An efficient shooting algorithm for Evans function calculations in large systems

In Evans function computations of the spectra of asymptotically constant-coefficient linear operators, a basic issue is the efficient and numerically stable computation of subspaces evolving according to the associated eigenvalue ODE. For small systems, a fast, shooting algorithm may be obtained by representing subspaces as single exterior products \cite{AS,Br.1,Br.2,BrZ,BDG}. For large systems, however, the dimension of the exterior-product space quickly becomes prohibitive, growing as $\binom{n}{k}$, where $n$ is the dimension of the system written as a first-order ODE and $k$ (typically $\sim n/2$) is the dimension of the subspace. We resolve this difficulty by the introduction of a simple polar coordinate algorithm representing ``pure'' (monomial) products as scalar multiples of orthonormal bases, for which the angular equation is a numerically optimized version of the continuous orthogonalization method of Drury--Davey \cite{Da,Dr} and the radial equation is evaluable by quadrature. Notably, the polar-coordinate method preserves the important property of analyticity with respect to parameters.Comment: 21 pp., two figure

Science in Focus: Combining Radiotherapy with Inhibitors of the DNA Damage Response

No abstract available

The Co-Regulation of Emotions Between Mothers and their Children with Autism

Thirty-four toddlers with autism and their mothers participated in an early intervention targeting joint engagement. Across the 24 intervention sessions, any significant distress episode in the child was coded for emotion regulation outcomes including child negativity, child emotion self-regulation, and mother emotion co-regulation. Results revealed that emotion regulation strategies by both mother and child were employed during distress episodes. An effect of intervention was found such that children decreased their expression of negativity across the intervention and mothers increased their emotional and motivational scaffolding. The results of this study indicate a positive effect of an intervention targeting joint engagement on emotion co-regulation outcomes

Hypoxia-induced switch in SNAT2/SLC38A2 regulation generates endocrine resistance in breast cancer

Tumor hypoxia is associated with poor patient outcomes in estrogen receptor-α–positive (ERα+) breast cancer. Hypoxia is known to affect tumor growth by reprogramming metabolism and regulating amino acid (AA) uptake. Here, we show that the glutamine transporter, SNAT2, is the AA transporter most frequently induced by hypoxia in breast cancer, and is regulated by hypoxia both in vitro and in vivo in xenografts. SNAT2 induction in MCF7 cells was also regulated by ERα, but it became predominantly a hypoxia-inducible factor 1α (HIF-1α)–dependent gene under hypoxia. Relevant to this, binding sites for both HIF-1α and ERα overlap in SNAT2’s cis-regulatory elements. In addition, the down-regulation of SNAT2 by the ER antagonist fulvestrant was reverted in hypoxia. Overexpression of SNAT2 in vitro to recapitulate the levels induced by hypoxia caused enhanced growth, particularly after ERα inhibition, in hypoxia, or when glutamine levels were low. SNAT2 up-regulation in vivo caused complete resistance to antiestrogen and, partially, anti-VEGF therapies. Finally, high SNAT2 expression levels correlated with hypoxia profiles and worse outcome in patients given antiestrogen therapies. Our findings show a switch in the regulation of SNAT2 between ERα and HIF-1α, leading to endocrine resistance in hypoxia. Development of drugs targeting SNAT2 may be of value for a subset of hormone-resistant breast cancer

Synthetic lethal therapies for cancer: what's next after PARP inhibitors?

The genetic concept of synthetic lethality has now been validated clinically through the demonstrated efficacy of poly(ADP-ribose) polymerase (PARP) inhibitors for the treatment of cancers in individuals with germline loss-of-function mutations in either BRCA1 or BRCA2. Three different PARP inhibitors have now been approved for the treatment of patients with BRCA-mutant ovarian cancer and one for those with BRCA-mutant breast cancer; these agents have also shown promising results in patients with BRCA-mutant prostate cancer. Here, we describe a number of other synthetic lethal interactions that have been discovered in cancer. We discuss some of the underlying principles that might increase the likelihood of clinical efficacy and how new computational and experimental approaches are now facilitating the discovery and validation of synthetic lethal interactions. Finally, we make suggestions on possible future directions and challenges facing researchers in this field

Functional diversity and co-operativity between subclonal populations of paediatric glioblastoma and diffuse intrinsic pontine glioma cells

