An immunologically relevant rodent model demonstrates safety of therapy using a tumour-specific IgE.

BACKGROUND: Designing biologically informative models for assessing the safety of novel agents, especially for cancer immunotherapy, carries substantial challenges. The choice of an in vivo system for studies on IgE antibodies represents a major impediment to their clinical translation, especially with respect to class-specific immunological functions and safety. Fcε receptor expression and structure are different in humans and mice, so that the murine system is not informative when studying human IgE biology. By contrast, FcεRI expression and cellular distribution in rats mirror that of humans. METHODS: We are developing MOv18 IgE, a human chimeric antibody recognizing the tumour-associated antigen folate receptor alpha. We created an immunologically congruent surrogate rat model likely to recapitulate human IgE-FcεR interactions and engineered a surrogate rat IgE equivalent to MOv18. Employing this model, we examined in vivo safety and efficacy of antitumour IgE antibodies. RESULTS: In immunocompetent rats, rodent IgE restricted growth of syngeneic tumours in the absence of clinical, histopathological or metabolic signs associated with obvious toxicity. No physiological or immunological evidence of a "cytokine storm" or allergic response was seen, even at 50 mg/kg weekly doses. IgE treatment was associated with elevated serum concentrations of TNFα, a mediator previously linked with IgE-mediated antitumour and antiparasitic functions, alongside evidence of substantially elevated tumoural immune cell infiltration and immunological pathway activation in tumour-bearing lungs. CONCLUSION: Our findings indicate safety of MOv18 IgE, in conjunction with efficacy and immune activation, supporting the translation of this therapeutic approach to the clinical arena.

Corrigendum to 'Inhalational induction in paediatric anaesthesia' [BJA Education 23 (2023) 32-8].

[This corrects the article DOI: 10.1016/j.bjae.2022.10.002.].

Single-well injection-withdrawal tests as a contaminant transport characterisation tool for landfilled waste.

A new single well injection withdrawal (SWIW) test was trialled at four landfills using the tracers lithium and deuterium, and by injecting clean water and measuring electrical conductivity. The aim of the research was to develop a practical test for measuring lateral contaminant transport to aid in the design of landfill flushing. Borehole dilution tests using dyes were undertaken prior to each SWIW test to determine background flow velocities. SWIW tests were performed at different scales by varying the volume of tracer injected (1 to 5,800 m3) and the test duration (2 to 266 days). Tracers were used individually, simultaneously or sequentially to examine repeatability and scaling. Mobile porosities, estimated from first arrival times in observation wells and from model fitting ranged from 0.02 to 0.14. The low mobile porosities measured rule out a purely advective-dispersive system and support a conceptual model of a highly preferential dual-porosity flow system with localised heterogeneity. A dual-porosity model was used to interpret the results. The model gave a good fit to the test data in 7 out of 11 tests (where R2 ≥ 0.98), and the parameters derived are compatible with previous experiments in MSW. Block diffusion times were estimated to range from 12 to 6,630 h, with a scaling relationship apparent between the size of the test (volume of tracer used and/or the duration) and the observed block diffusion time. This scaling relationship means affordable small-scale tests can inform larger-scale flushing operations.

Doublet tracer tests to determine the contaminant flushing properties of a municipal solid waste landfill.

This paper describes a programme of research investigating horizontal fluid flow and solute transport through saturated municipal solid waste (MSW) landfill. The purpose is to inform engineering strategies for future contaminant flushing. Solute transport between injection/abstraction well pairs (doublets) is investigated using three tracers over five separate tests at well separations between 5m and 20m. Two inorganic tracers (lithium and bromide) were used, plus the fluorescent dye tracer, rhodamine-WT. There was no evidence for persistent preferential horizons or pathways at the inter-well scale. The time for tracer movement to the abstraction wells varied with well spacing as predicted for a homogeneous isotropic continuum. The time for tracer movement to remote observation wells was also as expected. Mobile porosity was estimated as ~0.02 (~4% of total porosity). Good fits to the tracer breakthrough data were achieved using a dual-porosity model, with immobile regions characterised by block diffusion timescales in the range of about one to ten years. This implies that diffusional exchanges are likely to be very significant for engineering of whole-site contaminant flushing and possibly rate-limiting.

