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|
||
data-ga-category="featured_link"
|
||
data-ga-action="user_guide">
|
||
User Guide
|
||
</a>
|
||
</span>
|
||
|
||
</div>
|
||
</div>
|
||
|
||
|
||
</form>
|
||
|
||
|
||
<div id="article-page-header">
|
||
<div id="article-top-actions-bar" class="article-top-actions-bar">
|
||
<div class="inner-wrap">
|
||
<div class="actions-container">
|
||
<div class="return-to-search">
|
||
|
||
|
||
</div>
|
||
|
||
<div class="multiple-results-actions " role="region" aria-label="save, email, send to">
|
||
<button id="save-results-panel-trigger"
|
||
type="button"
|
||
class="save-results save-results-panel-trigger"
|
||
aria-expanded="false"
|
||
aria-controls="save-action-panel"
|
||
data-ga-category="save_share"
|
||
data-ga-action="save"
|
||
data-ga-label="open">
|
||
Save
|
||
</button><button id="email-results-panel-trigger"
|
||
type="button"
|
||
class="email-results email-results-panel-trigger"
|
||
aria-expanded="false"
|
||
aria-controls="email-action-panel"
|
||
data-ga-category="save_share"
|
||
data-ga-action="email"
|
||
data-ga-label="open">
|
||
Email
|
||
</button><div class="more-actions dropdown-block"><button id="more-actions-trigger"
|
||
type="button"
|
||
class="trigger more-actions-trigger"
|
||
ref="linksrc=show_moreactions_btn"
|
||
aria-label="Send to"
|
||
aria-controls="more-actions-dropdown">Send to</button><div id="more-actions-dropdown" class="dropdown dropdown-container" hidden><div class="content"><ul class="more-actions-links"><li><a class="clipboard-panel-trigger dropdown-block-link "
|
||
href="#"
|
||
role="button"
|
||
data-ga-category="save_share"
|
||
data-ga-action="clipboard"
|
||
data-ga-label="send">
|
||
Clipboard
|
||
</a></li><li><a role="button" class="dropdown-block-link bibliography-trigger-target" href="https://account.ncbi.nlm.nih.gov/?back_url=https%3A%2F%2Fpubmed.ncbi.nlm.nih.gov%2F30002298%2F%23open-bibliography-panel">My Bibliography</a></li><li><a role="button" class="dropdown-block-link collections-trigger-target" href="https://account.ncbi.nlm.nih.gov/?back_url=https%3A%2F%2Fpubmed.ncbi.nlm.nih.gov%2F30002298%2F%23open-collections-panel">Collections</a></li><li><a role="button" class="citation-manager-panel-trigger dropdown-block-link citation-manager-trigger-target" href="#">Citation manager</a></li></ul></div></div></div>
|
||
</div>
|
||
|
||
|
||
|
||
<div class="display-options" data-format-key="format"
|
||
data-default-format-value="abstract"
|
||
data-current-format-value="abstract" role="region">
|
||
<button
|
||
class="trigger usa-button"
|
||
title="Change format"
|
||
data-ga-category="display_options"
|
||
data-ga-action="display_options_dialog">
|
||
<span class="button-label">Display options</span>
|
||
</button>
|
||
|
||
<div class="dropdown" hidden>
|
||
<div class="title">
|
||
Display options
|
||
</div>
|
||
|
||
<div class="content">
|
||
|
||
<div class="format-container">
|
||
<span class="option-label">
|
||
Format
|
||
</span>
|
||
<select name="format" data-initial-value="abstract" aria-label="Display format" id="article-display-format">
|
||
<option value="abstract">Abstract</option>
|
||
|
||
<option value="pubmed">PubMed</option>
|
||
|
||
<option value="pmid">PMID</option>
|
||
|
||
</select>
|
||
</div>
|
||
|
||
</div>
|
||
</div>
|
||
</div>
|
||
<input type="hidden" name="csrfmiddlewaretoken" value="QBqJLaS61yvugHyvDuJFJYtUCkQXbNQJ7oaOo0lsB9iYa8ElgNmHd6Zyaoy94oo3">
|
||
</div>
|
||
</div>
|
||
</div>
|
||
|
||
<div id="article-panels-container" class="article-panels-container">
|
||
<div id="save-action-panel" class="save-action-panel action-panel" aria-hidden="true">
|
||
<div class="inner-wrap">
|
||
<h2 class="action-panel-heading">
|
||
Save citation to file
|
||
</h2>
|
||
<form id="save-action-panel-form"
|
||
class="action-panel-content action-form"
|
||
action="/results-export-ids/"
|
||
data-by-search-action="/results-export-search-data/"
|
||
data-by-ids-action="/results-export-ids/"
|
||
method="post"
|
||
data-by-search-method="post"
|
||
data-by-ids-method="post">
|
||
|
||
<input type="hidden" name="csrfmiddlewaretoken" value="QBqJLaS61yvugHyvDuJFJYtUCkQXbNQJ7oaOo0lsB9iYa8ElgNmHd6Zyaoy94oo3">
|
||
|
||
|
||
|
||
<div class="action-panel-control-wrap">
|
||
<label for="save-action-format" class="action-panel-label">
|
||
Format:
|
||
</label>
|
||
<select id="save-action-format" name="results-format" class="action-panel-selector">
|
||
<option value="summary-text">Summary (text)</option>
|
||
<option value="pubmed-text">PubMed</option>
|
||
<option value="pmid">PMID</option>
|
||
<option value="abstract">Abstract (text)</option>
|
||
<option value="csv">CSV</option>
|
||
</select>
|
||
</div>
|
||
|
||
<div class="action-panel-actions">
|
||
<button class="action-panel-submit"
|
||
type="submit"
|
||
data-loading-label="Saving..."
|
||
data-ga-category="save_share"
|
||
data-ga-action="save"
|
||
data-ga-label="save">
|
||
Create file
|
||
</button>
|
||
<button class="action-panel-cancel"
|
||
aria-label="Close 'Save citations to file' panel"
|
||
ref="linksrc=close_save_panel"
|
||
aria-controls="save-action-panel"
|
||
aria-expanded="false"
|
||
data-ga-category="save_share"
|
||
data-ga-action="save"
|
||
data-ga-label="cancel">
|
||
Cancel
|
||
</button>
|
||
</div>
|
||
</form>
|
||
</div>
|
||
</div>
|
||
|
||
|
||
|
||
|
||
<div id="email-action-panel"
|
||
class="email-action-panel action-panel"
|
||
aria-hidden="true"
|
||
data-recaptcha-script-url="https://www.recaptcha.net/recaptcha/enterprise.js?render=explicit&onload=onloadCaptchaCallback"
|
||
data-recaptcha-enabled="true">
|
||
<div class="inner-wrap">
|
||
<h2 class="action-panel-heading">
|
||
Email citation
|
||
</h2>
|
||
<form id="email-action-panel-form"
|
||
class="action-panel-content action-form"
|
||
action="/send-email/"
|
||
data-by-search-action="/results-export-email-by-search-data/"
|
||
data-by-ids-action="/send-email/"
|
||
data-by-search-method="post"
|
||
data-by-ids-method="post"
|
||
method="post"
|
||
>
|
||
<input type="hidden" name="csrfmiddlewaretoken" value="QBqJLaS61yvugHyvDuJFJYtUCkQXbNQJ7oaOo0lsB9iYa8ElgNmHd6Zyaoy94oo3">
|
||
|
||
<div class="action-panel-control-wrap">
|
||
<span class="action-panel-label">
|
||
Subject:
|
||
</span>
|
||
<span class="email-subject" id="email-subject" aria-label="Email subject">1 selected item: 30002298 - PubMed</span>
|
||
<input type="hidden" name="email-subject" value="1 selected item: 30002298"/>
|
||
<input type="hidden" name="email-subject-hash" value="2c0885d02979d0e946885de9c78b83594d9cc3b139bd82c44b801ed3fad3ec52"/>
|
||
</div>
|
||
|
||
<div class="action-panel-control-wrap">
|
||
<label for="email-to" class="action-panel-label required-field-asterisk">
|
||
To:
|
||
</label>
|
||
<input type="email" aria-label="Recipient Email Address" placeholder="email@example.com" id="email-to" class="email-to" pattern="^[a-zA-Z0-9_.+-]+@[a-zA-Z0-9-]+\.[a-zA-Z0-9-.]+$" maxlength="100" required>
|
||
</div>
|
||
|
||
<div class="action-panel-control-wrap">
|
||
<label for="email-from" class="action-panel-label">
|
||
From:
|
||
</label>
|
||
<input type="email" aria-label="Sender Email Address" placeholder="email@example.com" id="email-from" class="email-from" pattern="^[a-zA-Z0-9_.+-]+@[a-zA-Z0-9-]+\.[a-zA-Z0-9-.]+$" maxlength="256">
|
||
</div>
|
||
|
||
|
||
|
||
<div class="action-panel-control-wrap">
|
||
<label for="email-citation-format" class="action-panel-label">
|
||
Format:
|
||
</label>
|
||
<select id="email-citation-format" name="citation-format" class="action-panel-selector email-citation-format">
|
||
<option selected="selected" value="summary">Summary</option>
|
||
<option value="summary-text">Summary (text)</option>
|
||
<option value="abstract">Abstract</option>
|
||
<option value="abstract-text">Abstract (text)</option>
|
||
|
||
</select>
|
||
</div>
|
||
<div class="include-supplemental-container">
|
||
<input type="checkbox" aria-label="Include MeSH and other data" name="include-supplemental" id="email-include-supplemental" class="email-include-supplemental">
|
||
<label for="email-include-supplemental" class="email-include-supplemental-label">MeSH and other data</label>
|
||
</div>
|
||
|
||
|
||
|
||
<div class="form-field recaptcha ">
|
||
|
||
|
||
|
||
<div class="g-recaptcha" id="id-recaptcha" data-sitekey="6LfsWHMdAAAAAClKbtOpjQ2pMjgsGxvv7NdZW9uI"></div>
|
||
|
||
|
||
|
||
|
||
|
||
</div>
|
||
<div id="captcha-error-message" class="usa-input-error-message captcha-validation-message" role="alert"></div>
|
||
|
||
|
||
|
||
<div class="action-panel-actions">
|
||
<button class="action-panel-submit"
|
||
type="submit"
|
||
data-loading-label="Sending..."
