Beta-glucan contamination of pharmaceutical products:How much should we accept?

Beta-glucans are large polysaccharides produced by a range of prokaryotic and eukaryotic organisms. They have potential immunostimulatory properties and have been used with therapeutic intent as anti-microbial and anti-tumour agents. A range of other potentially beneficial effects have been described, and oral forms of beta-glucans are widely available over-the-counter and online. Parenteral formulations are popular in parts of Asia and are the subject of ongoing trials, worldwide. Beta-glucans are also potential contaminants of pharmaceutical products, and high levels have been described in some blood products. However, little is known about the clinical effects of such contamination, considerable uncertainty exists over the level at which immunostimulation may occur, and there are no guidelines available on acceptable levels. We encountered beta-glucan contamination of one of our products, and we suspect that others may encounter similar issues since the origin of beta-glucan contamination includes commonly used filters and solutions applied in the manufacture of biotherapeutic agents. It is likely that regulators will increasingly enquire about beta-glucan levels in pharmaceutical products, especially those with an immunomodulatory mechanism of action. Here, we review the literature on beta-glucans in pharmaceutical products and propose an acceptable level for therapeutic agents for parenteral use

Effect of fuel temperature on flame characteristics of supersonic turbulent combustion

A comprehensive numerical study is undertaken to investigate the dynamics of hydrogen-air supersonic turbulent flames in a shear coaxial configuration. The effects of fuel temperature on the flow and flame characteristics are examined systematically. The numerical methodology is based on a hybrid RANS/LES model for compressible, multi-species flows with finite-rate chemical reactions. Results from simulations employing different levels of grid resolution and numerical schemes are compared and validated against experimental data. The importance of adequate grid resolution and high-order numerical schemes to achieve high-fidelity prediction of fine-scale flow features is underscored. In particular, the multi-dimensional high-order oMLP scheme shows remarkable pre-diction capabilities without incurring excessive computational cost. The lifted turbulent flame characteristics with combustion occurring mostly in a premixed mode downstream after turbulent mixing in the shear layer are identified and elaborated. A parametric study is subsequently performed to investigate the effect of fuel tem-perature. It is found that the combustion regime changes from partially-premixed to non-premixed mode as the fuel temperature is increased. The flame width and combustion efficiency increase with increasing fuel tem-perature, due to the enhancement of mixing following the reduced convective Mach number. The most promi-nent effect of fuel temperature is the reduction of flame length, a crucial factor for the design of supersonic combustors.N

Preclinical evaluation of a novel CEA-targeting near-infrared fluorescent tracer delineating colorectal and pancreatic tumors

Surgery is the cornerstone of oncologic therapy with curative intent. However, identification of tumor cells in the resection margins is difficult, resulting in non-radical resections, increased cancer recurrence and subsequent decreased patient survival. Novel imaging techniques that aid in demarcating tumor margins during surgery are needed. Overexpression of carcinoembryonic antigen (CEA) is found in the majority of gastro-intestinal carcinomas, including colorectal and pancreas. We developed ssSM3E/800CW, a novel CEA-targeted near-infrared fluorescent (NIRF) tracer, based on a disulphide stabilized single-chain antibody fragment (ssScFv), to visualize colorectal and pancreatic tumors in a clinically translatable setting. The applicability of the tracer was tested for cell and tissue binding characteristics and dosing using immunohistochemistry, flow cytometry, cell-based plate assays and orthotopic colorectal (HT-29, well differentiated) and pancreatic (BXPC-3, poorly differentiated) xenogeneic human-mouse models. NIRF signals were visualized using the clinically compatible FLARE™ imaging system. Calculated clinically relevant doses of ssSM3E/800CW selectively accumulated in colorectal and pancreatic tumors/cells, with highest tumor-to-background ratios of 5.1±0.6 at 72 h post-injection, which proved suitable for intra-operative detection and delineation of tumor boarders and small (residual) tumor-nodules in mice, between 8 h and 96 h post-injection. Ex vivo fluorescence imaging and pathologic examination confirmed tumor-specificity and the distribution of the tracer. Our results indicate that ssSM3E/800CW shows promise as a diagnostic tool to recognize colorectal and pancreatic cancers for fluorescent-guided surgery applications. If successful translated clinically, this tracer could help improve the completeness of surgery and thus survival