Citations

Abstract Aneurysmal bone cyst (ABC) is a locally aggressive osseous lesion that typically occurs during the first two decades of life. ABC was regarded historically as a nonneoplastic process, but recent cytogenetic data have shown clonal rearrangements of chromosomal bands 16q22 and 17p13, indicating a neoplastic basis in at least some ABCs. Herein we show that a recurring ABC chromosomal translocation t(16;17)(q22;p13) creates a fusion gene in which the osteoblast cadherin 11 gene (CDH11) promoter region on 16q22 is juxtaposed to the entire ubiquitin-specific protease USP6 (Tre2) coding sequence on 17p13. CDH11-USP6 fusion transcripts were demonstrated only in ABC with t(16;17) but other ABCs had CDH11 or USP6 rearrangements resulting from alternate cytogenetic mechanisms. CDH11 is expressed strongly in bone, and our findings implicate a novel oncogenic mechanism in which deregulated USP6 transcription results from juxtaposition to the highly active CDH11 promoter.

ABSTRACTLatently human immunodeficiency virus (HIV)-infected memory CD4+T cells represent the major obstacle to eradicating HIV from infected patients. Antigens, T-cell receptor (TCR) ligation, and phorbol esters can reactivate HIV from latency in a protein kinase C (PKC)-dependent manner; however, it is unknown which specific PKC isoforms are required for this effect. We demonstrate that constitutively active (CA) forms of both PKCθ, PKCθA148E, and PKCα, PKCαA25E, induce HIV long terminal repeat (LTR)-dependent transcription in Jurkat and primary human CD4+T cells and that both PKCθA148E and PKCαA25E cause HIV reactivation in J1.1 T cells. Suppression of both PKCα and PKCθ with short hairpinned (sh) RNA inhibited CD3/CD28-induced HIV LTR-dependent transcription and HIV reactivation in J1.1 T cells. Both prostratin and phorbol myristate 13-acetate induced HIV LTR-dependent transcription and HIV reactivation in J1.1 T cells that was blocked by shRNA against either PKCα or PKCθ. Since suppression of PKCα and PKCθ together has no greater inhibitory effect on HIV reactivation than inhibition of PKCα alone, our data confirm that PKCα and PKCθ act in sequence. The requirement for PKCα and PKCθ for prostratin-induced HIV reactivation and the ability of selective PKCα or PKCθ agonists to induce HIV transcription indicate that these PKC isoforms are important targets for therapeutic drug design.

ABSTRACT Globoid cell leukodystrophy (GLD) or Krabbe disease is a devastating, degenerative neurological disorder caused by mutations in the galactosylceramidase (GALC) gene that severely affect enzyme activity. Currently, treatment options for this disorder are very limited. Enzyme replacement therapy (ERT) has been shown to be effective in lysosomal storage disorders with predominantly peripheral manifestations such as type I Gaucher's and Fabry's disease. Little however is known about the possible benefit of ERT in GLD, which has a substantial central nervous system component. In this study, we examined the effect of peripheral GALC injections in the twitcher mouse model of the disease. Although we were unable to block the precipitous decline that normally occurs just before death, we did observe significant early improvements in motor performance, a substantial attenuation in the initial failure to thrive, and an increase in life span. Immunohistochemical and activity analyses demonstrated GALC uptake in multiple tissues, including the brain. This was associated with a decrease in the abnormal accumulation of the GALC substrate psychosine, which is thought to play a pivotal role in disease pathology. These results indicate that peripheral ERT is likely to be beneficial in GLD.

AbstractWe have reviewed 108 cases of bacterial endocarditis treated surgically since 1968. The mean age of the patients was 47.7±15.6 years (± SD) (range, 14–79 yr). Seventy‐seven percent were male. The most common causative organisms were staphylococci (46%), streptococci viridans group (25%), and other streptococci (20%). Forty‐five percent, 25%, and 13% of patients had native aortic valve, native mitral valve, or native double valve (AV/MV) involvement, respectively. Eighteen patients had prosthetic valve endocarditis. No patient underwent surgery for tricuspid valve endocarditis. Seventy‐three patients were considered to have active endocarditis (AE) (positive blood or tissue cultures and/or annular abscesses). The 35 remaining patients had healed endocarditis (HE). Preoperative complications in patients with either AE or HE were stroke (11%, 11%), renal failure (33%, 3%;p<0.001), pulmonary edema (83%, 34%;p<0.001), anemia (36%, 8%;p<0.01), and inotrope dependence (22%, 6%;p<0.05). Hospital mortality for native valve AE was 19.6% (11/56), and for healed endocarditis, 5.7% (2/35). Independent predictors of hospital mortality were inotrope dependence (p<0.001), annular abscess (p<0.01), pulmonary edema (p<0.01), and staphylococcal infection (p<0.05). The 5‐year actuarial survival for operative survivors was 68.4±7.5% (AE) and 78.3±9.2% (HE). We conclude that the operative mortality for patients with continuing sepsis is high and that surgery should be undertaken early in staphylococcal endocarditis. If surgery is successful, then the long‐term prognosis is good.

Abstract Exuberant inflammatory responses are associated with respiratory failure during Pneumocystis pneumonia. Alveolar epithelial cells (AECs) promote Pneumocystis attachment and proliferation, but also contribute prominently to host cytokine-mediated inflammation during pneumonia. Recent investigations indicate that AECs produce macrophage inflammatory protein-2 (MIP-2) and tumor necrosis factor-α (TNF-α) following challenge with Pneumocystis carinii. Nuclear factor-κB (NF-κB) is a ubiquitous transcription factor critical for regulation of proinflammatory cytokine expression. Herein, we assess rat AEC NF-κB responses to challenge with a P. carinii β-glucan cell wall component (PCBG). Prominent nuclear translocation of p65 NF-κB was demonstrated following PCBG challenge. NF-κB activation was in part mediated through Protein Kinase C (PKC) signaling pathways. PCBG challenge of AECs was also shown to induce MIP-2 and TNF-α mRNA production, a response that was ameliorated by NF-κB inhibition. MIP-2 protein expression was also dramatically increased by PCBG challenge, in a manner that was significantly attenuated by both PKC and NF-κB inhibition. The data further demonstrate that AEC chemokine responses were not mediated by the recently described dectin-1 receptor, but instead involved participation of cell surface lactosylceramide. These data support a significant role for AECs in host responses during Pneumocystis pneumonia, and further indicate that β-glucan induces inflammatory cytokine production through NF-κB–dependent mechanisms.

Clinical Pharmacology & Therapeutics (2003) 73, P81–P81; doi: