Methylation of DNA and chromatin as a mechanism of oncogenesis and therapeutic target in neuroblastoma.

Neuroblastoma (NB), a developmental cancer, is often fatal, emphasizing the need to understand its pathogenesis and identify new therapeutic targets. The heterogeneous pathological and clinical phenotype of NB underscores the cryptic biological and genetic features of this tumor that result in outcomes ranging from rapid progression to spontaneous regression. Despite recent genome-wide mutation analyses, most primary NBs do not harbor driver mutations, implicating epigenetically-mediated gene regulatory mechanisms in the initiation and maintenance of NB.

p75NTR-dependent modulation of cellular handling of reactive oxygen species.

Our previous studies demonstrated that p75NTR confers protection against oxidative stress-induced apoptosis upon PC12 cells; however, the mechanisms responsible for this effect are not known. The present studies reveal decreased mitochondrion membrane potential and increased generation of reactive oxygen species (ROS) in p75NTR-deficient PC12 cells as well as diminution of ROS generation after transfection of a full-length p75NTR construct into these cells. They also show that p75NTR deficiency attenuates activation of the phosphatidylinositol 3-kinase --> phospho-Akt/protein kinase B pathway in PC12 cells by oxidative stress or neurotrophic ligands and inhibition of Akt phosphorylation decreases the glutathione (GSH) content in PC12 cells.

Bcl-2 overexpression disrupts the morphology of PC12 cells through reduced ERK activation.

Bcl-2 has been hypothesized to regulate many cellular functions in addition to its well-characterized role in the prevention of programmed cell death. To understand the role of Bcl-2 in regulating cell morphology and to explore the mechanism of this effect, we examined the effects of Bcl-2 overexpression on the morphology of PC12 cells in culture. We demonstrate that the overexpression of Bcl-2 in PC12 cells results in altered cell morphology and reduced actin expression.

The p75 neurotrophin receptor in human development and disease.

The functional effects of nerve growth factor (NGF) and its precursor, pro-NGF, are thought to be mediated through binding of these ligands to one or both of their receptors, TrkA and p75NTR. While the signaling pathways and downstream effects of NGF binding to TrkA are reasonably well known, those related to the binding of NGF and pro-NGF to p75NTR are less well understood. Furthermore, p75NTR appears to play functional roles that are unrelated to its ability to bind NGF and pro-NGF, some of which are ligand-independent and others of which are dependent upon binding to other neurotrophins.

Neuroprotective effects of TEMPOL in central and peripheral nervous system models of Parkinson's disease.

TEMPOL (4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl) is a stable nitroxyl antioxidant. Previous studies have suggested that TEMPOL is protective in acute disorders thought to involve reactive oxygen species (ROS), such as ischemic stroke and cardiac reperfusion injury. Oxidized TEMPOL can be recycled to its redox-active reducing form by co-administration with polynitroxylated albumin, making it a candidate as a pharmacological "reservoir" for reducing potential of use in chronic disorders involving ROS.

The Scholarly Project Initiative: introducing scholarship in medicine through a longitudinal, mentored curricular program.

Many U.S. medical schools offer students the opportunity to undertake laboratory or clinical research or another form of scholarly project over the summer months, yet few require this as a prerequisite for graduation, and even fewer provide comprehensive didactic material in preparation for the performance of such a project as an integrated component of their curricula.

Bcl-2-mediated potentiation of neocarzinostatin-induced apoptosis: requirement for caspase-3, sulfhydryl groups, and cleavable Bcl-2.

Overexpression of antiapoptotic Bcl-2 family members is thought to contribute to chemotherapeutic resistance of neural crest tumors. Paradoxical potentiation by Bcl-2 of apoptosis induced by the antineoplastic prodrug, neocarzinostatin (NCS), has been observed in PC12 pheochromocytoma cells. Prior studies have indicated that the cleavage of Bcl-2 to its proapoptotic counterpart mediated by caspase-3 is responsible for this potentiation of apoptosis.

Cholesterol biosynthesis and the pro-apoptotic effects of the p75 nerve growth factor receptor in PC12 pheochromocytoma cells.

Neocarzinostatin (NCS), an enediyne antimitotic agent, induces cell death in both p75NTR neurotrophin receptor (NTR)-positive and p75NTR-negative PC12 cells in a concentration-dependent fashion. However, p75NTR-positive cells demonstrate a higher susceptibility to NCS-induced cell damage. Furthermore, treatment of p75NTR-positive cells with the p75NTR-specific ligand, MC192, resulted in apoptosis, while treatment of these cells with the TrkA-specific ligand, NGF-mAbNGF30, protected them from NCS-induced death, implying that both the naked and liganded p75NTR receptors have a pro-apoptotic effect on PC12 cells.

Toward the definition of acute disseminated encephalitis of childhood.

Purpose Of Review: Acute disseminated encephalomyelitis (ADEM) is a demyelinating disorder most common in childhood and adolescence and thought to have an immune pathogenesis. Some children with ADEM develop additional temporally remote episodes of demyelination with localizations that differ from those of the initial episode and multiple sclerosis is diagnosed. Others have only a single episode.

Brain imaging and prophylactic therapy in children with migraine: recommendations versus reality.

Objectives: To determine the concordance between referring physician behavior and published criteria for performance of imaging studies and institution of prophylactic therapy, respectively, in children referred to an academic children's hospital headache clinic. Study design A retrospective review of the records of 106 consecutive patients referred to an academic children's hospital headache clinic.

Results: Approximately half of patients referred to the clinic had already had head computed tomography or magnetic resonance imaging ordered by the referring doctor and performed before their clinic appointment.

Bcl-2 mediates induction of neural differentiation.

Bcl-2 is an antiapoptotic protein expressed in a wide variety of cell types. We have found that overexpression of bcl-2 in PC12 neural crest tumor cells leads to increased expression of neural differentiation-associated genes and decreased expression of proliferation-related genes. Culture growth rate decreases as well.

TrkA as a life and death receptor: receptor dose as a mediator of function.

Nerve growth factor (NGF) has been implicated as both an inhibitor and an inducer of apoptosis. Binding of NGF to its TrkA receptor is generally considered to have an antiapoptotic effect. However, neuroblastomas that overexpress TrkA have a good prognosis and frequently regress by apoptosis either spontaneously or after chemotherapeutic treatment, whereas those that express little or no TrkA are lethal in 80-95% of patients, despite maximal therapy.

p75-nerve growth factor as an antiapoptotic complex: independence versus cooperativity in protection from enediyne chemotherapeutic agents.

Growth factors, including nerve growth factor (NGF), have been hypothesized to play a role in resistance to chemotherapeutic agent-induced apoptosis. Induction by NGF of resistance to apoptosis is primarily thought to be the result of its binding to its high-affinity receptor, TrkA. The low-affinity NGF receptor, p75, has long been thought merely to facilitate NGF binding to TrkA.

Role of caspase 3-dependent Bcl-2 cleavage in potentiation of apoptosis by Bcl-2.

Previous studies from our laboratory have demonstrated that Bcl-2 has a proapoptotic effect on neocarzinostatin (NCS)-treated PC12 pheochromocytoma cells. In the present study, we examine the mechanisms of this effect and demonstrate its relevance for the in vivo situation. Four hours after NCS treatment, a 23-kDa cleavage product of Bcl-2 was detected in whole cell lysates of bcl-2-transfected PC12 cells.