25 research outputs found
BRAF(E600)-associated senescence-like cell cycle arrest of human naevi
Most normal mammalian cells have a finite lifespan(1), thought to constitute a protective mechanism against unlimited proliferation(2-4). This phenomenon, called senescence, is driven by telomere attrition, which triggers the induction of tumour suppressors including p16(INK4a) (ref. 5). In cultured cells, senescence can be elicited prematurely by oncogenes(6); however, whether such oncogene-induced senescence represents a physiological process has long been debated. Human naevi ( moles) are benign tumours of melanocytes that frequently harbour oncogenic mutations ( predominantly V600E, where valine is substituted for glutamic acid) in BRAF(7), a protein kinase and downstream effector of Ras. Nonetheless, naevi typically remain in a growth-arrested state for decades and only rarely progress into malignancy (melanoma)(8-10). This raises the question of whether naevi undergo BRAF(V600E)- induced senescence. Here we show that sustained BRAF(V600E) expression in human melanocytes induces cell cycle arrest, which is accompanied by the induction of both p16(INK4a) and senescence- associated acidic beta-galactosidase (SA-beta-Gal) activity, a commonly used senescence marker. Validating these results in vivo, congenital naevi are invariably positive for SA-beta-Gal, demonstrating the presence of this classical senescence-associated marker in a largely growth-arrested, neoplastic human lesion. In growth-arrested melanocytes, both in vitro and in situ, we observed a marked mosaic induction of p16(INK4a), suggesting that factors other than p16(INK4a) contribute to protection against BRAF(V600E)- driven proliferation. Naevi do not appear to suffer from telomere attrition, arguing in favour of an active oncogene-driven senescence process, rather than a loss of replicative potential. Thus, both in vitro and in vivo, BRAF(V600E)-expressing melanocytes display classical hallmarks of senescence, suggesting that oncogene-induced senescence represents a genuine protective physiological process.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/62941/1/nature03890.pd
Non-invasive assessment of local arterial pulse pressure: comparison of applanation tonometry and echo-tracking.
Modified Quad surgery significantly improves the median nerve conduction and functional outcomes in obstetric brachial plexus nerve injury
Liver function disturbances in Guillain-Barre syndrome:A prospective longitudinal study in 100 patients
In 100 consecutive patients with Guillain-Barre syndrome, we assessed liver function on admission and at fixed intervals after either intravenous immunoglobulin (IgIV) or plasma-exchange (PE) treatment. On admission, 38% showed a plasma alanine aminotransferase elevation, gamma glutamyl transferase elevation, or both of more than 1.5 times the upper limit of normal. Ten of these patients had serologic evidence of recent cytomegalovirus infection. The remaining 28 patients were negative for other known causes of liver damage, including infection with Epstein-Barr virus or hepatitis A, B, and C; alcohol abuse; hepatotoxic drugs; recent surgery; and concurrent liver disease. In a hospital control group of 100 consecutive patients with subarachnoid hemorrhage, only 5 had unexplained liver function disturbances on admission (p <0.0001). In the IgIV-treated group, the percentage of patients with elevated liver function tests increased from 35% before to 69% shortly after treatment at 2 weeks postadmission (p <0.005). In the PE-treated group, this percentage decreased somewhat from 41% to 36% (not significant). There was also a significant rise in median plasma activity of the various liver enzymes in the IgIV group. At 1 month, however, significant difference had disappeared. At 3 and 6 months, the percentage of patients with liver function disturbances reached a significantly lower level in both treatment groups compared with the time of admission. We concluded that many patients with Guillain-Barre syndrome had mild liver function disturbances without obvious cause. In addition, IgIV treatment was associated with mild transient liver function disturbances through an unknown mechanism