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Ultrasound-Guided Cancer Immunotherapy Platform Generates Systemic Antitumor Immunity

By MedImaging International staff writers
Posted on 01 Jun 2022

Image: Ultrasound-guided microbubbles boost immunotherapy efficacy (Photo courtesy of MD Anderson Cancer Center)

Immunotherapy has transformed cancer treatment, offering clinical benefits for patients with treatment-refractory metastatic cancers such as melanoma, non-small cell lung cancer and renal cell cancer. However, not all patients respond to immune checkpoint blockade. Therefore, developing a more effective immunotherapy strategy to benefit larger numbers of cancer patients with localized and metastatic disease remains an unmet clinical need. Natural agonists, such as cyclic dinucleotides, activate the cGAS-STING pathway, but concerns over poor cytosolic entry, serum stability and systemic toxicity have been major limitations for clinical translation. To overcome these challenges, researchers have developed the first-ever image-guided cancer immunotherapy strategy that uses antibody targeting to activate STING in APCs through delivery of molecular drugs.

The ultrasound-guided cancer immunotherapy platform developed by researchers at The University of Texas MD Anderson Cancer Center (Houston, TX, USA) generates systemic antitumor immunity and improves the therapeutic efficacy of immune checkpoint blockade. As the first-of-its-kind platform, the Microbubble-assisted UltraSound-guided Immunotherapy of Cancer (MUSIC) approach employs nanocomplexes combined with microbubbles to effectively deliver cyclic guanosine monophosphate-adenosine monophosphate (cGAMP), an immunotransmitter involved in anticancer immunity, into antigen-presenting cells (APCs). Inside the APCs, the microbubbles release cGAMP to activate the GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway, which stimulates type I interferon responses that are essential for priming tumor-specific T cells.

Because the microbubbles also serve as contrast agents for ultrasound, the researchers use ultrasound scanners to image the tumor and to precisely identify the location where the microbubbles have accumulated. After confirming the microbubbles are bound to the tumors, the researchers activate ultrasonic frequencies, which cause the microbubbles to oscillate and burst, creating transient pores in the cell membrane that allow nucleic acids to be transferred directly into the cell cytosol. This technique, called sonoporation, previously has been used on tumor cells, but the MUSIC platform is the first to bind nanocomplexes to microbubbles to deliver cGAMP immunotransmitters directly into APCs.

In the preclinical study, the MUSIC strategy demonstrated a complete tumor eradication rate of 60% when administered as monotherapy in breast cancer models. When combined with an anti-PD-1 antibody, MUSIC significantly improved antitumor responses with minimal toxicity effects, including enhanced primary tumor control and decreased systemic disease progression. In addition, the combination therapy demonstrated superior survival benefit, with a 76% increase in median survival compared to either therapy alone. The same concept and design principle behind the MUSIC platform’s microbubble technology could be readily translated to nanoscale systems for targeted systemic delivery and activation of innate immune sensors under image guidance for cancer immunotherapy applications, according to the researchers.

“The beauty of our platform is that ultrasound machines are already clinically available in many outpatient settings and microbubbles are FDA-approved contrast agents for ultrasound imaging,” said Wen Jiang, M.D., Ph.D., assistant professor of Radiation Oncology and the study’s co-senior author. “Therefore, we expect there is a very real opportunity to translate MUSIC into a clinic application to benefit cancer patients.”

“Our MUSIC platform is exciting because it provides a new framework for developing image-guided immunotherapy by using acoustically responsive biomaterials to enable efficient, targeted and robust immune activation to produce potent antitumor effects while minimizing systemic toxicity,” Jiang added. “The versatility of the MUSIC platform could potentially be applied to targeted delivery of other immune-stimulating agents, such as nucleotide-based vaccines, mRNAs and other gene therapies for multiple human diseases.”