Prescribed vitamin D and calcium preparations in patients treated with bone remodelling agents in primary care: a report of a pilot study.

BACKGROUND: Recent guidelines recommend that patients receiving treatment for osteoporosis should also receive supplementation with calcium and vitamin D unless they are calcium and vitamin D replete. Given that the majority of elderly patients have inadequate levels of vitamin D and that determining nutritional status is time-consuming and costly, it seems prudent to ensure that the majority of patients aged over 65 and receiving medication for osteoporosis should receive supplementation as a matter of course. OBJECTIVES: To determine the level of co-prescription of calcium and vitamin D in patients receiving treatment for osteoporosis with bisphosphonates, teriparatide, raloxifene or strontium. STUDY DESIGN AND METHODS: A pilot audit of nine general practices covering a population of 61 202. RESULTS: Overall, 1.1% (n = 662) of patients were receiving treatment for osteoporosis; of those, only 34.1% of patients were co-prescribed calcium or calcium and vitamin D. Levels of co-prescription varied considerably across practices from 74.0% to 12.2%. CONCLUSIONS: Despite national guidelines, co-prescription of calcium and vitamin D with treatment for osteoporosis remains sub-optimal with considerable variation between practices. Strategies should be adopted to increase physician awareness of widespread vitamin D inadequacy, the rationale for supplementation and poor compliance.

Lamellipodin promotes invasive 3D cancer cell migration via regulated interactions with Ena/VASP and SCAR/WAVE.

Cancer invasion is a hallmark of metastasis. The mesenchymal mode of cancer cell invasion is mediated by elongated membrane protrusions driven by the assembly of branched F-actin networks. How deregulation of actin regulators promotes cancer cell invasion is still enigmatic. We report that increased expression and membrane localization of the actin regulator Lamellipodin correlate with reduced metastasis-free survival and poor prognosis in breast cancer patients. In agreement, we find that Lamellipodin depletion reduced lung metastasis in an orthotopic mouse breast cancer model. Invasive 3D cancer cell migration as well as invadopodia formation and matrix degradation was impaired upon Lamellipodin depletion. Mechanistically, we show that Lamellipodin promotes invasive 3D cancer cell migration via both actin-elongating Ena/VASP proteins and the Scar/WAVE complex, which stimulates actin branching. In contrast, Lamellipodin interaction with Scar/WAVE but not with Ena/VASP is required for random 2D cell migration. We identified a phosphorylation-dependent mechanism that regulates selective recruitment of these effectors to Lamellipodin: Abl-mediated Lamellipodin phosphorylation promotes its association with both Scar/WAVE and Ena/VASP, whereas Src-dependent phosphorylation enhances binding to Scar/WAVE but not to Ena/VASP. Through these selective, regulated interactions Lamellipodin mediates directional sensing of epidermal growth factor (EGF) gradients and invasive 3D migration of breast cancer cells. Our findings imply that increased Lamellipodin levels enhance Ena/VASP and Scar/WAVE activities at the plasma membrane to promote 3D invasion and metastasis.

Multiple-tracer tests for contaminant transport process identification in saturated municipal solid waste.

