神経伝達物質の数理機構を用いたスパイク予測

プロジェクト番号 : A12-53若手展開研究 : カテゴリBtextapplication/pdfresearch repor

アルバイトに関する学生の実態と保護者の意識調査

application/pdfArticle大阪府立工業高等専門学校研究紀要, 1988, 22, p.101-108departmental bulletin pape

Regional and multilayered diversity of medicinal plant knowledge in Tanzania: How people and traditional healers choose to keep or share their information

text紀要論文 / Departmental Bulletin Paperdepartmental bulletin pape

Measurement of inclusive production of neutral pions from Υ(4S) decays

journal articl

センサ フュージョン ニヨル トモズレ タイオウ ニュウタイシツ ジョウホウ キロク システム

奈良先端科学技術大学院大学修士(工学)master thesi

Biomarkers of Residual Disease, Disseminated Tumor Cells, and Metastases in the MMTV-PyMT Breast Cancer Model

<div><p>Cancer metastases arise in part from disseminated tumor cells originating from the primary tumor and from residual disease persisting after therapy. The identification of biomarkers on micro-metastases, disseminated tumors, and residual disease may yield novel tools for early detection and treatment of these disease states prior to their development into metastases and recurrent tumors. Here we describe the molecular profiling of disseminated tumor cells in lungs, lung metastases, and residual tumor cells in the MMTV-PyMT breast cancer model. MMTV-PyMT mice were bred with actin-GFP mice, and focal hyperplastic lesions from pubertal MMTV-PyMT;actin-GFP mice were orthotopically transplanted into FVB/n mice to track single tumor foci. Tumor-bearing mice were treated with TAC chemotherapy (docetaxel, doxorubicin, cyclophosphamide), and residual and relapsed tumor cells were sorted and profiled by mRNA microarray analysis. Data analysis revealed enrichment of the Jak/Stat pathway, Notch pathway, and epigenetic regulators in residual tumors. Stat1 was significantly up-regulated in a DNA-damage-resistant population of residual tumor cells, and a pre-existing Stat1 sub-population was identified in untreated tumors. Tumor cells from adenomas, carcinomas, lung disseminated tumor cells, and lung metastases were also sorted from MMTV-PyMT transplant mice and profiled by mRNA microarray. Whereas disseminated tumors cells appeared similar to carcinoma cells at the mRNA level, lung metastases were genotypically very different from disseminated cells and primary tumors. Lung metastases were enriched for a number of chromatin-modifying genes and stem cell-associated genes. Histone analysis of H3K4 and H3K9 suggested that lung metastases had been reprogrammed during malignant progression. These data identify novel biomarkers of residual tumor cells and disseminated tumor cells and implicate pathways that may mediate metastasis formation and tumor relapse after therapy.</p> </div

Gene families enriched in residual MMTV-PyMT tumors after chemotherapy.

<p>Gene families enriched in residual MMTV-PyMT tumors after chemotherapy.</p

Histone-3 methylation marks in cancer progression.

<p>(A) Western blot of H3K4 tri-methyl, H3K9 tri-methyl, H3K27 tri-methyl and actin control in tumor lysates from adenomas (5 week outgrowth), carcinomas (18 week outgrowth), and lung metastasis; n = 3 per group. (B) Western blot of H3K4 tri-methyl, H3K4 di-methyl, H3K4 mono-methyl and Histone 3 control performed with serial dilutions of tumor lysates (1 ug, 5 ug, 10 ug total protein loaded per well). (C) Fluidigm RT-PCR analysis of Il-6, Il-6ra, and Prdm1 in the indicated tumor populations. GFP-positive tumor populations were FACS-sorted from the indicated groups and mRNA was harvested for the analysis; mean ± s.e.m., n = 5 per group. Data was normalized to Gapdh expression.</p

Profiling of disseminated cells and metastases in MMTV-PyMT hyperplasia transplant model.

<p>Representative brightfield (A) and GFP fluorescence (A′) images of the lungs of mice with advanced carcinoma (18 week outgrowths). Disseminated tumors cells were detected as single, GFP-positive cells in the lungs as early as 8-weeks post-transplant. (B) Representative image of a single disseminated tumor cell in the lung of an 18-week-tumor-bearing mouse. Green indicates GFP and blue indicates DAPI. (C) Whole mount image of lung metastases. Mice with 18-week tumor outgrowths were anesthetized and the primary tumor was surgically removed. Mice were sacrificed when they developed the first signs of respiratory distress, indicating the growth of lung metastases (typically 8–10 weeks after primary tumor removal). (D) Number of genes differentially expressed by 2-fold (light blue) and 4-fold (dark blue) in microarray dataset comparisons. (E) Hierarchical clustering of chromatin modifying genes in tumor populations. Tumor populations from adenoma (red), carcinoma (green), disseminated cells (blue), and metastases (purple) were FACS-sorted for profiling. Inset shows clustering of H3K4, H3K9, and H3K27 methyltransferases. Scale bars correspond to 1 mm (A, C) and 5 um (B).</p

Ifn-γ/Jak/Stat signaling in MMTV-PyMT residual tumor cells after chemotherapy.

<p>(A) Ingenuity pathway analysis of genes up-regulated in chemotherapy-treated residual tumors in the MMTV-PyMT transplant model. (B) Microarray expression values of Ifn-γ/Jak/Stat-associated genes in untreated (green), residual (red) and relapsed (blue) tumors; mean, n = 5 per group. (C) Fluidigm RT-PCR analysis of Ifn-γ/Jak/Stat-associated genes. GFP-positive tumor populations were FACS-sorted from the indicated groups and mRNA was harvested for the analysis; mean ± s.e.m., n = 5 per group. Data was normalized to Gapdh expression.</p