Farnesyl diphosphate-based inhibitors of Ras farnesyl protein transferase

The rational design, synthesis, and biological activity of farnesyl diphosphate (FPP)-based inhibitors of the enzyme Ras farnesyl protein transferase (FPT) is described. Compound 3, wherein a beta-carboxylic phosphonic acid type pyrophosphate (PP) surrogate is connected to the hydrophobic farnesyl group by an amide linker, was found to be a potent (I50(FPT) = 75 nM) and selective inhibitor of FPT, as evidenced by its inferior activity against squalene synthetase (I50(SS) = 516 microM) and mevalonate kinase (I50(MK) = > 200 microM). A systematic structure-activity relationship study involving modifications of the farnesyl group, the amide linker, and the PP surrogate of 3 was undertaken. Both the carboxylic and phosphonic acid groups of the beta-carboxylic phosphonic acid PP surrogate are essential for activity, since deletion of either group results in 50-2600-fold loss in activity (6-9, I50 = 4.6-220 microM). The farnesyl group also displays very stringent requirements and does not tolerate one carbon homologation (12, I50 = 17.7 microM), substitution by a dodecyl fragment (14, I50 = 9 microM), or introduction of an extra methyl group at the allylic position (18, I50 = 55 microM). Modifications around the amide linker group of 3 were more forgiving, as evidenced by the activity of N-methyl analog (21, I50 = 0.53 microM), the one carbon atom shorter farnesoic acid-derived retroamide analog (32, I50 = 250 nM), and the exact retroamide analog (49, I50 = 50 nM). FPP analogs such as 3, 32, and 49 are novel, potent, selective, small-sized, nonpeptidic inhibitors of FPT that may find utility as antitumor agents.     

Versatile high-repetition-rate phase-locked chopper system for fast timing experiments in the vacuum ultraviolet and x-ray spectral region

A novel light chopper system for fast timing experiments in the vacuum-ultraviolet (VUV) and x-ray spectral region has been developed. It can be phase-locked and synchronized with a synchrotron radiation storage ring, accommodating repetition rates in the range of ~8 to ~120 kHz by choosing different sets of apertures and subharmonics of the ring frequency (MHz range). Also the opening time of the system can be varied from some nanoseconds to several microseconds to meet the needs of a broad range of applications. Adjusting these parameters, the device can be used either for the generation of single light pulses or pulse packages from a microwave driven, continuous He gas discharge lamp or from storage rings which are otherwise often considered as quasi-continuous light sources. This chopper can be utilized for many different kinds of experiments enabling, for example, unambiguous time-of-flight (TOF) multi-electron coincidence studies of atoms and molecules excited by a single light pulse as well as time-resolved visible laser pump x-ray probe electron spectroscopy of condensed matter in the valence and core level region.     

Off-axis cavity enhanced spectroscopy based on a pulsed quantum cascade laser for sensitive detection of ammonia and ethylene

A pulsed, distributed feedback (DFB) quantum cascade (QC) laser centered at 970 cm(-1) was used in combination with an off-axis cavity enhanced absorption (CEA) spectroscopic technique for the detection of ammonia and ethylene. Here, the laser is coupled into a high-finesse cavity with an optical path length of ～76 m. The cavity is installed into a 53 cm long sample cell with a volume of 0.12 L. The laser is excited with short current pulses (5-10 ns), and the pulse amplitude is modulated with an external current ramp, resulting in a ～0.3 cm(-1) frequency scan. A demodulation approach followed by numerical filtering was utilized to improve the signal-to-noise ratio. We demonstrated detection limits of ~15 ppb and ～20 ppb for ammonia and ethylene, respectively, with less than 5 s averaging time.     

Functional impairment, marital quality, and patient psychological distress as predictors of psychological distress among cancer patients' spouses.

This study investigated contextual determinants of psychological distress among 197 spouses of cancer patients. women, 30–82 years old). It was hypothesized that higher levels of patient functional impairment would lead to greater patient distress. Patient distress, in turn, would lead to lower spouse marital satisfaction and ultimately to higher spouse distress. Spouses completed measures of distress and marital quality at three time points. Cancer patients rated their functional impairment and psychological distress at the same time points. Results indicated that at all time points, greater patient impairment was associated with higher levels of patient distress which, in turn, was related to lower marital satisfaction. However, marital quality was related to spouse distress at only 1 time point, but spouse distress was directly associated with patient distress at each time point. Implications for cancer patients and spouses are discussed. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Partner unsupportive responses, avoidant coping, and distress among women with early stage breast cancer: Patient and partner perspectives.

