Safety and efficacy of an engineered hepatotropic AAV gene therapy for ornithine transcarbamylase deficiency in cynomolgus monkeys

X-linked inherited ornithine transcarbamylase deficiency (OTCD) is the most common disorder affecting the liver-based urea cycle, a pathway enabling detoxification of nitrogen waste and endogenous arginine biosynthesis. Patients develop acute hyperammonemia leading to neurological sequelae or death despite the best-accepted therapy based on ammonia scavengers and protein-restricted diet. Liver transplantation is curative but associated with procedure-related complications and lifelong immunosuppression. Adeno-associated viral (AAV) vectors have demonstrated safety and clinical benefits in a rapidly growing number of clinical trials for inherited metabolic liver diseases. Engineered AAV capsids have shown promising enhanced liver tropism. Here, we conducted a good-laboratory practice-compliant investigational new drug-enabling study to assess the safety of intravenous liver-tropic AAVLK03 gene transfer of a human codon-optimized OTC gene. Juvenile cynomolgus monkeys received vehicle and a low and high dose of vector (2 × 1012 and 2 × 1013 vector genome (vg)/kg, respectively) and were monitored for 26 weeks for in-life safety with sequential liver biopsies at 1 and 13 weeks post-vector administration. Upon completion of monitoring, animals were euthanized to study vector biodistribution, immune responses, and histopathology. The product was well tolerated with no adverse clinical events, predominant hepatic biodistribution, and sustained supra-physiological OTC overexpression. This study supports the clinical deployment of intravenous AAVLK03 for severe OTCD

Stem cell differentiation increases membrane-actin adhesion regulating cell blebability, migration and mechanics

This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder in order to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/K. S. is funded by an EPSRC PhD studentship. S.T. is funded by an EU Marie Curie Intra European Fellowship (GENOMICDIFF)

A phase II trial of preoperative chemotherapy with epirubicin, cisplatin and capecitabine for patients with localised gastro-oesophageal junctional adenocarcinoma

Preoperative cisplatin/fluorouracil is used for the treatment of localised oesophageal carcinoma. This phase II study aimed to assess the efficacy and safety of administering preoperative epirubicin/cisplatin/capecitabine (ECX). Patients with stage II or III oesophageal/gastro-oesophageal junctional adenocarcinoma from one institution received 4 cycles of ECX (epirubicin 50 mg m−2 day 1, cisplatin 60 mg m−2 day 1, capecitabine 625 mg m−2 b.i.d. daily) followed by surgery. The primary end point was the pathological complete response (pCR) rate based on a Simon two-stage design. Secondary end points included overall and progression-free survival (OS/PFS). Thirty-four patients were recruited: median age 60 years (range 41–81), 91% male, 97% PS 0/1, 80% T3, 68% N1. Thirty-one patients completed four ECX cycles. Grade 3/4 toxicities ⩾5% included neutropenia (62%), hand–foot syndrome (15%) and nausea/vomiting (9%). Thirteen out of 28 (46%) evaluable patients responded to chemotherapy by EUS (⩾30% reduction in maximal tumour thickness). Twenty-six out of 34 (76%) patients underwent resection (R0=73%, R1=27%). Post-operatively, two patients died within 60 days of surgery. The pCR rate was 5.9% (95% CI 0–14%) in the intent-to-treat population. According to the statistical design, this prompted early study termination. However, with a median follow-up of 34 months the median OS and 1- and 2-year survival rates were 17 months, 67 and 39% respectively. Median PFS was 13 months. Of the 14 relapsed patients, 10 presented with distant metastases. Preoperative ECX is feasible and well tolerated. Although associated with a low pCR rate, survival with ECX was comparable with published studies suggesting that pCR may not correlate with satisfactory outcome from preoperative chemotherapy for localised oesophageal adenocarcinoma

