Ever since Pasteur noticed that tartrate crystals exist in two non-superimposable forms that are mirror images of one another--as are left and right hands--the phenomenon of chirality has intrigued scientists. On the molecular level, chirality often has a profound impact on recognition and interaction events and is thus important to biochemistry and pharmacology. In chemical synthesis, much effort has been directed towards developing asymmetric synthesis strategies that yield product molecules with a significant excess of either the left-handed or right-handed enantiomer. This is usually achieved by making use of chiral auxiliaries or catalysts that influence the course of a reaction, with the enantiomeric excess (ee) of the product linearly related to the ee of the auxiliary or catalyst used. In recent years, however, an increasing number of asymmetric reactions have been documented where this relationship is nonlinear, an effect that can lead to asymmetric amplification. Theoretical models have long suggested that autocatalytic processes can result in kinetically controlled asymmetric amplification, a prediction that has now been verified experimentally and rationalized mechanistically for an autocatalytic alkylation reaction. Here we show an alternative mechanism that gives rise to asymmetric amplification based on the equilibrium solid-liquid phase behaviour of amino acids in solution. This amplification mechanism is robust and can operate in aqueous systems, making it an appealing proposition for explaining one of the most tantalizing examples of asymmetric amplification-the development of high enantiomeric excess in biomolecules from a presumably racemic prebiotic world.

This Perspective highlights how the methodology of reaction progress kinetic analysis can provide a rapid and comprehensive kinetic profile of complex catalytic reaction networks under synthetically relevant conditions in a fraction of the number of experiments required by classical kinetic analysis. This approach relies on graphical manipulation of the extensive data sets available from accurate in situ monitoring of reaction progress under conditions where two concentration variables are changing simultaneously. A series of examples from Pd-catalyzed coupling reactions of aryl halides demonstrates how a wealth of kinetic information may be extracted from just three experiments in each case. Even before proposing a reaction mechanism, we can determine reaction orders in substrates, propose a resting state for the catalyst, and probe catalyst stability. Carrying out this kinetic analysis at the outset of a mechanistic investigation provides a framework for further work aimed at seeking a molecular-level understanding of the nature of the species within the catalytic cycle. To be considered plausible, any independent mechanistic proposal must be shown to be consistent with this global kinetic analysis.

A kinetic study on the Rh/binap-catalyzed 1,4-addition of phenylboronic acid using reaction calorimetry revealed that the catalytically inactive dimeric hydroxorhodium complex [Rh(OH)((R)-binap)]2 (RR-4) is the resting state. A negative NLE in eeprod and an amplified reaction rate were predicted and observed in the present reaction system characterized by the preferential formation of homochiral dimer.

Using proteomic analysis, we previously identified calreticulin (CRT) as a potentially useful urinary marker for bladder cancer. Now, we have also identified γ γ γ γ-synuclein (SNCG) and a soluble isoform of catechol-o-methyltransferase (s-COMT) as novel candidates for tumor markers in bladder cancer, by means of proteomic analysis. In the process of establishing a superior tumor marker system, we investigated the diagnostic value of a combination assay of these three proteins. Voided urine samples were obtained from 112 bladder cancer and 230 control patients. Urinary CRT, SNCG, and s-COMT were measured as a combined marker by quantitative western blot analysis. Relative concentration of each protein was calculated and the diagnostic value of a concomitant examination of these markers was evaluated by receiver operator characteristic analysis. With the best diagnostic cutoff, the overall sensitivity of the combined markers was 76.8% (95% confidence interval, 69-81%) with a specificity of 77.4% (72-80%), while those of a single use of CRT were 71.4% and 77.8%, respectively. When evaluated in relation to tumor characteristics, such as grade, stage, size, and outcome of urinary cytology, the diagnostic capacity of the combined markers was equal to or better than that of CRT in all categories. Concomitant use of CRT, SNCG, and s-COMT had higher sensitivity for detection of bladder cancer than did single use of CRT. Our study suggests that use of this panel of markers will improve the diagnosis of bladder cancer and may allow the development of a protein microarray assay or multi-channel enzyme-linked immunosorbent assay. (Cancer Sci 2004; 95: 955-961) ladder cancer is a common urothelial cancer with an estimated 57,400 and 13,000 diagnosed cases per year in the United States and Japan, respectively. 1, 2) Approximately 70% of bladder cancers are superficial 3) and respond well to endoscopic transurethral resection. However, 50% to 70% of these patients experience tumor recurrence, and 10% to 15% of recurrent tumors progress to muscle invasive disease. 4) Because the propensity for local recurrence extends over the lifetime, patients with superficial bladder cancer must undergo life-long surveillance.Cystoscopy is the mainstay in diagnosing bladder cancer. However, this procedure is unsuitable for screening of large groups because of its invasiveness and expense. In addition, follow-up cystoscopy for bladder cancer patients treated endoscopically represents a considerable part of the workload of any urological unit. Therefore, new tests with high specificity and sensitivity that are easy to perform are needed for both screening and monitoring the response to treatment of bladder cancer. Voided urine cytology (VUC) has been used in both diagnosis and follow-up of superficial bladder cancer since its first description by Papanicolaou and Marshall in 1945, but it has poor sensitivity although high specificity, particularly in well-differentiated cancer.5) To date, several urine-based markers for bladder cancer have ...