Related Links:
MD Anderson Cancer Center

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56 (!!!!! 1073.1220245361): SELECT dp.*, ch.title as channel, exp.name as author_name, exp.specialization as author_specialization, exp.images as author_photo FROM jos_deeppockets_archive as dp LEFT JOIN jos_experts as exp ON exp.id = dp.author LEFT JOIN jos_deeppockets as ch ON dp.fid = ch.id WHERE 1=1 AND dp.cat=10 AND dp.id=294793204 AND (dp.type='deeppockets_item' OR dp.type='deeppockets_item_link') AND dp.published='1' LIMIT 1

57 (!!!!! 15146.970748901): SELECT * FROM jos_deeppockets WHERE 1=1 AND id=294793204 AND published='1' union SELECT * FROM jos_deeppockets_archive WHERE 1=1 AND id=294793204 AND published='1' LIMIT 1

58 (!!!!! 5285.0246429443): SELECT * FROM jos_deeppockets WHERE 1=1 AND id=294793204 AND published='1' union SELECT * FROM jos_deeppockets_archive WHERE 1=1 AND id=294793204 AND published='1' LIMIT 1

59 (!!!!! 4397.8691101074): SELECT * FROM jos_deeppockets WHERE 1=1 AND id=294793204 AND published='1' union SELECT * FROM jos_deeppockets_archive WHERE 1=1 AND id=294793204 AND published='1' LIMIT 1

60 (!!!!! 2085.2088928223): SELECT * FROM jos_deeppockets WHERE 1=1 AND id=294793204 AND published='1' union SELECT * FROM jos_deeppockets_archive WHERE 1=1 AND id=294793204 AND published='1' LIMIT 1

61 (!!!!! 8153.2001495361): select cover from jos_number where journalid in (5) and cover is not null order by left(issue,2)+right(issue,2)*12 desc limit 1

62 (639.91546630859): SELECT fid FROM jos_deeppockets WHERE id=294793204 AND published='1' union SELECT fid FROM jos_deeppockets_archive WHERE id=294793204 AND published='1' LIMIT 1

63 (231.98127746582): SELECT id,name,sponsor_text FROM jos_deeppockets dp left outer join jos_channel_sponsor cs on dp.id=cs.fid WHERE cat=10 AND TYPE='file_folder' AND published=1 AND id=214 ORDER BY `ordering`

64 (!!!!! 1271.9631195068): select jos_twitters.link from jos_twitters where cat=10

65 (92.983245849609): select jos_facebook.link from jos_facebook where cat=10

66 (199.0795135498): select jos_google_plus.link from jos_google_plus where cat=10

67 (183.8207244873): select jos_linkedin.link from jos_linkedin where cat=10

68 (!!!!! 2892.9710388184): SELECT fid FROM jos_deeppockets WHERE id=294793204 AND published='1' union SELECT fid FROM jos_deeppockets_archive WHERE id=294793204 AND published='1' LIMIT 1

69 (55.074691772461): SELECT id,name,sponsor_text FROM jos_deeppockets dp left outer join jos_channel_sponsor cs on dp.id=cs.fid WHERE cat=10 AND TYPE='file_folder' AND published=1 AND id=214 ORDER BY `ordering`

70 (461.10153198242): SELECT fid FROM jos_deeppockets WHERE cat=10 AND id=294793204 AND (type='deeppockets_item' OR type='deeppockets_item_link') AND published='1' LIMIT 1

71 (466.10832214355): SELECT fid FROM jos_deeppockets_archive WHERE cat=10 AND id=294793204 AND (type='deeppockets_item' OR type='deeppockets_item_link') AND published='1' LIMIT 1

72 (39.100646972656): SELECT id,name,title FROM jos_deeppockets WHERE cat=10 AND TYPE='file_folder' AND published=1 AND id != 294743300 AND id != 294743301 AND id != 294743302 AND id != 294743303 AND id != 294743304 AND id != 294743305 AND id != 294743306 AND id != 294743307 AND id != 294743308 AND id != 294743309 AND id != 294743310 AND metakey != 'aacc' ORDER BY `ordering`