The failure to develop effective therapies for pediatric glioblastoma (pGBM) and diffuse intrinsic pontine glioma (DIPG) is in part due to their intrinsic heterogeneity. We aimed to quantitatively assess the extent to which this was present in these tumors through subclonal genomic analyses and to determine whether distinct tumor subpopulations may interact to promote tumorigenesis by generating subclonal patient-derived models in vitro and in vivo. Analysis of 142 sequenced tumors revealed multiple tumor subclones, spatially and temporally coexisting in a stable manner as observed by multiple sampling strategies. We isolated genotypically and phenotypically distinct subpopulations that we propose cooperate to enhance tumorigenicity and resistance to therapy. Inactivating mutations in the H4K20 histone methyltransferase KMT5B (SUV420H1), present in <1% of cells, abrogate DNA repair and confer increased invasion and migration on neighboring cells, in vitro and in vivo, through chemokine signaling and modulation of integrins. These data indicate that even rare tumor subpopulations may exert profound effects on tumorigenesis as a whole and may represent a new avenue for therapeutic development. Unraveling the mechanisms of subclonal diversity and communication in pGBM and DIPG will be an important step toward overcoming barriers to effective treatments

Towards improved decision support in the assessment and management of pain for people with dementia in hospital: a systematic meta-review and observational study

BackgroundPain and dementia are common in older people, and impaired cognitive abilities make it difficult for them to communicate their pain. Pain, if poorly managed, impairs health and well-being. Accurate pain assessment in this vulnerable group is challenging for hospital staff, but essential for appropriate management. Robust methods for identifying, assessing and managing pain are needed.Aims and objectivesTwo studies were undertaken to inform the development of a decision support tool to aid hospital staff in the recognition, assessment and management of pain. The first was a meta-review of systematic reviews of observational pain assessment instruments with three objectives: (1) to identify the tools available to assess pain in adults with dementia; (2) to identify in which settings they were used and with what patient populations; and (3) to assess their reliability, validity and clinical utility. The second was a multisite observational study in hospitals with four objectives: (1) to identify information currently used by clinicians when detecting and managing pain in patients with dementia; (2) to explore existing processes for detecting and managing pain in these patients; (3) to identify the role (actual/potential) of carers in this process; and (4) to explore the organisational context in which health professionals operate. Findings also informed development of health economics data collection forms to evaluate the implementation of a new decision support intervention in hospitals.MethodsFor the meta-review of systematic reviews, 12 databases were searched. Reviews of observational pain assessment instruments that provided psychometric data were included. Papers were quality assessed and data combined using narrative synthesis. The observational study used an ethnographic approach in 11 wards in four UK hospitals. This included non-participant observation of 31 patients, audits of patient records, semistructured interviews with 52 staff and four carers, informal conversations with staff and carers and analysis of ward documents and policies. Thematic analysis of the data was undertaken by the project team.ResultsData from eight systematic reviews including 28 tools were included in the meta-review. Most tools showed moderate to good reliability, but information about validity, feasibility and clinical utility was scarce. The observational study showed complex ward cultures and routines, with variations in time spent with patients, communication patterns and management practices. Carer involvement was rare. No pain decision support tools were observed in practice. Information about pain was elicited in different ways, at different times, by different health-care staff and recorded in separate documents. Individual staff made sense of patients’ pain by creating their own ‘overall picture’ from available information.LimitationsGrey literature and non-English-language papers were excluded from the meta-review. Sample sizes in the observational study were smaller than planned owing to poor documentation of patients’ dementia diagnoses, gatekeeping by staff and difficulties in gaining consent/assent. Many patients had no or geographically distant carers, or a spouse who was too unwell and/or reluctant to participate.ConclusionsNo single observational pain scale was clearly superior to any other. The traditional linear concept of pain being assessed, treated and reassessed by single individuals did not ‘fit’ with clinical reality. A new approach enabling effective communication among patients, carers and staff, centralised recording of pain-related information, and an extended range of pain management interventions is proposed [Pain And Dementia Decision Support (PADDS)]. This was not tested with users, but a follow-on study aims to codesign PADDS with carers and clinicians, then introduce education on staff/patient/carer communications and use of PADDS within a structured implementation plan. PADDS will need to be tested in differing ward contexts