Two column tests were performed in conditions emulating vertical flow beneath the leachate table in a biologically active landfill to determine dominant transport mechanisms occurring in landfills. An improved understanding of contaminant transport process in wastes is required for developing better predictions about potential length of the long term aftercare of landfills, currently measured in timescales of centuries. Three tracers (lithium, bromide and deuterium) were used. Lithium did not behave conservatively. Given that lithium has been used extensively for tracing in landfill wastes, the tracer itself and the findings of previous tests which assume that it has behaved conservatively may need revisiting. The smaller column test could not be fitted with continuum models, probably because the volume of waste was below a representative elemental volume. Modelling compared advection-dispersion (AD), dual porosity (DP) and hybrid AD-DP models. Of these models, the DP model was found to be the most suitable. Although there is good evidence to suggest that diffusion is an important transport mechanism, the breakthrough curves of the different tracers did not differ from each other as would be predicted based on the free-water diffusion coefficients. This suggested that solute diffusion in wastes requires further study.

Investigating the effect of compression on solute transport through degrading municipal solid waste.

The effect of applied compression on the nature of liquid flow and hence the movement of contaminants within municipal solid waste was examined by means of thirteen tracer tests conducted on five separate waste samples. The conservative nature of bromide, lithium and deuterium tracers was evaluated and linked to the presence of degradation in the sample. Lithium and deuterium tracers were non-conservative in the presence of degradation, whereas the bromide remained effectively conservative under all conditions. Solute diffusion times into and out of less mobile blocks of waste were compared for each test under the assumption of dominantly dual-porosity flow. Despite the fact that hydraulic conductivity changed strongly with applied stress, the block diffusion times were found to be much less sensitive to compression. A simple conceptual model, whereby flow is dominated by sub-parallel low permeability obstructions which define predominantly horizontally aligned less mobile zones, is able to explain this result. Compression tends to narrow the gap between the obstructions, but not significantly alter the horizontal length scale. Irrespective of knowledge of the true flow pattern, these results show that simple models of solute flushing from landfill which do not include depth dependent changes in solute transport parameters are justified.

Quantifying the effect of settlement and gas on solute flow and transport through treated municipal solid waste.

The effect of degradation and settlement on transport properties of mechanically and biologically treated (MBT) waste was examined by applying three different tracers to two waste columns (~0.5 m diameter) in a series of closed-loop experiments. One column was allowed to biodegrade and the other was bio-suppressed. Permeability and drainable porosity were reduced by settlement, in line with previous results. A dual-porosity model performed well against the data and suggested that more preferential flow occurred early on in the un-degraded column. Diffusion timescales were found to be between 0.8 and 6 days. Volumetric water contents of the mobile region were found to be small in the bio-suppressed cell (~0.01) and even smaller values were found in the degrading waste, possibly due to displacement by gas. Once either settlement or gas production had disrupted this pattern into a more even flow, subsequent compression made little difference to the diffusion time-scale. This may indicate that transport was thereafter dominated by other aspects of the waste structure such as the distribution of low-permeability objects. The presence of gas in the degrading waste reduced the volumetric water content through displacement. The model indicated that the gas was primarily located in the more mobile porosity fraction. Primary compression of the degrading waste tended to squeeze this gas out of the waste in preference to water.

The challenges of integrating molecular imaging into the optimization of cancer therapy.

We review novel, in vivo and tissue-based imaging technologies that monitor and optimize cancer therapeutics. Recent advances in cancer treatment centre around the development of targeted therapies and personalisation of treatment regimes to individual tumour characteristics. However, clinical outcomes have not improved as expected. Further development of the use of molecular imaging to predict or assess treatment response must address spatial heterogeneity of cancer within the body. A combination of different imaging modalities should be used to relate the effect of the drug to dosing regimen or effective drug concentration at the local site of action. Molecular imaging provides a functional and dynamic read-out of cancer therapeutics, from nanometre to whole body scale. At the whole body scale, an increase in the sensitivity and specificity of the imaging probe is required to localise (micro)metastatic foci and/or residual disease that are currently below the limit of detection. The use of image-guided endoscopic biopsy can produce tumour cells or tissues for nanoscopic analysis in a relatively patient-compliant manner, thereby linking clinical imaging to a more precise assessment of molecular mechanisms. This multimodality imaging approach (in combination with genetics/genomic information) could be used to bridge the gap between our knowledge of mechanisms underlying the processes of metastasis, tumour dormancy and routine clinical practice. Treatment regimes could therefore be individually tailored both at diagnosis and throughout treatment, through monitoring of drug pharmacodynamics providing an early read-out of response or resistance.