73 (!!!!! 7508.9931488037): SELECT show_live FROM jos_com_show_setting LIMIT 1

74 (65.088272094727): SELECT show_live FROM jos_com_show_setting LIMIT 1

75 (30.994415283203): SELECT show_live FROM jos_com_show_setting LIMIT 1

76 (28.133392333984): SELECT show_live FROM jos_com_show_setting LIMIT 1

77 (183.10546875): SELECT show_live FROM jos_com_show_setting LIMIT 1

78 (434.87548828125): SELECT show_live FROM jos_com_show_setting LIMIT 1

79 (!!!!! 3927.9460906982): SELECT show_live FROM jos_com_show_setting LIMIT 1

80 (786.06605529785): SELECT show_live FROM jos_com_show_setting LIMIT 1

81 (58.174133300781): SELECT show_live FROM jos_com_show_setting LIMIT 1

82 (36.954879760742): SELECT show_live FROM jos_com_show_setting LIMIT 1

83 (39.815902709961): SELECT show_live FROM jos_com_show_setting LIMIT 1

84 (30.040740966797): SELECT show_live FROM jos_com_show_setting LIMIT 1

85 (28.848648071289): SELECT show_live FROM jos_com_show_setting LIMIT 1

86 (29.087066650391): SELECT show_live FROM jos_com_show_setting LIMIT 1

87 (56.982040405273): SELECT fid FROM jos_deeppockets WHERE cat=10 AND id=294793204 AND (type='deeppockets_item' OR type='deeppockets_item_link') AND published='1' LIMIT 1

88 (!!!!! 1099.1096496582): SELECT fid FROM jos_deeppockets_archive WHERE cat=10 AND id=294793204 AND (type='deeppockets_item' OR type='deeppockets_item_link') AND published='1' LIMIT 1

89 (46.968460083008): SELECT id,name,title FROM jos_deeppockets WHERE cat=10 AND TYPE='file_folder' AND published=1 AND id != 294743300 AND id != 294743301 AND id != 294743302 AND id != 294743303 AND id != 294743304 AND id != 294743305 AND id != 294743306 AND id != 294743307 AND id != 294743308 AND id != 294743309 AND id != 294743310 AND metakey != 'aacc' ORDER BY `ordering`

90 (!!!!! 2516.9849395752): SELECT show_live FROM jos_com_show_setting LIMIT 1

91 (46.014785766602): SELECT show_live FROM jos_com_show_setting LIMIT 1

92 (46.014785766602): SELECT show_live FROM jos_com_show_setting LIMIT 1

93 (38.862228393555): SELECT show_live FROM jos_com_show_setting LIMIT 1

94 (89.883804321289): SELECT show_live FROM jos_com_show_setting LIMIT 1

95 (34.093856811523): SELECT show_live FROM jos_com_show_setting LIMIT 1

96 (35.04753112793): SELECT show_live FROM jos_com_show_setting LIMIT 1

97 (29.087066650391): SELECT show_live FROM jos_com_show_setting LIMIT 1

98 (27.179718017578): SELECT show_live FROM jos_com_show_setting LIMIT 1

99 (97.990036010742): SELECT show_live FROM jos_com_show_setting LIMIT 1

100 (370.02563476562): SELECT show_live FROM jos_com_show_setting LIMIT 1

101 (!!!!! 3371.9539642334): SELECT show_live FROM jos_com_show_setting LIMIT 1

102 (!!!!! 2162.9333496094): SELECT show_live FROM jos_com_show_setting LIMIT 1

103 (68.902969360352): SELECT show_live FROM jos_com_show_setting LIMIT 1

104 (!!!!! 1755.952835083): SELECT * FROM jos_deeppockets WHERE 1=1 AND id=294793204 AND published='1' union SELECT * FROM jos_deeppockets_archive WHERE 1=1 AND id=294793204 AND published='1' LIMIT 1

105 (67.949295043945): SELECT * FROM jos_deeppockets WHERE 1=1 AND id=294793204 AND published='1' union SELECT * FROM jos_deeppockets_archive WHERE 1=1 AND id=294793204 AND published='1' LIMIT 1

106 (643.96858215332): SELECT dp.*, ch.title as channel, exp.name as author_name, exp.specialization as author_specialization, exp.images as author_photo FROM jos_deeppockets as dp LEFT JOIN jos_experts as exp ON exp.id = dp.author LEFT JOIN jos_deeppockets as ch ON dp.fid = ch.id WHERE 1=1 AND dp.cat=10 AND dp.id=294793204 AND (dp.type='deeppockets_item' OR dp.type='deeppockets_item_link') AND dp.published='1' LIMIT 1

