A= }=0A= else if (name =3D=3D "line-break") {=0A= e.style.lineBreak =3D value;=0A= }=0A= else if (name =3D=3D "line-height") {=0A= e.style.lineHeight =3D value;=0A= }=0A= else if (name =3D=3D "list-style") {=0A= e.style.listStyle =3D value;=0A= }=0A= else if (name =3D=3D "list-style-image") {=0A= e.style.listStyleImage =3D value;=0A= }=0A= else if (name =3D=3D "list-style-position") {=0A= e.style.listStylePosition =3D value;=0A= }=0A= else if (name =3D=3D "list-style-type") {=0A= e.style.listStyleType =3D value;=0A= }=0A= else if (name =3D=3D "margin") {=0A= e.style.margin =3D value;=0A= }=0A= else if (name =3D=3D "margin-bottom") {=0A= e.style.marginBottom =3D value;=0A= }=0A= else if (name =3D=3D "margin-left") {=0A= e.style.marginLeft =3D value;=0A= }=0A= else 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quoted-printable Content-Location: http://jco.ascopubs.org/javascript/entrez/callback.js /************************************************************************= *****=0A= * javascript/entrez/callback.js=0A= *=0A= * Entrez Linking callback to populate content box.=0A= *=0A= * Copyright 2006 Board of Trustees of the Leland Stanford Junior = University.=0A= = *************************************************************************= ***/=0A= =0A= /*=0A= * Execute callback to fill content box with Entrez Linking information.=0A= */=0A= function entrez_callback(pmid, callback_url) {=0A= /*=0A= * MSIE 5.5 and below have issues with the JavaScript=0A= * used for Entrez Linking. For now we have to disable=0A= * the callback until we can track down a proper fix=0A= * (or everybody sanely upgrades to version 6 or 7!).=0A= */=0A= if (navigator) {=0A= var appname =3D navigator.appName;=0A= if (appname =3D=3D "Microsoft Internet Explorer") {=0A= var userAgent =3D navigator["userAgent"];=0A= var s =3D "MSIE ";=0A= var n =3D -1; =0A= if ((n =3D userAgent.indexOf(s)) !=3D -1) {=0A= var v =3D parseFloat(userAgent.substring(n+s.length));=0A= if (v < 6) {=0A= return;=0A= }=0A= }=0A= }=0A= }=0A= =0A= /*=0A= * Acquire table row element to update, initiate callback=0A= * to update table with Entrez Links.=0A= */=0A= var tr =3D document.getElementById('entrez_callback_'+pmid);=0A= if (!tr) {=0A= return;=0A= }=0A= var req =3D new XMLHttpRequest();=0A= if (!req) {=0A= return;=0A= }=0A= req.onreadystatechange =3D function() {=0A= if (req.readyState =3D=3D 4 && (req.status =3D=3D 200 || req.status = =3D=3D 304)) {=0A= var src =3D req.responseXML.documentElement;=0A= var dst =3D document.createDocumentFragment();=0A= for (var i =3D 0; i < src.childNodes.length; i++) {=0A= copy_xml_to_html(src.childNodes[i], dst);=0A= }=0A= var tbl =3D tr.parentNode;=0A= tbl.replaceChild(dst, tr);=0A= }=0A= }=0A= req.open('GET', callback_url, true);=0A= req.send(null);=0A= }=0A= ------=_NextPart_000_00AC_01CAD4D7.C8F8B4C0 Content-Type: application/octet-stream Content-Transfer-Encoding: quoted-printable Content-Location: http://jco.ascopubs.org/misc/folders.js ------=_NextPart_000_00AC_01CAD4D7.C8F8B4C0 Content-Type: application/octet-stream