|
||
data-ga-category="save_share"
|
||
data-ga-action="email"
|
||
data-ga-label="send">
|
||
Send email
|
||
</button>
|
||
<button class="action-panel-cancel"
|
||
aria-label="Close 'Email citations' panel"
|
||
ref="linksrc=close_email_panel"
|
||
aria-controls="email-action-panel"
|
||
aria-expanded="false"
|
||
data-ga-category="save_share"
|
||
data-ga-action="email"
|
||
data-ga-label="cancel">
|
||
Cancel
|
||
</button>
|
||
</div>
|
||
<input type="hidden" name="email-search-details" value="" />
|
||
<input type="hidden" name="email-search-details-hash" value="0e42663a6c3bd85498fcb88798998fed7bfdc45d457db35281e41afe13cc0524" />
|
||
</form>
|
||
</div>
|
||
</div>
|
||
|
||
<div id="collections-action-panel"
|
||
class="collections-action-panel action-panel in-progress-dots-panel"
|
||
aria-hidden="true"
|
||
data-collections-open-panel-enabled="false"
|
||
data-collections-open-panel-url-hash="#open-collections-panel">
|
||
<div class="inner-wrap">
|
||
<h3 class="action-panel-heading">
|
||
Add to Collections
|
||
</h3>
|
||
|
||
|
||
<form id="collections-action-panel-form"
|
||
class="collections-action-panel-form action-panel-content action-form action-panel-smaller-selectors"
|
||
data-existing-collections-url="/list-existing-collections/"
|
||
data-add-to-existing-collection-url="/add-to-existing-collection/"
|
||
data-create-and-add-to-new-collection-url="/create-and-add-to-new-collection/"
|
||
data-get-article-ids-by-search-url="/get-article-ids-by-search/"
|
||
data-myncbi-max-collection-name-length="100"
|
||
data-add-to-collection-max-amount="1000"
|
||
data-collections-root-url="https://www.ncbi.nlm.nih.gov/myncbi/collections/">
|
||
|
||
<input type="hidden" name="csrfmiddlewaretoken" value="QBqJLaS61yvugHyvDuJFJYtUCkQXbNQJ7oaOo0lsB9iYa8ElgNmHd6Zyaoy94oo3">
|
||
|
||
|
||
|
||
<div class="choice-group" role="radiogroup">
|
||
<ul class="radio-group-items">
|
||
<li>
|
||
<input type="radio"
|
||
id="collections-action-panel-new"
|
||
class="collections-new"
|
||
name="collections"
|
||
value="new"
|
||
data-ga-category="save_share"
|
||
data-ga-action="collections"
|
||
data-ga-label="collections_radio_new">
|
||
<label for="collections-action-panel-new">Create a new collection</label>
|
||
</li>
|
||
<li>
|
||
<input type="radio"
|
||
id="collections-action-panel-existing"
|
||
class="collections-existing"
|
||
name="collections"
|
||
value="existing"
|
||
checked="true"
|
||
data-ga-category="save_share"
|
||
data-ga-action="collections"
|
||
data-ga-label="collections_radio_existing">
|
||
<label for="collections-action-panel-existing">Add to an existing collection</label>
|
||
</li>
|
||
</ul>
|
||
</div>
|
||
|
||
<div class="controls-wrapper">
|
||
<div class="action-panel-control-wrap new-collections-controls">
|
||
<label for="collections-action-panel-add-to-new" class="action-panel-label required-field-asterisk">
|
||
Name your collection:
|
||
</label>
|
||
<input
|
||
type="text"
|
||
name="add-to-new-collection"
|
||
id="collections-action-panel-add-to-new"
|
||
class="collections-action-add-to-new"
|
||
pattern="[^"&=<>\/]*" title="The following characters are not allowed in the Name field: "&=<>/"
|
||
maxlength="100"
|
||
data-ga-category="save_share"
|
||
data-ga-action="create_collection"
|
||
data-ga-label="non_favorties_collection">
|
||
<div class="collections-new-name-too-long usa-input-error-message selection-validation-message">
|
||
Name must be less than 100 characters
|
||
</div>
|
||
</div>
|
||
<div class="action-panel-control-wrap existing-collections-controls">
|
||
<label for="collections-action-panel-add-to-existing" class="action-panel-label">
|
||
Choose a collection:
|
||
</label>
|
||
<select id="collections-action-panel-add-to-existing"
|
||
class="action-panel-selector collections-action-add-to-existing"
|
||
data-ga-category="save_share"
|
||
data-ga-action="select_collection"
|
||
data-ga-label="($('#collections-action-add-to-existing').val() === 'Favorites') ? 'Favorites' : 'non_favorites_collection'">
|
||
</select>
|
||
<div class="collections-retry-load-on-error usa-input-error-message selection-validation-message">
|
||
Unable to load your collection due to an error<br>
|
||
<a href="#">Please try again</a>
|
||
</div>
|
||
</div>
|
||
</div>
|
||
|
||
<div class="action-panel-actions">
|
||
<button class="action-panel-submit"
|
||
type="submit"
|
||
data-loading-label="Adding..."
|
||
data-pinger-ignore
|
||
data-ga-category="save_share"
|
||
data-ga-action="collections"
|
||
data-ga-label="add">
|
||
Add
|
||
</button>
|
||
<button class="action-panel-cancel"
|
||
aria-label="Close 'Add to Collections' panel"
|
||
ref="linksrc=close_collections_panel"
|
||
aria-controls="collections-action-panel"
|
||
aria-expanded="false"
|
||
data-ga-category="save_share"
|
||
data-ga-action="collections"
|
||
data-ga-label="cancel">
|
||
Cancel
|
||
</button>
|
||
</div>
|
||
</form>
|
||
</div>
|
||
</div>
|
||
|
||
<div id="bibliography-action-panel"
|
||
class="bibliography-action-panel action-panel in-progress-dots-panel"
|
||
aria-hidden="true"
|
||
data-bibliography-open-panel-enabled="false"
|
||
data-bibliography-open-panel-url-hash="#open-bibliography-panel">
|
||
<div class="inner-wrap">
|
||
<h3 class="action-panel-heading">
|
||
Add to My Bibliography
|
||
</h3>
|
||
<form id="bibliography-action-panel-form"
|
||
class="bibliography-action-panel-form action-panel-content action-form action-panel-smaller-selectors"
|
||
data-add-to-bibliography-max-amount="100"
|
||
data-add-to-bibliography-batch-size="10"
|
||
data-bibliography-delegates-url="/list-bibliography-delegates/"
|
||
data-add-to-bibliography-url="/add-to-bibliography/"
|
||
data-get-article-ids-by-search-url="/get-article-ids-by-search/"
|
||
data-mybib-root-url="https://www.ncbi.nlm.nih.gov/myncbi/collections/mybibliography/">
|
||
|
||
<input type="hidden" name="csrfmiddlewaretoken" value="QBqJLaS61yvugHyvDuJFJYtUCkQXbNQJ7oaOo0lsB9iYa8ElgNmHd6Zyaoy94oo3">
|
||
|
||
|
||
|
||
<div class="action-panel-control-wrap bibliographies-controls">
|
||
<div class="choice-group">
|
||
<ul class="bibliographies-action-add radio-group-items">
|
||
<li>
|
||
<input name="bibliography" id="my-bibliography" class="my-bibliography" type="radio" checked/>
|
||
<label for="my-bibliography">My Bibliography</label>
|
||
</li>
|
||
</ul>
|
||
</div>
|
||
</div>
|
||
|
||
<div class="bibliographies-retry-load-on-error usa-input-error-message selection-validation-message">
|
||
Unable to load your delegates due to an error<br>
|
||
<a href="#">Please try again</a>
|
||
</div>
|
||
|
||
<div class="action-panel-actions">
|
||
<button class="action-panel-submit"
|
||
type="submit"
|
||
data-loading-label="Adding..."
|
||
data-pinger-ignore>
|
||
Add
|
||
</button>
|
||
<button class="action-panel-cancel"
|
||
aria-label="Close 'Add to bibliography' panel"
|
||
ref="linksrc=close_bibliography_panel"
|
||
aria-controls="bibliography-action-panel"
|
||
aria-expanded="false"
|
||
data-ga-category="save_share"
|
||
data-ga-action="mybib"
|
||
data-ga-label="cancel">
|
||
Cancel
|
||
</button>
|
||
</div>
|
||
</form>
|
||
</div>
|
||
</div>
|
||
|
||
|
||
|
||
|
||
<div id="saved-search-action-panel" class="saved-search-action-panel action-panel " aria-hidden="true"
|
||
data-saved-search-open-panel-enabled="false"
|
||
data-saved-search-open-panel-url-hash="#open-saved-search-panel">
|
||
<div class="inner-wrap">
|
||
<h2 class="action-panel-heading">
|
||
Your saved search
|
||
</h2>
|
||
|
||
<form id="saved-search-action-panel-form"
|
||
class="saved-search-action-panel-form action-panel-content action-form"
|
||
data-create-saved-search-url="/create-saved-search/"
|
||
data-try-search-terms-url="/try-search-term/"
|
||
data-saved-search-root-url="https://www.ncbi.nlm.nih.gov/myncbi/searches/">
|
||
|
||
<input type="hidden" name="csrfmiddlewaretoken" value="QBqJLaS61yvugHyvDuJFJYtUCkQXbNQJ7oaOo0lsB9iYa8ElgNmHd6Zyaoy94oo3">
|
||
|
||
<div class="action-panel-control-wrap">
|
||
<label for="saved-search-name" class="action-panel-label saved-search-name-label required-field-asterisk">
|
||
Name of saved search:
|
||
</label>
|
||
<input maxlength="200"
|
||
type="text"
|
||
name="saved-search-name"
|
||
id="saved-search-name"
|
||
class="saved-search-name"
|
||
value=""
|
||
required
|
||
pattern="[^"&=<>\/]*" title="The following characters are not allowed in the Name field: "&=<>/">
|
||
</div>
|
||
|
||
<div class="action-panel-control-wrap">
|
||
<label for="saved-search-term" class="action-panel-label required-field-asterisk">
|
||
Search terms:
|
||
</label>
|
||
<textarea name="saved-search-term" id="saved-search-term" class="saved-search-term" required></textarea>
|
||
</div>
|
||
<div class="test-search-term-wrap">
|
||
<a href="#" class="try-search-term">Test search terms</a>
|
||
</div>
|
||
<div class="choice-group action-panel-extra-margin-top">
|
||
<span class="action-panel-label" id="fieldset-label">
|
||
Would you like email updates of new search results?
|
||
</span>
|
||
<fieldset id="saved-search-alert" aria-describedby="fieldset-label">
|
||
<legend class="usa-sr-only">Saved Search Alert Radio Buttons</legend>
|
||
<ul class="radio-group-items">
|
||
<li>
|
||
<input type="radio" id="saved-search-alert-yes" class="saved-search-alert-yes" name="saved-search-alert" value="yes" checked>
|
||
<label for="saved-search-alert-yes" class="action-panel-label">Yes</label>
|
||
</li>
|
||
<li>
|
||
<input aria-label="No radio input" type="radio" id="saved-search-alert-no" class="saved-search-alert-no" name="saved-search-alert" value="no">
|
||
<label for="saved-search-alert-no" class="action-panel-label">No</label>
|
||
</li>
|
||
</ul>
|
||
</fieldset>
|
||
</div>
|
||
|
||
<div class="alert-schedule-wrap">
|
||
<div class="action-panel-control-wrap">
|
||
<label class="action-panel-label">
|
||
Email:
|
||
</label>
|
||
<span aria-label="Email address" id="saved-search-email" class="action-panel-label"><span class="action-panel-label-bold"></span> (<a class="myncbi-account-settings" href="https://www.ncbi.nlm.nih.gov/account/settings/">change</a>)</span>
|
||
</div>
|
||
<div class="action-panel-control-wrap action-panel-extra-margin-top">
|
||
<label for="saved-search-frequency" class="action-panel-label">
|
||
Frequency:
|
||
</label>
|
||
<select id="saved-search-frequency" class="no-border-panel-selector saved-search-frequency">
|
||
<option value="monthly">Monthly</option>
|
||
<option value="weekly">Weekly</option>
|
||
<option value="daily">Daily</option>
|
||
</select>
|
||
</div>
|
||
<div class="action-panel-control-wrap saved-search-monthly-additional">
|
||
<label for="saved-search-monthly-on-day" class="action-panel-label">
|
||
Which day?
