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Long-standing Goal (long-standing + goal)
Selected AbstractsOptimizing flow cytometric DNA ploidy and S-phase fraction as independent prognostic markers for node-negative breast cancer specimensCYTOMETRY, Issue 3 2001C.B. Bagwell Abstract Developing a reliable and quantitative assessment of the potential virulence of a malignancy has been a long-standing goal in clinical cytometry. DNA histogram analysis provides valuable information on the cycling activity of a tumor population through S-phase estimates; it also identifies nondiploid populations, a possible indicator of genetic instability and subsequent predisposition to metastasis. Because of conflicting studies in the literature, the clinical relevance of both of these potential prognostic markers has been questioned for the management of breast cancer patients. The purposes of this study are to present a set of 10 adjustments derived from a single large study that optimizes the prognostic strength of both DNA ploidy and S-phase and to test the validity of this approach on two other large multicenter studies. Ten adjustments to both DNA ploidy and S-phase were developed from a single node-negative breast cancer database from Baylor College (n = 961 cases). Seven of the adjustments were used to reclassify histograms into low-risk and high-risk ploidy patterns based on aneuploid fraction and DNA index optimum thresholds resulting in prognostic P values changing from little (P < 0.02) or no significance to P < 0.000005. Other databases from Sweden (n = 210 cases) and France (n = 220 cases) demonstrated similar improvement of DNA ploidy prognostic significance, P < 0.02 to P < 0.0009 and P < 0.12 to P < 0.002, respectively. Three other adjustments were applied to diploid and aneuploid S-phases. These adjustments eliminated a spurious correlation between DNA ploidy and S-phase and enabled them to combine independently into a powerful prognostic model capable of stratifying patients into low, intermediate, and high-risk groups (P < 0.000005). When the Baylor prognostic model was applied to the Sweden and French databases, similar significant patient stratifications were observed (P < 0.0003 and P < 0.00001, respectively). The successful transference of the Baylor prognostic model to other studies suggests that the proposed adjustments may play an important role in standardizing this test and provide valuable prognostic information to those involved in the management of breast cancer patients. Cytometry (Comm. Clin. Cytometry) 46:121,135, 2001. © 2001 Wiley-Liss, Inc. [source] Therapeutic applications of glycosidic carbonic anhydrase inhibitorsMEDICINAL RESEARCH REVIEWS, Issue 3 2009Jean-Yves Winum Abstract The zinc enzymes carbonic anhydrases (CAs, EC 4.2.1.1) are very efficient catalysts for the reversible hydration of carbon dioxide to bicarbonate and hence play an important physiological role. In humans, 16 different isozymes have been described, some of them being involved in various pathological disorders. Several of these isozymes are considered as drug targets, and the design of selective inhibitors is a long-standing goal that has captured the attention of researchers for 40 years and has lead to clinical applications against different pathologies such as glaucoma, epilepsy, and cancer. Among the different strategies developed for designing selective CA inhibitors (CAIs), the "sugar approach" has recently emerged as a new attractive and versatile tool. Incorporation of glycosyl moieties in different aromatic/heterocyclic sulfonamide/sulfamides/sulfamates scaffolds has led to the development of numerous and very effective inhibitors of potential clinical value. The clinical use of a highly active carbohydrate-based CA inhibitor, i.e., topiramate, constitutes an interesting demonstration of the validity of this approach. Other carbohydrate-based compounds also demonstrate promising potential for the treatment of ophthalmologic diseases. This review will focus on the development of this emerging sugar-based approach for the development of CAIs. © 2008 Wiley Periodicals, Inc. Med Res Rev, 29, No. 3, 419-435, 2009 [source] Methods of gastric electrical stimulation and pacing: a review of their benefits and mechanisms of action in gastroparesis and obesityNEUROGASTROENTEROLOGY & MOTILITY, Issue 3 2009W. L. Hasler Abstract, Development of gastric electrical stimulation techniques for treatment of gastric dysmotility syndromes and obesity has been a long-standing goal of investigators and clinicians. Depending on stimulus parameters and sites of stimulation, such methods have a range of theoretical benefits including entrainment of intrinsic gastric electrical activity, eliciting propagating contractions and reducing symptomatology in patients with gastroparesis and