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<title>Combinatorial antileukemic disruption of oxidative homeostasis and mitochondrial stability by the redox reactive thalidomide 2-(2,4-difluoro-phenyl)-4,5,6,7-tetrafluoro-1H-isoindole-1,3(2H)-dione (CPS49) and flavopiridol - PubMed</title>
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id="id_term"/><a href="#" class="clear-btn" aria-label="Clear search input" title="Clear search input" role="button" data-pinger-ignore></a><button type="submit" class="search-btn" aria-label="Search" disabled data-pinger-ignore><span class="usa-search-submit-text">Search</span></button>
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||
|
||
|
||
|
||
|
||
|
||
</div>
|
||
|
||
</div>
|
||
|
||
<!-- Create alert and Create RSS are buttons that look like links -->
|
||
<!-- Better for them to look like buttons but no space -->
|
||
<div class="search-links-wrapper content-page-layout">
|
||
<div class="search-links">
|
||
<a href="/advanced/"
|
||
class="search-input-link adv-search-link"
|
||
data-ga-category="featured_link"
|
||
data-ga-action="adv_search">Advanced</a>
|
||
|
||
|
||
<a href="/clipboard/"
|
||
class="search-input-link clipboard-link hidden"
|
||
data-ga-category="featured_link"
|
||
data-ga-action="clipboard">
|
||
Clipboard <span class="amount-in-clipboard"></span>
|
||
</a>
|
||
</div>
|
||
|
||
<span class="search-input-link user-guide-link" role="navigation" aria-label="User guide">
|
||
<a href="/help/"
|
||
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%2F18556456%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%2F18556456%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="DiW5K9Wj84PZOtT8ImxX1GfEatzZgGfFU5GanZpFIFCtIUZYlFaZvOLiIxhb9hNZ">
|
||
</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="DiW5K9Wj84PZOtT8ImxX1GfEatzZgGfFU5GanZpFIFCtIUZYlFaZvOLiIxhb9hNZ">
|
||
|
||
|
||
|
||
<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="DiW5K9Wj84PZOtT8ImxX1GfEatzZgGfFU5GanZpFIFCtIUZYlFaZvOLiIxhb9hNZ">
|
||
|
||
<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: 18556456 - PubMed</span>
|
||
<input type="hidden" name="email-subject" value="1 selected item: 18556456"/>
|
||
<input type="hidden" name="email-subject-hash" value="3969c153d7883830aca380b79f1bfef393450291526e550ca67704e97e4f2f3d"/>
|
||
</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="DiW5K9Wj84PZOtT8ImxX1GfEatzZgGfFU5GanZpFIFCtIUZYlFaZvOLiIxhb9hNZ">
|
||
|
||
|
||
|
||
<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="DiW5K9Wj84PZOtT8ImxX1GfEatzZgGfFU5GanZpFIFCtIUZYlFaZvOLiIxhb9hNZ">
|
||
|
||
|
||
|
||
<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="DiW5K9Wj84PZOtT8ImxX1GfEatzZgGfFU5GanZpFIFCtIUZYlFaZvOLiIxhb9hNZ">
|
||
|
||
<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="DiW5K9Wj84PZOtT8ImxX1GfEatzZgGfFU5GanZpFIFCtIUZYlFaZvOLiIxhb9hNZ">
|
||
|
||
|
||
|
||
<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="DiW5K9Wj84PZOtT8ImxX1GfEatzZgGfFU5GanZpFIFCtIUZYlFaZvOLiIxhb9hNZ">
|
||
|
||
<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="18556456">
|
||
<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://linkinghub.elsevier.com/retrieve/pii/S0026-895X(24)14544-0"
|
||
target="_blank"
|
||
rel="noopener"
|
||
|
||
ref="linksrc=fulltextorjournal_fulltext&is_pmc=False&PrId=3048&itool=Abstract-def&log$=linkouticon&uid=18556456&db=pubmed&nlmid=0035623"
|
||
title="See full text options at Elsevier Science"
|
||
|
||
data-ga-category="full_text"
|
||
data-ga-action="Elsevier Science"
|
||
data-ga-label="18556456"
|
||
><img src="https://cdn.ncbi.nlm.nih.gov/corehtml/query/egifs/https:--linkinghub.elsevier.com-ihub-images-PubMedLink.gif" alt="Elsevier Science full text link"><span class="text">
|
||
|
||
Elsevier Science
|
||
|
||
</span></a><a class="link-item
|
||
pmc
|
||
"
|
||
href="https://pmc.ncbi.nlm.nih.gov/articles/pmid/18556456/"
|
||
target="_blank"
|
||
rel="noopener"
|
||
|
||
ref="linksrc=fulltextorjournal_fulltext&is_pmc=True&PrId=3494&itool=Abstract-def&log$=linkouticon&uid=18556456&db=pubmed&nlmid=0035623"
|
||
title="Free full text at PubMed Central"
|
||
|
||
data-ga-category="full_text"
|
||
data-ga-action="PMC"
|
||
data-ga-label="18556456"
|
||
><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="/18556456/citations/"
|
||
data-citation-style="nlm"
|
||
data-pubmed-format-link="/18556456/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="18556456" 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%2F18556456%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="DiW5K9Wj84PZOtT8ImxX1GfEatzZgGfFU5GanZpFIFCtIUZYlFaZvOLiIxhb9hNZ"><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..."
|
||
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Combinatorial antileukemic disruption of oxidative homeostasis and mitochondrial stability by the redox reactive thalidomide 2-(2,4-difluoro-phenyl)-4,5,6,7-tetrafluoro-1H-isoindole-1,3(2H)-dione (CPS49) and flavopiridol
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Combinatorial antileukemic disruption of oxidative homeostasis and mitochondrial stability by the redox reactive thalidomide 2-(2,4-difluoro-phenyl)-4,5,6,7-tetrafluoro-1H-isoindole-1,3(2H)-dione (CPS49) and flavopiridol
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2-(2,4-Difluoro-phenyl)-4,5,6,7-tetrafluoro-1H-isoindole-1,3(2H)-dione (CPS49) is a member of a recently identified class of redox-reactive thalidomide analogs that show selective killing of leukemic cells by increasing intracellular reactive oxygen species (ROS) and targeting multiple transcriptional pathways. Flavopiridol is a semisynthetic flavonoid that inhibits cyclin-dependent kinases and also shows selective lethality against leukemic cells. The purpose of this study is to explore the efficacy and mechanism of action of the combinatorial use of the redox-reactive thalidomide CPS49 and the cyclin-dependent kinase inhibitor flavopiridol as a selective antileukemic therapeutic strategy. In combination, CPS49 and flavopiridol were found to induce selective cytotoxicity associated with mitochondrial dysfunction and elevations of ROS in leukemic cells ranging from additive to synergistic activity at low micromolar concentrations. Highest synergy was observed at the level of ROS generation with a strong correlation between cell-specific cytotoxicity and reciprocal coupling of drug-induced ROS elevation with glutathione depletion. Examination of the transcriptional targeting of CPS49 and flavopiridol combinations reveals that the drugs act in concert to initiate a cell specific transcriptional program that manipulates nuclear factor-kappaB (NF-kappaB), E2F-1, and p73 activity to promote enhanced mitochondrial instability by simultaneously elevating the expression of the proapoptotic factors BAX, BAD, p73, and PUMA while depressing expression of the antiapoptotic genes MCL1, XIAP, BCL-xL, SURVIVIN, and MDM2. The coadministration of CPS49 and flavopiridol acts through coordinate targeting of transcriptional pathways that enforce selective mitochondrial dysfunction and ROS elevation and is therefore a promising new therapeutic combination that warrants further preclinical exploration.
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<a href="/disclaimer/" target="_blank" data-ga-category="literature_resources"
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data-ga-action="disclaimer_link" data-ga-label="under_abstract">PubMed Disclaimer</a>
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Figures
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src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/da55/2778846/3b346fba22c1/nihms-53716-f0001.gif"
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<p> Fig. 1 </p>
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</strong>
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<div class="figure-caption-contents"><p> Combinatorial treatment with CPS49 and… </p></div>
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<strong class="figure-label">
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<p> Fig. 1 </p>
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</strong>
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<div class="figure-caption-contents"><p> Combinatorial treatment with CPS49 and flavopiridol shows selective cytotoxic synergy against transformed leukemic… </p></div>
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Fig. 1
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</strong>
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<div class="figure-caption-contents">Combinatorial treatment with CPS49 and flavopiridol shows selective cytotoxic synergy against transformed leukemic cells. (A) PBMCs, Jurkat, K562, HeLa, and 8226 cells were incubated with increasing concentrations of CPS49 alone (left panel) or Flavo alone (right panel). Cell viability was measured by MTT assay at 16 h following the drug treatments. * Asterisk indicates that 20 times higher concentrations of CPS49 were used in 8226 cells (left panel). (B) Jurkat cells (left panel) were incubated with increasing concentrations (0−5 μM) of CPS49 alone, Flavo (flavopiridol) alone, or CPS49 plus flavopiridol with a fixed ratio of 1:1. Cell viability was determined after 16 h incubation time with the drugs. CI values (right panel) for each fractional effect were calculated using a commercially available software (Calcusyn; Biosoft). (C) Following 8 h pretreatment with 0.2 μM Flavo (flavopiridol), Jurkat cells (left panel) were incubated with increasing concentrations (0−5 μM) of CPS49 alone, Flavo alone, or CPS49 plus flavopiridol (a fixed ratio of 1:1) for an additional 16 h, and cell viability was assessed at the termination of incubation. The viability of the Jurkat cells after 16 h exposure to flavopiridol at 0.2 μM was around 90%. The data presented are the means of three independent determinations after normalization to those of the untreated cells. CI values (right panel) for each fractional effect were calculated using the software, and a CI value < 1.0 indicates synergism, CI = 1.0 indicates an additive effect, and CI > 1.0 indicates antagonism. (D) FACS measurement of acute increase in annexin positive staining of Jurkat cells 3 hours following addition of increasing doses (0−10 μM) of flavopiridol and CPS49 either alone or in combination as indicated.</div>
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src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/da55/2778846/8cb4361ad430/nihms-53716-f0002.gif"
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alt="Fig. 2" />
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<p> Fig. 2 </p>
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<div class="figure-caption-contents"><p> CPS49 and flavopiridol demonstrate selective… </p></div>
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<p> Fig. 2 </p>