The endogenous cannabinoid, anandamide, induces cell death in colorectal carcinoma cells: a possible role for cyclooxygenase 2.

BACKGROUND AND AIMS: Cyclooxygenase 2 (COX-2) is upregulated in most colorectal cancers and is responsible for metabolism of the endogenous cannabinoid, anandamide, into prostaglandin-ethanolamides (PG-EAs). The aims of this study were to determine whether anandamide and PG-EAs induce cell death in colorectal carcinoma (CRC) cells, and whether high levels of COX-2 in CRC cells could be utilised for their specific targeting for cell death by anandamide. METHODS: We determined the effect of anandamide on human CRC cell growth by measuring cell growth and cell death, whether this was dependent on COX-2 protein expression or enzyme activity, and the potential involvement of PG-EAs in induction of cell death. RESULTS: Anandamide inhibited the growth of CRC cell lines HT29 and HCA7/C29 (moderate and high COX-2 expressors, respectively) but had little effect on the very low COX-2 expressing CRC cell line, SW480. Induction of cell death in HT29 and HCA7/C29 cell lines was partially rescued by the COX-2 selective inhibitor NS398. Cell death induced by anandamide was neither apoptosis nor necrosis. Furthermore, inhibition of fatty acid amide hydrolase potentiated the non-apoptotic cell death, indicating that anandamide induced cell death was mediated via metabolism of anandamide by COX-2, rather than its degradation into arachidonic acid and ethanolamine. Interestingly, both PGE2-EA and PGD2-EA induced classical apoptosis. CONCLUSIONS: These findings suggest anandamide may be a useful chemopreventive/therapeutic agent for colorectal cancer as it targets cells that are high expressors of COX-2, and may also be used in the eradication of tumour cells that have become resistant to apoptosis.

Current practice for induction of labour in the United Kingdom: time for a review?

This paper presents the results of postal survey of protocols for induction of labour. The drug regimes used for the induction of labour in NHS hospitals in England and Wales have been compared to both RCOG guidelines and to the drug manufacturer's recommendations. A wide variation in practice was found, with many units using dosages that are different from those recommended. The implications of such departures from the norm are discussed in terms of the importance of evidence-based practice and the role of national guidelines in ensuring optimum care.

Can an advanced nurse practitioner take on the role of senior house officer within a specialised area of practice: an evaluation.

This study looked at the impact of advanced nurse practitioners (ANPs) taking on the role of senior house officer (SHO) within obstetrics and gynaecology. It was anticipated that such a change would have benefits for patients and for service delivery. The project took place in the gynaecology department of a district general hospital. All patients who would normally be under the care of the SHOs with one medical team received this care from one or other of two ANPs. Focus groups were used to look at the impact of the changes on other staff within the unit. Patient questionnaires were used to assess the opinions of patients about the care they received. Length of stay, readmissions and cancellations were used to assess the impact on patient care. The change in role of the ANPs has had lasting benefits in terms of better communication and multidisciplinary working and the development of an informal referral system that allowed patients to be seen more quickly and appropriately. There were no ill effects on patient care.

Influence of early discharge after hysterectomy on patient outcome and GP workloads.

This paper examines the impact of early discharge following hysterectomy on patient outcome and GP workload. Results are presented from a survey of patient attitudes on care and recovery, pain relief and contacts overall with their general practitioner (GP) surgery. The findings are compared with those of a previous study where a policy of early discharge had been shown to increase GP workloads. The paper discusses the importance of preparing patients adequately for their surgery and postoperative recovery, and highlights the beneficial effects on patient attitudes of the introduction of patient information leaflets, a preadmission clinic and a telephone advice service following discharge.