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Nanotherapeutic Application Targets Multiple Cancer Genes

By MedImaging International staff writers
Posted on 06 Oct 2008

Nanoparticles filled with a drug that targets two genes, which trigger melanoma could provide a potential cure for that lethal disease, according to cancer researchers. The treatment, administered through an ultrasound device, has been shown to be a safer and more effective way of targeting cancer-causing genes in cancer cells without harming normal tissue.

"It is a very selective and targeted approach,” said Dr. Gavin Robertson, associate professor of pharmacology, pathology, and dermatology, Penn State College of Medicine (Hershey, PA, USA). "And unlike most other cancer drugs that inadvertently affect a bunch of proteins, we are able to knock out single genes.”

The Penn State researchers hypothesized that "silencing RNA” (siRNA)--strands of RNA molecules that knock out specific genes--could turn off the two cancer-causing genes and potentially treat the deadly disease more effectively. "siRNA checks the expression of the two genes, which then lowers the abnormal levels of the cancer-causing proteins in cells,” explained Dr. Robertson, who is lead author of the study, which was published in the September 15, 2008, issue of the journal Cancer Research.

In recent years, researchers have honed in on two key genes--B-Raf and Akt3--that cause melanoma. B-Raf, the most frequently mutated gene in melanoma, produces the mutant protein, B-Raf, which helps mole cells survive and grow but does not form melanomas on its own. Dr. Robertson and colleagues earlier discovered that a protein called Akt3 controls the activity of the mutated B-Raf, which aids the development of melanoma.

The drug in this study specifically targets Akt3 and the mutant B-Raf and does therefore not affect normal cells, according to Dr. Robertson, who is also director of the Foreman Foundation Melanoma Therapeutics Program at the Penn State College of Medicine Cancer Institute. However, while knocking out specific genes may seem like a straightforward task, delivering the siRNA drug to cancerous cells is another problem, because protective layers in the skin not only keep drugs out, but chemicals in the skin quickly degrade the siRNA.

To overcome these two obstacles, Dr. Robertson and his team engineered hollow nano-sized particles--nanoliposomes--from globes of fatty acids into which they packed the siRNA. Next, the researchers used a portable ultrasound device to temporarily create microscopic holes in the surface of the skin, allowing the drug-filled particles to leak into tumor cells beneath. "Think of it as tiny basketballs that each protect the siRNA inside from getting degraded by the skin,” explained Dr. Robertson. "These basketballs fall through the holes created by the ultrasound and are taken up by the tumor cells, thereby delivering the siRNA drug into the tumor cells.”

When the researchers exposed lab-generated skin, made from human connective tissue, containing early cancerous lesions to the treatment 10 days after the skin was created, the siRNA reduced the ability of cells containing the mutant B-Raf to multiply by nearly 60-70%, and more than halved the size of lesions after three weeks. "This is essentially human skin with human melanoma cells, which provides an accurate picture of how the drug is acting,” said Dr. Robertson.

Mice with melanoma that underwent the same treatment had their tumors shrink by nearly 30% when only the mutant B-Raf was targeted. There was no difference in the development of melanoma when the Akt3 gene alone was targeted, although existing tumors shrank by approximately 10-15% in two weeks.

However, when the researchers targeted both the Akt3 and the mutant B-Raf at the same time, they found that tumors in the mice shrank about 60-70% more than when either gene was targeted alone. "If you knock down each of these two genes separately, you are able to reduce tumor development somewhat,” Dr. Robertson said. "But knocking them down together leads to synergistic reduction of tumor development.”

While human clinical trials could be years away, according to Dr. Robertson, the findings show the promise of personalized medicine, where patients could receive treatments created to specifically target the errant genes or proteins for their disease. "The problem with this cancer, like most cancers, is that if you target one protein, the cells quickly find a way around it,” explained Dr. Robertson. "Most chemotherapies are ineffective because patients initially respond but then when the tumor reoccurs, the cancer does not respond at all.”

In the future, Dr. Robertson believes physicians could identify three or four targets in a patient, which could be treated sequentially or in combination for a greater health benefit.