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<div class="figure-caption-contents"><p> CPS49 and flavopiridol demonstrate selective disruption of homeostasis of intracellular glutathione (GSH) and… </p></div>
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Fig. 2
|
||
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<div class="figure-caption-contents">CPS49 and flavopiridol demonstrate selective disruption of homeostasis of intracellular glutathione (GSH) and reactive oxygen species (ROS) in transformed leukemia cells. (A) The profile of ROS generation in Jurkat cells after 1 h drug treatment and the profile of cellular GSH depletion in Jurkat cells after 16 h exposure to CPS49 alone (top panel), Flavo alone (flavopiridol; middle panel), or CPS49 plus flavopiridol (bottom panel) at the indicated concentrations. (B) The profile of ROS generation in PBMCs, K562, HeLa, and 8226 cells after 1 h drug treatment and the profile of intracellular GSH depletion in these cells after 16 h drug exposure to CPS49 alone (top panels), Flavo alone (flavopiridol; middle panels), or CPS49 plus flavopiridol (bottom panels) at the concentrations indicated. GSH and ROS were measured as described in the Materials and Methods. The data shown are the means of three independent experiments after normalized to those of the untreated cells.</div>
|
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|
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|
||
data-image-alt="Fig. 3"
|
||
data-pmc-id="PMC2778846"
|
||
data-figure-id="F3">
|
||
<img class="figure-thumb" itemprop="thumbnail"
|
||
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src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/da55/2778846/eeb88e332c40/nihms-53716-f0003.gif"
|
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alt="Fig. 3" />
|
||
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|
||
|
||
|
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|
||
<strong class="figure-label">
|
||
<p> Fig. 3 </p>
|
||
</strong>
|
||
|
||
|
||
|
||
<div class="figure-caption-contents"><p> CPS49 and flavopiridol combinations synergistically… </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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|
||
<p> Fig. 3 </p>
|
||
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|
||
|
||
|
||
|
||
<div class="figure-caption-contents"><p> CPS49 and flavopiridol combinations synergistically reduce the mitochondrial membrane potential and NF-κB activation… </p></div>
|
||
|
||
|
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|
||
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|
||
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<figcaption id="figure-caption-2" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description">
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|
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Fig. 3
|
||
</strong>
|
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|
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|
||
|
||
<div class="figure-caption-contents">CPS49 and flavopiridol combinations synergistically reduce the mitochondrial membrane potential and NF-κB activation but differentially influence E2F-1 and caspase activation in transformed leukemic cells. (A) Flow cytometric measurement of CPS49-and/or flavopiridol-mediated loss of mitochondrial membrane potential in Jurkat cells following exposure to CPS49, flavopiridol, and CPS49 plus flavopiridol, respectively, for 1 h (left panel) or 3 h (right panel), as outlined above. (B) Jurkat cells were preincubated for 15 min in the presence or absence of 10 μM CPS49 and/or flavopiridol prior to stimulation with PHA (1 μg/ml) and PMA (50 ng/ml) for an additional 15 min. Whole cellular lysates were then prepared for immunoblot analysis of phospho-IkB-α (Ser32) and IkB-α (total) levels in the whole cell lysates from the Jurkat cells as described in the Materials and Methods. (C) Immunoblot analysis of phospho-relA (Ser536) and relA (p65) levels in the whole cell lysates from the Jurkat cells treated with the drugs as outlined above. (D) immunoblot analysis of E2F-1 and β−actin (ActB) protein levels. (E) Immunoblot analysis of caspase 3 in whole cell lysates from Jurkat cells pretreated 8 hr with 0.2 μM flavopiridol followed by the addition of 10 μM CPS49 and Flavo alone or in combination for an additional 8 hours.</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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|
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|
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|
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|
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|
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<p> Fig. 4 </p>
|
||
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|
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<div class="figure-caption-contents"><p> CPS49 and flavopiridol preferentially up-regulate… </p></div>
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|
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<p> Fig. 4 </p>
|
||
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|
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|
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<div class="figure-caption-contents"><p> CPS49 and flavopiridol preferentially up-regulate the expression of pro-apoptotic genes, while simultaneously down-regulate… </p></div>
|
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Fig. 4
|
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|
||
