The RAG Model: a new paradigm for genetic risk stratification in multiple myeloma

Molecular studies have shown that multiple myeloma is a highly genetically heterogonous disease which may manifest itself as any number of diverse subtypes each with variable clinicopathological features and outcomes. Given this genetic heterogeneity, a universal approach to treatment of myeloma is unlikely to be successful for all patients and instead we should strive for the goal of personalised therapy using rationally informed targeted strategies. Current DNA sequencing technologies allow for whole genome and exome analysis of patient myeloma samples that yield vast amounts of genetic data and provide a mutational overview of the disease. However, the clinical utility of this information currently lags far behind the sequencing technology which is increasingly being incorporated into clinical practice. This paper attempts to address this shortcoming by proposing a novel genetically based “traffic-light” risk stratification system for myeloma, termed the RAG (Red, Amber, Green) model, which represents a simplified concept of how complex genetic data may be compressed into an aggregate risk score. The model aims to incorporate all known clinically important trisomies, translocations, and mutations in myeloma and utilise these to produce a score between 1.0 and 3.0 that can be incorporated into diagnostic, prognostic, and treatment algorithms for the patient

Effects of Seasonal Variation in Milk Composition on the Quality of Pizza Cheese

End of Project ReportThe main aims of this study were to investigate the effects of diet and lactation stage on the composition and cheesemaking quality of milk produced under controlled conditions. The main conclusions were as follows: These studies clearly demonstrated that the Recommended Moorepark Milk Production System in conjunction with an objectively standardised cheesemaking process provides a model for year round production of quality Mozzarella cheese. Databases have been established on the effects of diet quantity and quality, and stage of lactation on the composition, processability and cheesemaking characteristics of milk from both Spring- and Autumn-calving herds. Increasing the daily herbage allowance from 16 to 24 kgs DM/cow/day during mid-lactation, resulted in increases in the level of milk casein and cheese yield but had little influence on cheese functionality. Similarily improving diet quality in mid-lactation by reducing the stocking density from 4.3 to 3.8 cows/ha combined with concentrate supplementation (3 kgs/cow/day) had the same effect. Using milk from a Spring-calving herd, produced according to the Recommended Moorepark Milk Production System, in conjunction with an objectively-standardised Mozzarella cheesemaking process, no major problems were encountered during the lactation period 170 - 273 days from calving. Extending the lactation period of the Spring-calving herd from ~ 273 to 286 days resulted in higher cheese moisture (by ~ 2%), softer cheese, and lower chewiness in the melted cheese. A sharp decline in both total protein, casein and lactose in the milk was observed during this period. However the blending of this milk with milk of an Autumn-calving herd overcame these cheesemaking problems. The yield of low moisture Mozzarella cheese (using milks from Spring- or Autumn-calved herds) was positively correlated with milk casein level. The yield of cheese from the Spring-calved herd increased concomitantly with increasing casein level to day 273 of lactation and decreased thereafter as the casein concentration declined. In these studies it was found that easy-to-use tests such as lactose level in the milk and rennet coagulation properties as determined by Formagraph were useful indicators of the suitability of milk for cheesemaking. The Recommended Moorepark Milk Production System, as applied in the late lactation period, was characterised by a high plane of nutrition and a drying-off strategy which ensured a minimum daily milk yield per cow of 9 kg. It resulted in milk of good cheesemaking quality - lactose > 4.25%, and casein > 2.6% and satisfactory rennet coagulation properties - curd firming rate of > 0.15 min ¯¹ curd firmness at 60 min of > 45mm - at the end of lactation.Department of Agriculture, Food and the Marin

Esterification Prevents Induction of the Mitochondrial Permeability Transition by N-Acetyl Perfluorooctane Sulfonamides