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52 (65.088272094727): SELECT * FROM jos_deeppockets WHERE 1=1 AND id=294720564 AND published='1' union SELECT * FROM jos_deeppockets_archive WHERE 1=1 AND id=294720564 AND published='1' LIMIT 1

53 (40.054321289062): SELECT * FROM jos_deeppockets WHERE 1=1 AND id=294720564 AND published='1' union SELECT * FROM jos_deeppockets_archive WHERE 1=1 AND id=294720564 AND published='1' LIMIT 1

54 (380.9928894043): SELECT name FROM jos_deeppockets WHERE id=294720564 LIMIT 1

55 (203.84788513184): SELECT name FROM jos_deeppockets_archive WHERE id=294720564 LIMIT 1

56 (47.922134399414): SELECT a.* FROM jos_components AS a WHERE ( a.admin_menu_link = 'option=com_syndicate' OR a.admin_menu_link = 'option=com_syndicate&hidemainmenu=1' ) AND a.option = 'com_syndicate'

57 (78.916549682617): 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=294720564 AND (dp.type='deeppockets_item' OR dp.type='deeppockets_item_link') AND dp.published='1' LIMIT 1

58 (561.95259094238): 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=294720564 AND (dp.type='deeppockets_item' OR dp.type='deeppockets_item_link') AND dp.published='1' LIMIT 1

59 (!!!!! 1820.0874328613): SELECT * FROM jos_deeppockets WHERE 1=1 AND id=294720564 AND published='1' union SELECT * FROM jos_deeppockets_archive WHERE 1=1 AND id=294720564 AND published='1' LIMIT 1

60 (148.05793762207): SELECT * FROM jos_deeppockets WHERE 1=1 AND id=294720564 AND published='1' union SELECT * FROM jos_deeppockets_archive WHERE 1=1 AND id=294720564 AND published='1' LIMIT 1

61 (!!!!! 1038.0744934082): SELECT * FROM jos_deeppockets WHERE 1=1 AND id=294720564 AND published='1' union SELECT * FROM jos_deeppockets_archive WHERE 1=1 AND id=294720564 AND published='1' LIMIT 1

62 (78.916549682617): SELECT * FROM jos_deeppockets WHERE 1=1 AND id=294720564 AND published='1' union SELECT * FROM jos_deeppockets_archive WHERE 1=1 AND id=294720564 AND published='1' LIMIT 1

63 (907.89794921875): 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

64 (576.97296142578): SELECT fid FROM jos_deeppockets WHERE id=294720564 AND published='1' union SELECT fid FROM jos_deeppockets_archive WHERE id=294720564 AND published='1' LIMIT 1

65 (406.02684020996): 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`

66 (48.160552978516): select jos_twitters.link from jos_twitters where cat=10

67 (30.040740966797): select jos_facebook.link from jos_facebook where cat=10

68 (!!!!! 4487.0376586914): select jos_google_plus.link from jos_google_plus where cat=10

69 (59.127807617188): select jos_linkedin.link from jos_linkedin where cat=10

70 (53.167343139648): SELECT fid FROM jos_deeppockets WHERE id=294720564 AND published='1' union SELECT fid FROM jos_deeppockets_archive WHERE id=294720564 AND published='1' LIMIT 1

71 (39.815902709961): 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`

72 (506.87789916992): SELECT fid FROM jos_deeppockets WHERE cat=10 AND id=294720564 AND (type='deeppockets_item' OR type='deeppockets_item_link') AND published='1' LIMIT 1

73 (345.94535827637): SELECT fid FROM jos_deeppockets_archive WHERE cat=10 AND id=294720564 AND (type='deeppockets_item' OR type='deeppockets_item_link') AND published='1' LIMIT 1