<div class="figure-caption-contents">CPS49 and flavopiridol preferentially up-regulate the expression of pro-apoptotic genes, while simultaneously down-regulate the expression of anti-apoptotic genes. (A) Jurkat cells were stimulated with 1 μg/ml PHA and 50 ng/ml PMA in the presence or absence of 10 μM CPS49 and/or flavopiridol for 3 h. Total cellular RNA was then isolated from the cell lysates and cDNA was synthesized. mRNA levels of <i>BAX</i>, <i>BAD</i>, <i>p73</i>, and <i>PUMA</i> gene expression were analyzed by qRT-PCR, as described in the Materials and Methods. (B) mRNA levels of <i>MCL1</i>, <i>XIAP</i>, <i>BCL-2</i>, <i>BCL-XL</i>, <i>Survivin</i>, and <i>MDM2</i> gene expression were assessed by qRT-PCR analysis in the Jurkat cells treated with the drugs, as outlined above. The data presented are the means of three separate determinations after normalized to those of the house-keeping gene β-actin. * P < 0.05 and ** P < 0.01 vs. the untreated controls. (C) The reversal of CPS49- and/or Flavo (flavopiridol)-induced cell killing by 10 mM of the antioxidant N-acetylcysteine (NAC) in Jurkat cells, as determined by MTT assay. The data shown are the means of three separate experiments after normalized to those of the untreated cells. (D) Jurkat cells were stimulated for 3 h with PHA (1 μg/ml) and PMA (50 ng/ml) in the presence or absence of 10 μM CPS49 and/or flavopiridol, as well as 15 mM of the antioxidant N-acetyl-cysteine (NAC). Total cellular RNA was then isolated from the cell lysates and cDNA was synthesized. The reversal of CPS49- and flavopiridol-mediated mRNA expression of p73 (left panel) and PUMA (right panel) genes by NAC was assessed by qRT-PCR analysis, as described in the Materials and Methods. * P < 0.05 and ** P < 0.01 for the cells with NAC treatment vs. the cells without NAC treatment.</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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<p> Fig. 5 </p>
|
||
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|
||
<div class="figure-caption-contents"><p> The combinatorial synergy by CPS49… </p></div>
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|
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<p> Fig. 5 </p>
|
||
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|
||
|
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|
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|
||
<div class="figure-caption-contents"><p> The combinatorial synergy by CPS49 and flavopiridol following low dose flavopiridol pretreatment is… </p></div>
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|
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<div class="figure-caption-contents">The combinatorial synergy by CPS49 and flavopiridol following low dose flavopiridol pretreatment is highly cell type specific . (A) HeLa, LNCaP, OPM2, 8226, and HH cell lines were incubated with increasing concentrations (0−10μM) of CPS49 alone, Flavo (flavopiridol) alone, or CPS49 plus flavopiridol at a fixed ratio of 1:1. Cell viability was determined after 16 h incubation time with the drugs. (B) CI values were determined for HH, OPM2 and 8226 and plotted against fractional effect to construct isobolograms. CI value < 1.0 indicates synergism, CI = 1.0 indicates an additive effect, and CI > 1.0 indicates antagonism. No isobologram for HeLa or LNCaP could be derived.</div>
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src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/da55/2778846/1eebabc702a9/nihms-53716-f0006.gif"
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<p> Fig 6 </p>
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<div class="figure-caption-contents"><p> Flavopiridol down-regulates genes important for… </p></div>
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<p> Fig 6 </p>
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</strong>
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<div class="figure-caption-contents"><p> Flavopiridol down-regulates genes important for mitochondrial stability and survival but CPS49 shows lower… </p></div>
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</div>
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Fig 6
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</strong>
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<div class="figure-caption-contents">Flavopiridol down-regulates genes important for mitochondrial stability and survival but CPS49 shows lower efficacy in 8226 myeloma cells. (A) 8226 myeloma cells were stimulated with 1 μg/ml PHA and 50 ng/ml PMA in the presence or absence of 10 μM CPS49 and/or flavopiridol for 3 h. Total cellular RNA was then isolated from the cell lysates and cDNA was synthesized. mRNA levels of <i>BAX</i>, <i>BAD</i>, <i>p73</i>, and <i>PUMA</i> gene expression were analyzed by qRT-PCR. (B) mRNA levels of <i>MCL1</i>, <i>XIAP</i>, <i>BCL-2</i>, <i>BCL-XL</i>, <i>Survivin</i>, and <i>MDM2</i> gene expression were assessed by qRT-PCR analysis in the 8226 cells treated with the drugs, as outlined above. The data presented are the means of three separate determinations after normalized to those of the house-keeping gene β-actin. * P < 0.05 and ** P < 0.01 vs. the untreated controls. (C) Jurkat cells (10<sup>7</sup>) were treated with and without 8 h pretreatment with 0.2 μM flavopiridol. Whole cell lysates were prepared and analyzed by immunoblot for total and serine 2 C-terminal domain phosphorylated pol II and for total and serine 807/811 phosphorylated Rb. Shown at the right is a densitometer scan showing relative amount of serine 2 phosphorylated pol II compared to serine 808/811 phosphorylated RB normalized to the total levels of each respectively. (D) This schematic diagram shows that CPS49 and flavopiridol increase p73 directly or indirectly through sustaining the transcription factor E2F-1 and down-regulating MDM2. p73 mediates mitochondrial dysfunction via either the transcription of the pro-apoptotic genes PUMA, BAD, and BAX or mitochondrial localization of these proteins. On the other hand, CPS49 and flavopiridol induce cell death by inhibiting NF-κB and down-regulating NF-κB targeting anti-apoptotic genes, such as Survivin, XIAP, Bcl-2, Bcl-XL, and MCL1. Since both CPS49 and flavopiridol cause mitochondrial damage through closely related but distinct mechanisms, they may act collaboratively or synergistically to promote apoptotic death of leukemia cells through p73 and NF-κB and their downstream molecular events. Such a mechanism may serve to integrate the roles of p73 and NF-κB in culmination in mitochondrial damage and cell death, which may underlie the mechanism of CPS49 and flavopiridol mediated mitochondrial dysfunction and cell killing in transformed leukemic cells.</div>
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Mechanism of immunomodulatory drugs' action in the treatment of multiple myeloma.
