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Journal of=20 the National Cancer Institute Advance Access originally published online = on=20 March 24, 2009
JNCI=20 Journal of the National Cancer Institute 2009 101(7):441-443;=20 doi:10.1093/jnci/djp047
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=A9 The=20 Author 2009. Published by Oxford University Press.

EDITORIALS

Activation of Telomerase in Glioma Cells by Human Cytomegalovirus: = Another=20 Piece of the Puzzle

Jindrich Cinatl, Jr, = Michael=20 Nevels, Christina Paulus, Martin = Michaelis=20

Affiliations of authors: Institut f=FCr = Medizinische=20 Virologie, Klinikum der Johann Wolfgang Goethe-Universit=E4t, Frankfurt = am Main,=20 Germany (JC, MM); Institut f=FCr Medizinische Mikrobiologie und Hygiene, = Universit=E4t Regensburg, Regensburg, Germany (MN, CP)

Correspondence to: Jindrich Cinatl Jr, PhD, = Institut f=FCr=20 Medizinische Virologie, Paul Ehrlich-Str. 40, 60596 Frankfurt am Main, = Germany=20 (e-mail: cinatl{at}em.uni-frankfurt.de ).

In this issue of the Journal, Str=E5=E5t et al. (1= )=20 show that human cytomegalovirus (HCMV) infection induces = telomerase=20 activation in human malignant glioma cells and fibroblasts.=20 These results reveal a novel mechanism that may be relevant = for=20 the potential of HCMV to promote oncogenesis and thus provide = another=20 piece of the puzzle that has drawn the attention of = oncologists and=20 virologists for almost four decades.

A possible relationship between HCMV and cancer has been = considered=20 since the beginning of the 1970s when Fuccillo et al. (2= )=20 found increased anti-HCMV antibody titers in cervix carcinoma = patients compared with healthy individuals. Although many=20 subsequent studies compared HCMV antibody titers between = cancer=20 patients and healthy people or investigated the presence of = HCMV=20 proteins, DNA, or RNA in tumor tissues from different cancer=20 entities, the role of HCMV in cancer is still unclear (3= ).=20

HCMV is a ubiquitous herpesvirus that after (subclinical) = primary=20 infection persists for the life of its host. The virus is = believed=20 to persist mainly in myeloid cells and may be reactivated in=20 immunocompromised patients with accompanying signs of HCMV = disease=20 and infection in cells of many different tissues. In = immunocompetent=20 hosts, subclinical virus reactivations may occur (4= ).=20 Several recent investigations suggest that in cancer = patients,=20 clinically manifest or subclinical HCMV reactivations occur = more=20 frequently than previously supposed. Reactivations may be = induced by=20 stimuli such as cancer-related immunosuppression, = conventional=20 chemotherapy, gamma radiation, or inflammation (3= ,5= =967= ).=20

Findings from the 1970s suggested that HCMV could transform = human=20 embryonal fibroblasts (8= ,9= ).=20 However, these studies failed to detect HCMV nucleic acids or = proteins after long-term subculture of the transformed cells. = Moreover, HCMV infection did not induce malignant = transformation of=20 normal human cells in most other studies. Although various = attempts=20 were made to explain the role of HCMV in oncogenesis (eg, = hit-and-run=20 hypothesis), the potential of the virus to initiate = transformation is=20 regarded with skepticism, and HCMV is not generally = considered an=20 oncogenic virus (3= ). We=20 hypothesized a process of HCMV oncomodulation in the 1990s to = explain=20 a possible contribution of HCMV to tumor progression (= 10).=20 Oncomodulation means that HCMV infects established tumor = cells and=20 increases tumor malignancy without necessarily being = oncogenic (3= ,= 10).=20 Support for this idea is mainly based on experimental = findings=20 indicating that HCMV regulatory proteins and noncoding RNAs = may=20 influence properties of tumor cells, including cell = proliferation,=20 survival, invasion, immunogenicity, tumor angiogenesis, and=20 chromosomal stability, as well as inflammatory processes (3= ,4= ).=20 Conceivably, HCMV infection of nontransformed cells in tumor = stroma=20 such as fibroblasts or infiltrating immune cells may also = influence=20 tumor behavior. According to the concept of oncomodulation, = tumor=20 cells provide a genetic environment, characterized by = disturbances in=20 intracellular signaling pathways, transcriptional control, = and tumor=20 suppressor proteins, that enables HCMV to manifest its = oncomodulatory=20 potential in cancer cells but not in normal cells. =