107 (446.79641723633): SELECT dp.*, ch.title as channel, exp.name as author_name, exp.specialization as author_specialization, exp.images as author_photo FROM jos_deeppockets_archive as dp LEFT JOIN jos_experts as exp ON exp.id = dp.author LEFT JOIN jos_deeppockets as ch ON dp.fid = ch.id WHERE 1=1 AND dp.cat=10 AND dp.id=294793204 AND (dp.type='deeppockets_item' OR dp.type='deeppockets_item_link') AND dp.published='1' LIMIT 1

108 (!!!!! 2756.8340301514): SELECT * FROM jos_deeppockets WHERE 1=1 AND id=294793204 AND published='1' union SELECT * FROM jos_deeppockets_archive WHERE 1=1 AND id=294793204 AND published='1' LIMIT 1

109 (86.069107055664): SELECT * FROM jos_deeppockets WHERE 1=1 AND id=294793204 AND published='1' union SELECT * FROM jos_deeppockets_archive WHERE 1=1 AND id=294793204 AND published='1' LIMIT 1

110 (184.05914306641): SELECT dp.*, ch.title as channel, exp.name as author_name, exp.specialization as author_specialization, exp.images as author_photo FROM jos_deeppockets as dp LEFT JOIN jos_experts as exp ON exp.id = dp.author LEFT JOIN jos_deeppockets as ch ON dp.fid = ch.id WHERE 1=1 AND dp.id=294793204 AND (dp.type='deeppockets_item' OR dp.type='deeppockets_item_link') AND dp.published='1' LIMIT 1

111 (857.83004760742): SELECT dp.*, ch.title as channel, exp.name as author_name, exp.specialization as author_specialization, exp.images as author_photo FROM jos_deeppockets_archive as dp LEFT JOIN jos_experts as exp ON exp.id = dp.author LEFT JOIN jos_deeppockets as ch ON dp.fid = ch.id WHERE 1=1 AND dp.id=294793204 AND (dp.type='deeppockets_item' OR dp.type='deeppockets_item_link') AND dp.published='1' LIMIT 1

112 (718.83201599121): SELECT dp.name, dp.id, dp2.name as channel, ex.name as author_name, ex.specialization, ex.images FROM jos_deeppockets as dp LEFT JOIN jos_experts as ex ON ex.id = dp.author LEFT JOIN jos_deeppockets as dp2 ON dp2.id = dp.fid WHERE dp.author != 0 AND dp.cat = 10 AND dp.published = 1 AND ( (dp.fid = 294743300) OR (dp.fid = 294743301) OR (dp.fid = 294743302) OR (dp.fid = 294743303) OR (dp.fid = 294743304) OR (dp.fid = 294743305) OR (dp.fid = 294743306) OR (dp.fid = 294743307) OR (dp.fid = 294743308) OR (dp.fid = 294743309) OR (dp.fid = 294743310) ) ORDER BY RAND() LIMIT 1

113 (392.19856262207): SELECT dp.name, dp.id, dp2.name as channel, ex.name as author_name, ex.specialization, ex.images FROM jos_deeppockets as dp LEFT JOIN jos_experts as ex ON ex.id = dp.author LEFT JOIN jos_deeppockets as dp2 ON dp2.id = dp.fid WHERE dp.author != 0 AND dp.cat = 10 AND dp.published = 1 AND ( (dp.fid = 294743300) OR (dp.fid = 294743301) OR (dp.fid = 294743302) OR (dp.fid = 294743303) OR (dp.fid = 294743304) OR (dp.fid = 294743305) OR (dp.fid = 294743306) OR (dp.fid = 294743307) OR (dp.fid = 294743308) OR (dp.fid = 294743309) OR (dp.fid = 294743310) ) ORDER BY RAND() LIMIT 1

114 (113.96408081055): SELECT * FROM jos_deeppockets WHERE 1=1 AND id=294793204 AND published='1' union SELECT * FROM jos_deeppockets_archive WHERE 1=1 AND id=294793204 AND published='1' LIMIT 1

115 (75.101852416992): SELECT * FROM jos_deeppockets WHERE 1=1 AND id=294793204 AND published='1' union SELECT * FROM jos_deeppockets_archive WHERE 1=1 AND id=294793204 AND published='1' LIMIT 1