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</a>
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<div class="docsum-citation full-citation">
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<span class="docsum-authors full-authors">Chang X, Zhu Y, Shi C, Stewart AK.</span>
|
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|
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||
<span class="docsum-authors short-authors">Chang X, et al.</span>
|
||
<span class="docsum-journal-citation full-journal-citation">Acta Biochim Biophys Sin (Shanghai). 2014 Mar;46(3):240-53. doi: 10.1093/abbs/gmt142. Epub 2013 Dec 29.</span>
|
||
<span class="docsum-journal-citation short-journal-citation">Acta Biochim Biophys Sin (Shanghai). 2014.</span>
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<span class="citation-part">PMID: <span class="docsum-pmid">24374776</span></span>
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<div class="docsum-content" style="display:inline;">
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<span class="docsum-authors full-authors">Liu Y, Li Q, Zhou L, Xie N, Nice EC, Zhang H, Huang C, Lei Y.</span>
|
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|
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|
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|
||
<span class="docsum-authors short-authors">Liu Y, et al.</span>
|
||
<span class="docsum-journal-citation full-journal-citation">Oncotarget. 2016 Jul 5;7(27):42740-42761. doi: 10.18632/oncotarget.8600.</span>
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<span class="docsum-journal-citation short-journal-citation">Oncotarget. 2016.</span>
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|
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<span class="docsum-authors full-authors">Guo D, Cain JP, O'Connell S, Gardner ER, Pisle S, Figg WD, Tabibi SE, Yalkowsky SH.</span>
|
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|
||
|
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|
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<span class="docsum-authors short-authors">Guo D, et al.</span>
|
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<span class="docsum-journal-citation full-journal-citation">AAPS PharmSciTech. 2012 Jun;13(2):661-73. doi: 10.1208/s12249-012-9784-5. Epub 2012 May 3.</span>
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<span class="docsum-journal-citation short-journal-citation">AAPS PharmSciTech. 2012.</span>
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References
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Blagosklonny MV. Flavopiridol, an Inhibitor of Transcription: Implications, Problems and Solutions. Cell Cycle. 2004;3:1537–1542.
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Chao SH, Price DH. Flavopiridol Inactivates P-TEFb and Blocks Most RNA Polymerase II Transcription in Vivo. J Biol Chem. 2001;276:31793–31799.
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Chou TC, Talalay P. Quantitative Analysis of Dose-Effect Relationships: the Combined Effects of Multiple Drugs or Enzyme Inhibitors. Adv Enzyme Regul. 1984;22:27–55.
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Craig RW. MCL1 Provides a Window on the Role of the BCL2 Family in Cell Proliferation, Differentiation and Tumorigenesis. Leukemia. 2002;16:444–454.
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Dai Y, Grant S. Cyclin-Dependent Kinase Inhibitors. Curr Opin Pharmacol. 2003;3:362–370.
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DNA-Binding Proteins / metabolism
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Drug Synergism
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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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Glutathione / metabolism
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</button><div id="keyword-actions-mesh-terms-10"
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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"
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Homeostasis / drug effects*
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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 Humans"
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Humans
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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"
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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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Intracellular Space / drug effects
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aria-label="Toggle dropdown menu for keyword Reactive Oxygen Species / metabolism"
|
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Reactive Oxygen Species / metabolism
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href="/?term=%22Reactive+Oxygen+Species%2Fmetabolism%22%5BMeSH%5D&sort=date&sort_order=desc"
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data-href="/?term=%22Reactive+Oxygen+Species%2Fmetabolism%22%5BMeSH%5D&sort=date&sort_order=desc"
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href="/?term=%22Thalidomide%2Fanalogs+and+derivatives%22%5BMAJR%5D&sort=date&sort_order=desc"
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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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</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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Transcription, Genetic / drug effects
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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 Tumor Suppressor Proteins / metabolism"
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Tumor Suppressor Proteins / metabolism
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</a></li></ul></div></div></div></li></ul>
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</div>