|
||
</label>
|
||
<select id="saved-search-monthly-on-day" class="no-border-panel-selector">
|
||
<option value="Sunday">The first Sunday</option>
|
||
<option value="Monday">The first Monday</option>
|
||
<option value="Tuesday">The first Tuesday</option>
|
||
<option value="Wednesday">The first Wednesday</option>
|
||
<option value="Thursday">The first Thursday</option>
|
||
<option value="Friday">The first Friday</option>
|
||
<option value="Saturday">The first Saturday</option>
|
||
<option value="day">The first day</option>
|
||
<option value="weekday">The first weekday</option>
|
||
</select>
|
||
</div>
|
||
<div class="action-panel-control-wrap saved-search-weekly-additional">
|
||
<label for="saved-search-weekly-on-day" class="action-panel-label">
|
||
Which day?
|
||
</label>
|
||
<select id="saved-search-weekly-on-day" class="no-border-panel-selector saved-search-weekly-on-day">
|
||
<option value="Sunday">Sunday</option>
|
||
<option value="Monday">Monday</option>
|
||
<option value="Tuesday">Tuesday</option>
|
||
<option value="Wednesday">Wednesday</option>
|
||
<option value="Thursday">Thursday</option>
|
||
<option value="Friday">Friday</option>
|
||
<option value="Saturday">Saturday</option>
|
||
</select>
|
||
</div>
|
||
<div class="action-panel-control-wrap">
|
||
<label for="saved-search-report" class="action-panel-label">
|
||
Report format:
|
||
</label>
|
||
<select id="saved-search-report" class="no-border-panel-selector saved-search-report">
|
||
<option value="DocSum">Summary</option>
|
||
<option value="DocSumText">Summary (text)</option>
|
||
<option value="Abstract">Abstract</option>
|
||
<option value="AbstractText">Abstract (text)</option>
|
||
<option value="MEDLINE">PubMed</option>
|
||
</select>
|
||
</div>
|
||
<div class="action-panel-control-wrap">
|
||
<label for="saved-search-amount" class="action-panel-label">
|
||
Send at most:
|
||
</label>
|
||
<select id="saved-search-amount" class="no-border-panel-selector saved-search-amount">
|
||
<option value="1">1 item</option>
|
||
<option value="5" selected>5 items</option>
|
||
<option value="10">10 items</option>
|
||
<option value="20">20 items</option>
|
||
<option value="50">50 items</option>
|
||
<option value="100">100 items</option>
|
||
<option value="200">200 items</option>
|
||
</select>
|
||
</div>
|
||
<div>
|
||
<input type="checkbox" id="saved-search-send-if-no-result" class="saved-search-send-if-no-result" name="saved-search-send-if-no-result">
|
||
<label for="saved-search-send-if-no-result" class="action-panel-label smaller-checkbox">
|
||
Send even when there aren't any new results
|
||
</label>
|
||
</div>
|
||
<div class="action-panel-control-wrap option-text-in-email-wrap">
|
||
<label for="saved-search-email-text" class="action-panel-label">
|
||
Optional text in email:
|
||
</label>
|
||
<textarea name="saved-search-email-text"
|
||
id="saved-search-email-text"
|
||
class="saved-search-email-text"></textarea>
|
||
</div>
|
||
|
||
</div>
|
||
|
||
<div class="action-panel-actions">
|
||
<button class="action-panel-submit"
|
||
type="submit"
|
||
data-loading-label="Saving..."
|
||
data-ga-category="save_share"
|
||
data-ga-action="alert"
|
||
data-ga-label="save">
|
||
Save
|
||
</button>
|
||
<button class="action-panel-cancel"
|
||
aria-label="Close 'Your saved search' panel"
|
||
ref="linksrc=close_saved_search_panel"
|
||
aria-controls="saved-search-action-panel"
|
||
aria-expanded="false"
|
||
data-ga-category="save_share"
|
||
data-ga-action="alert"
|
||
data-ga-label="cancel">
|
||
Cancel
|
||
</button>
|
||
</div>
|
||
</form>
|
||
</div>
|
||
</div>
|
||
|
||
<div id="citation-manager-action-panel" class="citation-manager-action-panel action-panel" aria-hidden="true">
|
||
<div class="inner-wrap">
|
||
<h2 class="action-panel-heading">
|
||
Create a file for external citation management software
|
||
</h2>
|
||
<form id="citation-manager-action-panel-form"
|
||
class="action-panel-content action-form"
|
||
action="/results-export-ids/"
|
||
data-by-search-action="/results-export-search-data/"
|
||
data-by-ids-action="/results-export-ids/"
|
||
method="post"
|
||
data-by-search-method="post"
|
||
data-by-ids-method="post">
|
||
|
||
<input type="hidden" name="csrfmiddlewaretoken" value="QBqJLaS61yvugHyvDuJFJYtUCkQXbNQJ7oaOo0lsB9iYa8ElgNmHd6Zyaoy94oo3">
|
||
|
||
|
||
|
||
<input name="results-format" type="hidden" value="pubmed"/>
|
||
|
||
<div class="action-panel-actions">
|
||
<button class="action-panel-submit"
|
||
type="submit"
|
||
data-loading-label="Sending..."
|
||
data-ga-category="save_share"
|
||
data-ga-action="citation_manager"
|
||
data-ga-label="save">
|
||
Create file
|
||
</button>
|
||
<button class="action-panel-cancel"
|
||
aria-label="Close 'Send citations to citation manager' panel"
|
||
ref="linksrc=close_citation_manager_panel"
|
||
aria-controls="citation-manager-action-panel"
|
||
aria-expanded="false"
|
||
data-ga-category="save_share"
|
||
data-ga-action="citation_manager"
|
||
data-ga-label="cancel">
|
||
Cancel
|
||
</button>
|
||
</div>
|
||
</form>
|
||
</div>
|
||
</div>
|
||
|
||
|
||
|
||
|
||
<div id="rss-action-panel" class="rss-action-panel action-panel " aria-hidden="true">
|
||
<div class="inner-wrap">
|
||
<h2 class="action-panel-heading">
|
||
Your RSS Feed
|
||
</h2>
|
||
|
||
<form id="rss-action-panel-form"
|
||
class="rss-action-panel-form action-panel-content action-form"
|
||
data-create-rss-feed-url="/create-rss-feed-url/"
|
||
data-search-form-term-value="">
|
||
|
||
<input type="hidden" name="csrfmiddlewaretoken" value="QBqJLaS61yvugHyvDuJFJYtUCkQXbNQJ7oaOo0lsB9iYa8ElgNmHd6Zyaoy94oo3">
|
||
|
||
<div class="action-panel-control-wrap">
|
||
<label for="rss-name" class="action-panel-label required-field-asterisk">
|
||
Name of RSS Feed:
|
||
</label>
|
||
<input maxlength="200"
|
||
placeholder="Name"
|
||
type="text"
|
||
name="rss-name"
|
||
id="rss-name"
|
||
class="rss-name"
|
||
value=''
|
||
required
|
||
pattern="[^"&=<>\/]*" title="The following characters are not allowed in the Name field: "&=<>/">
|
||
</div>
|
||
|
||
<div class="rss-limit-wrap">
|
||
<div class="action-panel-control-wrap action-panel-extra-margin-top">
|
||
<label for="rss-limit" class="action-panel-label">
|
||
Number of items displayed:
|
||
</label>
|
||
<select id="rss-limit" class="no-border-panel-selector rss-limit">
|
||
<option value="5">5</option>
|
||
<option value="10">10</option>
|
||
<option value="15" selected="selected">15</option>
|
||
<option value="20">20</option>
|
||
<option value="50">50</option>
|
||
<option value="100">100</option>
|
||
</select>
|
||
</div>
|
||
</div>
|
||
|
||
<div class="action-panel-actions">
|
||
<button class="action-panel-submit"
|
||
type="submit"
|
||
data-loading-label="Creating..."
|
||
data-ga-category="save_share"
|
||
data-ga-action="alert"
|
||
data-ga-label="save">
|
||
Create RSS
|
||
</button>
|
||
<button class="action-panel-cancel"
|
||
aria-label="Close 'Your RSS' panel"
|
||
ref="linksrc=close_rss_panel"
|
||
aria-controls="rss-action-panel"
|
||
aria-expanded="false"
|
||
data-ga-category="save_share"
|
||
data-ga-action="alert"
|
||
data-ga-label="cancel">
|
||
Cancel
|
||
</button>
|
||
</div>
|
||
|
||
<div class="action-panel-control-wrap rss-link-copy-wrap">
|
||
<label for="rss-link" class="usa-sr-only">RSS Link</label>
|
||
<input placeholder="Your RSS Feed Link" type="text" name="rss-link" id="rss-link" class="rss-link" title="RSS Link">
|
||
<button
|
||
type="button"
|
||
disabled
|
||
class="rss-link-copy-button disabled"
|
||
data-ga-category="save_share"
|
||
data-ga-action="rss"
|
||
data-ga-label="copy">
|
||
Copy
|
||
</button>
|
||
</div>
|
||
</form>
|
||
</div>
|
||
</div>
|
||
|
||
</div>
|
||
</div>
|
||
|
||
<div class="article-page" id="article-page" data-article-pmid="30002298">
|
||
<aside class="page-sidebar">
|
||
<div class="inner-wrap">
|
||
|
||
<div class="full-text-links">
|
||
<div class="full-view">
|
||
<h3 class="title">
|
||
Full text links
|
||
</h3>
|
||
<div class="full-text-links-list">
|
||
<a class="link-item
|
||
|
||
dialog-focus"
|
||
href="https://www.mdpi.com/resolver?pii=molecules23071700"
|
||
target="_blank"
|
||
rel="noopener"
|
||
|
||
ref="linksrc=fulltextorjournal_fulltext&is_pmc=False&PrId=6383&itool=Abstract-def&log$=linkouticon&uid=30002298&db=pubmed&nlmid=100964009"
|
||
title="See full text options at MDPI"
|
||
|
||
data-ga-category="full_text"
|
||
data-ga-action="MDPI"
|
||
data-ga-label="30002298"
|
||
><img src="https://cdn.ncbi.nlm.nih.gov/corehtml/query/egifs/https:--res.mdpi.com-data-pubmed-linkout.png" alt="MDPI full text link"><span class="text">
|
||
|
||
MDPI
|
||
|
||
</span></a><a class="link-item
|
||
pmc
|
||
"
|
||
href="https://pmc.ncbi.nlm.nih.gov/articles/pmid/30002298/"
|
||
target="_blank"
|
||
rel="noopener"
|
||
|
||
ref="linksrc=fulltextorjournal_fulltext&is_pmc=True&PrId=3494&itool=Abstract-def&log$=linkouticon&uid=30002298&db=pubmed&nlmid=100964009"
|
||
title="Free full text at PubMed Central"
|
||
|
||
data-ga-category="full_text"
|
||
data-ga-action="PMC"
|
||
data-ga-label="30002298"
|
||
><span class="text">
|
||
|
||
Free PMC article
|
||
|
||
</span></a>
|
||
</div>
|
||
|
||
</div>
|
||
|
||
<div class="short-view">
|
||
<a href="#" class="full-text-links-button full-text-links-dialog-trigger">
|
||
Full text links
|
||
</a>
|
||
</div>
|
||
</div>
|
||
|
||
|
||
|
||
|
||
<div class="actions-buttons sidebar"><h3 class="title">Actions</h3><div class="inner-wrap"><button class="citation-button citation-dialog-trigger"
|
||
aria-label="Open dialog with citation text in different styles"
|
||
data-ga-category="save_share"
|
||
data-ga-action="cite"
|
||
data-ga-label="open"
|
||
data-all-citations-url="/30002298/citations/"
|
||
data-citation-style="nlm"
|
||
data-pubmed-format-link="/30002298/export/"><span class="button-label">Cite</span></button><link type="text/css" href="ncbi-overlay-block/src/overlay-block.css"><div class="collections-button-container" data-article-id="30002298" data-article-db="pubmed"><button class="collections-button collections-dialog-trigger"
|
||
aria-label="Save article in MyNCBI collections."