Development of a Model System to Identify Differences in Spring and Winter Oat

Our long-term goal is to develop a Swedish winter oat (Avena sativa). To identify molecular differences that correlate with winter hardiness, a winter oat model comprising of both non-hardy spring lines and winter hardy lines is needed. To achieve this, we selected 294 oat breeding lines, originating from various Russian, German, and American winter oat breeding programs and tested them in the field in south- and western Sweden. By assaying for winter survival and agricultural properties during four consecutive seasons, we identified 14 breeding lines of different origins that not only survived the winter but also were agronomically better than the rest. Laboratory tests including electrolytic leakage, controlled crown freezing assay, expression analysis of the AsVrn1 gene and monitoring of flowering time suggested that the American lines had the highest freezing tolerance, although the German lines performed better in the field. Finally, six lines constituting the two most freezing tolerant lines, two intermediate lines and two spring cultivars were chosen to build a winter oat model system. Metabolic profiling of non-acclimated and cold acclimated leaf tissue samples isolated from the six selected lines revealed differential expression patterns of 245 metabolites including several sugars, amino acids, organic acids and 181 hitherto unknown metabolites. The expression patterns of 107 metabolites showed significant interactions with either a cultivar or a time-point. Further identification, characterisation and validation of these metabolites will lead to an increased understanding of the cold acclimation process in oats. Furthermore, by using the winter oat model system, differential sequencing of crown mRNA populations would lead to identification of various biomarkers to facilitate winter oat breeding

Do female association preferences predict the likelihood of reproduction?

Sexual selection acting on male traits through female mate choice is commonly inferred from female association preferences in dichotomous mate choice experiments. However, there are surprisingly few empirical demonstrations that such association preferences predict the likelihood of females reproducing with a particular male. This information is essential to confirm association preferences as good predictors of mate choice. We used green swordtails (<i>Xiphophorus helleri</i>) to test whether association preferences predict the likelihood of a female reproducing with a male. Females were tested for a preference for long- or short-sworded males in a standard dichotomous choice experiment and then allowed free access to either their preferred or non-preferred male. If females subsequently failed to produce fry, they were provided a second unfamiliar male with similar sword length to the first male. Females were more likely to reproduce with preferred than non-preferred males, but for those that reproduced, neither the status (preferred/non-preferred) nor the sword length (long/short) of the male had an effect on brood size or relative investment in growth by the female. There was no overall preference based on sword length in this study, but male sword length did affect likelihood of reproduction, with females more likely to reproduce with long- than short-sworded males (independent of preference for such males in earlier choice tests). These results suggest that female association preferences are good indicators of female mate choice but that ornament characteristics of the male are also important

An extracellular steric seeding mechanism for Eph-ephrin signaling platform assembly

Erythropoetin-producing hepatoma (Eph) receptors are cell-surface protein tyrosine kinases mediating cell-cell communication. Upon activation, they form signaling clusters. We report crystal structures of the full ectodomain of human EphA2 (eEphA2) both alone and in complex with the receptor-binding domain of the ligand ephrinA5 (ephrinA5 RBD). Unliganded eEphA2 forms linear arrays of staggered parallel receptors involving two patches of residues conserved across A-class Ephs. eEphA2-ephrinA5 RBD forms a more elaborate assembly, whose interfaces include the same conserved regions on eEphA2, but rearranged to accommodate ephrinA5 RBD. Cell-surface expression of mutant EphA2s showed that these interfaces are critical for localization at cell-cell contacts and activation-dependent degradation. Our results suggest a 'nucleation' mechanism whereby a limited number of ligand-receptor interactions 'seed' an arrangement of receptors which can propagate into extended signaling arrays

A Self-Reference False Memory Effect in the DRM Paradigm: Evidence from Eastern and Western Samples

