AZD8055 enhances in vivo efficacy of afatinib in chordomas

Chordomas are primary bone tumors that arise in the cranial base, mobile spine, and sacrococcygeal region, affecting patients of all ages. Currently, there are no approved agents for chordoma patients. Here, we evaluated the anti-tumor efficacy of small molecule inhibitors that target oncogenic pathways in chordoma, as single agents and in combination, to identify novel therapeutic approaches with the greatest translational potential. A panel of small molecule compounds was screened in vivo against patient-derived xenograft (PDX) models of chordoma, and potentially synergistic combinations were further evaluated using chordoma cell lines and xenograft models. Among the tested agents, inhibitors of EGFR (BIBX 1382, erlotinib, and afatinib), c-MET (crizotinib), and mTOR (AZD8055) significantly inhibited tumor growth in vivo but did not induce tumor regression. Co-inhibition of EGFR and c-MET using erlotinib and crizotinib synergistically reduced cell viability in chordoma cell lines but did not result in enhanced in vivo activity. Co-inhibition of EGFR and mTOR pathways using afatinib and AZD8055 synergistically reduced cell viability in chordoma cell lines. Importantly, this dual inhibition completely suppressed tumor growth in vivo, showing improved tumor control. Together, these data demonstrate that individual inhibitors of EGFR, c-MET, and mTOR pathways suppress chordoma growth both in vitro and in vivo. mTOR inhibition increased the efficacy of EGFR inhibition on chordoma growth in several preclinical models. The insights gained from our study potentially provide a novel combination therapeutic strategy for patients with chordoma. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland

Building a fault-tolerant quantum computer using concatenated cat codes

We present a comprehensive architectural analysis for a fault-tolerant quantum computer based on cat codes concatenated with outer quantum error-correcting codes. For the physical hardware, we propose a system of acoustic resonators coupled to superconducting circuits with a two-dimensional layout. Using estimated near-term physical parameters for electro-acoustic systems, we perform a detailed error analysis of measurements and gates, including CNOT and Toffoli gates. Having built a realistic noise model, we numerically simulate quantum error correction when the outer code is either a repetition code or a thin rectangular surface code. Our next step toward universal fault-tolerant quantum computation is a protocol for fault-tolerant Toffoli magic state preparation that significantly improves upon the fidelity of physical Toffoli gates at very low qubit cost. To achieve even lower overheads, we devise a new magic-state distillation protocol for Toffoli states. Combining these results together, we obtain realistic full-resource estimates of the physical error rates and overheads needed to run useful fault-tolerant quantum algorithms. We find that with around 1,000 superconducting circuit components, one could construct a fault-tolerant quantum computer that can run circuits which are intractable for classical supercomputers. Hardware with 32,000 superconducting circuit components, in turn, could simulate the Hubbard model in a regime beyond the reach of classical computing

Schools and civil society : corporate or community governance

School improvement depends upon mediating the cultural conditions of learning as young people journey between their parochial worlds and the public world of cosmopolitan society. Governing bodies have a crucial role in including or diminishing the representation of different cultural traditions and in enabling or frustrating the expression of voice and deliberation of differences whose resolution is central to the mediation of and responsiveness to learning needs. A recent study of governing bodies in England and Wales argues that the trend to corporatising school governance will diminish the capacity of schools to learn how they can understand cultural traditions and accommodate them in their curricula and teaching strategies. A democratic, stakeholder model remains crucial to the effective practice of governing schools. By deliberating and reconciling social and cultural differences, governance constitutes the practices for mediating particular and cosmopolitan worlds and thus the conditions for engaging young people in their learning, as well as in the preparation for citizenship in civil society

Measuring health inequalities in Albania: a focus on the distribution of general practitioners

BACKGROUND: The health workforce has a dynamically changing nature and the regular documentation of the distribution of health professionals is a persistent policy concern. The aim of the present study was to examine available human medical resources in primary care and identify possible inequalities regarding the distribution of general practitioners in Albania between 2000 and 2004. METHODS: With census data, we investigated the degree of inequality by calculating relative inequality indices. We plotted the Lorenz curves and calculated the Gini, Atkinson and Robin Hood indices and decile ratios, both before and after adjusting for mortality and consultation rates. RESULTS: The Gini index for the distribution of general practitioners in 2000 was 0.154. After adjusting for mortality it was 0.126, while after adjusting for consultation rates it was 0.288. The Robin Hood index for 2000 was 11.2%, which corresponds to 173 general practitioners who should be relocated in order to achieve equality. The corresponding figure after adjusting for mortality was 9.2% (142 general practitioners), while after adjusting for consultation rates the number was 20.6% (315). These figures changed to 6.3% (100), 6.3% (115) and 19.8% (315) in 2004. CONCLUSION: There was a declining trend in the inequality of distribution of general practitioners in Albania between 2000 and 2004. The trend in inequality was apparent irrespective of the relative inequality indicator used. The level of inequality varied depending on the adjustment method used. Reallocation strategies for general practitioners in Albania could be the key in alleviating the inequalities in primary care workforce distribution