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|
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<div id="substances" class="substances keywords-section">
|
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<h2 class="title">
|
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Substances
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</h2>
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<ul class="keywords-list"><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 Antineoplastic Agents"
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tabindex="0"
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Antineoplastic Agents
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aria-label="Dropdown menu for keyword Antineoplastic Agents"><div class="title">Actions</div><div class="content"><ul class="keyword-actions-links"><li><a class="search-in-pubmed-link dropdown-block-link"
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data-href="/?term=%22Antineoplastic+Agents%22%5Bnm%5D&sort=date&sort_order=desc"
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ref="linksrc=search_in_pubmed_keyword_link&keyword="Antineoplastic Agents"[nm]"
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Search in MeSH
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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 Apoptosis Regulatory Proteins"
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tabindex="0"
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aria-expanded="false"
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Apoptosis Regulatory Proteins
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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 Apoptosis Regulatory Proteins"><div class="title">Actions</div><div class="content"><ul class="keyword-actions-links"><li><a class="search-in-pubmed-link dropdown-block-link"
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Search in PubMed
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data-ga-category="search"
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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 BBC3 protein, human"
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tabindex="0"
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BBC3 protein, human
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</button><div id="keyword-actions-substances-2"
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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 BBC3 protein, human"><div class="title">Actions</div><div class="content"><ul class="keyword-actions-links"><li><a class="search-in-pubmed-link dropdown-block-link"
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data-href="/?term=%22BBC3+protein%2C+human%22%5Bnm%5D&sort=date&sort_order=desc"
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Search in 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 CPS 49"
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tabindex="0"
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aria-expanded="false"
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data-pinger-ignore>
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CPS 49
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</button><div id="keyword-actions-substances-3"
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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 CPS 49"><div class="title">Actions</div><div class="content"><ul class="keyword-actions-links"><li><a class="search-in-pubmed-link dropdown-block-link"
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Search in MeSH
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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 DNA-Binding Proteins"
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tabindex="0"
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aria-expanded="false"
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data-pinger-ignore>
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DNA-Binding Proteins
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</button><div id="keyword-actions-substances-4"
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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 DNA-Binding Proteins"><div class="title">Actions</div><div class="content"><ul class="keyword-actions-links"><li><a class="search-in-pubmed-link dropdown-block-link"
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Search in PubMed
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Search in 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 Flavonoids"
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tabindex="0"
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data-pinger-ignore>
|
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Flavonoids
|
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</button><div id="keyword-actions-substances-5"
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class="keyword-actions-dropdown dropdown dropdown-container"
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hidden
|
||
aria-label="Dropdown menu for keyword Flavonoids"><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=%22Flavonoids%22%5Bnm%5D&sort=date&sort_order=desc"
|
||
data-href="/?term=%22Flavonoids%22%5Bnm%5D&sort=date&sort_order=desc"
|
||
ref="linksrc=search_in_pubmed_keyword_link&keyword="Flavonoids"[nm]"
|
||
data-ga-category="search"
|
||
data-ga-action="substance"
|
||
data-ga-label="Flavonoids">
|
||
Search in PubMed
|
||
</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=%22Flavonoids%22"
|
||
data-ga-category="search_mesh"
|
||
data-ga-action="substance_link"
|
||
data-ga-label="Flavonoids">
|
||
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=""Flavonoids"[nm]"
|
||
data-ga-category="search"
|
||
data-ga-action="add_to_search"
|
||
data-ga-label=""Flavonoids"[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 Free Radical Scavengers"