It is well established that processing information in relation to oneself (i.e., selfreferencing) leads to better memory for that information than processing that same information in relation to others (i.e., other-referencing). However, it is unknown whether self-referencing also leads to more false memories than other-referencing. In the current two experiments with European and East Asian samples, we presented participants the Deese-Roediger/McDermott (DRM) lists together with their own name or other people’s name (i.e., “Trump” in Experiment 1 and “Li Ming” in Experiment 2). We found consistent results across the two experiments; that is, in the self-reference condition, participants had higher true and false memory rates compared to those in the other-reference condition. Moreover, we found that selfreferencing did not exhibit superior mnemonic advantage in terms of net accuracy compared to other-referencing and neutral conditions. These findings are discussed in terms of theoretical frameworks such as spreading activation theories and the fuzzytrace theory. We propose that our results reflect the adaptive nature of memory in the sense that cognitive processes that increase mnemonic efficiency may also increase susceptibility to associative false memories

The impact of socio-economic disadvantage on rates of hospital separations for diabetes-related foot disease in Victoria, Australia

<p>Abstract</p> <p>Background</p> <p>Information describing variation in health outcomes for individuals with diabetes related foot disease, across socioeconomic strata is lacking. The aim of this study was to investigate variation in rates of hospital separations for diabetes related foot disease and the relationship with levels of social advantage and disadvantage.</p> <p>Methods</p> <p>Using the Index of Relative Socioeconomic Disadvantage (IRSD) each local government area (LGA) across Victoria was ranked from most to least disadvantaged. Those LGAs ranked at the lowest end of the scale and therefore at greater disadvantage (Group D) were compared with those at the highest end of the scale (Group A), in terms of total and per capita hospital separations for peripheral neuropathy, peripheral vascular disease, foot ulceration, cellulitis and osteomyelitis and amputation. Hospital separations data were compiled from the Victorian Admitted Episodes Database.</p> <p>Results</p> <p>Total and per capita separations were 2,268 (75.3/1,000 with diabetes) and 2,734 (62.3/1,000 with diabetes) for Group D and Group A respectively. Most notable variation was for foot ulceration (Group D, 18.1/1,000 <it>versus </it>Group A, 12.7/1,000, rate ratio 1.4, 95% CI 1.3, 1.6) and below knee amputation (Group D 7.4/1,000 <it>versus </it>Group A 4.1/1,000, rate ratio 1.8, 95% CI 1.5, 2.2). Males recorded a greater overall number of hospital separations across both socioeconomic strata with 66.2% of all separations for Group D and 81.0% of all separations for Group A recorded by males. However, when comparing mean age, males from Group D tended to be younger compared with males from Group A (mean age; 53.0 years <it>versus </it>68.7 years).</p> <p>Conclusion</p> <p>Variation appears to exist for hospital separations for diabetes related foot disease across socioeconomic strata. Specific strategies should be incorporated into health policy and planning to combat disparities between health outcomes and social status.</p

Views of addiction neuroscientists and clinicians on the clinical impact of a ‘Brain Disease Model of Addiction’

Addiction is increasingly described as a "chronic and relapsing brain disease". The potential impact of the brain disease model on the treatment of addiction or addicted individuals' treatment behaviour remains uncertain. We conducted a qualitative study to examine: (i) the extent to which leading Australian addiction neuroscientists and clinicians accept the brain disease view of addiction; and (ii) their views on the likely impacts of this view on addicted individuals' beliefs and behaviour. Thirty-one Australian addiction neuroscientists and clinicians (10 females and 21 males; 16 with clinical experience and 15 with no clinical experience) took part in 1 h semi-structured interviews. Most addiction neuroscientists and clinicians did not uncritically support the use of brain disease model of addiction. Most were cautious about the potential for adverse impacts on individuals' recovery and motivation to enter treatment. While some recognised the possibility that the brain disease model of addiction may provide a rationale for addicted persons to seek treatment and motivate behaviour change, Australian addiction neuroscientist and clinicians do not assume that messages about "diseased brains" will always lead to increased treatment-seeking and reduced drug use. Research is needed on how neuroscience research could be used in ways that optimise positive outcomes for addicted persons