116 (91.075897216797): SELECT * FROM jos_deeppockets WHERE 1=1 AND id=294793204 AND published='1' union SELECT * FROM jos_deeppockets_archive WHERE 1=1 AND id=294793204 AND published='1' LIMIT 1

117 (63.180923461914): SELECT * FROM jos_deeppockets WHERE 1=1 AND id=294793204 AND published='1' union SELECT * FROM jos_deeppockets_archive WHERE 1=1 AND id=294793204 AND published='1' LIMIT 1

118 (59.127807617188): SELECT * FROM jos_deeppockets WHERE 1=1 AND id=294793204 AND published='1' union SELECT * FROM jos_deeppockets_archive WHERE 1=1 AND id=294793204 AND published='1' LIMIT 1

119 (55.074691772461): SELECT * FROM jos_deeppockets WHERE 1=1 AND id=294793204 AND published='1' union SELECT * FROM jos_deeppockets_archive WHERE 1=1 AND id=294793204 AND published='1' LIMIT 1

120 (416.99409484863): SELECT * FROM jos_deeppockets WHERE 1=1 AND id=294793204 AND published='1' union SELECT * FROM jos_deeppockets_archive WHERE 1=1 AND id=294793204 AND published='1' LIMIT 1

121 (66.041946411133): SELECT * FROM jos_deeppockets WHERE 1=1 AND id=294793204 AND published='1' union SELECT * FROM jos_deeppockets_archive WHERE 1=1 AND id=294793204 AND published='1' LIMIT 1

122 (511.16943359375): SELECT * FROM trending_articles WHERE `journal_id` = 10 AND `timestamp` <= NOW() + INTERVAL 7 DAY ORDER BY `order`

123 (!!!!! 47384.977340698): SELECT * FROM jos_deeppockets WHERE jos_deeppockets.cat = 10 AND jos_deeppockets.type = 'deeppockets_item' AND jos_deeppockets.published = 1 AND jos_deeppockets.created + INTERVAL 14 DAY >= NOW() ORDER BY jos_deeppockets.hits DESC LIMIT 7

124 (622.98774719238): SELECT fid FROM jos_deeppockets WHERE cat=10 AND id=294793204 AND type='deeppockets_item' AND published='1' union SELECT fid FROM jos_deeppockets_archive WHERE cat=10 AND id=294793204 AND type='deeppockets_item' AND published='1' LIMIT 1

125 (!!!!! 17279.863357544): ( SELECT dp.id, dp.name, dp.title, dp.video, dp.video_source, dp.created FROM jos_deeppockets AS dp WHERE dp.video != '' AND dp.video_source != '' AND dp.cat = 10 AND dp.published = 1 AND dp.type != 'deeppockets_item_link' ORDER BY created DESC LIMIT 3 ) UNION ( SELECT dpa.id, dpa.name, dpa.title, dpa.video, dpa.video_source, dpa.created FROM jos_deeppockets_archive AS dpa WHERE dpa.video != '' AND dpa.video_source != '' AND dpa.cat = 10 AND dpa.published = 1 AND dpa.type != 'deeppockets_item_link' ORDER BY created DESC LIMIT 3 ) ORDER BY created DESC LIMIT 3

126 (!!!!! 1299.1428375244): ( SELECT dp.id, dp.name, dp.title, dp.video, dp.video_source, dp.created FROM jos_deeppockets AS dp WHERE dp.video != '' AND dp.video_source != '' AND dp.cat = 10 AND dp.published = 1 AND dp.type != 'deeppockets_item_link' ORDER BY created DESC LIMIT 3 ) UNION ( SELECT dpa.id, dpa.name, dpa.title, dpa.video, dpa.video_source, dpa.created FROM jos_deeppockets_archive AS dpa WHERE dpa.video != '' AND dpa.video_source != '' AND dpa.cat = 10 AND dpa.published = 1 AND dpa.type != 'deeppockets_item_link' ORDER BY created DESC LIMIT 3 ) ORDER BY created DESC LIMIT 3

127 (550.0316619873): SELECT dp.id, dp.name, dp.title, dp.video, dp.video_source, dp.created FROM jos_deeppockets AS dp WHERE dp.id = 294803337 LIMIT 1