The cancer that has been most frequently investigated for its=20 association with HCMV is glioma. HCMV infection was for the=20 first time correlated with a tumor-promoting activity in = glioma=20 cells when the HCMV 72 kDa immediate early (IE) 1 protein was = found to decrease the expression of the endogenous = angiogenesis=20 inhibitor thrombospondin-1 independently of the tumor = suppressor=20 protein p53 (= 11,= 12).=20 Other cell culture experiments demonstrated that HCMV = infection of=20 glioma cells may stimulate tumor cell cycle progression and=20 invasiveness (= 13=96= 15).=20 Animal studies demonstrated that a single HCMV protein = increases the=20 malignancy of glioma cells. Human glioblastoma cells = expressing US28,=20 a chemokine receptor of HCMV, exhibited increased malignancy=20 after injection in nude mice. In contrast, US28 induced=20 apoptosis in nontumorigenic human cells, suggesting that US28 = oncomodulatory properties are limited to tumorigenic cells = (= 16).=20

Histological studies using highly sensitive techniques for virus = detection found genomic sequence and antigens of HCMV in = tumor=20 cells but not in adjacent normal tissue in a large fraction = of=20 glioma patients (3= ,4= ,7= ,= 17,= 18).=20 Groups that used less sensitive histological methods = established for=20 the detection of active (high-level) HCMV infection failed to = detect=20 low-level HCMV infection in glioma cells (3= ,= 19=96= 21).=20 Clearly, HCMV infection of glioma tissue(s) does not prove = that the=20 virus contributes to tumor progression or increases tumor = malignancy.=20 However, additional data suggest that low-grade HCMV = infection of=20 cancer cells is sufficient to influence the severity of = cancer=20 diseases. In support of a role for the virus in tumor = progression,=20 increased numbers of infected cancer cells were associated = with a=20 more unfavorable outcome in glioma patients (4= ). It=20 has also been reported that the fraction of HCMV-infected = tumors was=20 higher in glioblastoma multiforme (79%) than in lower grade=20 tumors (48%) (= 18).=20

The elegant experiments of Str=E5=E5t et al. describe a = novel=20 molecular mechanism that may turn out to be critical to the=20 relationship between HCMV and cancer (1= ).=20 The authors show for the first time that infection with = several=20 different strains of HCMV results in the induction of human=20 telomerase reverse transcriptase (hTERT) expression and = increases=20 telomerase activity in normally telomerase-silent human = diploid=20 fibroblasts. The authors also found that telomerase induction = correlated with increased hTERT promoter activity following = infection=20 in both primary fibroblasts and malignant glioblastoma cell=20 lines.

Str=E5=E5t et al. have further demonstrated that HCMV-dependent=20 telomerase induction depends on active viral gene expression. = In fact, ectopic expression of only one viral protein (IE1),=20 out of the roughly 200 different HCMV gene products, was = sufficient=20 to recapitulate (at least partly) the viral effects on hTERT=20 promoter activation. This finding may not come as a big = surprise=20 for many HCMV researchers because IE1 has long been known to = be=20 a promiscuous transcriptional activator of numerous viral and = host=20 cell genes. This protein reportedly interacts with several = common=20 cellular transcription factors including CTF1, E2Fs, and Sp1 = (= 22).=20 We have shown that IE1 also targets histone deacetylases = (HDACs) to=20 promote histone acetylation (= 23).=20 Str=E5=E5t et al. demonstrate that some IE1 are physically = associated=20 with hTERT promoter sequences during HCMV infection of=20 fibroblasts. They also provide evidence that the viral = protein=20 activates transcription from the hTERT promoter via = mechanisms that=20 involve both Sp1 recruitment and HDAC sequestration, followed = by=20 increased histone H3 acetylation. These findings are = additional=20 confirmation that epigenetic modifications are of fundamental = importance for infection and pathogenesis.

Several groups have previously reported the presence of the = IE1=20 protein in HCMV-positive tumor cells [reviewed in (3= )],=20 and intriguingly, the authors demonstrate a striking = correlation=20 between IE1 and hTERT protein levels in histological = glioblastoma=20 samples. This is the first time that expression of a protein=20 known to play an important part in cancer formation and/or=20 progression has been directly linked to HCMV infection of = tumor=20 cells.

