Dam 2,8 ✉ & the SHINE study group* Cancer cell metabolism leads to a uniquely acidic microenvironment in solid tumors, but exploiting the labile extracellular pH differences between cancer and normal tissues for clinical use has been challenging. Here we describe the clinical translation of ONM-100, a nanoparticle-based fluorescent imaging agent. This is comprised of an ultra-pH sensitive amphiphilic polymer, conjugated with indocyanine green, which rapidly and irreversibly dissociates to fluoresce in the acidic extracellular tumor microenvironment due to the mechanism of nanoscale macromolecular cooperativity. Primary outcomes were safety, pharmacokinetics and imaging feasilibity of ONM-100. Secondary outcomes were to determine a range of safe doses of ONM-100 for intra-operative imaging using commonly used fluorescence camera systems. In this study (Netherlands National Trial Register #7085), we report that ONM-100 was well tolerated, and four solid tumor types could be visualized both in-and ex vivo in thirty subjects. ONM-100 enables detection of tumor-positive resection margins in 9/9 subjects and four additional otherwise missed occult lesions. Consequently, this pH-activatable optical imaging agent may be clinically beneficial in differentiating previously unexploitable narrow physiologic differences.

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OBJECTIVE -Hypoglycemia is a common acute complication of diabetes therapy. The GlucoWatch biographer provides frequent and automatic glucose measurements with an adjustable low-glucose alarm. We have analyzed the performance of the biographer low-glucose alarm relative to hypoglycemia as defined by blood glucose Յ3.9 mmol/l. RESEARCH DESIGN AND METHODS -The analysis was based on 1,091 biographer uses from four clinical trials, which generated 14,487 paired (biographer and blood glucose) readings.RESULTS -The results show that as the low-glucose alert level of the biographer is increased, the number of true positive alerts (alarm sounds and blood glucose Յ3.9 mmol/l) and false positive alerts (alarm sounds but blood glucose Ͼ3.9 mmol/l) increased. When analyzed as a function of varying low-glucose alert levels, the results show receiver operator characteristic curves consistent with a highly useful diagnostic tool. Setting the alert level from 1.1 to 1.7 mmol/l above the level of concern is likely to optimize the trade-off between true positives and false positives for each user. When the same blood glucose data are analyzed for typical monitoring practices (two or four measurements per day), the results show that fewer hypoglycemic events are detected than those detected with the biographer.CONCLUSIONS -The frequent and automatic nature of the biographer readings allows more effective detection of hypoglycemia than that achieved with current medical practice. Diabetes Care 24:881-885, 2001H ypoglycemia is a common acute complication of diabetes therapy. The frequency of severe hypoglycemia has been shown to increase with more intensive treatment. Increasing the frequency of glucose measurements, regardless of the technique used, makes it possible to detect a greater number of hypoglycemic events. However, as many as seven glucose measurements per day may fail to detect hypoglycemic events (1).A device providing automatic readings could make frequent monitoring easier and enable an alarm to be sounded in response to glucose readings below userselected alert levels. Such an alarm could reduce the risk of hypoglycemia, making intensive therapy safer and more acceptable for patients. The GlucoWatch biographer (Cygnus, Redwood City, CA) provides frequent, automatic, and noninvasive glucose measurements-up to three readings per hour for as long as 12 h after a blood glucose measurement for calibration. Clinical studies in controlled and home environments have demonstrated high accuracy and precision (2,3). The results presented here evaluate the hypoglycemia alert performance in a large and demographically diverse patient population using the biographer both in controlled and normal daily environments. The accuracy and precision results from these studies have been described (4).The performance of the hypoglycemia alert depends on the selection of a low-glucose alert level that will trigger an audible alarm. The performance of the alert function can be best evaluated by an analysis of the receiver operator characteri...

Phase separation dynamics is studied in a density-matched liquid mixture in the presence of a weak linear concentration gradient. This novel situation enables nucleation and spinodal decomposition to be studied simultaneously. We observe at all quench depths (i) a central zone of nearly constant concentration width where interconnected domains grow linearly with time, surrounded by (ii) a zone of isolated droplets whose width increases with time, with the droplet growth compatible with a j law. These findings suggest generalized nucleation as the phase separation process.PACS numbers: 64.70.Ja, 05.70.Jk, In this Letter we report the phase separation dynamics of a binary liquid mixture under a weak concentration gradient when it is quenched from a temperature at which it is homogeneous to a temperature where it is a two-phase mixture. This is a general process that occurs in many areas of scientific and technological interest such as material science and heat and mass transfer [1][2][3]. The experiment has been carried out near a critical point where the phase separation behavior can easily be generalized by the use of scaling functions. We have chosen the density-matched mixture cyclohexane (C) -f deuterated cyclohexane (C*) + methanol (M) in order to maintain the concentration gradient against gravitydriven convection and to suppress the influence of gravity during phase separation [4]. The phase separation process is expected to proceed [1] through spinodal decomposition (SD) or through nucleation and growth. During SD spontaneous fluctuations grow and generally give rise to interconnected domains. For nucleation and growth an energy barrier exists that prevents the droplets with a radius smaller than a critical radius /?* from growing. Classical theories predict a sharp limiting boundary called the spinodal curve between these two separation processes [2]. However, for real systems, Binder [3] proposes a smooth transition zone (spinodal nucleation) between the two processes at early stages. At late stages, during coarsening, additional effects like hydrodynamic flows in percolating clusters are expected to enhance the growth of the domains for volume fractions exceeding the percolation limit [5]. Wong and Knobler [6] report this expected crossover in the growth exponent from t^ io t '-^ (here / is the time elapsed after the quench) as the volume fraction decreases below 10%.In the present study the sample is submitted to a weak concentration gradient over its height. This enables the phase separation structures to be observed simultaneously in the unstable and metastable regions for the same quench depth. Our purpose is to determine the concentration dependence of the phase separation structures and the growth laws. In a computer simulation study of spinodal decomposition under concentration gradients, Kolb et al. [7] do not see any specific eff'ect of the gradient.Although they do not take into account hydrodynamics in their analysis, we expect a similar insensitivity to the gradient.The experimental cell is ...