Combined changes in Wnt signalling response and contact inhibition induce altered proliferation in radiation treated intestinal crypts

Curative intervention is possible if colorectal cancer is identified early, underscoring the need to detect the earliest stages of malignant transformation. A candidate biomarker is the expanded proliferative zone observed in crypts before adenoma formation, also found in irradiated crypts. However, the underlying driving mechanism for this is not known. Wnt signaling is a key regulator of proliferation, and elevated Wnt signaling is implicated in cancer. Nonetheless, how cells differentiate Wnt signals of varying strengths is not understood. We use computational modeling to compare alternative hypotheses about how Wnt signaling and contact inhibition affect proliferation. Direct comparison of simulations with published experimental data revealed that the model that best reproduces proliferation patterns in normal crypts stipulates that proliferative fate and cell cycle duration are set by the Wnt stimulus experienced at birth. The model also showed that the broadened proliferation zone induced by tumorigenic radiation can be attributed to cells responding to lower Wnt concentrations and dividing at smaller volumes. Application of the model to data from irradiated crypts after an extended recovery period permitted deductions about the extent of the initial insult. Application of computational modeling to experimental data revealed how mechanisms that control cell dynamics are altered at the earliest stages of carcinogenesis

An economic model of long-term use of celecoxib in patients with osteoarthritis

<p>Abstract</p> <p>Background</p> <p>Previous evaluations of the cost-effectiveness of the cyclooxygenase-2 selective inhibitor celecoxib (Celebrex, Pfizer Inc, USA) have produced conflicting results. The recent controversy over the cardiovascular (CV) risks of rofecoxib and other coxibs has renewed interest in the economic profile of celecoxib, the only coxib now available in the United States. The objective of our study was to evaluate the long-term cost-effectiveness of celecoxib compared with nonselective nonsteroidal anti-inflammatory drugs (nsNSAIDs) in a population of 60-year-old osteoarthritis (OA) patients with average risks of upper gastrointestinal (UGI) complications who require chronic daily NSAID therapy.</p> <p>Methods</p> <p>We used decision analysis based on data from the literature to evaluate cost-effectiveness from a modified societal perspective over patients' lifetimes, with outcomes expressed as incremental costs per quality-adjusted life-year (QALY) gained. Sensitivity tests were performed to evaluate the impacts of advancing age, CV thromboembolic event risk, different analytic horizons and alternate treatment strategies after UGI adverse events.</p> <p>Results</p> <p>Our main findings were: 1) the base model incremental cost-effectiveness ratio (ICER) for celecoxib versus nsNSAIDs was $31,097 per QALY; 2) the ICER per QALY was$19,309 for a model in which UGI ulcer and ulcer complication event risks increased with advancing age; 3) the ICER per QALY was $17,120 in sensitivity analyses combining serious CV thromboembolic event (myocardial infarction, stroke, CV death) risks with base model assumptions.</p> <p>Conclusion</p> <p>Our model suggests that chronic celecoxib is cost-effective versus nsNSAIDs in a population of 60-year-old OA patients with average risks of UGI events.</p

The affinities of Codazziceras Etayo-Serna, 1979 (Cretaceous ammonoidea)

The typespecies of the Cretaceous ammonite Codazziceras Etayo-Serna, 1979 is redescribed and shows the genus to be the last, Coniacian representative of the dominantly Cenomanian-Turonian subfamily Euomphaloceratinae. It is interpreted as a paedomorphic offshoot of Romaniceras Spath, 1923. It is suggested that Yubariceras gosavicum Wiedmann, 1979 is a European representative of the genus. © 1983 Academic Press Inc. (London) Ltd

The Cretaceous ammonite Eopachydiscus and the origin of the Pachydiscidae.

Eopachydiscus Wright, 1955 is confirmed as the earliest, Upper Albian representative of the Pachydiscidae, derived in all probability from a bullate member of the Beaudanticeratinae and giving rise to the Cenomanian-Coniacian Lewesiceras Spath, 1939. Nuclei of Eopachydiscus are ribbed, tuberculate, and constricted, showing even at this stage and date typical pachydiscid ornament; the evolution of Lewesiceras simply involved retention of these features into middle growth. The suggestion that the Pachydiscidae arose from Arrhaphoceras Whitehouse, 1927 of the Hoplitinae is discounted on morphological, stratigraphical, and biogeographical grounds. -Author