|
||
data-ga-category="collections_button"
|
||
data-ga-action="click"
|
||
data-ga-label="collections_button"
|
||
data-collections-open-dialog-enabled="false"
|
||
data-collections-open-dialog-url="https://account.ncbi.nlm.nih.gov/?back_url=https%3A%2F%2Fpubmed.ncbi.nlm.nih.gov%2F30002298%2F%23open-collections-dialog"
|
||
data-in-collections="false"><span class="button-label">Collections</span></button><div class="overlay" role="dialog"><div id="collections-action-dialog"
|
||
class="dialog collections-dialog"
|
||
aria-hidden="true"><div class="title">Add to Collections</div><div class="collections-action-panel action-panel"><form id="collections-action-dialog-form"
|
||
class="collections-action-panel-form action-panel-content action-form action-panel-smaller-selectors"
|
||
data-existing-collections-url="/list-existing-collections/"
|
||
data-add-to-existing-collection-url="/add-to-existing-collection/"
|
||
data-create-and-add-to-new-collection-url="/create-and-add-to-new-collection/"
|
||
data-myncbi-max-collection-name-length="100"
|
||
data-collections-root-url="https://www.ncbi.nlm.nih.gov/myncbi/collections/"><input type="hidden" name="csrfmiddlewaretoken" value="QBqJLaS61yvugHyvDuJFJYtUCkQXbNQJ7oaOo0lsB9iYa8ElgNmHd6Zyaoy94oo3"><div class="choice-group" role="radiogroup"><ul class="radio-group-items"><li><input type="radio"
|
||
id="collections-action-dialog-new"
|
||
class="collections-new"
|
||
name="collections"
|
||
value="new"
|
||
data-ga-category="collections_button"
|
||
data-ga-action="click"
|
||
data-ga-label="collections_radio_new"><label for="collections-action-dialog-new">Create a new collection</label></li><li><input type="radio"
|
||
id="collections-action-dialog-existing"
|
||
class="collections-existing"
|
||
name="collections"
|
||
value="existing"
|
||
checked="true"
|
||
data-ga-category="collections_button"
|
||
data-ga-action="click"
|
||
data-ga-label="collections_radio_existing"><label for="collections-action-dialog-existing">Add to an existing collection</label></li></ul></div><div class="controls-wrapper"><div class="action-panel-control-wrap new-collections-controls"><label for="collections-action-dialog-add-to-new" class="action-panel-label required-field-asterisk">
|
||
Name your collection:
|
||
</label><input
|
||
type="text"
|
||
name="add-to-new-collection"
|
||
id="collections-action-dialog-add-to-new"
|
||
class="collections-action-add-to-new"
|
||
pattern="[^"&=<>\/]*" title="The following characters are not allowed in the Name field: "&=<>/"
|
||
maxlength="100"
|
||
data-ga-category="collections_button"
|
||
data-ga-action="create_collection"
|
||
data-ga-label="non_favorties_collection"><div class="collections-new-name-too-long usa-input-error-message selection-validation-message">
|
||
Name must be less than 100 characters
|
||
</div></div><div class="action-panel-control-wrap existing-collections-controls"><label for="collections-action-dialog-add-to-existing" class="action-panel-label">
|
||
Choose a collection:
|
||
</label><select id="collections-action-dialog-add-to-existing"
|
||
class="action-panel-selector collections-action-add-to-existing"
|
||
data-ga-category="collections_button"
|
||
data-ga-action="select_collection"
|
||
data-ga-label="($('.collections-action-add-to-existing').val() === 'Favorites') ? 'Favorites' : 'non_favorites_collection'"></select><div class="collections-retry-load-on-error usa-input-error-message selection-validation-message">
|
||
Unable to load your collection due to an error<br><a href="#">Please try again</a></div></div></div><div class="action-panel-actions"><button class="action-panel-submit"
|
||
type="submit"
|
||
data-loading-label="Adding..."
|
||
data-pinger-ignore
|
||
data-ga-category="collections_button"
|
||
data-ga-action="click"
|
||
data-ga-label="add">
|
||
Add
|
||
</button><button class="action-panel-cancel"
|
||
aria-label="Close 'Add to Collections' panel"
|
||
ref="linksrc=close_collections_panel"
|
||
aria-controls="collections-action-panel"
|
||
aria-expanded="false"
|
||
data-ga-category="collections_button"
|
||
data-ga-action="click"
|
||
data-ga-label="cancel">
|
||
Cancel
|
||
</button></div></form></div></div></div></div><button class="more-actions-button more-actions-dialog-trigger"
|
||
title="Open dialog with more actions to take"
|
||
ref="linksrc=more_actions_btn"></button><div class="display-options" data-format-key="format"
|
||
data-default-format-value="abstract"
|
||
data-current-format-value="abstract" role="region"><button
|
||
class="trigger usa-button"
|
||
title="Change format"
|
||
data-ga-category="display_options"
|
||
data-ga-action="display_options_dialog"><span class="button-label">Display options</span></button><div class="dropdown" hidden><div class="title">
|
||
Display options
|
||
</div><div class="content"><div class="format-container"><span class="option-label">
|
||
Format
|
||
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Understanding the Role of Anti-PEG Antibodies in the Complement Activation by Doxil in Vitro
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Understanding the Role of Anti-PEG Antibodies in the Complement Activation by Doxil in Vitro
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Infusion reactions (IRs) are common immune-mediated side effects in patients treated with a variety of drug products, including, but not limited to, nanotechnology formulations. The mechanism of IRs is not fully understood. One of the best studied mechanisms of IRs to nanomedicines is the complement activation. However, it is largely unknown why some patients develop reactions to nanomedicines while others do not, and why some nanoparticles are more reactogenic than others. One of the theories is that the pre-existing anti-polyethylene glycol (PEG) antibodies initiate the complement activation and IRs in patients. In this study, we investigated this hypothesis in the case of PEGylated liposomal doxorubicin (Doxil), which, when used in a clinical setting, is known to induce IRs; referred to as complement activation-related pseudoallergy (CARPA) in sensitive individuals. We conducted the study in vitro using plasma derived from C57BL/6 mice and twenty human donor volunteers. We used mouse plasma to test a library of well-characterized mouse monoclonal antibodies with different specificity and affinity to PEG as it relates to the complement activation by Doxil. We determined the levels of pre-existing polyclonal antibodies that bind to PEG, methoxy-PEG, and PEGylated liposomes in human plasma, and we also assessed complement activation by Doxil and concentrations of complement inhibitory factors H and I in these human plasma specimens. The affinity, specificity, and other characteristics of the human polyclonal antibodies are not known at this time. Our data demonstrate that under in vitro conditions, some anti-PEG antibodies contribute to the complement activation by Doxil. Such contribution, however, needs to be considered in the context of other factors, including, but not limited to, antibody class, type, clonality, epitope specificity, affinity, and titer. In addition, our data contribute to the knowledge base used to understand and improve nanomedicine safety.
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CARPA; anti-PEG antibody; complement activation; hypersensitivity; immunotoxicity; infusion reaction; liposomes; nanoparticles.
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<p xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:p1="http://pubmed.gov/pub-one">The authors declare no conflict of interest.</p>
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<figure class="figure-item "
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data-slide-index="0"
|
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data-label-slug="figure-1">
|
||
<a class="figure-link"
|
||
href="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6de5/6100003/b92fc6c2d058/molecules-23-01700-g001.jpg"
|
||
itemprop="contentUrl"
|
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aria-describedby="figure-caption-0"
|
||
role="button"
|
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data-image-width="788"
|
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data-image-height="747"
|
||
data-image-alt="Figure 1"
|
||
data-pmc-id="PMC6100003"
|
||
data-figure-id="molecules-23-01700-f001">
|
||
<img class="figure-thumb" itemprop="thumbnail"
|
||
id="article-image-0"
|
||
src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6de5/6100003/ee280aad1109/molecules-23-01700-g001.gif"
|
||
alt="Figure 1" />
|
||
</a>
|
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<meta itemprop="width" itemtype="http://schema.org/ImageObject" content="788">
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<meta itemprop="height" itemtype="http://schema.org/ImageObject" content="747">
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<div class="figure-caption figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="caption" aria-hidden="true">
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|
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<strong class="figure-label">
|
||
<p> Figure 1 </p>
|
||
</strong>
|
||
|
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|
||
|
||
<div class="figure-caption-contents"><p> Study design. ( <b> A </b> )… </p></div>
|
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|
||
</div>
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<div class="figure-caption-medium figure-caption-text" aria-hidden="true">
|
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<strong class="figure-label">
|
||
<p> Figure 1 </p>
|
||
</strong>
|
||
|
||
|
||
|
||
<div class="figure-caption-contents"><p> Study design. ( <b> A </b> ) The role of well-characterized mouse antibody in the… </p></div>
|
||
|
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|
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|
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|
||
</div>
|
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|
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<figcaption id="figure-caption-0" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description">
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<strong class="figure-label">
|
||
Figure 1
|
||
</strong>
|
||
|
||
|
||
|
||
<div class="figure-caption-contents">Study design. (<b>A</b>) The role of well-characterized mouse antibody in the complement activation by Doxil in mouse plasma; (<b>B</b>) detecting and understanding the role of pre-existing anti-PEG antibodies in the complement activation by Doxil in human plasma. Ab—antibody; ELISA—enzyme-linked immunosorbent assay; CFI—complement factor I; CFH—complement factor H; PEG—polyethylene glycol; CRL—Charles River Laboratories.</div>
|
||
|
||
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||
|
||
|
||
</figcaption>
|
||
|
||
|
||
</figure>
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||
<figure class="figure-item "
|
||
itemscope itemtype="http://schema.org/ImageObject"
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itemprop="associatedMedia"
|
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data-slide-index="1"
|
||
data-label-slug="figure-2">
|
||
<a class="figure-link"
|
||
href="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6de5/6100003/66fe9d7b371a/molecules-23-01700-g002a.jpg"
|
||
itemprop="contentUrl"
|
||
aria-describedby="figure-caption-1"
|
||
role="button"
|
||
data-image-width="764"
|
||
data-image-height="527"
|
||
data-image-alt="Figure 2"
|
||
data-pmc-id="PMC6100003"
|
||
data-figure-id="molecules-23-01700-f002">
|
||
<img class="figure-thumb" itemprop="thumbnail"
|
||
id="article-image-1"
|
||
src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6de5/6100003/e503c79ca57f/molecules-23-01700-g002a.gif"
|
||
alt="Figure 2" />
|
||
</a>
|
||
|
||
<meta itemprop="width" itemtype="http://schema.org/ImageObject" content="764">
|
||
<meta itemprop="height" itemtype="http://schema.org/ImageObject" content="527">
|
||
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||
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||
<div class="figure-caption figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="caption" aria-hidden="true">
|
||
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||
<div class="caption-wrap">
|
||
|
||
|
||
|
||
|
||
|
||
<strong class="figure-label">
|
||
<p> Figure 2 </p>
|
||
</strong>
|
||
|
||
|
||
|
||
<div class="figure-caption-contents"><p> Influence of the anti-PEG antibodies… </p></div>
|
||
|
||
|
||
|
||
|
||
</div>
|
||
</div>
|
||
|
||
<div class="figure-caption-medium figure-caption-text" aria-hidden="true">
|
||
|
||
|
||
|
||
|
||
|
||
|
||
<strong class="figure-label">
|
||
<p> Figure 2 </p>
|
||
</strong>
|
||
|
||
|
||
|
||
<div class="figure-caption-contents"><p> Influence of the anti-PEG antibodies on the complement activation by Doxil in murine… </p></div>
|
||
|
||
|
