Glioblastoma is both the most common and lethal primary malignant brain tumor. Extensive multiplatform genomic characterization has provided a higher-resolution picture of the molecular alterations underlying this disease. These studies provide the emerging view that “glioblastoma” represents several histologically similar yet molecularly heterogeneous diseases, which influences taxonomic classification systems, prognosis, and therapeutic decisions.

Respiratory syncytial virus (RSV) belongs to the Pneumovirus genus of the Paramyxovirus virus family. RSV is the leading cause of virus-induced lower respiratory tract disease among infants and children (6,21,26) and is the most common pathogen found in children under 5 years of age admitted to the hospital. Essentially every child develops an RSV infection during the first 2 years of life, and recurrent infections are common (20,24,42,44). RSV is especially serious in premature infants and children with bronchopulmonary dysplasia or congenital heart disease. Additionally, in recent studies, RSV was the most common virus identified in the middle-ear fluid of children suffering from acute otitis media (25,43). RSV infection has also been implicated in the development of childhood asthma and other long-term conditions involving pulmonary dysfunction (54-56).

The p53 tumor suppressor protein can function as an activator and a repressor of gene transcription. Currently, the mechanism of transcriptional repression by p53 is poorly understood. To aid in clarifying this mechanism, we carried out studies designed to identify specific target genes that are down-regulated following p53 induction. Among the negative p53-response genes revealed by our screening protocols are those encoding stathmin (Op18), a tubulin-associated protein implicated in cell signaling pathways, and an FK506/rapamycin-binding protein, FKBP25. Stathmin and FKBP25 exhibit decreased expression in both human and murine immortalized and transformed cell lines following induction of wild-type p53 by several stimuli that result in DNA damage. Candidate p53-repressed genes such as these provide the necessary markers to delineate the mechanism and biological consequences of transcriptional repression mediated by p53.

Hematogenous metastasis is initiated by a subset of circulating tumor cells (CTC) shed from primary or metastatic tumors into the blood circulation. Thus, CTCs provide a unique patient biopsy resource to decipher the cellular subpopulations that initiate metastasis and their molecular properties. However, one crucial question is whether CTCs derived and expanded ex vivo from patients recapitulate human metastatic disease in an animal model. Here, we show that CTC lines established from patients with breast cancer are capable of generating metastases in mice with a pattern recapitulating most major organs from corresponding patients. Genome-wide sequencing analyses of metastatic variants identifi ed semaphorin 4D as a regulator of tumor cell transmigration through the blood-brain barrier and MYC as a crucial regulator for the adaptation of disseminated tumor cells to the activated brain microenvironment. These data provide the direct experimental evidence of the promising role of CTCs as a prognostic factor for site-specifi c metastasis. SIGNIFICANCE:Interests abound in gaining new knowledge of the physiopathology of brain metastasis. In a direct metastatic tropism analysis, we demonstrated that ex vivo -cultured CTCs from 4 patients with breast cancer showed organotropism, revealing molecular features that allow a subset of CTCs to enter and grow in the brain.

In the U.S. Medicare population, patients with IPF incurred substantial health care resource utilization. The annual IPF-attributable medical cost to the U.S. health care system, excluding medication costs, is estimated at close to $2 billion.