|
||
tabindex="0"
|
||
aria-controls="keyword-actions-substances-6"
|
||
aria-expanded="false"
|
||
data-pinger-ignore>
|
||
Free Radical Scavengers
|
||
</button><div id="keyword-actions-substances-6"
|
||
class="keyword-actions-dropdown dropdown dropdown-container"
|
||
hidden
|
||
aria-label="Dropdown menu for keyword Free Radical Scavengers"><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=%22Free+Radical+Scavengers%22%5Bnm%5D&sort=date&sort_order=desc"
|
||
data-href="/?term=%22Free+Radical+Scavengers%22%5Bnm%5D&sort=date&sort_order=desc"
|
||
ref="linksrc=search_in_pubmed_keyword_link&keyword="Free Radical Scavengers"[nm]"
|
||
data-ga-category="search"
|
||
data-ga-action="substance"
|
||
data-ga-label="Free Radical Scavengers">
|
||
Search in PubMed
|
||
</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=%22Free+Radical+Scavengers%22"
|
||
data-ga-category="search_mesh"
|
||
data-ga-action="substance_link"
|
||
data-ga-label="Free Radical Scavengers">
|
||
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=""Free Radical Scavengers"[nm]"
|
||
data-ga-category="search"
|
||
data-ga-action="add_to_search"
|
||
data-ga-label=""Free Radical Scavengers"[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 NF-kappa B"
|
||
tabindex="0"
|
||
aria-controls="keyword-actions-substances-7"
|
||
aria-expanded="false"
|
||
data-pinger-ignore>
|
||
NF-kappa B
|
||
</button><div id="keyword-actions-substances-7"
|
||
class="keyword-actions-dropdown dropdown dropdown-container"
|
||
hidden
|
||
aria-label="Dropdown menu for keyword NF-kappa B"><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=%22NF-kappa+B%22%5Bnm%5D&sort=date&sort_order=desc"
|
||
data-href="/?term=%22NF-kappa+B%22%5Bnm%5D&sort=date&sort_order=desc"
|
||
ref="linksrc=search_in_pubmed_keyword_link&keyword="NF-kappa B"[nm]"
|
||
data-ga-category="search"
|
||
data-ga-action="substance"
|
||
data-ga-label="NF-kappa B">
|
||
Search in PubMed
|
||
</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=%22NF-kappa+B%22"
|
||
data-ga-category="search_mesh"
|
||
data-ga-action="substance_link"
|
||
data-ga-label="NF-kappa B">
|
||
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=""NF-kappa B"[nm]"
|
||
data-ga-category="search"
|
||
data-ga-action="add_to_search"
|
||
data-ga-label=""NF-kappa B"[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 Nuclear Proteins"
|
||
tabindex="0"
|
||
aria-controls="keyword-actions-substances-8"
|
||
aria-expanded="false"
|
||
data-pinger-ignore>
|
||
Nuclear Proteins
|
||
</button><div id="keyword-actions-substances-8"
|
||
class="keyword-actions-dropdown dropdown dropdown-container"
|
||
hidden
|
||
aria-label="Dropdown menu for keyword Nuclear Proteins"><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=%22Nuclear+Proteins%22%5Bnm%5D&sort=date&sort_order=desc"
|
||
data-href="/?term=%22Nuclear+Proteins%22%5Bnm%5D&sort=date&sort_order=desc"
|
||
ref="linksrc=search_in_pubmed_keyword_link&keyword="Nuclear Proteins"[nm]"
|
||
data-ga-category="search"
|
||
data-ga-action="substance"
|
||
data-ga-label="Nuclear Proteins">
|
||
Search in PubMed
|
||
</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=%22Nuclear+Proteins%22"
|
||
data-ga-category="search_mesh"
|
||
data-ga-action="substance_link"
|
||
data-ga-label="Nuclear Proteins">
|
||
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=""Nuclear Proteins"[nm]"
|
||
data-ga-category="search"
|
||
data-ga-action="add_to_search"
|
||
data-ga-label=""Nuclear Proteins"[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 Piperidines"
|
||
tabindex="0"
|
||
aria-controls="keyword-actions-substances-9"
|
||
aria-expanded="false"
|
||
data-pinger-ignore>
|
||
Piperidines
|
||
</button><div id="keyword-actions-substances-9"
|
||
class="keyword-actions-dropdown dropdown dropdown-container"
|
||
hidden
|
||
aria-label="Dropdown menu for keyword Piperidines"><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=%22Piperidines%22%5Bnm%5D&sort=date&sort_order=desc"
|
||
data-href="/?term=%22Piperidines%22%5Bnm%5D&sort=date&sort_order=desc"
|
||
ref="linksrc=search_in_pubmed_keyword_link&keyword="Piperidines"[nm]"
|
||
data-ga-category="search"
|
||
data-ga-action="substance"
|
||
data-ga-label="Piperidines">
|
||
Search in PubMed
|
||
</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=%22Piperidines%22"
|
||
data-ga-category="search_mesh"
|
||
data-ga-action="substance_link"
|
||
data-ga-label="Piperidines">
|
||
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=""Piperidines"[nm]"
|
||
data-ga-category="search"
|
||
data-ga-action="add_to_search"
|
||
data-ga-label=""Piperidines"[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 Proto-Oncogene Proteins"
|
||
tabindex="0"
|
||
aria-controls="keyword-actions-substances-10"
|
||
aria-expanded="false"
|
||
data-pinger-ignore>
|
||
Proto-Oncogene Proteins
|
||
</button><div id="keyword-actions-substances-10"
|
||
class="keyword-actions-dropdown dropdown dropdown-container"
|
||
hidden
|
||
aria-label="Dropdown menu for keyword Proto-Oncogene Proteins"><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=%22Proto-Oncogene+Proteins%22%5Bnm%5D&sort=date&sort_order=desc"
|
||
data-href="/?term=%22Proto-Oncogene+Proteins%22%5Bnm%5D&sort=date&sort_order=desc"
|
||
ref="linksrc=search_in_pubmed_keyword_link&keyword="Proto-Oncogene Proteins"[nm]"
|
||
data-ga-category="search"
|
||
data-ga-action="substance"
|
||
data-ga-label="Proto-Oncogene Proteins">
|
||
Search in PubMed
|
||
</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=%22Proto-Oncogene+Proteins%22"
|
||
data-ga-category="search_mesh"
|
||
data-ga-action="substance_link"
|
||
data-ga-label="Proto-Oncogene Proteins">
|
||
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=""Proto-Oncogene Proteins"[nm]"
|
||
data-ga-category="search"
|
||
data-ga-action="add_to_search"
|
||
data-ga-label=""Proto-Oncogene Proteins"[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 Reactive Oxygen Species"
