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      Glioblastoma microvesicles transport RNA and protein that promote tumor growth and provide diagnostic biomarkers

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          Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma.

          Glioblastoma, the most common primary brain tumor in adults, is usually rapidly fatal. The current standard of care for newly diagnosed glioblastoma is surgical resection to the extent feasible, followed by adjuvant radiotherapy. In this trial we compared radiotherapy alone with radiotherapy plus temozolomide, given concomitantly with and after radiotherapy, in terms of efficacy and safety. Patients with newly diagnosed, histologically confirmed glioblastoma were randomly assigned to receive radiotherapy alone (fractionated focal irradiation in daily fractions of 2 Gy given 5 days per week for 6 weeks, for a total of 60 Gy) or radiotherapy plus continuous daily temozolomide (75 mg per square meter of body-surface area per day, 7 days per week from the first to the last day of radiotherapy), followed by six cycles of adjuvant temozolomide (150 to 200 mg per square meter for 5 days during each 28-day cycle). The primary end point was overall survival. A total of 573 patients from 85 centers underwent randomization. The median age was 56 years, and 84 percent of patients had undergone debulking surgery. At a median follow-up of 28 months, the median survival was 14.6 months with radiotherapy plus temozolomide and 12.1 months with radiotherapy alone. The unadjusted hazard ratio for death in the radiotherapy-plus-temozolomide group was 0.63 (95 percent confidence interval, 0.52 to 0.75; P<0.001 by the log-rank test). The two-year survival rate was 26.5 percent with radiotherapy plus temozolomide and 10.4 percent with radiotherapy alone. Concomitant treatment with radiotherapy plus temozolomide resulted in grade 3 or 4 hematologic toxic effects in 7 percent of patients. The addition of temozolomide to radiotherapy for newly diagnosed glioblastoma resulted in a clinically meaningful and statistically significant survival benefit with minimal additional toxicity. Copyright 2005 Massachusetts Medical Society.
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            Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells.

            Exosomes are vesicles of endocytic origin released by many cells. These vesicles can mediate communication between cells, facilitating processes such as antigen presentation. Here, we show that exosomes from a mouse and a human mast cell line (MC/9 and HMC-1, respectively), as well as primary bone marrow-derived mouse mast cells, contain RNA. Microarray assessments revealed the presence of mRNA from approximately 1300 genes, many of which are not present in the cytoplasm of the donor cell. In vitro translation proved that the exosome mRNAs were functional. Quality control RNA analysis of total RNA derived from exosomes also revealed presence of small RNAs, including microRNAs. The RNA from mast cell exosomes is transferable to other mouse and human mast cells. After transfer of mouse exosomal RNA to human mast cells, new mouse proteins were found in the recipient cells, indicating that transferred exosomal mRNA can be translated after entering another cell. In summary, we show that exosomes contain both mRNA and microRNA, which can be delivered to another cell, and can be functional in this new location. We propose that this RNA is called "exosomal shuttle RNA" (esRNA).
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              Angiogenesis in cancer and other diseases.

               P Carmeliet,  R Jain (2000)
              Pathological angiogenesis is a hallmark of cancer and various ischaemic and inflammatory diseases. Concentrated efforts in this area of research are leading to the discovery of a growing number of pro- and anti-angiogenic molecules, some of which are already in clinical trials. The complex interactions among these molecules and how they affect vascular structure and function in different environments are now beginning to be elucidated. This integrated understanding is leading to the development of a number of exciting and bold approaches to treat cancer and other diseases. But owing to several unanswered questions, caution is needed.
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                Author and article information

                Affiliations
                [1 ] Departments of Neurology and Radiology, Massachusetts General Hospital, and Neuroscience Program, Harvard Medical School, Boston, Massachusetts, USA
                [2 ] Neuro-oncology Research Group, Department of Neurosurgery, Cancer Center Amsterdam, VU Medical Center, Amsterdam, The Netherlands
                [3 ] Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School
                [4 ] Department of Neurology, Brigham and Women’s Hospital, Harvard Medical School, Boston MA, USA
                Author notes
                [5 ]Correspondence should be addressed to: Xandra O. Breakefield, Ph.D., Molecular Neurogenetics Unit, Massachusetts General Hospital-East, 13 th Street, Building 149, Charlestown, MA, 02129 USA, Phone 617-726-5728, Fax 617-724-1537, E-mail: breakefield@ 123456hms.harvard.edu
                Journal
                100890575
                21417
                Nat Cell Biol
                Nature cell biology
                1465-7392
                1476-4679
                25 September 2008
                16 November 2008
                December 2008
                21 August 2012
                : 10
                : 12
                : 1470-1476
                3423894
                19011622
                10.1038/ncb1800
                nihpa70106
                Funding
                Funded by: National Cancer Institute : NCI
                Award ID: P50 CA086355-060003 ||CA
                Funded by: National Cancer Institute : NCI
                Award ID: P01 CA069246-120003 ||CA
                Categories
                Article

                Cell biology

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