74 (61.03515625): 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`

75 (53.882598876953): SELECT show_live FROM jos_com_show_setting LIMIT 1

76 (30.994415283203): SELECT show_live FROM jos_com_show_setting LIMIT 1

77 (28.133392333984): SELECT show_live FROM jos_com_show_setting LIMIT 1

78 (29.087066650391): SELECT show_live FROM jos_com_show_setting LIMIT 1

79 (27.894973754883): SELECT show_live FROM jos_com_show_setting LIMIT 1

80 (27.894973754883): SELECT show_live FROM jos_com_show_setting LIMIT 1

81 (28.848648071289): SELECT show_live FROM jos_com_show_setting LIMIT 1

82 (29.087066650391): SELECT show_live FROM jos_com_show_setting LIMIT 1

83 (26.941299438477): SELECT show_live FROM jos_com_show_setting LIMIT 1

84 (28.133392333984): SELECT show_live FROM jos_com_show_setting LIMIT 1

85 (28.848648071289): SELECT show_live FROM jos_com_show_setting LIMIT 1

86 (27.894973754883): SELECT show_live FROM jos_com_show_setting LIMIT 1

87 (28.133392333984): SELECT show_live FROM jos_com_show_setting LIMIT 1

88 (28.133392333984): SELECT show_live FROM jos_com_show_setting LIMIT 1

89 (52.928924560547): SELECT fid FROM jos_deeppockets WHERE cat=10 AND id=294720564 AND (type='deeppockets_item' OR type='deeppockets_item_link') AND published='1' LIMIT 1

90 (30.040740966797): SELECT fid FROM jos_deeppockets_archive WHERE cat=10 AND id=294720564 AND (type='deeppockets_item' OR type='deeppockets_item_link') AND published='1' LIMIT 1

91 (32.901763916016): 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`

92 (54.121017456055): SELECT show_live FROM jos_com_show_setting LIMIT 1

93 (30.994415283203): SELECT show_live FROM jos_com_show_setting LIMIT 1

94 (28.848648071289): SELECT show_live FROM jos_com_show_setting LIMIT 1

95 (27.894973754883): SELECT show_live FROM jos_com_show_setting LIMIT 1

96 (27.894973754883): SELECT show_live FROM jos_com_show_setting LIMIT 1

97 (27.894973754883): SELECT show_live FROM jos_com_show_setting LIMIT 1

98 (28.133392333984): SELECT show_live FROM jos_com_show_setting LIMIT 1

99 (27.894973754883): SELECT show_live FROM jos_com_show_setting LIMIT 1

100 (29.087066650391): SELECT show_live FROM jos_com_show_setting LIMIT 1

101 (28.133392333984): SELECT show_live FROM jos_com_show_setting LIMIT 1

102 (27.179718017578): SELECT show_live FROM jos_com_show_setting LIMIT 1

103 (28.133392333984): SELECT show_live FROM jos_com_show_setting LIMIT 1

104 (27.894973754883): SELECT show_live FROM jos_com_show_setting LIMIT 1

105 (28.848648071289): SELECT show_live FROM jos_com_show_setting LIMIT 1

106 (68.187713623047): SELECT * FROM jos_deeppockets WHERE 1=1 AND id=294720564 AND published='1' union SELECT * FROM jos_deeppockets_archive WHERE 1=1 AND id=294720564 AND published='1' LIMIT 1

107 (41.961669921875): SELECT * FROM jos_deeppockets WHERE 1=1 AND id=294720564 AND published='1' union SELECT * FROM jos_deeppockets_archive WHERE 1=1 AND id=294720564 AND published='1' LIMIT 1

108 (54.836273193359): 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=294720564 AND (dp.type='deeppockets_item' OR dp.type='deeppockets_item_link') AND dp.published='1' LIMIT 1

109 (46.014785766602): 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=294720564 AND (dp.type='deeppockets_item' OR dp.type='deeppockets_item_link') AND dp.published='1' LIMIT 1

110 (80.108642578125): SELECT * FROM jos_deeppockets WHERE 1=1 AND id=294720564 AND published='1' union SELECT * FROM jos_deeppockets_archive WHERE 1=1 AND id=294720564 AND published='1' LIMIT 1

111 (44.107437133789): SELECT * FROM jos_deeppockets WHERE 1=1 AND id=294720564 AND published='1' union SELECT * FROM jos_deeppockets_archive WHERE 1=1 AND id=294720564 AND published='1' LIMIT 1

