New Synthetic Control Charts for Monitoring Process Mean and Process Dispersion

A statistical quality control chart is widely recognized as a potentially powerful tool that is frequently used in many manufacturing and service industries to monitor the quality of the product or manufacturing processes. In this paper, we propose new synthetic control charts for monitoring the process mean and the process dispersion. The proposed synthetic charts are based on ranked set sampling (RSS), median RSS (MRSS), and ordered RSS (ORSS) schemes, named synthetic‐RSS, synthetic‐MRSS, and synthetic‐ORSS charts, respectively. Average run lengths are used to evaluate the performances of the control charts. It is found that the synthetic‐RSS and synthetic‐MRSS mean charts perform uniformly better than the Shewhart mean chart based on simple random sampling (Shewhart‐SRS), synthetic‐SRS, double sampling‐SRS, Shewhart‐RSS, and Shewhart‐MRSS mean charts. The proposed synthetic charts generally outperform the exponentially weighted moving average (EWMA) chart based on SRS in the detection of large mean shifts. We also compare the performance of the synthetic‐ORSS dispersion chart with the existing powerful dispersion charts. It turns out that the synthetic‐ORSS chart also performs uniformly better than the Shewhart‐R, Shewhart‐S, synthetic‐R, synthetic‐S, synthetic‐D, cumulative sum (CUSUM) ln S², CUSUM‐R, CUSUM‐S, EWMA‐ln S², and change point CUSUM charts for detecting increases in the process dispersion. A similar trend is observed when the proposed synthetic charts are constructed under imperfect RSS schemes. Illustrative examples are used to demonstrate the implementation of the proposed synthetic charts. Copyright © 2014 John Wiley & Sons, Ltd.     

The in vitro and in vivo investigation of inhaled migraine therapies using a novel aerosol delivery system consisting of an air pressurized capsule device (APCD) in combination with a pMDI spacer for endotracheal dosing into beagle dogs

Abstract

Context: Aerosol delivery to animals in preclinical settings has historically been very challenging, requiring the use of techniques, such as intratracheal instillation and dry powder insufflation, that are somewhat invasive, inefficient and not representative of clinical inhalation.

Objective: The objective of this work is to develop a system to deliver dry powder to dogs in an efficient and effective manner for the study of new anti-migraine compounds in development.

Materials and methods: The new device uses a metered aliquot of a dry gas to force dry powder drug from a pre-filled HPMC capsule into an AeroChamber® spacer for subsequent inhalation by the animal.

Results: The delivery of two invesigational migraine drugs via the new device was assessed in vitro using abbreviated Andersen cascade impaction and showed the device is capable of generating a reproducible delivered dose of up to ～68% with more than 50% of the dose in the respirable range. In vivo studies have also been performed showing that this device effectively delivered the migraine drugs to spontaneously breathing dogs using a proprietary validated dog inhalation model.

Discussion: Results confirmed that the air pressurized capsule device (APCD) was effective in delivering the APIs to lungs of the animals. The in vivo data verified the advantages of inhaled delivery over oral delivery for this class of drugs and were used to establish the cardiopulmonary and respiratory side effect liability profile for these compounds.

Conclusions: This work has demonstrated the utility of this device for quick and accurate screening of prospective drug candidates, representing a significant improvement in ease of use and reprodicibility over current delivery methods.     

Biophysical Modulation of Mesenchymal Stem Cell Differentiation in the Context of Skeletal Repair

A prominent feature of the skeleton is its ability to remodel in response to biophysical stimuli and to repair under varied biophysical conditions. This allows the skeleton considerable adaptation to meet its physiological roles of stability and movement. Skeletal cells and their mesenchymal precursors exist in a native environment rich with biophysical signals, and they sense and respond to those signals to meet organismal demands of the skeleton. While mechanical strain is the most recognized of the skeletal biophysical stimuli, signaling phenomena also include fluid flow, hydrostatic pressure, shear stress, and ion-movement-related electrokinetic phenomena including, prominently, streaming potentials. Because of the complex interactions of these electromechanical signals, it is difficult to isolate the significance of each. The application of external electrical and electromagnetic fields allows an exploration of the effects of these stimuli on cell differentiation and extra-cellular matrix formation in the absence of mechanical strain. This review takes a distinctly translational approach to mechanistic and preclinical studies of differentiation and skeletal lineage commitment of mesenchymal cells under biophysical stimulation. In vitro studies facilitate the examination of isolated cellular responses while in vivo studies permit the observation of cell differentiation and extracellular matrix synthesis.     

