Aberrant apoptosis-mediated cell death is believed to result in a number of different human diseases. For example, excessive apoptosis in the liver can result in fulminant and autoimmune forms of hepatitis. We have explored the possibility that inhibition of Fas expression in mice would reduce the severity of fulminant hepatitis. To do this, we have developed a chemically modified 2'-O-(2-methoxy)ethyl antisense oligonucleotide (ISIS 22023) inhibitor of mouse Fas expression. In tissue culture, this oligonucleotide induced a reduction in Fas mRNA expression that was both concentration- and sequence-specific. In Balb/c mice, dosing with ISIS 22023 reduced Fas mRNA and protein expressions in liver by 90%. The ID50 for this response was 8-10 mg kg-1 daily dosing, and the reduction was highly dependent on oligonucleotide sequence, oligonucleotide concentration in liver, and treatment time. Pretreatment with ISIS 22023 completely protected mice from fulminant hepatitis induced by agonistic Fas antibody, by a mechanism entirely consistent with an oligonucleotide antisense mechanism of action. In addition, oligonucleotide-mediated suppression of Fas expression reduced the severity of acetaminophen-mediated fulminant hepatitis, but was without effect on concanavalin A-mediated hepatitis. Our results demonstrate that 2'-O-(2-methoxy)ethyl containing antisense oligonucleotides targeting Fas can exert in vivo pharmacological activity in liver, and suggest that oligonucleotide inhibitors of Fas may be useful in the treatment of human liver disease.

Deregulation of the phosphoinositide 3-kinase (PI3K) signaling pathway such as by PTEN loss or PIK3CA mutation occurs frequently in human cancer and contributes to resistance to antitumor therapies. Inhibition of key signaling proteins in the pathway therefore represents a valuable targeting strategy for diverse cancers.

Movement over the surface of the temporomandibular joint (TMJ) disc produces tractional forces. These forces potentially increase the magnitude of shear stresses and contribute to wear and fatigue of the disc. Theoretically, tractional forces in all synovial joints are the result of frictional forces, due to rubbing of the cartilage surfaces, and plowing forces, due to translation of the stress-field through the cartilage matrix as the joint surface congruency changes during motion. For plowing forces to occur in the TMJ, there must be mediolateral translation of the stress-field as the condyle moves dorsoventrally during jaw function. To test whether mediolateral stress-field translation occurs in the intact TMJ, we measured stress-field position and translation velocities in ten normal individuals during rhythmic jaw opening and closing. Magnetic resonance imaging and jaw tracking were combined to animate the three-dimensional position of the stress-field between the articulating surfaces. This allowed for mediolateral translation velocity measurements of the centroid of the stress-field. The results showed that during jaw opening and closing at 0.5 Hz, the average peak mediolateral translation velocity was 35 ± 17 mm/sec. When opening and closing increased to 1.0 Hz, the average peak velocity was 40 ± 19 mm/sec. Theoretical model estimates of the work done during such translation ranged from 6 to 709 mJ between the individual joints studied. The potential clinical importance of this measure is that long-term exposure of the TMJ disc to high work may result in fatigue failure of the TMJ disc.