128 (576.01928710938): SELECT dp.id, dp.name, dp.title, dp.video, dp.video_source, dp.created FROM jos_deeppockets AS dp WHERE dp.id = 294803337 LIMIT 1

129 (!!!!! 1302.0038604736): SELECT dp.id, dp.name, dp.title, dp.video, dp.video_source, dp.created FROM jos_deeppockets AS dp WHERE dp.id = 294803276 LIMIT 1

130 (41.007995605469): SELECT dp.id, dp.name, dp.title, dp.video, dp.video_source, dp.created FROM jos_deeppockets AS dp WHERE dp.id = 294803276 LIMIT 1

131 (242.94853210449): SELECT dp.id, dp.name, dp.title, dp.video, dp.video_source, dp.created FROM jos_deeppockets_archive AS dp WHERE dp.id = 294803276 LIMIT 1

132 (37.908554077148): SELECT dp.id, dp.name, dp.title, dp.video, dp.video_source, dp.created FROM jos_deeppockets_archive AS dp WHERE dp.id = 294803276 LIMIT 1

133 (627.04086303711): SELECT dp.id, dp.name, dp.title, dp.video, dp.video_source, dp.created FROM jos_deeppockets AS dp WHERE dp.id = 294802958 LIMIT 1

134 (47.922134399414): SELECT dp.id, dp.name, dp.title, dp.video, dp.video_source, dp.created FROM jos_deeppockets AS dp WHERE dp.id = 294802958 LIMIT 1

135 (523.80561828613): SELECT * FROM jos_deeppockets WHERE 1=1 AND id=294793204 AND (type='deeppockets_item' OR type='deeppockets_item_link') AND published='1' LIMIT 1

136 (355.95893859863): SELECT * FROM jos_deeppockets_archive WHERE 1=1 AND id=294793204 AND (type='deeppockets_item' OR type='deeppockets_item_link') AND published='1' LIMIT 1

137 (!!!!! 1771.9268798828): SELECT name FROM jos_deeppockets WHERE id=214

138 (63.896179199219): SELECT name FROM jos_deeppockets WHERE id=214

139 (571.01249694824): SELECT *, DATE_FORMAT(publish_up,'%d %b %Y') AS date_publish_up, DATE_FORMAT(publish_down,'%d %b %Y') AS date_publish_down FROM jos_events WHERE state=1 AND publish_up > NOW() and extra_info REGEXP '((;)|(^))214((;)|($))' AND catid IN (0,110) ORDER BY publish_up ASC LIMIT 3

140 (515.93780517578): SELECT *, DATE_FORMAT(publish_up,'%d %b %Y') AS date_publish_up, DATE_FORMAT(publish_down,'%d %b %Y') AS date_publish_down FROM jos_events WHERE state=1 AND publish_up > NOW() and extra_info REGEXP '((;)|(^))214((;)|($))' AND catid IN (0,110) ORDER BY publish_up ASC LIMIT 3

141 (!!!!! 1128.9119720459): SELECT * FROM jos_deeppockets WHERE 1=1 AND id=294793204 AND published='1' union SELECT * FROM jos_deeppockets_archive WHERE 1=1 AND id=294793204 AND published='1' LIMIT 1

142 (66.995620727539): SELECT * FROM jos_deeppockets WHERE 1=1 AND id=294793204 AND published='1' union SELECT * FROM jos_deeppockets_archive WHERE 1=1 AND id=294793204 AND published='1' LIMIT 1

143 (!!!!! 14066.934585571): TRUNCATE TABLE jos_trademed_module

144 (!!!!! 7781.0287475586): SELECT dp.*, ch.title as channel, exp.name as author_name, exp.specialization as author_specialization, exp.images as author_photo FROM jos_deeppockets as dp LEFT JOIN jos_experts as exp ON exp.id = dp.author LEFT JOIN jos_deeppockets as ch ON dp.fid = ch.id WHERE 1=1 AND dp.cat=10 AND dp.id=294793204 AND (dp.type='deeppockets_item' OR dp.type='deeppockets_item_link') AND dp.published='1' LIMIT 1

145 (808.9542388916): SELECT dp.*, ch.title as channel, exp.name as author_name, exp.specialization as author_specialization, exp.images as author_photo FROM jos_deeppockets_archive as dp LEFT JOIN jos_experts as exp ON exp.id = dp.author LEFT JOIN jos_deeppockets as ch ON dp.fid = ch.id WHERE 1=1 AND dp.cat=10 AND dp.id=294793204 AND (dp.type='deeppockets_item' OR dp.type='deeppockets_item_link') AND dp.published='1' LIMIT 1

146 (552.89268493652): SELECT * FROM jos_deeppockets WHERE 1=1 AND id=294793204 AND (type='deeppockets_item' OR type='deeppockets_item_link') AND published='1' LIMIT 1

147 (59.127807617188): SELECT * FROM jos_deeppockets WHERE 1=1 AND id=294793204 AND (type='deeppockets_item' OR type='deeppockets_item_link') AND published='1' LIMIT 1

148 (!!!!! 2310.037612915): SELECT * FROM jos_deeppockets WHERE 1=1 AND id=294793204 AND published='1' union SELECT * FROM jos_deeppockets_archive WHERE 1=1 AND id=294793204 AND published='1' LIMIT 1

149 (115.15617370605): SELECT * FROM jos_deeppockets WHERE 1=1 AND id=294793204 AND published='1' union SELECT * FROM jos_deeppockets_archive WHERE 1=1 AND id=294793204 AND published='1' LIMIT 1

150 (!!!!! 15313.863754272): SELECT jos_item.* FROM jos_item INNER JOIN jos_number ON jos_item.numberID=jos_number.id WHERE 1=1 AND (jos_item.imgMini<>'') AND jos_item.type='L' AND jos_item.numberID= ( SELECT jos_number.id FROM jos_number WHERE jos_number.journalID IN (10) and jos_number.id in (select distinct jos_number.id from jos_number join jos_item on jos_item.numberid=jos_number.id where jos_item.type='P') ORDER BY (CONVERT(SUBSTRING(issue,1,2),SIGNED) + (CONVERT(SUBSTRING(issue,3,2),SIGNED)*100)) DESC LIMIT 0,1 ) ORDER BY RAND() DESC LIMIT 6

151 (144.95849609375): SELECT * FROM jos_deeppockets WHERE 1=1 AND id=294793204 AND published='1' union SELECT * FROM jos_deeppockets_archive WHERE 1=1 AND id=294793204 AND published='1' LIMIT 1

152 (83.92333984375): SELECT * FROM jos_deeppockets WHERE 1=1 AND id=294793204 AND published='1' union SELECT * FROM jos_deeppockets_archive WHERE 1=1 AND id=294793204 AND published='1' LIMIT 1

153 (149.01161193848): SELECT fid FROM jos_deeppockets WHERE cat=10 AND id=294793204 AND type='deeppockets_item' AND published='1' union SELECT fid FROM jos_deeppockets_archive WHERE cat=10 AND id=294793204 AND type='deeppockets_item' AND published='1' LIMIT 1

154 (962.0189666748): select distinct links.* from jos_textlinks links join jos_textlinks_placement placement on links.id=placement.link_id where journal_id=(10) and (channel_id=214 or channel_id is null)

155 (68.902969360352): select distinct links.* from jos_textlinks links join jos_textlinks_placement placement on links.id=placement.link_id where journal_id=(10) and (channel_id=214 or channel_id is null)

156 (56.982040405273): SELECT livesite FROM jos_dp_categories WHERE id=10 AND published='1' LIMIT 1

157 (!!!!! 2054.9297332764): SELECT * FROM jos_deeppockets WHERE 1=1 AND id=294793204 AND published='1' union SELECT * FROM jos_deeppockets_archive WHERE 1=1 AND id=294793204 AND published='1' LIMIT 1

158 (117.06352233887): SELECT * FROM jos_deeppockets WHERE 1=1 AND id=294793204 AND published='1' union SELECT * FROM jos_deeppockets_archive WHERE 1=1 AND id=294793204 AND published='1' LIMIT 1

159 (125.16975402832): select jos_twitters.link from jos_twitters where cat=10

160 (34.809112548828): select jos_facebook.link from jos_facebook where cat=10

161 (36.001205444336): select jos_google_plus.link from jos_google_plus where cat=10

162 (41.961669921875): select jos_linkedin.link from jos_linkedin where cat=10

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