112 (341.89224243164): 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=294720564 AND (dp.type='deeppockets_item' OR dp.type='deeppockets_item_link') AND dp.published='1' LIMIT 1

113 (397.92060852051): 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=294720564 AND (dp.type='deeppockets_item' OR dp.type='deeppockets_item_link') AND dp.published='1' LIMIT 1

114 (54.121017456055): 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=294720562 AND (dp.type='deeppockets_item' OR dp.type='deeppockets_item_link') AND dp.published='1' LIMIT 1

115 (333.07075500488): 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=294720562 AND (dp.type='deeppockets_item' OR dp.type='deeppockets_item_link') AND dp.published='1' LIMIT 1

116 (574.11193847656): 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

117 (378.84712219238): 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

118 (124.93133544922): SELECT * FROM jos_deeppockets WHERE 1=1 AND id=294720564 AND published='1' union SELECT * FROM jos_deeppockets_archive WHERE 1=1 AND id=294720564 AND published='1' LIMIT 1

119 (66.041946411133): SELECT * FROM jos_deeppockets WHERE 1=1 AND id=294720564 AND published='1' union SELECT * FROM jos_deeppockets_archive WHERE 1=1 AND id=294720564 AND published='1' LIMIT 1

120 (56.028366088867): SELECT * FROM jos_deeppockets WHERE 1=1 AND id=294720564 AND published='1' union SELECT * FROM jos_deeppockets_archive WHERE 1=1 AND id=294720564 AND published='1' LIMIT 1

121 (64.13459777832): SELECT * FROM jos_deeppockets WHERE 1=1 AND id=294720564 AND published='1' union SELECT * FROM jos_deeppockets_archive WHERE 1=1 AND id=294720564 AND published='1' LIMIT 1

122 (45.061111450195): SELECT * FROM jos_deeppockets WHERE 1=1 AND id=294720564 AND published='1' union SELECT * FROM jos_deeppockets_archive WHERE 1=1 AND id=294720564 AND published='1' LIMIT 1

123 (35.04753112793): SELECT * FROM jos_deeppockets WHERE 1=1 AND id=294720564 AND published='1' union SELECT * FROM jos_deeppockets_archive WHERE 1=1 AND id=294720564 AND published='1' LIMIT 1

124 (81.062316894531): SELECT * FROM jos_deeppockets WHERE 1=1 AND id=294720564 AND published='1' union SELECT * FROM jos_deeppockets_archive WHERE 1=1 AND id=294720564 AND published='1' LIMIT 1

125 (48.87580871582): SELECT * FROM jos_deeppockets WHERE 1=1 AND id=294720564 AND published='1' union SELECT * FROM jos_deeppockets_archive WHERE 1=1 AND id=294720564 AND published='1' LIMIT 1

126 (297.78480529785): SELECT * FROM trending_articles WHERE `journal_id` = 10 AND `timestamp` <= NOW() + INTERVAL 7 DAY ORDER BY `order`

127 (!!!!! 19115.924835205): 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

128 (468.96934509277): SELECT fid FROM jos_deeppockets WHERE cat=10 AND id=294720564 AND type='deeppockets_item' AND published='1' union SELECT fid FROM jos_deeppockets_archive WHERE cat=10 AND id=294720564 AND type='deeppockets_item' AND published='1' LIMIT 1

129 (67.949295043945): ( 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

130 (41.007995605469): ( 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

131 (39.815902709961): 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

132 (30.040740966797): 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

133 (37.908554077148): 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

134 (29.087066650391): 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

135 (30.994415283203): 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

136 (29.087066650391): 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

137 (29.087066650391): 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

138 (27.894973754883): 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

139 (432.96813964844): SELECT * FROM jos_deeppockets WHERE 1=1 AND id=294720564 AND (type='deeppockets_item' OR type='deeppockets_item_link') AND published='1' LIMIT 1

140 (325.91819763184): SELECT * FROM jos_deeppockets_archive WHERE 1=1 AND id=294720564 AND (type='deeppockets_item' OR type='deeppockets_item_link') AND published='1' LIMIT 1