Telomerase activation is also caused by infection with other=20 prominent tumor viruses including Epstein=96Barr virus, = Kaposi=20 sarcoma=96associated herpesvirus, human papillomavirus, = hepatitis B=20 virus, hepatitis C virus, and human T-cell leukemia virus-1 = (= 24).=20 In fact, telomerase is commonly activated in cancer cells of = both=20 viral and nonviral origin (= 25),=20 and hTERT activation is sufficient to immortalize normal = diploid=20 cells (= 26).=20 Besides elongation of telomeres, telomerase may favor tumor = cell=20 survival and proliferation by several other mechanisms. The = enzyme=20 may inhibit cancer cell apoptosis, promote cancer cell = growth,=20 favor emergence of cancer stem cells, and enhance DNA repair = (= 25,= 27,= 28).=20 Therefore, HCMV-induced telomerase activation represents a = mechanism=20 that is of possible relevance for both (initiation of) = malignant=20 transformation and oncomodulation by HCMV infection.

General antiviral therapeutic strategies (= 29)=20 or inhibition of HCMV IE gene expression (= 30)=20 was shown to revert HCMV-induced malignant changes in = experimental=20 models. Such strategies may also be effective to suppress=20 HCMV-induced telomerase activation, thus possibly preventing = tumor=20 progression. Moreover, antiviral treatment may reverse = HCMV-induced=20 chemoresistance of tumor cells as already demonstrated in=20 experimental models (3= ).=20 The first clinical trial in which the anti-HCMV drug=20 valganciclovir was used to treat glioma patients has been = recently=20 completed at the Karolinska Institutet (= 31),=20 and information about the results is eagerly awaited. =

Naturally, the report of Str=E5=E5t et al. also leaves = some open=20 questions. First, it is difficult to really judge the role of = HCMV-induced telomerase activation in a possible HCMV-induced = oncogenic transformation process because no transformation = was shown.=20 The cell types used were either subject to lytic infection = and=20 therefore destroyed by HCMV (human diploid fibroblasts) or = already=20 transformed cancer (glioblastoma) cells. Moreover, the = oncomodulatory=20 effects that might be exerted by HCMV-induced telomerase = activation=20 remain to be defined in functional assays. Nevertheless, the = work of=20 Str=E5=E5t et al. represents a very important step toward the = elucidation=20 of the complicated relationship between HCMV and cancer. =

