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Brain metastases are an increasing burden among breast cancer patients, particularly for those with HER2+ and triple negative (TN) subtypes. Mechanistic insight into the pathophysiology of brain metastases and preclinical validation of therapies has relied almost exclusively on intracardiac injection of brain-homing cells derived from highly aggressive TN MDA-MB-231 and HER2+ BT474 breast cancer cell lines. Yet, these well characterized models are far from representing the tumor heterogeneity observed clinically and, due to their fast progression in vivo, their suitability to validate therapies for established brain metastasis remains limited. The goal of this study was to develop and characterize novel human brain metastasis breast cancer patient-derived xenografts (BM-PDXs) to study the biology of brain metastasis and to serve as tools for testing novel therapeutic approaches. We obtained freshly resected brain metastases from consenting donors with breast cancer. Tissue was immediately implanted in the mammary fat pad of female immunocompromised mice and expanded as BM-PDXs. Brain metastases from 3/4 (75%) TN, 1/1 (100%) estrogen receptor positive (ER+), and 5/9 (55.5%) HER2+ clinical subtypes were established as transplantable BM-PDXs. To facilitate tracking of metastatic dissemination using BM-PDXs, we labeled PDX-dissociated cells with EGFP-luciferase followed by reimplantation in mice, and generated a BM-derived cell line (F2-7). Immunohistologic analyses demonstrated that parental and labeled BM-PDXs retained expression of critical clinical markers such as ER, progesterone receptor, epidermal growth factor receptor, HER2, and the basal cell marker cytokeratin 5. Similarly, RNA sequencing analysis showed clustering of parental, labeled BM-PDXs and their corresponding cell line derivative. Intracardiac injection of dissociated cells from BM-E22-1, resulted in magnetic resonance imaging-detectable macrometastases in 4/8 (50%) and micrometastases (8/8) (100%) mice, suggesting that BM-PDXs remain capable of colonizing the brain at high frequencies. Brain metastases developed 8–12 weeks after ic injection, located to the brain parenchyma, grew around blood vessels, and elicited astroglia activation characteristic of breast cancer brain metastasis. These novel BM-PDXs represent heterogeneous and clinically relevant models to study mechanisms of brain metastatic colonization, with the added benefit of a slower progression rate that makes them suitable for preclinical testing of drugs in therapeutic settings.

This article describes Picasso's first visit to the French capital in 1900, and the events that led to his first major exhibition at the acclaimed Galerie Ambroise Vollard in Paris in 1901. The first section provides a narrative of his early experiences abroad as a young unknown artist, his influences, and the contacts he established with friends, artists and dealers during this important period of his career; the second section traces the histories of the sixty-five artworks that were exhibited, identifying the collections those items went through after they were exhibited, their current locations, as well as the exhibitions in which they have been featured since Vollard first displayed them in his gallery. The last section elaborates on some of the immediate repercussions of the exhibition. The reported findings are the result of extensive research on hundreds of books and catalogs published on Pablo Picasso from 1901 to the present. The new facts we have uncovered are published here for the first time. Readers of the article will learn that the works included in Picasso's first exhibition in France have been part of the most prestigious art collections, such as those of Justin K. Thannhauser, Gertrude Stein, Chester Dale, Paul Guillaume, Walter P. Chrysler, Jr., Paul Mellon, Helena Rubinstein, Alfred Flechtheim, Walter C. Arensberg, among others. The works have also been featured in such important overviews of his career as "Picasso, 75th Anniversary" 1957–1958, and "Picasso: An American Tribute", 1962. Thus, while Vollard claimed that the exhibition at his gallery had no major impact, the facts show that it not only played an important role in Picasso's acceptance as a groundbreaking newcomer, but also left a significant mark on the rest of his career, as evidenced by the works' inclusion in the retrospectives held in Paris and Zürich in 1932, and New York in 1980. [ABSTRACT FROM AUTHOR]