Objective-Progressive multifocal leukoencephalopathy (PML) is a fatal demyelinating disease of the white matter affecting immunocompromised patients that results from the cytolytic destruction of glial cells by the human neurotropic JC virus (JCV). According to one model, during the course of immunosuppression, JCV departs from its latent state in the kidney and after entering the brain, productively infects and destroys oligodendrocytes. The goal of this study was to test the hypothesis that JCV may reside in a latent state in a specific region of the brains of immunocompetent (non-PML) individuals without any neurological conditions. Methods-Gene amplification was performed together with immunohistochemistry to examine the presence of JCV DNA sequences and expression of its genome in five distinct regions of the brain from seven immunocompetent non-PML individuals.Results-Although no viral proteins were expressed in any of these cases, fragments of the viral DNA were present in various regions of normal brain. Laser-capture microdissection showed the presence of JCV DNA in oligodendrocytes and astrocytes, but not in neurons.Interpretation-The detection of fragments of viral DNA in non-PML brain suggests that JCV has full access to all regions of the brain in immunocompetent individuals. Thus, should the immune system become impaired, the passing and/or the resident virus may gain the opportunity to express its genome and initiate its lytic cycle in oligodendrocytes. The brain as a site of JCV latency is a possibility.The human polyomavirus, JC virus (JCV), infects greater than 80% of the human population by early adulthood and remains in a persistent state throughout life. 1-3 Under certain pathological conditions, when the immune system is severely impaired, JCV becomes reactivated and its productive replication in oligodendrocytes causes the fatal demyelinating disease, progressive multifocal leukoencephalopathy (PML). 4,5 Once a rare disease of white matter seen in patients with lymphoproliferative and myeloproliferative disease, 5 PML has been seen more frequently in acquired immune deficiency syndrome patients. 6,7 More recently, it was shown that manipulation of immune cells, both T and B cells, by specific monoclonal antibodies that impair trafficking to the brain may promote JCV replication and the development of PML. 8 The histopathological hallmarks of PML include demyelinated Address correspondence to Dr Khalili, Department of Neuroscience, Center for Neurovirology, Temple University School of Medicine, 1900 North 12th Street, 015-96, Room 203, Philadelphia, PA 19122. E-mail: kamel.khalili@temple Similar to its well-studied family member, SV40, the genome of JCV consists of closed, circular, double-stranded DNA of 5130 nucleotides in size 10 with 3 distinct domains: early, late, and control regions (Fig 1). The early region is responsible for expression of a series of proteins, called T antigens, which possess regulatory functions on the viral replication cycle and affect several cellular p...

Immunoliposome (IL) targeting to areas of inflammation after an acute myocardial infarction (MI) could provide the means by which pro-angiogenic compounds can be selectively targeted to the infarcted region. The adhesion of model drug carriers and ILs coated with an antibody to P-selectin was quantified in a rat model of MI following left coronary artery ligation. Anti-P-selectin coated model drug carriers showed a 140% and 180% increase in adhesion in the border zone of the MI 1 and 4 h post-MI, respectively. Radiolabeled anti-P-selectin ILs injected immediately post-MI and allowed to circulate 24 h showed an 83% increase in targeting to infarcted myocardium when compared to adjacent non-infarcted myocardium. Radiolabeled anti-P-selectin ILs injected 4 h post-MI and allowed to circulate for 24 h showed a 92% increase in accumulation in infarcted myocardium when compared to adjacent non-infarcted myocardium. Targeting to upregulated adhesion molecules on the endothelium provides a promising strategy for selectively delivering compounds to the infarct region of the myocardium using our liposomal-based drug delivery vehicle.

Particularly interesting cysteine histidine-rich (PINCH) protein functions as a shuttling protein in Schwann cells after peripheral nerve damage, during repair and remodeling, and in maintaining neuronal polarity. However, the presence of PINCH in the human CNS during disease has not been addressed. Because HIV-associated damage to cells of the CNS involves dysregulation of neuronal signaling and white matter damage, we hypothesized that PINCH may play a role in neuropathological processes during the course of HIV infection. To determine the expression of PINCH in the CNS, brain, and cerebrospinal fluid (CSF) obtained at autopsy from HIV patients with no CNS alterations, HIV encephalitic (HIVE) patients, and HIV-negative individuals with no CNS alterations were examined for PINCH immunoreactivity. Our results show that PINCH is expressed robustly in the brains and CSF of HIV patients, but is nearly undetectable in HIV-negative individuals. However, HIVE patients' CSF contained significantly less PINCH than HIV patients with no CNS alterations. PINCH immunolabeling was significantly more intense in the white matter than in the grey matter and was associated exclusively with neuronal cell bodies or processes, or with the extracellular matrix. Given the recently discovered importance of PINCH in maintaining neuronal fitness, our observations that PINCH is robustly expressed in the CNS of HIV patients suggests an important role for PINCH in HIV-associated neurodegenerative processes. Understanding mechanisms by which PINCH functions during HIV-associated CNS alterations will provide new insight into potential treatments to limit neurological alterations in HIV.

There is a need to identify more effective drugs for the treatment of ovarian cancer as it is the leading cause of death among gynecologic tumors. All-trans retinoic acid (ATRA), a natural retinoid, arrests the growth of CA-OV3 ovarian carcinoma cells in G 0 -G 1 . Because the insulin-like growth factor-I receptor has been implicated in the proliferation of various tumors, we investigated its potential role in the suppression of ovarian cancer cell growth by ATRA. Our studies revealed that insulin receptor substrate-1 (IRS-1) protein levels decrease in CA-OV3 cells on ATRA treatment, whereas no differences in IRS-1 levels were seen in the ATRA-resistant SK-OV3 cells. Moreover, CA-OV3 clones overexpressing IRS-1 were growth inhibited less by ATRA, whereas SK-OV3 clones in which levels of IRS-1 were reduced by expression of antisense IRS-1 became sensitive to growth inhibition by ATRA treatment. Studies to determine the mechanism by which ATRA reduced IRS-1 expression showed that ATRA altered steady-state levels of IRS-1 mRNA and the stability of IRS-1 protein. Finally, the role of IRS-1 as a potential molecular target of ATRA in ovarian tumors was assessed by immunohistochemistry in an ovarian cancer tissue array. Compared with normal ovary, the majority of malignant epithelial ovarian tumors overexpressed IRS-1. Thus, there seems to be a correlation between IRS-1 expression and malignancy in ovarian tumors. Our results suggest that IRS-1 is in fact an important growth-regulatory molecule that can be a potential effective target for chemotherapeutic intervention with growth-suppressive agents, including retinoids. [Cancer Res 2007;67(19):9266-75]