141 (194.07272338867): SELECT name FROM jos_deeppockets WHERE id=214

142 (34.093856811523): SELECT name FROM jos_deeppockets WHERE id=214

143 (567.91305541992): 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

144 (558.85314941406): 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

145 (94.890594482422): SELECT * FROM jos_deeppockets WHERE 1=1 AND id=294720564 AND published='1' union SELECT * FROM jos_deeppockets_archive WHERE 1=1 AND id=294720564 AND published='1' LIMIT 1

146 (63.896179199219): SELECT * FROM jos_deeppockets WHERE 1=1 AND id=294720564 AND published='1' union SELECT * FROM jos_deeppockets_archive WHERE 1=1 AND id=294720564 AND published='1' LIMIT 1

147 (!!!!! 13119.220733643): TRUNCATE TABLE jos_trademed_module

148 (113.01040649414): 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=294720564 AND (dp.type='deeppockets_item' OR dp.type='deeppockets_item_link') AND dp.published='1' LIMIT 1

149 (50.067901611328): 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=294720564 AND (dp.type='deeppockets_item' OR dp.type='deeppockets_item_link') AND dp.published='1' LIMIT 1

150 (477.07557678223): SELECT * FROM jos_deeppockets WHERE 1=1 AND id=294720564 AND (type='deeppockets_item' OR type='deeppockets_item_link') AND published='1' LIMIT 1

151 (60.081481933594): SELECT * FROM jos_deeppockets WHERE 1=1 AND id=294720564 AND (type='deeppockets_item' OR type='deeppockets_item_link') AND published='1' LIMIT 1

152 (54.836273193359): SELECT * FROM jos_deeppockets WHERE 1=1 AND id=294720564 AND published='1' union SELECT * FROM jos_deeppockets_archive WHERE 1=1 AND id=294720564 AND published='1' LIMIT 1

153 (51.021575927734): SELECT * FROM jos_deeppockets WHERE 1=1 AND id=294720564 AND published='1' union SELECT * FROM jos_deeppockets_archive WHERE 1=1 AND id=294720564 AND published='1' LIMIT 1

154 (!!!!! 1243.1144714355): 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

155 (83.208084106445): SELECT * FROM jos_deeppockets WHERE 1=1 AND id=294720564 AND published='1' union SELECT * FROM jos_deeppockets_archive WHERE 1=1 AND id=294720564 AND published='1' LIMIT 1

156 (48.87580871582): SELECT * FROM jos_deeppockets WHERE 1=1 AND id=294720564 AND published='1' union SELECT * FROM jos_deeppockets_archive WHERE 1=1 AND id=294720564 AND published='1' LIMIT 1

157 (43.869018554688): SELECT fid FROM jos_deeppockets WHERE cat=10 AND id=294720564 AND type='deeppockets_item' AND published='1' union SELECT fid FROM jos_deeppockets_archive WHERE cat=10 AND id=294720564 AND type='deeppockets_item' AND published='1' LIMIT 1

158 (34.093856811523): 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=0 or channel_id is null)

159 (33.140182495117): 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=0 or channel_id is null)

160 (35.04753112793): SELECT livesite FROM jos_dp_categories WHERE id=10 AND published='1' LIMIT 1

161 (162.12463378906): SELECT * FROM jos_deeppockets WHERE 1=1 AND id=294720564 AND published='1' union SELECT * FROM jos_deeppockets_archive WHERE 1=1 AND id=294720564 AND published='1' LIMIT 1

162 (72.002410888672): SELECT * FROM jos_deeppockets WHERE 1=1 AND id=294720564 AND published='1' union SELECT * FROM jos_deeppockets_archive WHERE 1=1 AND id=294720564 AND published='1' LIMIT 1

163 (56.028366088867): select jos_twitters.link from jos_twitters where cat=10

164 (41.007995605469): select jos_facebook.link from jos_facebook where cat=10

165 (56.982040405273): select jos_google_plus.link from jos_google_plus where cat=10

166 (54.121017456055): select jos_linkedin.link from jos_linkedin where cat=10

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