SOAT1: A Suitable Target for Therapy in High-Grade Astrocytic Glioma?

Targeting molecular alterations as an effective treatment for isocitrate dehydrogenase-wildtype glioblastoma (GBM) patients has not yet been established. Sterol-O-Acyl Transferase 1 (SOAT1), a key enzyme in the conversion of endoplasmic reticulum cholesterol to esters for storage in lipid droplets (LD), serves as a target for the orphan drug mitotane to treat adrenocortical carcinoma. Inhibition of SOAT1 also suppresses GBM growth. Here, we refined SOAT1-expression in GBM and IDH-mutant astrocytoma, CNS WHO grade 4 (HGA), and assessed the distribution of LD in these tumors. Twenty-seven GBM and three HGA specimens were evaluated by multiple GFAP, Iba1, IDH1 R132H, and SOAT1 immunofluorescence labeling as well as Oil Red O staining. To a small extent SOAT1 was expressed by tumor cells in both tumor entities. In contrast, strong expression was observed in glioma-associated macrophages. Triple immunofluorescence labeling revealed, for the first time, evidence for SOAT1 colocalization with Iba1 and IDH1 R132H, respectively. Furthermore, a notable difference in the amount of LD between GBM and HGA was observed. Therefore, SOAT1 suppression might be a therapeutic option to target GBM and HGA growth and invasiveness. In addition, the high expression in cells related to neuroinflammation could be beneficial for a concomitant suppression of protumoral microglia/macrophages.     

APOB CRISPR-Cas9 Engineering in Hypobetalipoproteinemia: A Promising Tool for Functional Studies of Novel Variants

Hypobetalipoproteinemia is characterized by LDL-cholesterol and apolipoprotein B (apoB) plasma levels below the fifth percentile for age and sex. Familial hypobetalipoproteinemia (FHBL) is mostly caused by premature termination codons in the APOB gene, a condition associated with fatty liver and steatohepatitis. Nevertheless, many families with a FHBL phenotype carry APOB missense variants of uncertain significance (VUS). We here aimed to develop a proof-of-principle experiment to assess the pathogenicity of VUS using the genome editing of human liver cells. We identified a novel heterozygous APOB-VUS (p.Leu351Arg), in a FHBL family. We generated APOB knock-out (KO) and APOB-p.Leu351Arg knock-in Huh7 cells using CRISPR-Cas9 technology and studied the APOB expression, synthesis and secretion by digital droplet PCR and ELISA quantification. The APOB expression was decreased by 70% in the heterozygous APOB-KO cells and almost abolished in the homozygous-KO cells, with a consistent decrease in apoB production and secretion. The APOB-p.Leu351Arg homozygous cells presented with a 40% decreased APOB expression and undetectable apoB levels in cellular extracts and supernatant. Thus, the p.Leu351Arg affected the apoB secretion, which led us to classify this new variant as likely pathogenic and to set up a hepatic follow-up in this family. Therefore, the functional assessment of APOB-missense variants, using gene-editing technologies, will lead to improvements in the molecular diagnosis of FHBL and the personalized follow-up of these patients.     

Quantitative determination of fluorotelomer sulfonates in groundwater by LC MS/MS

Aqueous film-forming foams (AFFF) are complex mixtures containing fluorocarbon- and hydrocarbon-based surfactants that are used to fight hydrocarbon-fueled fires. The military is the largest consumer of AFFF in the United States, and fire-training activities conducted at military bases have led to groundwater contamination by unspent fuels and AFFF chemicals. A direct-injection, liquid-chromatography tandem mass spectrometry (LC MS/MS) method was developed to quantify a suite of fluorotelomer sulfonate surfactants in groundwater collected from military bases where fire-training activities were conducted. The 4:2, 6:2, and 8:2 fluorotelomer sulfonates were detected and quantified in groundwater from two of the three military bases. The total fluorotelomer sulfonate concentrations observed at Wurtsmith AFB, MI, and Tyndall AFB, FL, ranged respectively from below quantitation (< or = 0.60) to 182 microg/L and from 1100 to 14,600 microg/L. Analyses of a fluorotelomer-based AFFF concentrate by negative ion fast atom bombardment/mass spectrometry and LC MS/MS analyses indicate that the AFFF concentrate contains only a small amount of fluorotelomer sulfonates and that fluoroalkylthioamido sulfonates are the main anionic fluorosurfactant in the mixtures. More research is needed to determine the fate of fluoroalkylthioamido sulfonates in the environment.