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京都大学0048新制・課程博士博士(工学)甲第10470号工博第2321号新制||工||1294(附属図書館)UT51-2003-T296京都大学大学院工学研究科高分子化学専攻(主査)教授 岩田 博夫, 教授 伊藤 紳三郎, 教授 田畑 泰彦学位規則第4条第1項該当Doctor of EngineeringKyoto UniversityDA

17p12 deletion in breast cancer predicts resistance to neoadjuvant chemotherapy

Numerous studies have attempted to identify gene expression profiles which can be utilized to predict responses to neoadjuvant chemotherapy (NAC), but their findings are not clinically applicable at present. In the present study, we sought to determine DNA copy number alterations (CNAs) in breast cancer tissues which are associated with the response to NAC. Frozen tumor tissues from 63 breast cancer patients were obtained using core needle biopsy prior to NAC (3 cycles of docetaxel plus adriamycin) and were microdissected. Array comparative genomic hybridization (array CGH) with 4,045 bacterial artificial chromosome (BAC) probes was performed to identify the CNAs. Changes in tumor size in response to NAC were measured via magnetic resonance imaging. Fluorescence in situ hybridization (FISH) was conducted to verify array CGH results and for independent validation studies. CNAs at eight chromosomal loci encompassing 24 clones were correlated with changes in tumor size after NAC (p<0.05; t-test). Two CNAs were selected, 17p12 deletion and 17q21.32-33 gain, which were significantly associated with a smaller reduction in tumor size following NAC, via prioritization of the regions containing the candidate genes. In an independent validation set of samples from 39 patients, FISH assay further showed that the 17p12 deletion was markedly associated with smaller changes in tumor size (p=0.006), while the 17q21.32-33 gain was not significant (p=0.309). In conclusion, we successfully identified a 17p12 deletion in breast cancer tissue which can be applied in predicting tumor resistance to NAC

Targeting Improves MSC Treatment of Inflammatory Bowel Disease

Inflammatory bowel disease (IBD), which includes Crohn's disease and ulcerative colitis, is an inflammatory autoimmune disease characterized by T-cell infiltration to the colon. Mesenchymal stem cells (MSCs) have the potential to rescue IBD owing to their immunosuppressive capabilities and clinical studies have shown positive influence on intestinal graft versus host disease. We demonstrate here a new method to coat MSCs with antibodies against addressins to enhance their delivery to the colon and thereby increase the therapeutic effectiveness. Bioluminescence imaging (BLI) demonstrated that vascular cell adhesion molecule antibody (Ab)-coated MSCs (AbVCAM-1- MSCs) had the highest delivery efficiency to inflamed mesenteric lymph node (MLN) and colon compared to untreated MSCs, Abisotype-MSCs, and AbMAdCAM-MSCs. Therapeutically, when mice with IBD were injected with addressin Ab-coated MSCs, they showed dramatically improved survival rates, higher IBD therapeutic scores, and significantly improved body weight gain compared to mice injected with MSCs only, isotype Ab, free Ab plus MSCs, or vehicle-only controls. These data demonstrate that anti-addressin Ab coating on MSC increased cell delivery to inflamed colon and increased the efficacy of MSC treatment of IBD. This is the first study showing an increased therapeutic efficacy when stem cells are first coated with antibodies specifically target them to inflamed sites