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To: scaram(o)uche who wrote (557)	3/30/1999 2:17:00 PM
From: scaram(o)uche	Respond to of 4974

just parking some stuff....... Science 1999 Jan 22;283(5401):543-6 Prevention of constitutive TNF receptor 1 signaling by silencer of death domains. Jiang Y, Woronicz JD, Liu W, Goeddel DV Tularik, Two Corporate Drive, South San Francisco, CA 94080, USA. Tumor necrosis factor receptor type 1 (TNF-R1) contains a cytoplasmic death domain that is required for the signaling of TNF activities such as apoptosis and nuclear factor kappa B (NF-kappaB) activation. Normally, these signals are generated only after TNF-induced receptor aggregation. However, TNF-R1 self-associates and signals independently of ligand when overexpressed. This apparent paradox may be explained by silencer of death domains (SODD), a widely expressed approximately 60-kilodalton protein that was found to be associated with the death domain of TNF-R1. TNF treatment released SODD from TNF-R1, permitting the recruitment of proteins such as TRADD and TRAF2 to the active TNF-R1 signaling complex. SODD also interacted with death receptor-3 (DR3), another member of the TNF receptor superfamily. Thus, SODD association may be representative of a general mechanism for preventing spontaneous signaling by death domain-containing receptors. Science 1998 Sep 11;281(5383):1680-3 NF-kappaB antiapoptosis: induction of TRAF1 and TRAF2 and c-IAP1 and c-IAP2 to suppress caspase-8 activation. Wang CY, Mayo MW, Korneluk RG, Goeddel DV, Baldwin AS Jr Department of Endodontics, School of Dentistry, Lineberger Comprehensive Cancer Center, and Curriculum in Genetics and Molecular Biology, University of North Carolina, Chapel Hill, NC 27599-7295, USA. Tumor necrosis factor alpha (TNF-alpha) binding to the TNF receptor (TNFR) potentially initiates apoptosis and activates the transcription factor nuclear factor kappa B (NF-kappaB), which suppresses apoptosis by an unknown mechanism. The activation of NF-kappaB was found to block the activation of caspase-8. TRAF1 (TNFR-associated factor 1), TRAF2, and the inhibitor-of-apoptosis (IAP) proteins c-IAP1 and c-IAP2 were identified as gene targets of NF-kappaB transcriptional activity. In cells in which NF-kappaB was inactive, all of these proteins were required to fully suppress TNF-induced apoptosis, whereas c-IAP1 and c-IAP2 were sufficient to suppress etoposide-induced apoptosis. Thus, NF-kappaB activates a group of gene products that function cooperatively at the earliest checkpoint to suppress TNF-alpha-mediated apoptosis and that function more distally to suppress genotoxic agent-mediated apoptosis.

To: scaram(o)uche who wrote (557)	3/30/1999 10:28:00 PM
From: Miljenko Zuanic	Read Replies (1) \| Respond to of 4974

I will vote today. With all respect to SIBI TBA patents and science, IMO REGN news on Axokine PI trial (today Axokine is very speculative bet with lot of IF and unknown) may have great impact on bt universe, 2-3 years down the road. Approach is interesting (after leptin failure so far) and animal data indicate good results. Miljenko

To: scaram(o)uche who wrote (557)	4/1/1999 7:49:00 PM
From: scaram(o)uche	Read Replies (1) \| Respond to of 4974

2 1/2 votes for REGN, 1 1/2 votes for SIBI... reluctantly.... 03/30/99 REGN, PG starts phase I, CNTF for obesity, Type II diabetes 03/25/99 VRTX, 3-D structure of ribavirin bound to IMPDH 03/10/99 MLNM, clones mahogany, obesity target or lab curiosity? 03/09/99 VRTX, initiates phase I trial with p38 MAP kinase inhibitor 03/08/99 CNTO, sales force leverage, LMW heparin with PNU 03/04/99 AGPH, describes crystal structure for VEGFR2 kinase 03/02/99 INCY, using new chemistry from Amersham Pharmacia, flying 03/01/99 GLIA, finishes single-dose portion of phase I, GT-2331 03/01/99 GILD, NXTR merger 02/26/99 MEDI/Ixsys, MAb alliance, including anti-alpha-v beta-3 02/25/99 ONXX, Bayer selects lead compound, ras pathway inhibitor