Targeted Doxorubicin Delivery to Brain Tumors via Minicells: Proof of Principle Using Dogs with Spontaneously Occurring Tumors as a Model

BACKGROUND: Cytotoxic chemotherapy can be very effective for the treatment of cancer but toxicity on normal tissues often limits patient tolerance and often causes long-term adverse effects. The objective of this study was to assist in the preclinical development of using modified, non-living bacterially-derived minicells to deliver the potent chemotherapeutic doxorubicin via epidermal growth factor receptor (EGFR) targeting. Specifically, this study sought to evaluate the safety and efficacy of EGFR targeted, doxorubicin loaded minicells (designated EGFRminicellsDox) to deliver doxorubicin to spontaneous brain tumors in 17 companion dogs; a comparative oncology model of human brain cancers. METHODOLOGY/PRINCIPLE FINDINGS: EGFRminicellsDox were administered weekly via intravenous injection to 17 dogs with late-stage brain cancers. Biodistribution was assessed using single-photon emission computed tomography (SPECT) and magnetic resonance imaging (MRI). Anti-tumor response was determined using MRI, and blood samples were subject to toxicology (hematology, biochemistry) and inflammatory marker analysis. Targeted, doxorubicin-loaded minicells rapidly localized to the core of brain tumors. Complete resolution or marked tumor regression (>90% reduction in tumor volume) were observed in 23.53% of the cohort, with lasting anti-tumor responses characterized by remission in three dogs for more than two years. The median overall survival was 264 days (range 49 to 973). No adverse clinical, hematological or biochemical effects were observed with repeated administration of EGFRminicellsDox (30 to 98 doses administered in 10 of the 17 dogs). CONCLUSIONS/SIGNIFICANCE: Targeted minicells loaded with doxorubicin were safely administered to dogs with late stage brain cancer and clinical activity was observed. These findings demonstrate the strong potential for clinical applications of targeted, doxorubicin-loaded minicells for the effective treatment of patients with brain cancer. On this basis, we have designed a Phase 1 clinical study of EGFR-targeted, doxorubicin-loaded minicells for effective treatment of human patients with recurrent glioblastoma

Multi-centre parallel arm randomised controlled trial to assess the effectiveness and cost-effectiveness of a group-based cognitive behavioural approach to managing fatigue in people with multiple sclerosis

Abstract (provisional) Background Fatigue is one of the most commonly reported and debilitating symptoms of multiple sclerosis (MS); approximately two-thirds of people with MS consider it to be one of their three most troubling symptoms. It may limit or prevent participation in everyday activities, work, leisure, and social pursuits, reduce psychological well-being and is one of the key precipitants of early retirement. Energy effectiveness approaches have been shown to be effective in reducing MS-fatigue, increasing self-efficacy and improving quality of life. Cognitive behavioural approaches have been found to be effective for managing fatigue in other conditions, such as chronic fatigue syndrome, and more recently, in MS. The aim of this pragmatic trial is to evaluate the clinical and cost-effectiveness of a recently developed group-based fatigue management intervention (that blends cognitive behavioural and energy effectiveness approaches) compared with current local practice. Methods This is a multi-centre parallel arm block-randomised controlled trial (RCT) of a six session group-based fatigue management intervention, delivered by health professionals, compared with current local practice. 180 consenting adults with a confirmed diagnosis of MS and significant fatigue levels, recruited via secondary/primary care or newsletters/websites, will be randomised to receive the fatigue management intervention or current local practice. An economic evaluation will be undertaken alongside the trial. Primary outcomes are fatigue severity, self-efficacy and disease-specific quality of life. Secondary outcomes include fatigue impact, general quality of life, mood, activity patterns, and cost-effectiveness. Outcomes in those receiving the fatigue management intervention will be measured 1 week prior to, and 1, 4, and 12 months after the intervention (and at equivalent times in those receiving current local practice). A qualitative component will examine what aspects of the fatigue management intervention participants found helpful/unhelpful and barriers to change. Discussion This trial is the fourth stage of a research programme that has followed the Medical Research Council guidance for developing and evaluating complex interventions. What makes the intervention unique is that it blends cognitive behavioural and energy effectiveness approaches. A potential strength of the intervention is that it could be integrated into existing service delivery models as it has been designed to be delivered by staff already working with people with MS. Service users will be involved throughout this research. Trial registration: Current Controlled Trials ISRCTN7651747

Molecular complexity determines the number of olfactory notes and the pleasantness of smells

One major unresolved problem in olfaction research is to relate the percept to the molecular structure of stimuli. The present study examined this issue and showed for the first time a quantitative structure-odor relationship in which the more structurally complex a monomolecular odorant, the more numerous the olfactory notes it evokes. Low-complexity odorants were also rated as more aversive, reflecting the fact that low molecular complexity may serve as a warning cue for the olfactory system. Taken together, these findings suggest that molecular complexity provides a framework to explain the subjective experience of smells