Content-Transfer-Encoding: quoted-printable Content-Location: http://www.asco.org/v7jsplib/common/site_catalyst_code.js /* Version as of 1-21-10 for ASCO - Updated plugins, code for = Genesis/Exact Target */ /* SiteCatalyst code version: H.20.3. Copyright 1997-2009 Omniture, Inc. More info available at http://www.omniture.com */ /************************ ADDITIONAL FEATURES ************************ Plugins */ var s=3Ds_gi(s_account) /************************** CONFIG SECTION **************************/ /* You may add or alter any code config here. */ /* Conversion Config */ s.currencyCode=3D"USD" /* Link Tracking Config */ s.trackDownloadLinks=3Dtrue s.trackExternalLinks=3Dtrue s.trackInlineStats=3Dtrue s.linkDownloadFileTypes=3D"exe,zip,wav,mp3,mp4,asx,mov,mpg,avi,wmv,pdf,do= c,docx,xls,xlsx,ppt,pptx,pps,xml,cab,prc,jad" s.linkInternalFilters=3Ds_linkInternalFilters; s.linkLeaveQueryString=3Dfalse s.linkTrackVars=3D"None" s.linkTrackEvents=3D"None" /* Plugin Config */ /* Page Name Plugin Config */ s.siteID=3D"" // leftmost value in pagename s.defaultPage=3D"" // filename to add when none exists s.queryVarsList=3D"" // query parameters to keep s.pathExcludeDelim=3D";" // portion of the path to exclude s.pathConcatDelim=3D"/" // page name component separator s.pathExcludeList=3D"" // elements to exclude from the path s.usePlugins=3Dtrue function s_doPlugins(s) { /* External Campaigns */ if(!s.campaign) s.campaign=3Ds.getQueryParam('cmpid'); =09 /* Internal Campaigns */ if(!s.eVar4) s.eVar4=3Ds.getQueryParam('intcmp'); =20 /*Exact Target Code*/ if(!s.eVar20)=20 s.eVar20=3Ds.getQueryParam('et_cid'); =20 s.eVar20=3Ds.getValOnce(s.eVar20,'s_ev20',0);=09 =09 if(!s.eVar21)=20 s.eVar21=3Ds.getQueryParam('et_rid'); =20 s.eVar21=3Ds.getValOnce(s.eVar21,'s_ev21',0); =09 /* Site Search */ var prevPage=3Ds.getPreviousValue(s.pageName,'gpv_p11'); if(s.prop5){ s.prop5=3Ds.eVar5=3Ds.prop5.toLowerCase(); var t_search=3Ds.getValOnce(s.eVar5,'ev5',0); if(t_search){ s.events=3Ds.apl(s.events,"event5",",",2); } =20 // search origination s.prop11=3DprevPage; } /*********** Flash Detection ****************/ s.detectRIA('s_ria','prop34','prop35','','',''); =09 /* Direct Influence Pages */ s.eVar3=3Ds.pageName; =09 /* Enhanced download tracking */ s.url=3Ds.downloadLinkHandler(); =09 if(s.url){ //Track FileName = s.prop7=3Ds.eVar7=3Ds.url.substring(s.url.lastIndexOf("/")+1,s.url.length= ); s.prop8 =3D s.pageName; s.events=3Ds.apl(s.events,"event4",",",2) = =20 //Track eVar & Event s.linkTrackVars=3D"prop7,prop8,eVar7,events" s.linkTrackEvents=3D"event4" } /* SETUP HIERARCHIES */ if ( s.prop1 ) { s.hier2 =3D s.prop1; } if ( s.prop2 ) { s.hier2 =3D s.prop2; } if ( s.prop3 ) { s.hier2 =3D s.prop3; } if ( s.prop4 ) { s.hier2 =3D s.prop4; } =09 if(!s.pageType && !s.pageName) s.pageName=3Ds.getPageName(); =09 } s.doPlugins=3Ds_doPlugins; /************************** PLUGINS SECTION *************************/ /* You may insert any plugins you wish to use here. */ /********************************************************************* * * Plugins * ********************************************************************/ /* * Plugin: getQueryParam 2.3 */ s.getQueryParam=3Dnew Function("p","d","u","" +"var = s=3Dthis,v=3D'',i,t;d=3Dd?d:'';u=3Du?u:(s.pageURL?s.pageURL:s.wd.locati" +"on);if(u=3D=3D'f')u=3Ds.gtfs().location;while(p){i=3Dp.indexOf(',');i=3D= i<0?p" +".length:i;t=3Ds.p_gpv(p.substring(0,i),u+'');if(t){t=3Dt.indexOf('#')>-= " +"1?t.substring(0,t.indexOf('#')):t;}if(t)v+=3Dv?d+t:t;p=3Dp.substring(i=3D= " +"=3Dp.length?i:i+1)}return v"); s.p_gpv=3Dnew Function("k","u","" +"var = s=3Dthis,v=3D'',i=3Du.indexOf('?'),q;if(k&&i>-1){q=3Du.substring(i+1);v" +"=3Ds.pt(q,'&','p_gvf',k)}return v"); s.p_gvf=3Dnew Function("t","k","" +"if(t){var = s=3Dthis,i=3Dt.indexOf('=3D'),p=3Di<0?t:t.substring(0,i),v=3Di<0?'T" +"rue':t.substring(i+1);if(p.toLowerCase()=3D=3Dk.toLowerCase())return = s." +"epa(v)}return ''"); /* * Plugin: getValOnce_v1.0 */ s.getValOnce=3Dnew Function("v","c","e","" +"var s=3Dthis,a=3Dnew = Date,v=3Dv?v:v=3D'',c=3Dc?c:c=3D's_gvo',e=3De?e:0,k=3Ds.c_r(c" +");if(v){a.setTime(a.getTime()+e*86400000);s.c_w(c,v,e?a:0);}return" +" v=3D=3Dk?'':v"); /* * Utility Function: split v1.5 - split a string (JS 1.0 compatible) */ s.split=3Dnew Function("l","d","" +"var i,x=3D0,a=3Dnew = Array;while(l){i=3Dl.indexOf(d);i=3Di>-1?i:l.length;a[x" +"++]=3Dl.substring(0,i);l=3Dl.substring(i+d.length);}return a"); /* * Plugin Utility: apl v1.1 */ s.apl=3Dnew Function("L","v","d","u","" +"var s=3Dthis,m=3D0;if(!L)L=3D'';if(u){var = i,n,a=3Ds.split(L,d);for(i=3D0;i0?m:e;v=3Di<0?'':s.epa(c.substring(i+2+k.length,m<0?c.length:= " +"m));if(m>0&&m!=3De)if(parseInt(c.substring(m+1,e<0?c.length:e))-1){pv=3Dpv.substr" +"ing(0,i)+pv.substring(pv.indexOf(';',i)+1);pc=3D1;}sv=3Ds.c_rr(sn);i=3D= sv" +".indexOf(' = '+k+'=3D');if(i>-1){sv=3Dsv.substring(0,i)+sv.substring(sv.i" +"ndexOf(';',i)+1);sc=3D1;}d=3Dnew = Date;if(e){if(e.getTime()>d.getTime())" +"{pv+=3D' '+k+'=3D'+s.ape(v)+'|'+e.getTime()+';';pc=3D1;}}else{sv+=3D' = '+k+'" +"=3D'+s.ape(v)+';';sc=3D1;}if(sc) = s.c_wr(sn,sv,0);if(pc){t=3Dpv;while(t&&t" +".indexOf(';')!=3D-1){var = t1=3DparseInt(t.substring(t.indexOf('|')+1,t.i" +"ndexOf(';')));t=3Dt.substring(t.indexOf(';')+1);ht=3Dht=3D3&&result!=3Dtrue;i--){execScri" +"pt('on error resume next: result =3D IsObject(CreateObject(\"Shockwav" +"eFlash.ShockwaveFlash.'+i+'\"))','VBScript');fv=3Di;}}fr=3Dfv=3D=3D-1?'= flas" +"h not detected':fv=3D=3D0?'flash enabled (no version)':'flash = '+fv;}if(" +"!sk&&sp&&s.apv>=3D4.1){var tc=3D'try{x=3Dnew = ActiveXObject(\"AgControl.A'" +"+'gControl\");for(var i=3Dmsv;i>0;i--){for(var = j=3D9;j>=3D0;j--){if(x.is'" +"+'VersionSupported(i+\".\"+j)){sv=3Di+\".\"+j;break;}}if(sv){break;}'" +"+'}}catch(e){try{x=3Dnavigator.plugins[\"Silverlight = Plug-In\"];sv=3Dx'" +"+'.description.substring(0,x.description.indexOf(\".\")+2);}catch('" +"+'e){}}';eval(tc);sr=3Dsv=3D=3D''?'silverlight not = detected':'silverlight" +" '+sv;}if((fr&&fp)||(sr&&sp)){s.c_w(cn,fr+'|'+sr,0);if(fr)s[fp]=3Dfr;" +"if(sr)s[sp]=3Dsr;}}"); 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