This 18-month longitudinal study examined the associations among partner unsupportive behavior, avoidant coping, and distress experienced by 219 women with early stage breast cancer. The role of patient and partner ratings of unsupportive behavior were evaluated. Results indicated that patient and partner ratings of unsupportive behavior were highly correlated. Growth curve modeling suggested that unsupportive behavior, from both patient and partner perspectives, predicted more avoidant coping and distress. When partner and patient perceptions were placed in the same model, patient perceptions mediated the association between partners' ratings of their unsupportive behavior and patient distress. Avoidance also mediated the association between unsupportive behavior and distress, extending prior cross-sectional findings. Results highlight the long-term detrimental effects of partners' unsupportive behavior on the quality of life of women with early stage breast cancer. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Pulsed quantum cascade laser-based cavity ring-down spectroscopy for ammonia detection in breath

Breath analysis can be a valuable, noninvasive tool for the clinical diagnosis of a number of pathological conditions. The detection of ammonia in exhaled breath is of particular interest for it has been linked to kidney malfunction and peptic ulcers. Pulsed cavity ringdown spectroscopy in the mid-IR region has developed into a sensitive analytical technique for trace gas analysis. A gas analyzer based on a pulsed mid-IR quantum cascade laser operating near 970 cm(-1) has been developed for the detection of ammonia levels in breath. We report a sensitivity of approximately 50 parts per billion with a 20 s time resolution for ammonia detection in breath with this system. The challenges and possible solutions for the quantification of ammonia in human breath by the described technique are discussed.     

Using a molten organic conducting material to infiltrate a nanoporous semiconductor film and its use in solid-state dye-sensitized solar cells

We describe a method to fill thin films of nanoporous TiO₂ with solid organic hole-conducting materials and demonstrate the procedure specifically for use in the preparation of dye-sensitized solar cells. Cross-sections of the films were investigated by scanning electron microscopy and it was observed that a hot molten organic material fills pores that are 10 μm below the surface of the film. We characterized the incident photon to current conversion efficiency properties of the solid TiO₂/organic dye/organic hole-conductor heterojunctions and the spectra show that the dye is still active after the melting process.     

Mobile Fair Diary: hybrid interface for taking,browsing and sharing context-aware notes

This paper describes the Mobile Fair Diary (MFD), which is designed to allow a housing fair customer to make a personalized digital recording of his/her visit to a hectic fairground for later use. The MFD is a hybrid interface service comprising of an application for a camera equipped smart phone and a website accessed by a PC. The smart phone application is used for taking context-aware notes such as visual codes, photos, dictations and text. The notes are uploaded onto a website, where they can be viewed with a PC in a contextually ordered view for browsing, organizing and sharing. The MFD was empirically evaluated in a real-life environment of use with genuine end users by a large-scale field trial at a national housing fair. The results testify to the very successful design of the MFD with high usefulness.     

Spouse criticism and support: Their association with coping and psychological adjustment among women with rheumatoid arthritis.

Examined whether psychological adjustment of women with rheumatoid arthritis would be related to the support and criticism the patient received from the husband. Interviews were conducted with the husbands of 103 women with rheumatoid arthritis. Spouse interviews were content coded for critical remarks. Wives completed a revised version of the Ways of Coping Scale and a scale of the perceived supportiveness of the spouse. Husbands completed rating scales assessing their perceived vulnerability to illness and the degree of burden they experienced in providing assistance to their wives. Path analyses revealed that patient adjustment was significantly related to the attitude of the spouse. Patients with a highly critical spouse engaged in more maladaptive coping behaviors and reported a poorer psychological adjustment. Independent of spousal criticism, patients who perceived their spouse as being supportive engaged in more adaptive coping. A path model was fit to the data that suggested that the spouse may affect adjustment indirectly through influencing the patient's selection of adaptive or maladaptive coping responses. (PsycINFO Database Record (c) 2010 APA, all rights reserved)