Optimizing biomedical discoveries as an engine of culture change in an academic medical center.

Academic discovery in biomedicine is a growing enterprise with tens of billions of dollars in research funding available to universities and hospitals. Protecting and optimizing the resultant intellectual property is required in order for the discoveries to have an impact on society. To achieve that, institutions must create a multidisciplinary, collaborative system of review and support, and utilize connections to industry partners.

The PPARγ agonist pioglitazone crosses the blood-brain barrier and reduces tumor growth in a human xenograft model.

Purpose: The peroxisome proliferator-activated receptor gamma (PPARγ), a member of the nuclear hormone receptor family, represents a target in glioma therapy due to its antineoplastic effects in vitro on human glioma cell lines. We investigate the antineoplastic effects of the PPARγ agonist pioglitazone (pio) in a human glioma xenograft model to define the minimal required dose to induce antineoplastic effects. Additionally, we assess the ability of pio to cross the blood-brain barrier by measuring brain parenchymal concentration after oral administration.

Hepatocyte growth factor mediates mesenchymal stem cell–induced recovery in multiple sclerosis models.

Mesenchymal stem cells (MSCs) have emerged as a potential therapy for a range of neural insults. In animal models of multiple sclerosis, an autoimmune disease that targets oligodendrocytes and myelin, treatment with human MSCs results in functional improvement that reflects both modulation of the immune response and myelin repair. Here we demonstrate that conditioned medium from human MSCs (MSC-CM) reduces functional deficits in mouse MOG35–55-induced experimental autoimmune encephalomyelitis (EAE) and promotes the development of oligodendrocytes and neurons.

Elevation of osteopontin levels in brain tumor cells reduces burden and promotes survival through the inhibition of cell dispersal.

Osteopontin (OPN) is a pleotrophic molecule that has been associated with multiple disorders of the central nervous system (CNS). Its roles in CNS malignancy are unclear but suggest that higher levels of OPN expression correlate with increased tumor grade and increased migratory capacity of tumor cells. In this study OPN cDNA was cloned into a retroviral vector and used to infect F98 Fischer rat-derived glioma cells and U87 human-derived glioblastoma multiforme (GBM) cells in vitro.

Bone morphogenetic proteins promote gliosis in demyelinating spinal cord lesions.

Objective: To determine the role of bone morphogenetic proteins (BMPs) in stimulating glial scar formation in demyelinating lesions of the adult spinal cord.

Methods: The dorsal columns of adult rats were injected with lysolecithin to induce a local demyelinating lesion. Levels of BMP4 and BMP7 proteins were assayed and compared with glial fibrillary acidic protein expression in the injury area.

Neonatal loss of gamma-aminobutyric acid pathway expression after human perinatal brain injury.

Object: Perinatal brain injury leads to chronic neurological deficits in children. Damage to the premature brain produces white matter lesions (WMLs), but the impact on cortical development is less well defined. Gamma-aminobutyric acid(GABA)ergic neurons destined for the cerebral cortex migrate through the developing white matter and form the subplate during late gestation.

Developmental changes induced by graded prenatal systemic hypoxic-ischemic insults in rats.

In infants, a common consequence of systemic perinatal insults is disruption of neonatal brain development. Such insults can cause cerebral palsy, cognitive delay, epilepsy and other chronic neurologic deficits in children. The mechanisms underlying disruption of brain development after perinatal insults are poorly defined.

Differential signaling through NFkappaB does not ameliorate skeletal myoblast apoptosis during differentiation.

During 23A2 skeletal myoblast differentiation, roughly 30% of the population undergoes apoptosis. Further, constitutive signaling by G12V:H-Ras or Raf:CAAX abrogates this apoptosis. In this study, we demonstrate an increase in NFkappaB activity in myoblasts that have survived and are expressing muscle-specific genes.

Loss of ypk1 function causes rapamycin sensitivity, inhibition of translation initiation and synthetic lethality in 14-3-3-deficient yeast.

14-3-3 proteins bind to phosphorylated proteins and regulate a variety of cellular activities as effectors of serine/threonine phosphorylation. To define processes requiring 14-3-3 function in yeast, mutants with increased sensitivity to reduced 14-3-3 protein levels were identified by synthetic lethal screening. One mutation was found to be allelic to YPK1, which encodes a Ser/Thr protein kinase.

Raf-induced effects on the differentiation and apoptosis of skeletal myoblasts are determined by the level of Raf signaling: abrogation of apoptosis by Raf is downstream of caspase 3 activation.

We examined the effect of a constitutively active Raf protein (Raf-CAAX) on the differentiation and the coincident apoptosis of skeletal myoblasts. We found that a low level of Raf signaling leads to accelerated differentiation when compared to parental myoblasts, while a higher level of Raf signaling induces a transformed morphology and abrogates both differentiation and the coincident apoptosis. Raf signaling abrogates apoptosis without blocking the activation of caspase 3 and the subsequent cleavage of caspase 3 substrates.