N-Alkyl perfluorooctane sulfonamides have been widely used as surfactants on fabrics and papers, fire retardants, and anticorrosion agents, among many other commercial applications. The broad use, global distribution, and environmental persistence of these compounds has generated considerable interest regarding potentially toxic effects. We have previously reported that perfluorooctanesulfonamidoacetate (FOSAA) and N-ethylperfluorooctanesulfonamidoacetate (N-EtFOSAA) induce the mitochondrial permeability transition (MPT) in vitro, resulting in cytochrome c release, inhibition of respiration, and generation of reactive oxygen species. By synthesizing the corresponding methyl esters of FOSAA and N-EtFOSAA (methyl perlfuorinated sulfonamide acetates), we tested the hypothesis that the N-acetate moiety of FOSAA and N-EtFOSAA is the functional group responsible for induction of the MPT. Swelling of freshly isolated liver mitochondria from Sprague−Dawley rats was monitored spectrophotometrically and membrane potential (ΔΨ) was measured using a tetraphenylphosphonium-selective (TPP+) electrode. In the presence of calcium, 40 μM FOSAA and 7 μM N-EtFOSAA each induced mitochondrial swelling and a biphasic depolarization of membrane potential. Mitochondrial swelling and the second-phase depolarization were inhibited by cyclosporin-A or the catalyst of K+/H+ exchange nigericin, whereas the first-phase depolarization was not affected by either. In contrast, the methyl esters of FOSAA and N-EtFOSAA exhibited no depolarizing or MPT inducing activity. Results of this investigation demonstrate that the carboxylic acid moiety of the N-acetates is the active functional group, which triggers the MPT by perfluorinated sulfonamides

Advances in mesenchymal stem cell-mediated gene therapy for cancer

Mesenchymal stem cells have a natural tropism for tumours and their metastases, and are also considered immunoprivileged. This remarkable combination of properties has formed the basis for many studies investigating their potential as tumour-specific delivery vehicles for suicide genes, oncolytic viruses and secreted therapeutic proteins. The aim of the present review is to discuss the range of approaches that have been used to exploit the tumour-homing capacity of mesenchymal stem cells for gene delivery, and to highlight advances required to realize the full potential of this promising approach

Cutaneous glucocorticoid receptor sensitivity and proinflammatory cytokine levels in antidepressant-resistant depression

ABSTRACT Background. There is evidence to indicate that peripheral glucocorticoid receptor (GR) function is reduced in major depression, and a possible molecular explanation for this is the impact of raised pro-inflammatory cytokines. The topical steroid vasoconstriction assay provides a convenient probe of peripheral GR function. The present study sought to assess the sensitivity of peripheral GRs in antidepressant-resistant major depressives and investigate the association between GR sensitivity and circulating plasma cytokines. Method. Nineteen antidepressant-resistant depressives together with age- and sex-matched healthy controls underwent the steroid vasoconstriction assay using three commercial preparations of corticosteroids containing clobetasol propionate 0.05%, betamethasone valerate 0.1%, and clobetasone butyrate 0.05%, corresponding to very potent, potent, and moderately potent steroid creams respectively. The pro-inflammatory cytokines, tumour necrosis factor-alpha (TNF-a) and interleukin-6 (IL-6) were measured using enzyme-linked immunosorbent assays. The severity of the depressive episode was assessed using the Hamilton Depression Scale (HAMD). Results. Depressed subjects had a significantly reduced vasoconstriction response across all three strengths of steroid. They also had significantly higher concentrations of TNF-a and IL-6. There was a significant inverse correlation between TNF-a concentration and vasoconstriction response and also between the HAMD score and vasoconstriction response. Conclusions. These findings suggest that cutaneous GR function is abnormal in antidepressantresistant depression, that circulating TNF-a may play a significant role in this abnormality and that the efficacy of topical steroids in antidepressant-resistant depressives is reduced

The Proportion of Fermented Milk in Dehydrated Fermented Milk–Parboiled Wheat Composites Significantly Affects Their Composition, Pasting Behaviour, and Flow Properties on Reconstitution

Peer reviewedDairy and cereal are frequently combined to create composite foods with enhanced nutritional benefits. Dehydrated fermented milk–wheat composites (FMWC) were prepared by blending fermented milk (FM) and parboiled wheat (W), incubating at 35 °C for 24 h, drying at 46 °C for 48 h, and milling to 1 mm. Increasing the weight ratio of FM to W from 1.5 to 4.0 resulted in reductions in total solids (from 96 to 92%) and starch (from 52 to 39%), and increases in protein (15.2–18.9%), fat (3.7–5.9%), lactose (6.4–11.4%), and lactic acid (2.7–4.2%). FMWC need to be reconstituted prior to consumption. The water-holding capacity, pasting viscosity, and setback viscosity of the reconstituted FMWC (16.7% total solids) decreased with the ratio of FM to W. The reconstituted FMWC exhibited pseudoplastic flow behaviour on shearing from 18 to 120 s−1. Increasing the FM:W ratio coincided with a lower yield stress, consistency index, and viscosity at 120 s−1. The results demonstrate the critical impact of the FM:W ratio on the composition, pasting behavior, and consistency of the reconstituted FMWC. The difference in consistency associated with varying the FM:W ratio is likely to impact on satiety and nutrient value of the FMWCs