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document.getElementById || = document.all ); function encrypt(part1,part2,part3) { var all=3D 'mai'+'lto:'+part1+"@"+part2; if( part3 ) all +=3D '?Sub'+'ject=3D'+part3; = document.location.href=3Deval('"'+all+'"'); } function toggle_display( id ) { if( supported ) { if( document.layers && document.layers[id] ) { document.layers[id].display =3D ( = document.layers[id].display =3D=3D 'block' ? 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Leave htext blank to hide again. function help_window(htext,field){ var hw =3D document.getElementById("help_window"); if(hw !=3D undefined ){ if(htext =3D=3D ''){ hw.className=3D"hidden"; } else { hw.innerHTML=3Dhtext; hw.className=3D"help_window"; hw.style.top=3DfindPos(field)+"px"; } } } //Archive list interactivity functions var tick_archive=3Dnew Array("Humanities", "Law", "Medicine", "Science", = "Social Sciences"); var tick_archive_x=3Dnew Array(true, true, true, true, true); var tick_year=3Dnew Array(); var tick_year_x=3Dnew Array(); var tick_status=3Dnew Array("I", "E", "L"); var tick_status_x=3Dnew Array(true, true, true); var line_id=3Dnew Array(); var line_archives=3Dnew Array(); var line_year_joined=3Dnew Array(); var line_status=3Dnew Array(); var year_count=3D-1; var line_count=3D-1; function add_year(year_to_add) { year_count+=3D1; tick_year[year_count]=3Dyear_to_add; tick_year_x[year_count]=3Dtrue; } function filter() { for(var i=3D0; i<=3Dline_count; i++) { var ok=3D""; for(var j=3D0; j.=0A= =0A= by Andrew Gregory=0A= http://www.scss.com.au/family/andrew/webdesign/xmlhttprequest/=0A= =0A= This work is licensed under the Creative Commons Attribution License. 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; // = 0=3Duninitialized,1=3Dloading,2=3Dloaded,3=3Dinteractive,4=3Dcomplete=0A= this.status =3D 0; // HTTP status codes=0A= this.statusText =3D '';=0A= this._headers =3D [];=0A= this._aborted =3D false;=0A= this._async =3D true;=0A= this._defaultCharset =3D 'ISO-8859-1';=0A= this._getCharset =3D function() {=0A= var charset =3D _defaultCharset;=0A= var contentType =3D = this.getResponseHeader('Content-type').toUpperCase();=0A= val =3D contentType.indexOf('CHARSET=3D');=0A= if (val !=3D -1) {=0A= charset =3D contentType.substring(val);=0A= }=0A= val =3D charset.indexOf(';');=0A= if (val !=3D -1) {=0A= charset =3D charset.substring(0, val);=0A= }=0A= val =3D charset.indexOf(',');=0A= if (val !=3D -1) {=0A= charset =3D charset.substring(0, val);=0A= }=0A= return charset;=0A= };=0A= this.abort =3D function() {=0A= this._aborted =3D true;=0A= };=0A= this.getAllResponseHeaders =3D function() {=0A= return this.getAllResponseHeader('*');=0A= };=0A= this.getAllResponseHeader =3D function(header) {=0A= var ret =3D '';=0A= for (var i =3D 0; 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_0044_01CA28A5.95496310 Content-Type: application/octet-stream Content-Transfer-Encoding: quoted-printable Content-Location: http://jnci.oxfordjournals.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 if (name =3D=3D "margin-right") {=0A= e.style.marginRight =3D value;=0A= }=0A= else if (name =3D=3D "margin-top") {=0A= e.style.marginTop =3D value;=0A= }=0A= else if (name =3D=3D "min-height") {=0A= e.style.minHeight =3D value;=0A= }=0A= else if (name =3D=3D "overflow") {=0A= e.style.overflow =3D value;=0A= }=0A= else if (name =3D=3D "overflow-x") {=0A= e.style.overflowX =3D value;=0A= }=0A= else if (name =3D=3D "overflow-y") {=0A= e.style.overflowY =3D value;=0A= }=0A= else if (name =3D=3D "padding") {=0A= e.style.padding =3D value;=0A= }=0A= else if (name =3D=3D "padding-bottom") {=0A= e.style.paddingBottom =3D value;=0A= }=0A= else if (name =3D=3D "padding-left") {=0A= e.style.paddingLeft =3D value;=0A= }=0A= else if (name =3D=3D "padding-right") {=0A= e.style.paddingRight =3D value;=0A= }=0A= else if (name =3D=3D "padding-top") {=0A= e.style.paddingTop =3D value;=0A= }=0A= else if (name =3D=3D "page-break-after") {=0A= e.style.pageBreakAfter =3D value;=0A= }=0A= else if (name =3D=3D "page-break-before") {=0A= e.style.pageBreakBefore =3D value;=0A= }=0A= else if (name =3D=3D "pixelBottom") {=0A= e.style.pixelBottom =3D value;=0A= }=0A= else if (name =3D=3D "pixelHeight") {=0A= e.style.pixelHeight =3D value;=0A= }=0A= else if (name =3D=3D "pixelLeft") {=0A= e.style.pixelLeft =3D value;=0A= }=0A= else if (name =3D=3D "pixelRight") {=0A= e.style.pixelRight =3D value;=0A= }=0A= else if (name =3D=3D "pixelTop") {=0A= e.style.pixelTop =3D value;=0A= }=0A= else if (name =3D=3D "pixelWidth") {=0A= e.style.pixelWidth =3D value;=0A= }=0A= else if (name =3D=3D "posBottom") {=0A= e.style.posBottom =3D value;=0A= }=0A= else if (name =3D=3D "posHeight") {=0A= e.style.posHeight =3D value;=0A= }=0A= else if (name =3D=3D "position") {=0A= e.style.position =3D value;=0A= }=0A= else if (name =3D=3D "posLeft") {=0A= e.style.posLeft =3D value;=0A= }=0A= else if (name =3D=3D "posRight") {=0A= e.style.posRight =3D value;=0A= }=0A= else if (name =3D=3D "posTop") {=0A= e.style.posTop =3D value;=0A= }=0A= else if (name =3D=3D "posWidth") {=0A= e.style.posWidth =3D value;=0A= }=0A= else if (name =3D=3D "right") {=0A= e.style.right =3D value;=0A= }=0A= else if (name =3D=3D "ruby-align") {=0A= e.style.rubyAlign =3D value;=0A= }=0A= else if (name =3D=3D "ruby-overhang") {=0A= e.style.rubyOverhang =3D value;=0A= }=0A= else if (name =3D=3D "ruby-position") {=0A= e.style.rubyPosition =3D value;=0A= }=0A= else if (name =3D=3D "scrollbar-3dlight-color") {=0A= e.style.scrollbar3dLightColor =3D value;=0A= }=0A= else if (name =3D=3D "scrollbar-arrow-color") {=0A= e.style.scrollbarArrowColor =3D value;=0A= }=0A= else if (name =3D=3D "scrollbar-base-color") {=0A= e.style.scrollbarBaseColor =3D value;=0A= }=0A= else if (name =3D=3D "scrollbar-darkshadow-color") {=0A= e.style.scrollbarDarkShadowColor =3D value;=0A= }=0A= else if (name =3D=3D "scrollbar-face-color") {=0A= e.style.scrollbarFaceColor =3D value;=0A= }=0A= else if (name =3D=3D "scrollbar-highlight-color") {=0A= e.style.scrollbarHighlightColor =3D value;=0A= }=0A= else if (name =3D=3D "scrollbar-shadow-color") {=0A= e.style.scrollbarShadowColor =3D value;=0A= }=0A= else if (name =3D=3D "scrollbar-track-color") {=0A= e.style.scrollbarTrackColor =3D value;=0A= }=0A= else if (name =3D=3D "float") {=0A= e.style.styleFloat =3D value;=0A= }=0A= else if (name =3D=3D "table-layout") {=0A= e.style.tableLayout =3D value;=0A= }=0A= else if (name =3D=3D "text-align") {=0A= e.style.textAlign =3D value;=0A= }=0A= else if (name =3D=3D "text-align-last") {=0A= e.style.textAlignLast =3D value;=0A= }=0A= else if (name =3D=3D "text-autospace") {=0A= e.style.textAutospace =3D value;=0A= }=0A= else if (name =3D=3D "text-decoration") {=0A= e.style.textDecoration =3D value;=0A= }=0A= else if (name =3D=3D "textDecorationBlink") {=0A= e.style.textDecorationBlink =3D value;=0A= }=0A= else if (name =3D=3D "textDecorationLineThrough") {=0A= e.style.textDecorationLineThrough =3D value;=0A= }=0A= else if (name =3D=3D 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"vertical-align") {=0A= e.style.verticalAlign =3D value;=0A= }=0A= else if (name =3D=3D "visibility") {=0A= e.style.visibility =3D value;=0A= }=0A= else if (name =3D=3D "white-space") {=0A= e.style.whiteSpace =3D value;=0A= }=0A= else if (name =3D=3D "width") {=0A= e.style.width =3D value;=0A= }=0A= else if (name =3D=3D "word-break") {=0A= e.style.wordBreak =3D value;=0A= }=0A= else if (name =3D=3D "word-spacing") {=0A= e.style.wordSpacing =3D value;=0A= }=0A= else if (name =3D=3D "word-wrap") {=0A= e.style.wordWrap =3D value;=0A= }=0A= else if (name =3D=3D "writing-mode") {=0A= e.style.writingMode =3D value;=0A= }=0A= else if (name =3D=3D "z-index") {=0A= e.style.zIndex =3D value;=0A= }=0A= else if (name =3D=3D "zoom") {=0A= e.style.zoom =3D value;=0A= }=0A= }=0A= catch (e) {=0A= /* ignore error on attempt to set e.style.[property] */=0A= }=0A= }=0A= }=0A= }=0A= ------=_NextPart_000_0044_01CA28A5.95496310 Content-Type: application/octet-stream Content-Transfer-Encoding: quoted-printable Content-Location: http://jnci.oxfordjournals.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_0044_01CA28A5.95496310--