A Tool for Predicting Regulatory Approval After Phase II Testing of New Oncology Compounds.

We developed an algorithm (ANDI) for predicting regulatory marketing approval for new cancer drugs after phase II testing has been conducted, with the objective of providing a tool to improve drug portfolio decision-making. We examined 98 oncology drugs from the top 50 pharmaceutical companies (2006 sales) that first entered clinical development from 1999 to 2007, had been taken to at least phase II development, and had a known final outcome (research abandonment or regulatory marketing approval). Data on safety, efficacy, operational, market, and company characteristics were obtained from public sources. Logistic regression and machine-learning methods were used to provide an unbiased approach to assess overall predictability and to identify the most important individual predictors. We found that a simple four-factor model (activity, number of patients in the pivotal phase II trial, phase II duration, and a prevalence-related measure) had high sensitivity and specificity for predicting regulatory marketing approval.

A transgenic mouse bearing an antisense construct of regulatory subunit type 1A of protein kinase A develops endocrine and other tumours: comparison with Carney complex and other PRKAR1A induced lesions.

BACKGROUND: Inactivation of the human type Ialpha regulatory subunit (RIalpha) of cyclic AMP dependent protein kinase (PKA) (PRKAR1A) leads to altered kinase activity, primary pigmented nodular adrenocortical disease (PPNAD), and sporadic adrenal and other tumours. METHODS AND RESULTS: A transgenic mouse carrying an antisense transgene for Prkar1a exon 2 (X2AS) under the control of a tetracycline responsive promoter (the Tg(Prkar1a*x2as)1Stra, Tg(tTAhCMV)3Uh or tTA/X2AS line) developed thyroid follicular hyperplasia and adenomas, adrenocortical hyperplasia and other features reminiscent of PPNAD, including late onset weight gain, visceral adiposity, and non-dexamethasone suppressible hypercorticosteronaemia, with histiocytic, epithelial hyperplasias, lymphomas, and other mesenchymal tumours. These lesions were associated with allelic losses of the mouse chromosome 11 Prkar1a locus, an increase in total type II PKA activity, and higher RIIbeta protein levels; the latter biochemical and protein changes were also documented in Carney complex tumours associated with PRKAR1A inactivating mutations and chromosome 17 PRKAR1A locus changes. CONCLUSION: We conclude that the tTA/X2AS mouse line with a downregulated Prkar1a gene replicates several of the findings in Carney complex patients and their affected tissues, supporting the role of RIalpha as a candidate tumour suppressor gene.

A pleiomorphic GH pituitary adenoma from a Carney complex patient displays universal allelic loss at the protein kinase A regulatory subunit 1A (PRKARIA) locus.

Carney complex (CNC) is a familial multiple endocrine neoplasia syndrome associated with GH-producing pituitary tumours and transmitted as an autosomal dominant trait. Mutations of the PRKAR1A gene are responsible for approximately half the known CNC cases but have never found in sporadic pituitary tumours. Pituitary tissue was obtained from an acromegalic CNC patient heterozygote for a common (PRKARIA)i-inactivating mutation. Both immunohistochemistry and electron microscopy showed a highly pleiomorphic pituitary adenoma. The cell culture population appeared morphologically heterogeneous and remained so after more than 30 passages. The mixture was comprised of cells strongly immunostained for GH, spindle-shaped myofibroblast-like cells, and cuboid cells with large axonal projections (negative for GH). The population appeared to have both epithelial and mesenchymal cells. Both at baseline and at passage 30, cytogenetic analysis indicated the presence of normal 46, XY diploid karyotype, whereas losses of the PRKARIA(i) locus were demonstrated in more than 98% of the cells by fluorescent in situ hybridisation, supporting this gene's involvement in pituitary tumorigenesis. Allelic loss may have occurred in a single precursor cell type that differentiated and clonally expanded into several phenotypes. Epithelial-to-mesenchymal transition may also occur in CNC-associated pleiomorphic pituitary adenomas.

Correcting organ motion artifacts in x-ray CT systems based on tracking of motion phase by the spatial overlap correlator. II. Experimental study.

This paper presents the experimental part of an investigation on tracking and eliminating organ motion artifacts in x-ray CT cardiac applications with emphasis on imaging coronary calcification. The system methodology consists of a software implementation of the spatial overlap correlator (SSOC) concept in x-ray CT scanners to track the net amplitude and phase of organ motion during the CT data acquisition process. A coherent sinogram synthesis (CSS) method is then used to identify the repeated phases of a periodic organ motion from the information provided by the SSOC process and hence synthesize a new sinogram with no motion effects. Since the SSOC scheme is capable of tracking cardiac motion, it identifies also the projection points associated with minimum amplitude cardiac motion effects. These points are used to identify a 180 degrees plus the fan angle sinogram for image reconstruction. This leads to a retrospective gating (RG) scheme that is based on the output of the SSOC process. Performance comparison of the proposed methodology with the retrospective ECG gating using real data sets with phantoms and human patients provides a performance assessment of the merits of the proposed methods. Real results demonstrate that the new methodology eliminates the requirement for ECG gating. Moreover, the CSS and the new RG methods do not require breath holding and they can be implemented in x-ray CT scanners to image coronary calcification and the heart's ventricles.

Polymorphonuclear cell-mediated vascular injury in anergic surgical patients.

We examined the responses of primed polymorphonuclear neutrophils (PMNs) adhered to vascular endothelium, which can lead to endothelial cell damage as a mechanism of the capillary leak syndrome, the main cause of death in anergic patients. We tested PMNs from (1) preoperative reactive patients, (2) preoperative anergic patients, (3) anergic patients in the surgical intensive care unit, and (4) healthy controls for in vitro adherence and cytotoxicity on cultured human vein endothelial cells. Adherence of PMNs was 12.9% +/- 3.9% in preoperative anergic patients and 13.1% +/- 3.2% in anergic patients in the surgical intensive care unit compared with 9.0% +/- 2.1% in preoperative reactive patients (P < .05). Cytotoxicity was 6.0% +/- 2.8% in preoperative reactive patients, 13.7% +/- 4.1% in preoperative anergic patients, and 14.3% +/- 4.6% in anergic patients in the surgical intensive care unit. The PMNs from preoperative anergic patients were more cytotoxic against human vein endothelial cells when stimulated by Staphylococcus epidermidis or formyl-methionyleucylphenylalanine. We conclude that PMNs from anergic surgical patients adhere more to endothelial cells and can produce increased cytotoxicity that may lead to detrimental results.