Comparison of the nutritional composition of experimental fermented milk:wheat bulgur blends and commercially available kishk and tarhana products

peer-reviewedDried, fermented blends of dairy products and cereals, such as kishk and tarhana, are foodstuffs traditionally consumed in many regions as they possess good nutritional qualities and extended storage stability. This study examined the nutritional composition of kishk or tarhana type products and compared with experimental blends of fermented milk and wheat bulgur containing 60–80% milk. The blends with higher milk contents had levels of protein (18.9%) and fat (5.8%) at the concentrations specified in fortified blended foods as outlined by the World Food Program. Higher milk contents were also associated with higher contents of calcium (323.2 mg/100 g), phosphorus (335.3 mg/100 g), vitamin A (486.7 µg/100 g) and α-tocopherol (174.5 µg/100 g). The nutritional content of the experimental fermented milk:wheat bulgur blends compared favourably with that of the commercial samples. These blends may be suitable as base products, to be fortified with micronutrients, for the development of fortified blended foods (FBFs) for humanitarian distribution

MicroRNA profiling reveals marker of motor neuron disease in ALS models

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder marked by the loss of motor neurons (MNs) in the brain and spinal cord, leading to fatally debilitating weakness. Because this disease predominantly affects MNs, we aimed to characterize the distinct expression profile of that cell type to elucidate underlying disease mechanisms and to identify novel targets that inform on MN health during ALS disease time course. microRNAs (miRNAs) are short, noncoding RNAs that can shape the expression profile of a cell and thus often exhibit cell-type-enriched expression. To determine MN-enriched miRNA expression, we used Cre recombinase-dependent miRNA tagging and affinity purification in mice. By defining thein vivomiRNA expression of MNs, all neurons, astrocytes, and microglia, we then focused on MN-enriched miRNAs via a comparative analysis and found that they may functionally distinguish MNs postnatally from other spinal neurons. Characterizing the levels of the MN-enriched miRNAs in CSF harvested from ALS models of MN disease demonstrated that one miRNA (miR-218) tracked with MN loss and was responsive to an ALS therapy in rodent models. Therefore, we have used cellular expression profiling tools to define the distinct miRNA expression of MNs, which is likely to enrich future studies of MN disease. This approach enabled the development of a novel, drug-responsive marker of MN disease in ALS rodents.SIGNIFICANCE STATEMENTAmyotrophic lateral sclerosis (ALS) is a neurodegenerative disease in which motor neurons (MNs) in the brain and spinal cord are selectively lost. To develop tools to aid in our understanding of the distinct expression profiles of MNs and, ultimately, to monitor MN disease progression, we identified small regulatory microRNAs (miRNAs) that were highly enriched or exclusive in MNs. The signal for one of these MN-enriched miRNAs is detectable in spinal tap biofluid from an ALS rat model, where its levels change as disease progresses, suggesting that it may be a clinically useful marker of disease status. Furthermore, rats treated with ALS therapy have restored expression of this MN RNA marker, making it an MN-specific and drug-responsive marker for ALS rodents.</jats:p

Calculating Unknown Eigenvalues with a Quantum Algorithm

Quantum algorithms are able to solve particular problems exponentially faster than conventional algorithms, when implemented on a quantum computer. However, all demonstrations to date have required already knowing the answer to construct the algorithm. We have implemented the complete quantum phase estimation algorithm for a single qubit unitary in which the answer is calculated by the algorithm. We use a new approach to implementing the controlled-unitary operations that lie at the heart of the majority of quantum algorithms that is more efficient and does not require the eigenvalues of the unitary to be known. These results point the way to efficient quantum simulations and quantum metrology applications in the near term, and to factoring large numbers in the longer term. This approach is architecture independent and thus can be used in other physical implementations