|
||
tabindex="0"
|
||
aria-controls="keyword-actions-substances-11"
|
||
aria-expanded="false"
|
||
data-pinger-ignore>
|
||
Reactive Oxygen Species
|
||
</button><div id="keyword-actions-substances-11"
|
||
class="keyword-actions-dropdown dropdown dropdown-container"
|
||
hidden
|
||
aria-label="Dropdown menu for keyword Reactive Oxygen Species"><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=%22Reactive+Oxygen+Species%22%5Bnm%5D&sort=date&sort_order=desc"
|
||
data-href="/?term=%22Reactive+Oxygen+Species%22%5Bnm%5D&sort=date&sort_order=desc"
|
||
ref="linksrc=search_in_pubmed_keyword_link&keyword="Reactive Oxygen Species"[nm]"
|
||
data-ga-category="search"
|
||
data-ga-action="substance"
|
||
data-ga-label="Reactive Oxygen Species">
|
||
Search in PubMed
|
||
</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=%22Reactive+Oxygen+Species%22"
|
||
data-ga-category="search_mesh"
|
||
data-ga-action="substance_link"
|
||
data-ga-label="Reactive Oxygen Species">
|
||
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=""Reactive Oxygen Species"[nm]"
|
||
data-ga-category="search"
|
||
data-ga-action="add_to_search"
|
||
data-ga-label=""Reactive Oxygen Species"[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 Tumor Suppressor Proteins"
|
||
tabindex="0"
|
||
aria-controls="keyword-actions-substances-12"
|
||
aria-expanded="false"
|
||
data-pinger-ignore>
|
||
Tumor Suppressor Proteins
|
||
</button><div id="keyword-actions-substances-12"
|
||
class="keyword-actions-dropdown dropdown dropdown-container"
|
||
hidden
|
||
aria-label="Dropdown menu for keyword Tumor Suppressor Proteins"><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=%22Tumor+Suppressor+Proteins%22%5Bnm%5D&sort=date&sort_order=desc"
|
||
data-href="/?term=%22Tumor+Suppressor+Proteins%22%5Bnm%5D&sort=date&sort_order=desc"
|
||
ref="linksrc=search_in_pubmed_keyword_link&keyword="Tumor Suppressor Proteins"[nm]"
|
||
data-ga-category="search"
|
||
data-ga-action="substance"
|
||
data-ga-label="Tumor Suppressor Proteins">
|
||
Search in PubMed
|
||
</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=%22Tumor+Suppressor+Proteins%22"
|
||
data-ga-category="search_mesh"
|
||
data-ga-action="substance_link"
|
||
data-ga-label="Tumor Suppressor Proteins">
|
||
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=""Tumor Suppressor Proteins"[nm]"
|
||
data-ga-category="search"
|
||
data-ga-action="add_to_search"
|
||
data-ga-label=""Tumor Suppressor Proteins"[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 alvocidib"
|
||
tabindex="0"
|
||
aria-controls="keyword-actions-substances-13"
|
||
aria-expanded="false"
|
||
data-pinger-ignore>
|
||
alvocidib
|
||
</button><div id="keyword-actions-substances-13"
|
||
class="keyword-actions-dropdown dropdown dropdown-container"
|
||
hidden
|
||
aria-label="Dropdown menu for keyword alvocidib"><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=%22alvocidib%22%5Bnm%5D&sort=date&sort_order=desc"
|
||
data-href="/?term=%22alvocidib%22%5Bnm%5D&sort=date&sort_order=desc"
|
||
ref="linksrc=search_in_pubmed_keyword_link&keyword="alvocidib"[nm]"
|
||
data-ga-category="search"
|
||
data-ga-action="substance"
|
||
data-ga-label="alvocidib">
|
||
Search in PubMed
|
||
</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=%22alvocidib%22"
|
||
data-ga-category="search_mesh"
|
||
data-ga-action="substance_link"
|
||
data-ga-label="alvocidib">
|
||
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=""alvocidib"[nm]"
|
||
data-ga-category="search"
|
||
data-ga-action="add_to_search"
|
||
data-ga-label=""alvocidib"[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 Thalidomide"
|
||
tabindex="0"
|
||
aria-controls="keyword-actions-substances-14"
|
||
aria-expanded="false"
|
||
data-pinger-ignore>
|
||
Thalidomide
|
||
</button><div id="keyword-actions-substances-14"
|
||
class="keyword-actions-dropdown dropdown dropdown-container"
|
||
hidden
|
||
aria-label="Dropdown menu for keyword Thalidomide"><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=%22Thalidomide%22%5Bnm%5D&sort=date&sort_order=desc"
|
||
data-href="/?term=%22Thalidomide%22%5Bnm%5D&sort=date&sort_order=desc"
|
||
ref="linksrc=search_in_pubmed_keyword_link&keyword="Thalidomide"[nm]"
|
||
data-ga-category="search"
|
||
data-ga-action="substance"
|
||
data-ga-label="Thalidomide">
|
||
Search in PubMed
|
||
</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=%22Thalidomide%22"
|
||
data-ga-category="search_mesh"
|
||
data-ga-action="substance_link"
|
||
data-ga-label="Thalidomide">
|
||
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=""Thalidomide"[nm]"
|
||
data-ga-category="search"
|
||
data-ga-action="add_to_search"
|
||
data-ga-label=""Thalidomide"[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 Glutathione"
|
||
tabindex="0"
|
||
aria-controls="keyword-actions-substances-15"
|
||
aria-expanded="false"
|
||
data-pinger-ignore>
|
||
Glutathione
|
||
</button><div id="keyword-actions-substances-15"
|
||
class="keyword-actions-dropdown dropdown dropdown-container"
|
||
hidden
|
||
aria-label="Dropdown menu for keyword Glutathione"><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=%22Glutathione%22%5Bnm%5D&sort=date&sort_order=desc"
|
||
data-href="/?term=%22Glutathione%22%5Bnm%5D&sort=date&sort_order=desc"
|
||
ref="linksrc=search_in_pubmed_keyword_link&keyword="Glutathione"[nm]"
|
||
data-ga-category="search"
|
||
data-ga-action="substance"
|
||
data-ga-label="Glutathione">
|
||
Search in PubMed
|
||
</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=%22Glutathione%22"
|
||
data-ga-category="search_mesh"
|
||
data-ga-action="substance_link"
|
||
data-ga-label="Glutathione">
|
||
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=""Glutathione"[nm]"
|
||
data-ga-category="search"
|
||
data-ga-action="add_to_search"
|
||
data-ga-label=""Glutathione"[nm]"
|
||
href="#">
|
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