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Volume 127, Issue 4, Pages (October 2004)

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1 Volume 127, Issue 4, Pages 1030-1037 (October 2004)
Suppression of Peutz—Jeghers polyposis by inhibition of cyclooxygenase-2  Lina Udd, Pekka Katajisto, Derrick J. Rossi, Anna Lepistö, Anna—Maria Lahesmaa, Antti Ylikorkala, Heikki J. Järvinen, Ari P. Ristimäki, Tomi P. Mäkelä  Gastroenterology  Volume 127, Issue 4, Pages (October 2004) DOI: /j.gastro Copyright © 2004 American Gastroenterological Association Terms and Conditions

2 Figure 1 Significance of COX-2 expression for polyposis in Lkb1+/− mice. (A) Western blotting analysis of COX-2 from lysates of unaffected stomach or polyps with indicated diameters from Lkb1+/− mice. Actin levels from the same blot are shown below. (B) Total polyp burden in 8.5-month Lkb1+/− mice wild-type (+/+; n = 11), heterozygote (+/−; n = 11), or null (−/−; n = 9) in regard to Cox-2. The mean polyp burden of Lkb1+/− mice wild-type for Cox-2 (284 ± 106 mm3; mean indicated by horizontal line) is significantly (P < 0.05) reduced both in Cox-2+/− (133 ± 55.0 mm3) and in Cox-2−/− (132 mm3 ± 83.5 mm3) mice. Gastroenterology  , DOI: ( /j.gastro ) Copyright © 2004 American Gastroenterological Association Terms and Conditions

3 Figure 2 Celecoxib treatment reduces polyp burden in Lkb1+/− mice. (A) Comparison of polyp size distribution between celecoxib-treated and control mice shown as a treated/control ratio for the indicated size categories (diameter in mm). No polyps of the largest size category (>5 mm) were found in treated mice, compared with 5 in the controls. (B) Total polyp burden in 10-month Lkb1+/− control mice (n = 17; 881 ± 585 mm3; mean indicated by horizontal line) or mice treated between 3.5 and 10 months with celecoxib (n = 17; 127 ± 60.2 mm3), demonstrating a highly significant decrease (P < 0.001). Gastroenterology  , DOI: ( /j.gastro ) Copyright © 2004 American Gastroenterological Association Terms and Conditions

4 Figure 3 Celecoxib treatment reduces the microvessel density (MVD) of Lkb1+/− polyps. (A) Analysis of histology (Herovici’s stain) from polyps of control and 3.5–10-month celecoxib-treated Lkb1+/− mice. (B) Apoptosis assay (TUNEL) of polyps of Lkb1+/− mice from the same experiment. Examples of apoptotic nuclei are shown in the higher magnification inserts. (C) Anti-CD31 immunostaining of polyp sections from control and 3.5–10-month celecoxib-treated Lkb1 +/− mice (Original magnification ×400); bar represents 50 μm. (D) Mean microvessel density from control and celecoxib-treated mice determined from the CD31 immunostainings (see Materials and Methods section). The mean MVD is significantly (P < 0.01) reduced from 23.9 ± 4.8 (control; n = 21) to 11.0 ± 2.61 (celecoxib; n = 6) vessels/400× microscope field. Gastroenterology  , DOI: ( /j.gastro ) Copyright © 2004 American Gastroenterological Association Terms and Conditions

5 Figure 4 Reduction of polyp burden following celecoxib treatment in a subset of PJS patients. (A) Herovici staining of a gastric Peutz–Jeghers polyp from patient P6. (B) Herovici staining of a small gastric polyp with hyperplasia, branching and irregular foveolae, and a slight increase in smooth-muscle cells. (C and D) Still images from gastroscopic video recordings with a view toward the anthrum of the stomach of patient P6 before and after the 6-month celecoxib treatment as indicated. A medium-sized polyp (<0.5 cm; asterisk) and 2 small polyps (arrowheads) are marked. (E) The change in polyposis grade of indicated patients (P1-P6) before and after celecoxib treatment, in which positive values indicate reduction in polyp burden (see Materials and Methods section). Error bars indicate the confidence intervals of the mean gradings of 5 evaluators. Asterisks mark significant (*P < 0.05) and highly significant (***P < 0.001) changes in polyposis grade. Gastroenterology  , DOI: ( /j.gastro ) Copyright © 2004 American Gastroenterological Association Terms and Conditions


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