||
|
||
|
||
</div>
|
||
|
||
<figcaption id="figure-caption-1" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description">
|
||
|
||
|
||
|
||
|
||
|
||
|
||
<strong class="figure-label">
|
||
Figure 2
|
||
</strong>
|
||
|
||
|
||
|
||
<div class="figure-caption-contents">Influence of the anti-PEG antibodies on the complement activation by Doxil in murine plasma. Mouse plasma anticoagulated with hirudin was spiked with either Doxil or Doxil mixed with anti-PEG antibodies. The concentration of Doxil was 0.4 mg/mL of doxorubicin and was constant between all samples. The concentration of all antibodies was 10 μg/mL. Complement activation was assessed by ELISA measuring levels of the murine C3a component of the complement. (<b>A</b>) Role of antibody class. Doxil mixed with a PEG-specific IgM (AB1, AB2, or AB7), regardless of the antibodies’ affinity, stimulated a higher level of complement activation than Doxil alone. Doxil combined with one PEG-specific IgG (AB4) stimulated a higher level of the complement activation than Doxil alone. Doxil mixed with two other PEG-specific IgG (AB3 or AB5) induced complement activation comparable to that induced by Doxil alone; (<b>B</b>) Role of epitope specificity. Doxil incubated with IgG reactive to the PEG backbone or IgG reactive to the PEG terminal methoxy group induced stronger complement activation than Doxil alone. However, in the presence of IgG specific to the methoxy group, the complement activation by Doxil was stronger than that in the presence of PEG backbone-reactive IgG. Mouse IgG and mouse IgM, as specified in the materials and methods, were used as isotype controls and did not show a physiologically significant (i.e., two-fold or higher) influence on the complement activation by Doxil. Each bar shows mean and standard deviation (<i>n</i> = 3). All antibodies were in storage buffer containing 50% glycerol. When tested alone, 50% glycerol storage buffer did not result in C3a levels above those in the negative control (data not shown). DXR—doxorubicin; AB—antibody; numbers following “AB” refer to the antibodies described in Table 1; NC—negative control (phosphate-buffered saline—PBS); CVF—cobra venom factor used as the assay positive control.</div>
|
||
|
||
|
||
|
||
|
||
</figcaption>
|
||
|
||
|
||
</figure>
|
||
|
||
<figure class="figure-item "
|
||
itemscope itemtype="http://schema.org/ImageObject"
|
||
itemprop="associatedMedia"
|
||
data-slide-index="2"
|
||
data-label-slug="figure-2">
|
||
<a class="figure-link"
|
||
href="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6de5/6100003/546d8210c06a/molecules-23-01700-g002b.jpg"
|
||
itemprop="contentUrl"
|
||
aria-describedby="figure-caption-2"
|
||
role="button"
|
||
data-image-width="703"
|
||
data-image-height="412"
|
||
data-image-alt="Figure 2"
|
||
data-pmc-id="PMC6100003"
|
||
data-figure-id="molecules-23-01700-f002">
|
||
<img class="figure-thumb" itemprop="thumbnail"
|
||
id="article-image-2"
|
||
src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6de5/6100003/e503c79ca57f/molecules-23-01700-g002a.gif"
|
||
alt="Figure 2" />
|
||
</a>
|
||
|
||
<meta itemprop="width" itemtype="http://schema.org/ImageObject" content="703">
|
||
<meta itemprop="height" itemtype="http://schema.org/ImageObject" content="412">
|
||
|
||
|
||
<div class="figure-caption figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="caption" aria-hidden="true">
|
||
|
||
<div class="caption-wrap">
|
||
|
||
|
||
|
||
|
||
|
||
<strong class="figure-label">
|
||
<p> Figure 2 </p>
|
||
</strong>
|
||
|
||
|
||
|
||
<div class="figure-caption-contents"><p> Influence of the anti-PEG antibodies… </p></div>
|
||
|
||
|
||
|
||
|
||
</div>
|
||
</div>
|
||
|
||
<div class="figure-caption-medium figure-caption-text" aria-hidden="true">
|
||
|
||
|
||
|
||
|
||
|
||
|
||
<strong class="figure-label">
|
||
<p> Figure 2 </p>
|
||
</strong>
|
||
|
||
|
||
|
||
<div class="figure-caption-contents"><p> Influence of the anti-PEG antibodies on the complement activation by Doxil in murine… </p></div>
|
||
|
||
|
||
|
||
|
||
</div>
|
||
|
||
<figcaption id="figure-caption-2" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description">
|
||
|
||
|
||
|
||
|
||
|
||
|
||
<strong class="figure-label">
|
||
Figure 2
|
||
</strong>
|
||
|
||
|
||
|
||
<div class="figure-caption-contents">Influence of the anti-PEG antibodies on the complement activation by Doxil in murine plasma. Mouse plasma anticoagulated with hirudin was spiked with either Doxil or Doxil mixed with anti-PEG antibodies. The concentration of Doxil was 0.4 mg/mL of doxorubicin and was constant between all samples. The concentration of all antibodies was 10 μg/mL. Complement activation was assessed by ELISA measuring levels of the murine C3a component of the complement. (<b>A</b>) Role of antibody class. Doxil mixed with a PEG-specific IgM (AB1, AB2, or AB7), regardless of the antibodies’ affinity, stimulated a higher level of complement activation than Doxil alone. Doxil combined with one PEG-specific IgG (AB4) stimulated a higher level of the complement activation than Doxil alone. Doxil mixed with two other PEG-specific IgG (AB3 or AB5) induced complement activation comparable to that induced by Doxil alone; (<b>B</b>) Role of epitope specificity. Doxil incubated with IgG reactive to the PEG backbone or IgG reactive to the PEG terminal methoxy group induced stronger complement activation than Doxil alone. However, in the presence of IgG specific to the methoxy group, the complement activation by Doxil was stronger than that in the presence of PEG backbone-reactive IgG. Mouse IgG and mouse IgM, as specified in the materials and methods, were used as isotype controls and did not show a physiologically significant (i.e., two-fold or higher) influence on the complement activation by Doxil. Each bar shows mean and standard deviation (<i>n</i> = 3). All antibodies were in storage buffer containing 50% glycerol. When tested alone, 50% glycerol storage buffer did not result in C3a levels above those in the negative control (data not shown). DXR—doxorubicin; AB—antibody; numbers following “AB” refer to the antibodies described in Table 1; NC—negative control (phosphate-buffered saline—PBS); CVF—cobra venom factor used as the assay positive control.</div>
|
||
|
||
|
||
|
||
|
||
</figcaption>
|
||
|
||
|
||
</figure>
|
||
|
||
<figure class="figure-item "
|
||
itemscope itemtype="http://schema.org/ImageObject"
|
||
itemprop="associatedMedia"
|
||
data-slide-index="3"
|
||
data-label-slug="figure-3">
|
||
<a class="figure-link"
|
||
href="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6de5/6100003/58d58193ffc0/molecules-23-01700-g003.jpg"
|
||
itemprop="contentUrl"
|
||
aria-describedby="figure-caption-3"
|
||
role="button"
|
||
data-image-width="788"
|
||
data-image-height="1014"
|
||
data-image-alt="Figure 3"
|
||
data-pmc-id="PMC6100003"
|
||
data-figure-id="molecules-23-01700-f003">
|
||
<img class="figure-thumb" itemprop="thumbnail"
|
||
id="article-image-3"
|
||
src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6de5/6100003/74214e9c0286/molecules-23-01700-g003.gif"
|
||
alt="Figure 3" />
|
||
</a>
|
||
|
||
<meta itemprop="width" itemtype="http://schema.org/ImageObject" content="788">
|
||
<meta itemprop="height" itemtype="http://schema.org/ImageObject" content="1014">
|
||
|
||
|
||
<div class="figure-caption figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="caption" aria-hidden="true">
|
||
|
||
<div class="caption-wrap">
|
||
|
||
|
||
|
||
|
||
|
||
<strong class="figure-label">
|
||
<p> Figure 3 </p>
|
||
</strong>
|
||
|
||
|
||
|
||
<div class="figure-caption-contents"><p> Inter-individual variability of the complement… </p></div>
|
||
|
||
|
||
|
||
|
||
</div>
|
||
</div>
|
||
|
||
<div class="figure-caption-medium figure-caption-text" aria-hidden="true">
|
||
|
||
|
||
|
||
|
||
|
||
|
||
<strong class="figure-label">
|
||
<p> Figure 3 </p>
|
||
</strong>
|
||
|
||
|
||
|
||
<div class="figure-caption-contents"><p> Inter-individual variability of the complement activation by Doxil in human plasma. Human plasma… </p></div>
|
||
|
||
|
||
|
||
|
||
</div>
|
||
|
||
<figcaption id="figure-caption-3" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description">
|
||
|
||
|
||
|
||
|
||
|
||
|
||
<strong class="figure-label">
|
||
Figure 3
|
||
</strong>
|
||
|
||
|
||
|
||
<div class="figure-caption-contents">Inter-individual variability of the complement activation by Doxil in human plasma. Human plasma anticoagulated with hirudin was collected from 20 healthy donor volunteers and tested in vitro. (<b>A</b>) Plasma from individual donors was spiked with controls or Doxil and incubated for 30 min. The concentration of Doxil was 0.4 mg/mL of doxorubicin and was constant between all samples. Complement activation was assessed by ELISA measuring levels of human iC3b. Each bar shows mean response and standard deviation (<i>n</i> = 3); (<b>B</b>) Stimulation index was calculated for each donor as described in the materials and methods. Donors were grouped into three categories according to the individual magnitude of the complement activation: SI ≤ 2 was assigned as low response, SI 2–6 was assigned as medium response, and SI ≥ 6 was assigned as high response; (<b>C</b>) Regression analysis shows no linear correlation between complement activation by Doxil and CVF in individual plasma samples (<i>p</i> = 0.2112 and r = 0.08521; F = 1.677). SI—stimulation index; CVF—cobra venom factor; NC—negative control; PC—positive control (CVF); D—donor.</div>
|
||
|
||
|
||
|
||
|
||
</figcaption>
|
||
|
||
|
||
</figure>
|
||
|
||
<figure class="figure-item "
|
||
itemscope itemtype="http://schema.org/ImageObject"
|
||
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|
||
data-slide-index="4"
|
||
data-label-slug="figure-4">
|
||
<a class="figure-link"
|
||
href="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6de5/6100003/416444af4eb5/molecules-23-01700-g004a.jpg"
|
||
itemprop="contentUrl"
|
||
aria-describedby="figure-caption-4"
|
||
role="button"
|
||
data-image-width="754"
|
||
data-image-height="389"
|
||
data-image-alt="Figure 4"
|
||
data-pmc-id="PMC6100003"
|
||
data-figure-id="molecules-23-01700-f004">
|
||
<img class="figure-thumb" itemprop="thumbnail"
|
||
id="article-image-4"
|
||
src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6de5/6100003/7fee5fec06b0/molecules-23-01700-g004a.gif"
|
||
alt="Figure 4" />
|
||
</a>
|
||
|
||
<meta itemprop="width" itemtype="http://schema.org/ImageObject" content="754">
|
||
<meta itemprop="height" itemtype="http://schema.org/ImageObject" content="389">
|
||
|
||
|
||
<div class="figure-caption figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="caption" aria-hidden="true">
|
||
|
||
<div class="caption-wrap">
|
||
|
||
|
||
|
||
|
||
|
||
<strong class="figure-label">
|
||
<p> Figure 4 </p>
|
||
</strong>
|
||
|
||
|
||
|
||
<div class="figure-caption-contents"><p> Analysis of pre-existing anti-PEG antibodies… </p></div>
|
||
|
||
|
||
|
||
|
||
</div>
|
||
</div>
|
||
|
||
<div class="figure-caption-medium figure-caption-text" aria-hidden="true">
|
||
|
||
|
||
|
||
|
||
|
||
|
||
<strong class="figure-label">
|
||
<p> Figure 4 </p>
|
||
</strong>
|
||
|
||
|
||
|
||
<div class="figure-caption-contents"><p> Analysis of pre-existing anti-PEG antibodies in human plasma. Human plasma anticoagulated with hirudin… </p></div>
|
||
|
||
|
||
|
||
|
||
</div>
|
||
|
||
<figcaption id="figure-caption-4" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description">
|
||
|
||
|
||
|
||
|
||
|
||
|
||
<strong class="figure-label">
|
||
Figure 4
|
||
</strong>
|
||
|
||
|
||
|
||
<div class="figure-caption-contents">Analysis of pre-existing anti-PEG antibodies in human plasma. Human plasma anticoagulated with hirudin was collected from 20 healthy donor volunteers and tested in vitro. (<b>A</b>) A summary of antibody titers detected in individual donor plasma specimens. Positive controls are monoclonal antibodies as described in the materials and methods. There is no positive control in the PEG2000 IgG assay because currently available anti-PEG IgG are reactive to methoxy group. The titer in all shown PC samples was above 3200. Plasma from each donor was tested in duplicate on four ELISA plates. Each bar shown the titer determined from the mean response between duplicates; (<b>B</b>) Frequency of positive responders in the IgM assay; (<b>C</b>) Frequency of positive responders in the IgG assay. In both B and C, two analyses were performed. In one analysis, positive response was considered at the titer of 100 or higher. In the second analysis, the positive response was considered at the titer of 800 or higher; (<b>D</b>) Frequency of donors with antibodies reactive to both PEG and PEG-liposomes; (<b>E</b>) Frequency of donors with an antibody reactive to PEG-liposomes only. In both D and E, the positive response was considered at the titer of 800 or higher.</div>
|
||
|
||
|
||
|
