Targeting hyaluronan interactions in malignant gliomas and their drug-resistant multipotent progenitors.

PURPOSE: To determine if hyaluronan oligomers (o-HA) antagonize the malignant properties of glioma cells and treatment-resistant glioma side population (SP) cells in vitro and in vivo. EXPERIMENTAL DESIGN: A single intratumoral injection of o-HA was given to rats bearing spinal cord gliomas 7 days after engraftment of C6 glioma cells. At 14 days, spinal cords were evaluated for tumor size, invasive patterns, proliferation, apoptosis, activation of Akt, and BCRP expression. C6SP were isolated by fluorescence-activated cell sorting and tested for the effects of o-HA on BCRP expression, activation of Akt and epidermal growth factor receptor, drug resistance, and glioma growth in vivo. RESULTS: o-HA treatment decreased tumor cell proliferation, increased apoptosis, and down-regulated activation of Akt and the expression of BCRP. o-HA treatment of C6SP inhibited activation of epidermal growth factor receptor and Akt, decreased BCRP expression, and increased methotrexate cytotoxicity. In vivo, o-HA also suppressed the growth of gliomas that formed after engraftment of C6 or BCRP+ C6SP cells, although most C6SP cells lost their expression of BCRP when grown in vivo. Interestingly, the spinal cord gliomas contained many BCRP+ cells that were not C6 or C6SP cells but that expressed nestin and/or CD45; o-HA treatment significantly decreased the recruitment of these BCRP+ progenitor cells into the engrafted gliomas. CONCLUSIONS: o-HA suppress glioma growth in vivo by enhancing apoptosis, down-regulating key cell survival mechanisms, and possibly by decreasing recruitment of host-derived BCRP+ progenitor cells. Thus, o-HA hold promise as a new biological therapy to inhibit HA-mediated malignant mechanisms in glioma cells and treatment-resistant glioma stem cells.

Spinal muscular atrophy: classification, diagnosis, management, pathogenesis, and future research directions.

Spinal muscular atrophy is an autosomal recessive neurodegenerative disorder that affects the motor neurons responsible for movement of the proximal muscles of the trunk and body. To date, the disease can be classified into 3 main categories based on severity and age of onset. During the October 18th symposium held in Pittsburgh, Pennsylvania, researchers met to (1) describe current diagnostic strategies, (2) discuss recent thoughts on pathogenesis, (3) review current therapies and clinical trials, and (4) define future research directions. In her opening remarks, Dr Story Landis, director of the National Institute of Neurological Disorders and Stroke, emphasized the degree to which the Neurobiology of Disease in Children conference series has broadened awareness of the many rare diseases affecting children, not only through the advancement of research but also by educating practitioners about diagnostic strategies. Dr Landis also discussed the role this conference may play in fostering research that seeks to develop a single mechanism of therapy for spinal muscular atrophy. She also discussed the current funding situation at the National Institutes of Health and addressed the crucial function of volunteer research organizations that sponsor research in further improving management of this condition. This article summarizes the presentations and includes the verbatim edited transcript of question-and-answer sessions.

Injury to the preterm brain and cerebral palsy: clinical aspects, molecular mechanisms, unanswered questions, and future research directions.

Cerebral palsy will affect nearly 10% of the 60,000 very low-birth-weight infants born in the United States in the next year, and an even greater percentage will display some form of permanent neurological impairment resulting from injury to the preterm brain. The 2008 Neurobiology of Disease in Children Symposium, held in conjunction with the 37th annual meeting of the Child Neurology Society, aimed to define current knowledge and to develop specific aims for future clinical, translational, and fundamental science. A complex interplay of both destructive and developmental forces is responsible for injury to the preterm brain. Advances in imaging and histology have implicated a variety of cell types, though preoligodendrocyte injury remains the focus. Research into different mechanisms of injury is facilitating new neuroprotective and rehabilitative interventions. A cooperative effort is necessary to translate basic research findings into clinically effective therapies and better care for these children.

Tumors of the central nervous system: clinical aspects, molecular mechanisms, unanswered questions, and future research directions.

Central nervous system tumors are the most common solid tumors in children. Many histological subtypes and biological variants exist. The 2007 Neurobiology of Disease in Children Symposium, held in conjunction with the 36th annual meeting of the Child Neurology Society, aimed to define current knowledge in the field and to develop specific aims for future clinical, translational, and fundamental science. Because of advances in structural and metabolic imaging, surgical technique, and combination therapies, the life expectancy of children with some of the most common tumors, such as cerebellar astrocytomas and medulloblastomas, has improved. Other common tumor types, including diffuse pontine gliomas and malignant embryonal tumors, still have a dismal prognosis. As novel therapies are identified for pediatric central nervous system tumors, long-term survival may be associated with considerable disability. A cooperative effort is crucial to early diagnosis and to translating basic research findings into safe, effective new treatments.