reducing appetite and food intake in individuals with morbid obesity. Additionally, gastric stimulation parameters have extragastrointestinal effects including alteration of systemic hormonal and autonomic neural activity and modulation of afferent nerve pathways projecting to the central nervous system that may represent important mechanisms of action. Numerous case series and smaller numbers of controlled trials suggest clinical benefits in these two conditions, however better controlled trials are mandated to confirm their efficacy. Current research is focusing on novel stimulation methods to better control symptoms in gastroparesis and promote weight reduction in morbid obesity. [source] A novel method reveals that solvent water favors polyproline II over ,-strand conformation in peptides and unfolded proteins: conditional hydrophobic accessible surface area (CHASA)PROTEIN SCIENCE, Issue 1 2005Patrick J. Fleming Abstract In aqueous solution, the ensemble of conformations sampled by peptides and unfolded proteins is largely determined by their interaction with water. It has been a long-standing goal to capture these solute-water energetics accurately and efficiently in calculations. Historically, accessible surface area (ASA) has been used to estimate these energies, but this method breaks down when applied to amphipathic peptides and proteins. Here we introduce a novel method in which hydrophobic ASA is determined after first positioning water oxygens in hydrogen-bonded orientations proximate to all accessible peptide/protein backbone N and O atoms. This conditional hydrophobic accessible surface area is termed CHASA. The CHASA method was validated by predicting the polyproline-II (PII) and ,-strand conformational preferences of non-proline residues in the coil library (i.e., non-,-helix, non-,-strand, non-,-turn library derived from X-ray elucidated structures). Further, the method successfully rationalizes the previously unexplained solvation energies in polyalanyl peptides and compares favorably with published experimentally determined PII residue propensities. We dedicate this paper to Frederic M. Richards. [source] Modified Stage-Gate® Regimes in New Product Development,THE JOURNAL OF PRODUCT INNOVATION MANAGEMENT, Issue 1 2007John E. Ettlie The purpose of this research was to explore the nature of the Stage-Gate®process in the context of innovative projects that not only vary in new product technology (i.e., radical versus incremental technology) but that also involve significant new product development technology (i.e., new virtual teaming hardware-software systems). Results indicate that firms modify their formal development regimes to improve the efficiency of this process while not significantly sacrificing product novelty (i.e., the degree to which new technology is incorporated in the new offering). Four hypotheses were developed and probed using 72 automotive engineering managers involved in supervision of the new product development process. There was substantial evidence to creatively replicate results from previous benchmarking studies; for example, 48.6% of respondents say their companies used a traditional Stage-Gate®process, and 60% of these new products were considered to be a commercial success. About a third of respondents said their companies are now using a modified Stage-Gate®process for new product development. Auto companies that have modified their Stage-Gate®procedures are also significantly more likely to report (1) use of virtual teams; (2) adoption of collaborative and virtual new product development software supporting tools; (3) having formalized strategies in place specifically to guide the new product development process; and (4) having adopted structured processes used to guide the new product development process. It was found that the most significant difference in use of phases or gates in the new product development process with radical new technology occurs when informal and formal phasing processes are compared, with normal Stage-Gate®usage scoring highest for technology departures in new products. Modified Stage-Gate®had a significant, indirect impact on organizational effectiveness. These findings, taken together, suggest companies optimize trade-offs between cost and quality after they graduate from more typical stage-process management to modified regimes. Implications for future research and management of this challenging process are discussed. In general, it was found that the long-standing goal of 50% reduction in product development time without sacrificing other development goals (e.g., quality, novelty) is finally within practical reach of many firms. Innovative firms are not just those with new products but also those that can modify their formal development process to accelerate change. [source] | ||||||||||