||
|
||
</figcaption>
|
||
|
||
|
||
</figure>
|
||
|
||
<figure class="figure-item "
|
||
itemscope itemtype="http://schema.org/ImageObject"
|
||
itemprop="associatedMedia"
|
||
data-slide-index="5"
|
||
data-label-slug="figure-4">
|
||
<a class="figure-link"
|
||
href="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6de5/6100003/7a492f8bc8a5/molecules-23-01700-g004b.jpg"
|
||
itemprop="contentUrl"
|
||
aria-describedby="figure-caption-5"
|
||
role="button"
|
||
data-image-width="747"
|
||
data-image-height="551"
|
||
data-image-alt="Figure 4"
|
||
data-pmc-id="PMC6100003"
|
||
data-figure-id="molecules-23-01700-f004">
|
||
<img class="figure-thumb" itemprop="thumbnail"
|
||
id="article-image-5"
|
||
src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6de5/6100003/7fee5fec06b0/molecules-23-01700-g004a.gif"
|
||
alt="Figure 4" />
|
||
</a>
|
||
|
||
<meta itemprop="width" itemtype="http://schema.org/ImageObject" content="747">
|
||
<meta itemprop="height" itemtype="http://schema.org/ImageObject" content="551">
|
||
|
||
|
||
<div class="figure-caption figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="caption" aria-hidden="true">
|
||
|
||
<div class="caption-wrap">
|
||
|
||
|
||
|
||
|
||
|
||
<strong class="figure-label">
|
||
<p> Figure 4 </p>
|
||
</strong>
|
||
|
||
|
||
|
||
<div class="figure-caption-contents"><p> Analysis of pre-existing anti-PEG antibodies… </p></div>
|
||
|
||
|
||
|
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<strong class="figure-label">
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<p> Figure 4 </p>
|
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</strong>
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<div class="figure-caption-contents"><p> Analysis of pre-existing anti-PEG antibodies in human plasma. Human plasma anticoagulated with hirudin… </p></div>
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<strong class="figure-label">
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Figure 4
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</strong>
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<div class="figure-caption-contents">Analysis of pre-existing anti-PEG antibodies in human plasma. Human plasma anticoagulated with hirudin was collected from 20 healthy donor volunteers and tested in vitro. (<b>A</b>) A summary of antibody titers detected in individual donor plasma specimens. Positive controls are monoclonal antibodies as described in the materials and methods. There is no positive control in the PEG2000 IgG assay because currently available anti-PEG IgG are reactive to methoxy group. The titer in all shown PC samples was above 3200. Plasma from each donor was tested in duplicate on four ELISA plates. Each bar shown the titer determined from the mean response between duplicates; (<b>B</b>) Frequency of positive responders in the IgM assay; (<b>C</b>) Frequency of positive responders in the IgG assay. In both B and C, two analyses were performed. In one analysis, positive response was considered at the titer of 100 or higher. In the second analysis, the positive response was considered at the titer of 800 or higher; (<b>D</b>) Frequency of donors with antibodies reactive to both PEG and PEG-liposomes; (<b>E</b>) Frequency of donors with an antibody reactive to PEG-liposomes only. In both D and E, the positive response was considered at the titer of 800 or higher.</div>
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data-figure-id="molecules-23-01700-f005">
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<img class="figure-thumb" itemprop="thumbnail"
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id="article-image-6"
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src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6de5/6100003/87de6c5d6738/molecules-23-01700-g005.gif"
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|
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<strong class="figure-label">
|
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<p> Figure 5 </p>
|
||
</strong>
|
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|
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|
||
<div class="figure-caption-contents"><p> Complement activation by Doxil does… </p></div>
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<strong class="figure-label">
|
||
<p> Figure 5 </p>
|
||
</strong>
|
||
|
||
|
||
|
||
<div class="figure-caption-contents"><p> Complement activation by Doxil does not correlate with the titer of antibodies reactive… </p></div>
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||
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|
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</div>
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<figcaption id="figure-caption-6" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description">
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<strong class="figure-label">
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Figure 5
|
||
</strong>
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||
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||
|
||
<div class="figure-caption-contents">Complement activation by Doxil does not correlate with the titer of antibodies reactive to PEG in individual human donors. (<b>A</b>) The complement activation and antibody titer data are presented in a heat map format. The complement stimulation index by Doxil (C-SI) is aligned with the antibody titer (Ab-titer). Darker red and blue show higher levels of the complement activation and antibody titer, respectively. The antibody titer is plotted for IgM and IgG and indicates the antigen used to capture the reactive antibodies (Doxebo, PEG, or mPEG). The molecular weight of PEG is 2000 and is equal in all samples. mPEG contains a methoxy terminal group that is also present in the PEG2000 used to produce Doxil and Doxebo. D—donor; (<b>B</b>–<b>G</b>) Regression analysis was performed to understand the correlation between the antibody titer and the complement activation by Doxil. Doxil stimulation index (SI) was compared with the titer of IgG reactive to Doxebo (<b>B</b>), PEG2000 (<b>C</b>), or mPEG2000 (<b>D</b>), as well as the titer of IgM reactive to Doxebo (<b>E</b>), PEG2000 (<b>F</b>), or mPEG2000 (<b>G</b>). <i>p</i>-value was used to assess the significance of the confidence interval of 95%. No analyses revealed a significant correlation. The residual analysis conducted in parallel with this test did not change the conclusions of the analysis (data not shown).</div>
|
||
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||
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data-image-width="739"
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data-image-alt="Figure 6"
|
||
data-pmc-id="PMC6100003"
|
||
data-figure-id="molecules-23-01700-f006">
|
||
<img class="figure-thumb" itemprop="thumbnail"
|
||
id="article-image-7"
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||
src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6de5/6100003/ef51b5343d0f/molecules-23-01700-g006a.gif"
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||
alt="Figure 6" />
|
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<strong class="figure-label">
|
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<p> Figure 6 </p>
|
||
</strong>
|
||
|
||
|
||
|
||
<div class="figure-caption-contents"><p> Plasma levels of complement inhibitory… </p></div>
|
||
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||
|
||
|
||
|
||
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|
||
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|
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|
||
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||
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||
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||
<strong class="figure-label">
|
||
<p> Figure 6 </p>
|
||
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|
||
|
||
|
||
|
||
<div class="figure-caption-contents"><p> Plasma levels of complement inhibitory factors and their role in the complement activation.… </p></div>
|
||
|
||
|
||
|
||
|
||
</div>
|
||
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<figcaption id="figure-caption-7" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description">
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<strong class="figure-label">
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||
Figure 6
|
||
</strong>
|
||
|
||
|
||
|
||
<div class="figure-caption-contents">Plasma levels of complement inhibitory factors and their role in the complement activation. Plasma collected from 20 healthy donor volunteers and used in the complement activation and antibody titer study was also analyzed for the levels of CFH (<b>A</b>) and CFI (<b>B</b>). Regression analysis was performed to understand the correlation between the concentration of CFH and the complement activation by CVF (<b>C</b>) or Doxil (<b>D</b>). Regression analysis was also performed to understand the correlation between the concentration of CFI and complement activation by CVF (<b>E</b>) or Doxil (<b>F</b>). The <i>p</i>-value indicates a significant positive correlation between CFI concentration and the complement activation by CVF. No correlation was observed between CFH concentrations and complement activation by both Doxil and CVF, nor was it observed between CFI concentrations and the complement activation by Doxil.</div>
|
||
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data-image-width="779"
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data-image-alt="Figure 6"
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data-figure-id="molecules-23-01700-f006">
|
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<img class="figure-thumb" itemprop="thumbnail"
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id="article-image-8"
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src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6de5/6100003/ef51b5343d0f/molecules-23-01700-g006a.gif"
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alt="Figure 6" />
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<meta itemprop="width" itemtype="http://schema.org/ImageObject" content="779">
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||
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<strong class="figure-label">
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<p> Figure 6 </p>
|
||
</strong>
|
||
|
||
|
||
|
||
<div class="figure-caption-contents"><p> Plasma levels of complement inhibitory… </p></div>
|
||
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|
||
|
||
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|
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|
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|
||
|
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|
||
|
||
|
||
|
||
|
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<strong class="figure-label">
|
||
<p> Figure 6 </p>
|
||
</strong>
|
||
|
||
|
||
|
||
<div class="figure-caption-contents"><p> Plasma levels of complement inhibitory factors and their role in the complement activation.… </p></div>
|
||
|
||
|
||
|
||
|
||
</div>
|
||
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<figcaption id="figure-caption-8" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description">
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<strong class="figure-label">
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Figure 6
|
||
</strong>
|
||
|
||
|
||
|
||
<div class="figure-caption-contents">Plasma levels of complement inhibitory factors and their role in the complement activation. Plasma collected from 20 healthy donor volunteers and used in the complement activation and antibody titer study was also analyzed for the levels of CFH (<b>A</b>) and CFI (<b>B</b>). Regression analysis was performed to understand the correlation between the concentration of CFH and the complement activation by CVF (<b>C</b>) or Doxil (<b>D</b>). Regression analysis was also performed to understand the correlation between the concentration of CFI and complement activation by CVF (<b>E</b>) or Doxil (<b>F</b>). The <i>p</i>-value indicates a significant positive correlation between CFI concentration and the complement activation by CVF. No correlation was observed between CFH concentrations and complement activation by both Doxil and CVF, nor was it observed between CFI concentrations and the complement activation by Doxil.</div>
|
||
|
||
|
||
|
||
|
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Johansson S.G.O., Bieber T., Dahl R., Friedmann P.S., Lanier B.Q., Lockey R.F., Motala C., Martell J.A.O., Platts-Mills T.A., Ring J., et al. Revised nomenclature for allergy for global use: Report of the Nomenclature Review Committee of the World Allergy Organization, October 2003. J. Allergy Clin. Immunol. 2004;113:832–836. doi: 10.1016/j.jaci.2003.12.591.
