Combining multiple biomarkers linearly to maximize the partial area under the ROC curve

It is now common in clinical practice to make clinical decisions based on combinations of multiple biomarkers. In this paper, we propose new approaches for combining multiple biomarkers linearly to maximize the partial area under the receiver operating characteristic curve (pAUC). The parametric and nonparametric methods that have been developed for this purpose have limitations. When the biomarker values for populations with and without a given disease follow a multivariate normal distribution, it is easy to implement our proposed parametric approach, which adopts an alternative analytic expression of the pAUC. When normality assumptions are violated, a kernel‐based approach is presented, which handles multiple biomarkers simultaneously. We evaluated the proposed as well as existing met…

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Combining multiple biomarkers linearly to maximize the partial area under the ROC curve

Development of docetaxel liposome surface modified with CD133 aptamers for lung cancer targeting

. (Source: Artificial Cells, Blood Substitutes, and Biotechnology)

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Development of docetaxel liposome surface modified with CD133 aptamers for lung cancer targeting

Public trust and ‘ethics review’ as a commodity: the case of Genomics England Limited and the UK’s 100,000 genomes project

AbstractThe UK Chief Medical Officer ’s 2016 Annual Report,Generation Genome, focused on a vision to fully integrate genomics into all aspects of the UK ’s National Health Service (NHS). This process of integration, which has now already begun, raises a wide range of social and ethical concerns, many of which were discussed in the final Chapter of the report. This paper explores how the UK’s 100,000 Genomes Project (100 kGP)—the catalyst forGeneration Genome, and for bringing genomics into the NHS —is negotiating these ethical concerns. The UK’s 100 kGP, promoted and delivered by Genomics England Limited (GEL), is an innovative venture aiming to sequence 100,000 genomes from NHS patients who have a rare disease, cancer, or an infectious disease. GEL has emphasised the importa…

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Public trust and ‘ethics review’ as a commodity: the case of Genomics England Limited and the UK’s 100,000 genomes project

New developments and clinical transition of hyaluronic acid-based nanotherapeutics for treatment of cancer: reversing multidrug resistance, tumour-specific targetability and improved anticancer efficacy

. (Source: Artificial Cells, Blood Substitutes, and Biotechnology)

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New developments and clinical transition of hyaluronic acid-based nanotherapeutics for treatment of cancer: reversing multidrug resistance, tumour-specific targetability and improved anticancer efficacy

Evaluation of the effect of new formulation, food, or a proton pump inhibitor on the relative bioavailability of the smoothened inhibitor glasdegib (PF-04449913) in healthy volunteers

Abstract

Purpose

This phase I open-label study investigated the oral bioavailability of two novel maleate salt-based glasdegib (PF-04449913) tablet formulations (small- and large-particle size) relative to the current clinical formulation (diHCl salt-based). In addition, the effect of a gastric pH-altering agent (rabeprazole) and food on the pharmacokinetics of the large-particle size formulation of glasdegib were evaluated. The pharmacokinetics of glasdegib oral solution was also assessed.

Methods

Thirty-four healthy subjects received glasdegib 100 mg as three different formulations in the fasted state (diHCl salt or small- or large-particle size maleate formulation); 13 received the large-particle maleate formulation (fed), and 14 concurrently with rabeprazole (fasted); six subjects received glasdegib 50 mg oral solution (fasted).

Results

For both new tablet formulations of glasdegib, ratios (Test:Reference) of adjusted geometric means (90% confidence interval) of area under the concentration–time curve from 0 to infinity and maximum plasma concentration were within 80–125% compared with the diHCl formulation (fasted). For the large-particle size formulation (fed), these ratios were 86.3% (81.0–92.0%) and 75.7% (65.3–87.7%), respectively, compared with fasted. When the large-particle maleate formulation was administered concurrently with rabeprazole versus alone (fasted), these ratios were 111.9% (102.8–121.9%) and 87.2% (75.9–100.3%), respectively. The pharmacokinetics of oral solution was similar to the tablet.

Conclusions

The maleate salt-based tablet formulations were bioequivalent to the diHCl tablet formulation. The extent of the observed effect of a high-fat, high-calorie meal or concurrent rabeprazole treatment on glasdegib exposure is not considered clinically meaningful.

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Evaluation of the effect of new formulation, food, or a proton pump inhibitor on the relative bioavailability of the smoothened inhibitor glasdegib (PF-04449913) in healthy volunteers

Correction to: Innovative intraoral cooling device better tolerated and equally effective as ice cooling

Unfortunately, the online published article has error in Table 1. The correct Table 1 is given in the following page.

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Correction to: Innovative intraoral cooling device better tolerated and equally effective as ice cooling

Therapeutic potential of the metabolic modulator Metformin on osteosarcoma cancer stem-like cells

Abstract

Purpose

Osteosarcoma is the most common primary bone tumour appearing in children and adolescents. Recent studies demonstrate that osteosarcoma possesses a stem-like cell subset, so-called cancer stem-like cells, refractory to conventional chemotherapeutics and pointed out as responsible for relapses frequently observed in osteosarcoma patients. Here, we explored the therapeutic potential of Metformin on osteosarcoma stem-like cells, alone and as a chemosensitizer of doxorubicin.

Methods

Stem-like cells were isolated from human osteosarcoma cell lines, MNNG/HOS and MG-63, using the sphere-forming assay. Metformin cytotoxicity alone and combined with doxorubicin were evaluated using MTT/BrdU assays. Protein levels of AMPK and AKT were evaluated by Western Blot. Cellular metabolic status was assessed based on [18F]-FDG uptake and lactate production measurements. Sphere-forming efficiency and expression of pluripotency transcription factors analysed by qRT-PCR were tested as readout of Metformin effects on stemness features.

Results

Metformin induced a concentration-dependent decrease in the metabolic activity and proliferation of sphere-forming cells and improved doxorubicin-induced cytotoxicity. This drug also down-regulated the expression of master regulators of pluripotency (OCT4, SOX2, NANOG), and decreased spheres’ self-renewal ability. Metformin effects on mitochondria led to the activation and phosphorylation of the energetic sensor AMPK along with an upregulation of the pro-survival AKT pathway in both cell populations. Furthermore, Metformin-induced mitochondrial stress increased [18F]-FDG uptake and lactate production in parental cells but not in the quiescent stem-like cells, suggesting the inability of the latter to cope with the energy crisis induced by metformin.

Conclusions

This preclinical study suggests that Metformin may be a potentially useful therapeutic agent and chemosensitizer of osteosarcoma stem-like cells to doxorubicin.

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Therapeutic potential of the metabolic modulator Metformin on osteosarcoma cancer stem-like cells