The NeST (Neoadjuvant systemic therapy in breast cancer) study: National Practice Questionnaire of United Kingdom multi-disciplinary decision making

Abstract: Background: Neoadjuvant systemic therapy (NST) is increasingly used in the treatment of breast cancer, yet it is clear that there is significant geographical variation in its use in the UK. This study aimed to examine stated practice across UK breast units, in terms of indications for use, radiological monitoring, pathological reporting of treatment response, and post-treatment surgical management. Methods: Multidisciplinary teams (MDTs) from all UK breast units were invited to participate in the NeST study. A detailed questionnaire assessing current stated practice was distributed to all participating units in December 2017 and data collated securely usingREDCap. Descriptive statistics were calculated for each questionnaire item. Results: Thirty-nine MDTs from a diverse range of hospitals responded. All MDTs routinely offered neoadjuvant chemotherapy (NACT) to a median of 10% (range 5–60%) of patients. Neoadjuvant endocrine therapy (NET) was offered to a median of 4% (range 0–25%) of patients by 66% of MDTs. The principal indication given for use of neoadjuvant therapy was for surgical downstaging. There was no consensus on methods of radiological monitoring of response, and a wide variety of pathological reporting systems were used to assess tumour response. Twenty-five percent of centres reported resecting the original tumour footprint, irrespective of clinical/radiological response. Radiologically negative axillae at diagnosis routinely had post-NACT or post-NET sentinel lymph node biopsy (SLNB) in 73.0 and 84% of centres respectively, whereas 16% performed SLNB pre-NACT. Positive axillae at diagnosis would receive axillary node clearance at 60% of centres, regardless of response to NACT. Discussion: There is wide variation in the stated use of neoadjuvant systemic therapy across the UK, with general low usage of NET. Surgical downstaging remains the most common indication of the use of NAC, although not all centres leverage the benefits of NAC for de-escalating surgery to the breast and/or axilla. There is a need for agreed multidisciplinary guidance for optimising selection and management of patients for NST. These findings will be corroborated in phase II of the NeST study which is a national collaborative prospective audit of NST utilisation and clinical outcomes

AI is a viable alternative to high throughput screening: a 318-target study

: High throughput screening (HTS) is routinely used to identify bioactive small molecules. This requires physical compounds, which limits coverage of accessible chemical space. Computational approaches combined with vast on-demand chemical libraries can access far greater chemical space, provided that the predictive accuracy is sufficient to identify useful molecules. Through the largest and most diverse virtual HTS campaign reported to date, comprising 318 individual projects, we demonstrate that our AtomNet® convolutional neural network successfully finds novel hits across every major therapeutic area and protein class. We address historical limitations of computational screening by demonstrating success for target proteins without known binders, high-quality X-ray crystal structures, or manual cherry-picking of compounds. We show that the molecules selected by the AtomNet® model are novel drug-like scaffolds rather than minor modifications to known bioactive compounds. Our empirical results suggest that computational methods can substantially replace HTS as the first step of small-molecule drug discovery

Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function.

Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways

Attributional style and depressive symptoms in a male prison sample

The reformulated learned helplessness model proposes that people who tend to make internal, stable, and global attributions in response to uncontrollable aversive events are more likely to develop depression. The present study sought to investigate the nature of the relationship between attributional style and depression in a male prison sample. One hundred and one adult male prisoners from four medium security prisons in Ireland completed the Attributional Style Questionnaire and measures of depression (BDI-II) and anxiety (BAI). Severity of self-reported depressive symptoms in the present sample was comparable to other prison and clinical samples, but higher than community samples. Participants were more severely affected by depressive symptoms than anxiety. The original attributional dimensions (i.e. internal, stable, and global) predicted a significant amount of variance in depression, but the model was not significant after controlling for anxiety. A subsequent regression model, comprising attributional dimensions for both negative events and positive events including a measure of \u27uncontrollability\u27, accounted for 35% of the variance in depression and the model retained significance while controlling for anxiety. An attributional model of depression may be relevant to the prison population and could provide a valid insight into the development and treatment of depressive symptoms in prisoners. The findings are interpreted in relation to previous research and implications for theory, clinical practice, and rehabilitation are discussed

Attributional style and depressive symptoms in a male prison sample

<div><p>The reformulated learned helplessness model proposes that people who tend to make internal, stable, and global attributions in response to uncontrollable aversive events are more likely to develop depression. The present study sought to investigate the nature of the relationship between attributional style and depression in a male prison sample. One hundred and one adult male prisoners from four medium security prisons in Ireland completed the Attributional Style Questionnaire and measures of depression (BDI-II) and anxiety (BAI). Severity of self-reported depressive symptoms in the present sample was comparable to other prison and clinical samples, but higher than community samples. Participants were more severely affected by depressive symptoms than anxiety. The original attributional dimensions (i.e. internal, stable, and global) predicted a significant amount of variance in depression, but the model was not significant after controlling for anxiety. A subsequent regression model, comprising attributional dimensions for both negative events and positive events including a measure of ‘uncontrollability’, accounted for 35% of the variance in depression and the model retained significance while controlling for anxiety. An attributional model of depression may be relevant to the prison population and could provide a valid insight into the development and treatment of depressive symptoms in prisoners. The findings are interpreted in relation to previous research and implications for theory, clinical practice, and rehabilitation are discussed.</p></div

Results of the hierarchical regression attributional model of depression.

<p>Results of the hierarchical regression attributional model of depression.</p

Frequency distributions for the qualitative categories on the beck inventories.

<p>Frequency distributions for the qualitative categories on the beck inventories.</p

Squeezing water from a stone: high-throughput sequencing from a 145-year old holotype resolves (barely) a cryptic species problem in flying lizards

We used Massively Parallel High-Throughput Sequencing to obtain genetic data from a 145-year old holotype specimen of the flying lizard, Draco cristatellus. Obtaining genetic data from this holotype was necessary to resolve an otherwise intractable taxonomic problem involving the status of this species relative to closely related sympatric Draco species that cannot otherwise be distinguished from one another on the basis of museum specimens. Initial analyses suggested that the DNA present in the holotype sample was so degraded as to be unusable for sequencing. However, we used a specialized extraction procedure developed for highly degraded ancient DNA samples and MiSeq shotgun sequencing to obtain just enough low-coverage mitochondrial DNA (721 base pairs) to conclusively resolve the species status of the holotype as well as a second known specimen of this species. The holotype was prepared before the advent of formalin-fixation and therefore was most likely originally fixed with ethanol and never exposed to formalin. Whereas conventional wisdom suggests that formalin-fixed samples should be the most challenging for DNA sequencing, we propose that evaporation during long-term alcohol storage and consequent water-exposure may subject older ethanol-fixed museum specimens to hydrolytic damage. If so, this may pose an even greater challenge for sequencing efforts involving historical samples