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Johansson S.G.O., Hourihane J.B., Bousquet J., Bruijnzeel-Koomen C., Dreborg S., Haahtela T., Kowalski M.L., Mygind N., Ring J., van Cauwenberge P., et al. A revised nomenclature for allergy: An EAACI position statement from the EAACI nomenclature task force. Allergy. 2001;56:813–824. doi: 10.1034/j.1398-9995.2001.t01-1-00001.x.
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Jutel M., Agache I., Bonini S., Burks A.W., Calderon M., Canonica W., Cox L., Demoly P., Frew A.J., O’Hehir R., et al. International consensus on allergy immunotherapy. J. Allergy Clin. Immunol. 2015;136:556–568. doi: 10.1016/j.jaci.2015.04.047.
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|
||
ref="linksrc=add_to_search_link"
|
||
role="button"
|
||
data-search-term=""Complement Inactivating Agents/immunology"[MAJR]"
|
||
data-ga-category="search"
|
||
data-ga-action="add_to_search"
|
||
data-ga-label=""Complement Inactivating Agents/immunology"[MAJR]"
|
||
href="#">
|
||
Add to Search
|
||
</a></li></ul></div></div></div></li><li><div class="keyword-actions dropdown-block"><button class="keyword-actions-trigger trigger keyword-link major"
|
||
aria-label="Toggle dropdown menu for keyword Doxorubicin / analogs & derivatives*"
|
||
tabindex="0"
|
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aria-controls="keyword-actions-mesh-terms-major-9"
|
||
aria-expanded="false"
|
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data-pinger-ignore>
|
||
Doxorubicin / analogs & derivatives*
|
||
</button><div id="keyword-actions-mesh-terms-major-9"
|
||
class="keyword-actions-dropdown dropdown dropdown-container"
|
||
hidden
|
||
aria-label="Dropdown menu for keyword Doxorubicin / analogs & derivatives*"><div class="title">Actions</div><div class="content"><ul class="keyword-actions-links"><li><a class="search-in-pubmed-link dropdown-block-link"
|
||
href="/?term=%22Doxorubicin%2Fanalogs+and+derivatives%22%5BMAJR%5D&sort=date&sort_order=desc"
|
||
data-href="/?term=%22Doxorubicin%2Fanalogs+and+derivatives%22%5BMAJR%5D&sort=date&sort_order=desc"
|
||
ref="linksrc=search_in_pubmed_keyword_link&mesh="Doxorubicin/analogs and derivatives"[MAJR]"
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data-ga-category="search"
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data-ga-action="mesh_term"
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data-ga-label="Doxorubicin / analogs & derivatives*">
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Search in PubMed
|
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</a></li><li><a class="search-in-mesh-link dropdown-block-link"
|
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ref="linksrc=search_in_mesh_link"
|
||
href="https://www.ncbi.nlm.nih.gov/mesh?term=Doxorubicin"
|
||
data-ga-category="search_mesh"
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data-ga-action="mesh_term_link"
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data-ga-label="Doxorubicin / analogs & derivatives*">
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Search in MeSH
|
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</a></li><li><a class="add-to-search-link dropdown-block-link"
|
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role="button"
|
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data-search-term=""Doxorubicin/analogs and derivatives"[MAJR]"
|
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data-ga-category="search"
|
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data-ga-action="add_to_search"
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data-ga-label=""Doxorubicin/analogs and derivatives"[MAJR]"
|
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href="#">
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Add to Search
|
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</a></li></ul></div></div></div></li><li><div class="keyword-actions dropdown-block"><button class="keyword-actions-trigger trigger keyword-link"
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aria-label="Toggle dropdown menu for keyword Doxorubicin / pharmacology"
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tabindex="0"
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aria-controls="keyword-actions-mesh-terms-10"
|
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aria-expanded="false"
|
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data-pinger-ignore>
|
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Doxorubicin / pharmacology
|
||
</button><div id="keyword-actions-mesh-terms-10"
|
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class="keyword-actions-dropdown dropdown dropdown-container"
|
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hidden
|
||
aria-label="Dropdown menu for keyword Doxorubicin / pharmacology"><div class="title">Actions</div><div class="content"><ul class="keyword-actions-links"><li><a class="search-in-pubmed-link dropdown-block-link"
|
||
href="/?term=%22Doxorubicin%2Fpharmacology%22%5BMeSH%5D&sort=date&sort_order=desc"
|
||
data-href="/?term=%22Doxorubicin%2Fpharmacology%22%5BMeSH%5D&sort=date&sort_order=desc"
|
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ref="linksrc=search_in_pubmed_keyword_link&mesh="Doxorubicin/pharmacology"[MeSH]"
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data-ga-category="search"
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data-ga-action="mesh_term"
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data-ga-label="Doxorubicin / pharmacology">
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Search in PubMed
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</a></li><li><a class="search-in-mesh-link dropdown-block-link"
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ref="linksrc=search_in_mesh_link"
|
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href="https://www.ncbi.nlm.nih.gov/mesh?term=Doxorubicin"
|
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data-ga-category="search_mesh"
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data-ga-action="mesh_term_link"
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data-ga-label="Doxorubicin / pharmacology">
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Search in MeSH
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</a></li><li><a class="add-to-search-link dropdown-block-link"
|
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ref="linksrc=add_to_search_link"
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role="button"
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data-search-term=""Doxorubicin/pharmacology"[MeSH]"
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data-ga-category="search"
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data-ga-action="add_to_search"
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data-ga-label=""Doxorubicin/pharmacology"[MeSH]"
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href="#">
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Add to Search
|
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</a></li></ul></div></div></div></li><li><div class="keyword-actions dropdown-block"><button class="keyword-actions-trigger trigger keyword-link"
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aria-label="Toggle dropdown menu for keyword Drug Hypersensitivity / immunology"
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tabindex="0"
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aria-controls="keyword-actions-mesh-terms-11"
|
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aria-expanded="false"
|
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data-pinger-ignore>
|
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Drug Hypersensitivity / immunology
|
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</button><div id="keyword-actions-mesh-terms-11"
|
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class="keyword-actions-dropdown dropdown dropdown-container"
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hidden
|
||
aria-label="Dropdown menu for keyword Drug Hypersensitivity / immunology"><div class="title">Actions</div><div class="content"><ul class="keyword-actions-links"><li><a class="search-in-pubmed-link dropdown-block-link"
|
||
href="/?term=%22Drug+Hypersensitivity%2Fimmunology%22%5BMeSH%5D&sort=date&sort_order=desc"
|
||
data-href="/?term=%22Drug+Hypersensitivity%2Fimmunology%22%5BMeSH%5D&sort=date&sort_order=desc"
|
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ref="linksrc=search_in_pubmed_keyword_link&mesh="Drug Hypersensitivity/immunology"[MeSH]"
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data-ga-category="search"
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data-ga-action="mesh_term"
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data-ga-label="Drug Hypersensitivity / immunology">
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Search in PubMed
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</a></li><li><a class="search-in-mesh-link dropdown-block-link"
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ref="linksrc=search_in_mesh_link"
|
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href="https://www.ncbi.nlm.nih.gov/mesh?term=Drug+Hypersensitivity"
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data-ga-category="search_mesh"
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data-ga-label="Drug Hypersensitivity / immunology">
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Search in MeSH
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</a></li><li><a class="add-to-search-link dropdown-block-link"
|
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role="button"
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data-search-term=""Drug Hypersensitivity/immunology"[MeSH]"
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data-ga-category="search"
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data-ga-action="add_to_search"
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data-ga-label=""Drug Hypersensitivity/immunology"[MeSH]"
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href="#">
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Add to Search
|
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</a></li></ul></div></div></div></li><li><div class="keyword-actions dropdown-block"><button class="keyword-actions-trigger trigger keyword-link"
|
||
aria-label="Toggle dropdown menu for keyword Humans"
|
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tabindex="0"
|
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aria-controls="keyword-actions-mesh-terms-12"
|
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aria-expanded="false"
|
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data-pinger-ignore>
|
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Humans
|
||
</button><div id="keyword-actions-mesh-terms-12"
|
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class="keyword-actions-dropdown dropdown dropdown-container"
|
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hidden
|
||
aria-label="Dropdown menu for keyword Humans"><div class="title">Actions</div><div class="content"><ul class="keyword-actions-links"><li><a class="search-in-pubmed-link dropdown-block-link"
|
||
href="/?term=%22Humans%22%5BMeSH%5D&sort=date&sort_order=desc"
|
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data-href="/?term=%22Humans%22%5BMeSH%5D&sort=date&sort_order=desc"
|
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ref="linksrc=search_in_pubmed_keyword_link&mesh="Humans"[MeSH]"
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data-ga-category="search"
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data-ga-action="mesh_term"
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data-ga-label="Humans">
|
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Search in PubMed
|
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</a></li><li><a class="search-in-mesh-link dropdown-block-link"
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ref="linksrc=search_in_mesh_link"
|
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href="https://www.ncbi.nlm.nih.gov/mesh?term=Humans"
|
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data-ga-category="search_mesh"
|
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data-ga-action="mesh_term_link"
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data-ga-label="Humans">
|
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Search in MeSH
|
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</a></li><li><a class="add-to-search-link dropdown-block-link"
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data-search-term=""Humans"[MeSH]"
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data-ga-category="search"
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data-ga-action="add_to_search"
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data-ga-label=""Humans"[MeSH]"
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Add to Search
|
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</a></li></ul></div></div></div></li><li><div class="keyword-actions dropdown-block"><button class="keyword-actions-trigger trigger keyword-link"
|
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aria-label="Toggle dropdown menu for keyword Mice"
|
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tabindex="0"
|
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aria-controls="keyword-actions-mesh-terms-13"
|
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aria-expanded="false"
|
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data-pinger-ignore>
|
||
Mice
|
||
</button><div id="keyword-actions-mesh-terms-13"
|
||
class="keyword-actions-dropdown dropdown dropdown-container"
|
||
hidden
|
||
aria-label="Dropdown menu for keyword Mice"><div class="title">Actions</div><div class="content"><ul class="keyword-actions-links"><li><a class="search-in-pubmed-link dropdown-block-link"
|
||
href="/?term=%22Mice%22%5BMeSH%5D&sort=date&sort_order=desc"
|
||
data-href="/?term=%22Mice%22%5BMeSH%5D&sort=date&sort_order=desc"
|
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ref="linksrc=search_in_pubmed_keyword_link&mesh="Mice"[MeSH]"
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data-ga-category="search"
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data-ga-action="mesh_term"
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data-ga-label="Mice">
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Search in PubMed
|
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</a></li><li><a class="search-in-mesh-link dropdown-block-link"
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ref="linksrc=search_in_mesh_link"
|
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href="https://www.ncbi.nlm.nih.gov/mesh?term=Mice"
|
||
data-ga-category="search_mesh"
|
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data-ga-action="mesh_term_link"
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data-ga-label="Mice">
|
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Search in MeSH
|
||
