An understanding of the 3-D anatomic organization of the fiber tracts of the brain is essential in planning safe and accurate cerebral surgery.
BackgroundDendritic cell (DC) vaccine efficacy is directly related to the efficiency of DC migration to the lymph node after delivery to the patient. We discovered that a naturally occurring metabolite, sarcosine, increases DC migration in human and murine cells resulting in significantly improved anti-tumor efficacy. We hypothesized that sarcosine induced cell migration was due to chemokine signaling.MethodsDCs were harvested from the bone marrow of wild type C57BL/6 mice and electroporated with tumor messenger RNA (mRNA). Human DCs were isolated from peripheral blood mononuclear cells (PBMCs). DCs were treated with 20 mM of sarcosine. Antigen specific T cells were isolated from transgenic mice and injected intravenously into tumor bearing mice. DC vaccines were delivered via intradermal injection. In vivo migration was evaluated by flow cytometry and immunofluorescence microscopy. Gene expression in RNA was investigated in DCs via RT-PCR and Nanostring.ResultsSarcosine significantly increased human and murine DC migration in vitro. In vivo sarcosine-treated DCs had significantly increased migration to both the lymph nodes and spleens after intradermal delivery in mice. Sarcosine-treated DC vaccines resulted in significantly improved tumor control in a B16F10-OVA tumor flank model and improved survival in an intracranial GL261-gp100 glioma model. Gene expression demonstrated an upregulation of CXCR2, CXCL3 and CXCL1 in sarcosine- treated DCs. Further metabolic analysis demonstrated the up-regulation of cyclooxygenase-1 and Pik3cg. Sarcosine induced migration was abrogated by adding the CXCR2 neutralizing antibody in both human and murine DCs. CXCR2 neutralizing antibody also removed the survival benefit of sarcosine-treated DCs in the tumor models.ConclusionSarcosine increases the migration of murine and human DCs via the CXC chemokine pathway. This platform can be utilized to improve existing DC vaccine strategies.
Dr. Rhoton’s key philosophies included “Keep working hard.”, “Make surgery more accurate, gentle and safe”, “We want perfect anatomical dissections, because we want perfect surgical operations”, “Competence without compassion is worthless. Compassion without competence is meaningless”, “Neurosurgeons share a great professional gift; our lives have yielded an opportunity to help mankind in a unique and exciting way” and “There is no finish line for this effort”. His words reveal his passion for microneurosurgery and infinite love for humankind. Although his reknown rested on his reputation as a researcher, Dr. Rhoton was also a devoted educator. The principal aim behind the enormous amount of work he performed was that of educating neurosurgeons worldwide, so that they could be better surgeons. His work included: (1) numerous dissection courses, (2) numerous lectures and publications including about 160 original papers (3) the textbook “RHOTON” and Rhoton Collection (4) the education of 119 research fellows. The projects directed in his lab, produced the international dissemination of neuroanatomical knowledge. The ultimate goal of his microsurgical research was to improve the care of patients with neurosurgical diseases around the world. The technical contributions and humble character of Dr. Rhoton should be remembered as we care for patients.
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