Development of a mobile low-field MRI scanner.

Magnetic resonance imaging (MRI) allows important visualization of the brain and central nervous system anatomy and organization. However, unlike electroencephalography (EEG) or functional near infrared spectroscopy, which can be brought to a patient or study participant, MRI remains a hospital or center-based modality. Low magnetic field strength MRI systems, however, offer the potential to extend beyond these traditional hospital and imaging center boundaries. Here we describe the development of a modified cargo van that incorporates a removable low-field permanent magnet MRI system and demonstrate its proof-of-concept. Using phantom scans and in vivo T2-weighted neuroimaging data, we show no significant differences with respect to geometric distortion, signal-to-noise ratio, or tissue segmentation outcomes in data acquired in the mobile system compared to a similar static system in a laboratory setting. These encouraging results show, for the first time, MRI that can be performed at a participant's home, community center, school, etc. Breaking traditional barriers of access, this mobile approach may enable imaging of patients and participants who have mobility challenges, live long distances from imaging centers, or are otherwise unable to travel to an imaging center or hospital.

Combination of automated high throughput platforms, flow cytometry, and hierarchical clustering to detect cell state.

BACKGROUND: This study examined whether hierarchical clustering could be used to detect cell states induced by treatment combinations that were generated through automation and high-throughput (HT) technology. Data-mining techniques were used to analyze the large experimental data sets to determine whether nonlinear, non-obvious responses could be extracted from the data. METHODS: Unary, binary, and ternary combinations of pharmacological factors (examples of stimuli) were used to induce differentiation of HL-60 cells using a HT automated approach. Cell profiles were analyzed by incorporating hierarchical clustering methods on data collected by flow cytometry. Data-mining techniques were used to explore the combinatorial space for nonlinear, unexpected events. Additional small-scale, follow-up experiments were performed on cellular profiles of interest. RESULTS: Multiple, distinct cellular profiles were detected using hierarchical clustering of expressed cell-surface antigens. Data-mining of this large, complex data set retrieved cases of both factor dominance and cooperativity, as well as atypical cellular profiles. Follow-up experiments found that treatment combinations producing "atypical cell types" made those cells more susceptible to apoptosis. CONCLUSIONS Hierarchical clustering and other data-mining techniques were applied to analyze large data sets from HT flow cytometry. From each sample, the data set was filtered and used to define discrete, usable states that were then related back to their original formulations. Analysis of resultant cell populations induced by a multitude of treatments identified unexpected phenotypes and nonlinear response profiles.

Determination of P-glycoprotein inhibition by excipients and their combinations using an integrated high-throughput process.

Excipients often used in pharmaceutical formulations have been reported to have inhibitory effects on P-glycoprotein, an important membrane-associated transport protein. Because inhibition of efflux transporters can have an effect on drug bioavailability, identification of these excipients and their extent of inhibition are therefore important for pharmaceutical development. We have developed an automated and integrated high-throughput process for identifying these excipients and their combinations. Common excipients containing polyethylene glycol (PEG) in the chemical structure were screened using a cytotoxic cell growth assay, and excipients giving inhibition were further combined to identify synergistic effects. Our screens identified excipients previously reported to inhibit P-glycoprotein, such as PEG stearates, PEG fatty acid esters, polysorbates, and poloxamers. We also found new excipients, such as those in the PEG glyceryl fatty acid family, which were among the best inhibitors identified. Dose-response studies of these compounds and of cyclosporin A indicated that the extent of inhibition depended logarithmically on the concentration. This suggests a similar mechanism by which inhibition is obtained, despite widely varying chemical structures. In the particular set of combinatorial studies performed, which involved >20,000 samples, we found that inhibitory effects in binary combinations followed the single-excipient logarithmic trend, rather than being synergistic. These experiments showcased the potential for integrated high-throughput processes that enable combinatorial screens which would otherwise be difficult to perform manually.

A high-throughput combinatorial approach for the discovery of a cremophor EL-free paclitaxel formulation.

PURPOSE: The purpose of this work was to replace Cremophor-EL in the commercial paclitaxel intravenous formulation, Taxol, using a novel high-throughput combinatorial formulation approach. METHODS: Full factorial combinations of 12 generally regarded as safe excipients at three different concentrations were screened using an automated liquid dispenser. The hit formulations were further optimized to give the final optimized formulation TPI-1. TPI-1 was then tested in rats to compare its pharmacokinetic profile to Taxol. RESULTS: Of the 9,880 combinations tested in the initial screen, 19 were identified as hit combinations. These were further optimized to give the final formulation TPI-1. When tested in rats, TPI-1 was well tolerated at both the low and high doses of 5 mg/kg and 10 mg/kg, whereas Taxol killed all the rats at the high dose. TPI-1 experienced slower elimination compared to Taxol. Similar to Taxol, TPI-1 also exhibited nonlinear pharmacokinetics. CONCLUSIONS: This study demonstrated the power of a high-throughput combinatorial approach for alternative paclitaxel formulations. We believe that this approach can be applied to drug formulation in general and it can improve the speed and efficiency of drug formulation design.

Iterative high-throughput polymorphism studies on acetaminophen and an experimentally derived structure for form III.

Three crystal forms of acetaminophen were prepared and characterized using a newly developed high-throughput crystallization platform, CrystalMax. The platform consists of design software, robotic sample dispensing and handling, and high-throughput microanalytics and is capable of running thousands of crystallizations in parallel using several different methods to drive supersaturation and subsequent crystallization. Additionally, structural models of the elusive third form of acetaminophen will be discussed on the basis of powder X-ray diffraction data. One structure suggested has a bilayer motif, held together by O-H...O(H) hydrogen bonds, and helps explain the difficulty associated with preparing this form from solution.