</a></li><li><a class="add-to-search-link dropdown-block-link"
|
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ref="linksrc=add_to_search_link"
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role="button"
|
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data-search-term=""Mice"[MeSH]"
|
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data-ga-category="search"
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data-ga-action="add_to_search"
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data-ga-label=""Mice"[MeSH]"
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href="#">
|
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Add to Search
|
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</a></li></ul></div></div></div></li><li><div class="keyword-actions dropdown-block"><button class="keyword-actions-trigger trigger keyword-link major"
|
||
aria-label="Toggle dropdown menu for keyword Polyethylene Glycols* / pharmacology"
|
||
tabindex="0"
|
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aria-controls="keyword-actions-mesh-terms-major-14"
|
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aria-expanded="false"
|
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data-pinger-ignore>
|
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Polyethylene Glycols* / pharmacology
|
||
</button><div id="keyword-actions-mesh-terms-major-14"
|
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class="keyword-actions-dropdown dropdown dropdown-container"
|
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hidden
|
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aria-label="Dropdown menu for keyword Polyethylene Glycols* / pharmacology"><div class="title">Actions</div><div class="content"><ul class="keyword-actions-links"><li><a class="search-in-pubmed-link dropdown-block-link"
|
||
href="/?term=%22Polyethylene+Glycols%2Fpharmacology%22%5BMAJR%5D&sort=date&sort_order=desc"
|
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data-href="/?term=%22Polyethylene+Glycols%2Fpharmacology%22%5BMAJR%5D&sort=date&sort_order=desc"
|
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ref="linksrc=search_in_pubmed_keyword_link&mesh="Polyethylene Glycols/pharmacology"[MAJR]"
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data-ga-category="search"
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data-ga-action="mesh_term"
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data-ga-label="Polyethylene Glycols* / pharmacology">
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Search in PubMed
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</a></li><li><a class="search-in-mesh-link dropdown-block-link"
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ref="linksrc=search_in_mesh_link"
|
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href="https://www.ncbi.nlm.nih.gov/mesh?term=Polyethylene+Glycols"
|
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data-ga-category="search_mesh"
|
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data-ga-action="mesh_term_link"
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data-ga-label="Polyethylene Glycols* / pharmacology">
|
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Search in MeSH
|
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</a></li><li><a class="add-to-search-link dropdown-block-link"
|
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ref="linksrc=add_to_search_link"
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role="button"
|
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data-search-term=""Polyethylene Glycols/pharmacology"[MAJR]"
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data-ga-category="search"
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data-ga-action="add_to_search"
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data-ga-label=""Polyethylene Glycols/pharmacology"[MAJR]"
|
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href="#">
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Add to Search
|
||
</a></li></ul></div></div></div></li></ul>
|
||
</div>
|
||
|
||
|
||
|
||
|
||
|
||
<div id="substances" class="substances keywords-section">
|
||
<h2 class="title">
|
||
Substances
|
||
</h2>
|
||
|
||
<ul class="keywords-list"><li><div class="keyword-actions dropdown-block"><button class="keyword-actions-trigger trigger keyword-link"
|
||
aria-label="Toggle dropdown menu for keyword Antibodies, Monoclonal"
|
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tabindex="0"
|
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aria-controls="keyword-actions-substances-0"
|
||
aria-expanded="false"
|
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data-pinger-ignore>
|
||
Antibodies, Monoclonal
|
||
</button><div id="keyword-actions-substances-0"
|
||
class="keyword-actions-dropdown dropdown dropdown-container"
|
||
hidden
|
||
aria-label="Dropdown menu for keyword Antibodies, Monoclonal"><div class="title">Actions</div><div class="content"><ul class="keyword-actions-links"><li><a class="search-in-pubmed-link dropdown-block-link"
|
||
href="/?term=%22Antibodies%2C+Monoclonal%22%5Bnm%5D&sort=date&sort_order=desc"
|
||
data-href="/?term=%22Antibodies%2C+Monoclonal%22%5Bnm%5D&sort=date&sort_order=desc"
|
||
ref="linksrc=search_in_pubmed_keyword_link&keyword="Antibodies, Monoclonal"[nm]"
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data-ga-category="search"
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data-ga-action="substance"
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data-ga-label="Antibodies, Monoclonal">
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Search in PubMed
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</a></li><li><a class="search-in-mesh-link dropdown-block-link"
|
||
ref="linksrc=search_in_mesh_link"
|
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href="https://www.ncbi.nlm.nih.gov/mesh?term=%22Antibodies%2C+Monoclonal%22"
|
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data-ga-category="search_mesh"
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data-ga-action="substance_link"
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data-ga-label="Antibodies, Monoclonal">
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Search in MeSH
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||
</a></li><li><a class="add-to-search-link dropdown-block-link"
|
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ref="linksrc=add_to_search_link"
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role="button"
|
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data-search-term=""Antibodies, Monoclonal"[nm]"
|
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data-ga-category="search"
|
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data-ga-action="add_to_search"
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data-ga-label=""Antibodies, Monoclonal"[nm]"
|
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href="#">
|
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Add to Search
|
||
</a></li></ul></div></div></div></li><li><div class="keyword-actions dropdown-block"><button class="keyword-actions-trigger trigger keyword-link"
|
||
aria-label="Toggle dropdown menu for keyword Complement Inactivating Agents"
|
||
tabindex="0"
|
||
aria-controls="keyword-actions-substances-1"
|
||
aria-expanded="false"
|
||
data-pinger-ignore>
|
||
Complement Inactivating Agents
|
||
</button><div id="keyword-actions-substances-1"
|
||
class="keyword-actions-dropdown dropdown dropdown-container"
|
||
hidden
|
||
aria-label="Dropdown menu for keyword Complement Inactivating Agents"><div class="title">Actions</div><div class="content"><ul class="keyword-actions-links"><li><a class="search-in-pubmed-link dropdown-block-link"
|
||
href="/?term=%22Complement+Inactivating+Agents%22%5Bnm%5D&sort=date&sort_order=desc"
|
||
data-href="/?term=%22Complement+Inactivating+Agents%22%5Bnm%5D&sort=date&sort_order=desc"
|
||
ref="linksrc=search_in_pubmed_keyword_link&keyword="Complement Inactivating Agents"[nm]"
|
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data-ga-category="search"
|
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data-ga-action="substance"
|
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data-ga-label="Complement Inactivating Agents">
|
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Search in PubMed
|
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</a></li><li><a class="search-in-mesh-link dropdown-block-link"
|
||
ref="linksrc=search_in_mesh_link"
|
||
href="https://www.ncbi.nlm.nih.gov/mesh?term=%22Complement+Inactivating+Agents%22"
|
||
data-ga-category="search_mesh"
|
||
data-ga-action="substance_link"
|
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data-ga-label="Complement Inactivating Agents">
|
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Search in MeSH
|
||
</a></li><li><a class="add-to-search-link dropdown-block-link"
|
||
ref="linksrc=add_to_search_link"
|
||
role="button"
|
||
data-search-term=""Complement Inactivating Agents"[nm]"
|
||
data-ga-category="search"
|
||
data-ga-action="add_to_search"
|
||
data-ga-label=""Complement Inactivating Agents"[nm]"
|
||
href="#">
|
||
Add to Search
|
||
</a></li></ul></div></div></div></li><li><div class="keyword-actions dropdown-block"><button class="keyword-actions-trigger trigger keyword-link"
|
||
aria-label="Toggle dropdown menu for keyword liposomal doxorubicin"
|
||
tabindex="0"
|
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aria-controls="keyword-actions-substances-2"
|
||
aria-expanded="false"
|
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data-pinger-ignore>
|
||
liposomal doxorubicin
|
||
</button><div id="keyword-actions-substances-2"
|
||
class="keyword-actions-dropdown dropdown dropdown-container"
|
||
hidden
|
||
aria-label="Dropdown menu for keyword liposomal doxorubicin"><div class="title">Actions</div><div class="content"><ul class="keyword-actions-links"><li><a class="search-in-pubmed-link dropdown-block-link"
|
||
href="/?term=%22liposomal+doxorubicin%22%5Bnm%5D&sort=date&sort_order=desc"
|
||
data-href="/?term=%22liposomal+doxorubicin%22%5Bnm%5D&sort=date&sort_order=desc"
|
||
ref="linksrc=search_in_pubmed_keyword_link&keyword="liposomal doxorubicin"[nm]"
|
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data-ga-category="search"
|
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data-ga-action="substance"
|
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data-ga-label="liposomal doxorubicin">
|
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Search in PubMed
|
||
</a></li><li><a class="search-in-mesh-link dropdown-block-link"
|
||
ref="linksrc=search_in_mesh_link"
|
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href="https://www.ncbi.nlm.nih.gov/mesh?term=%22liposomal+doxorubicin%22"
|
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data-ga-category="search_mesh"
|
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data-ga-action="substance_link"
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data-ga-label="liposomal doxorubicin">
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Search in MeSH
|
||
</a></li><li><a class="add-to-search-link dropdown-block-link"
|
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ref="linksrc=add_to_search_link"
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role="button"
|
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data-search-term=""liposomal doxorubicin"[nm]"
|
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data-ga-category="search"
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data-ga-action="add_to_search"
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data-ga-label=""liposomal doxorubicin"[nm]"
|
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href="#">
|
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Add to Search
|
||
</a></li></ul></div></div></div></li><li><div class="keyword-actions dropdown-block"><button class="keyword-actions-trigger trigger keyword-link"
|
||
aria-label="Toggle dropdown menu for keyword Polyethylene Glycols"
|
||
tabindex="0"
|
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aria-controls="keyword-actions-substances-3"
|
||
aria-expanded="false"
|
||
data-pinger-ignore>
|
||
Polyethylene Glycols
|
||
</button><div id="keyword-actions-substances-3"
|
||
class="keyword-actions-dropdown dropdown dropdown-container"
|
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hidden
|
||
aria-label="Dropdown menu for keyword Polyethylene Glycols"><div class="title">Actions</div><div class="content"><ul class="keyword-actions-links"><li><a class="search-in-pubmed-link dropdown-block-link"
|
||
href="/?term=%22Polyethylene+Glycols%22%5Bnm%5D&sort=date&sort_order=desc"
|
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data-href="/?term=%22Polyethylene+Glycols%22%5Bnm%5D&sort=date&sort_order=desc"
|
||
ref="linksrc=search_in_pubmed_keyword_link&keyword="Polyethylene Glycols"[nm]"
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data-ga-category="search"
|
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data-ga-action="substance"
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data-ga-label="Polyethylene Glycols">
|
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Search in PubMed
|
||
</a></li><li><a class="search-in-mesh-link dropdown-block-link"
|
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ref="linksrc=search_in_mesh_link"
|
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href="https://www.ncbi.nlm.nih.gov/mesh?term=%22Polyethylene+Glycols%22"
|
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data-ga-category="search_mesh"
|
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data-ga-action="substance_link"
|
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data-ga-label="Polyethylene Glycols">
|
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Search in MeSH
|
||
</a></li><li><a class="add-to-search-link dropdown-block-link"
|
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ref="linksrc=add_to_search_link"
|
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role="button"
|
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data-search-term=""Polyethylene Glycols"[nm]"
|
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data-ga-category="search"
|
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data-ga-action="add_to_search"
|
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data-ga-label=""Polyethylene Glycols"[nm]"
|
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href="#">
|
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Add to Search
|
||
</a></li></ul></div></div></div></li><li><div class="keyword-actions dropdown-block"><button class="keyword-actions-trigger trigger keyword-link"
|
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aria-label="Toggle dropdown menu for keyword Doxorubicin"
|
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tabindex="0"
|
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aria-controls="keyword-actions-substances-4"
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