Developing a Raman spectroscopy-based tool to stratify patient response to pre-operative radiotherapy in rectal cancer

Rectal cancer patients frequently receive pre-operative radiotherapy (RT), prior to surgical resection. However, colorectal cancer is heterogeneous and the degree of tumour response to pre-operative RT is highly variable. There are currently no clinically approved methods of predicting response to RT, and a significant proportion of patients will show no clinical benefit, despite enduring the side-effects. We evaluated the use of Raman spectroscopy (RS), a non-destructive technique able to provide the unique chemical fingerprint of tissues, as a potential tool to stratify patient response to pre-operative RT. Raman measurements were obtained from the formalin-fixed, paraffin-embedded (FFPE) pre-treatment biopsy specimens of 20 rectal cancer patients who received pre-operative RT. A principal component analysis and linear discriminant analysis algorithm was able to classify patient response to pre-operative RT as good or poor, with an accuracy of 86.04 ± 0.14% (standard error). Patients with a good response to RT showed greater contributions from protein-associated peaks, whereas patients who responded poorly showed greater lipid contributions. These results demonstrate that RS is able to reliably classify tumour response to pre-operative RT from FFPE biopsies and highlights its potential to guide personalised cancer patient treatment

Prediction of tumour pathological subtype from genomic profile using sparse logistic regression with random effects

The purpose of this study is to highlight the application of sparse logistic regression models in dealing with prediction of tumour pathological subtypes based on lung cancer patients' genomic information. We consider sparse logistic regression models to deal with the high dimensionality and correlation between genomic regions. In a hierarchical likelihood (HL) method, it is assumed that the random effects follow a normal distribution and its variance is assumed to follow a gamma distribution. This formulation considers ridge and lasso penalties as special cases. We extend the HL penalty to include a ridge penalty (called ‘HLnet’) in a similar principle of the elastic net penalty, which is constructed from lasso penalty. The results indicate that the HL penalty creates more sparse estimates than lasso penalty with comparable prediction performance, while HLnet and elastic net penalties have the best prediction performance in real data. We illustrate the methods in a lung cancer study

Causarum Investigatio and the Two Bell's Theorems of John Bell

"Bell's theorem" can refer to two different theorems that John Bell proved, the first in 1964 and the second in 1976. His 1964 theorem is the incompatibility of quantum phenomena with the joint assumptions of Locality and Predetermination. His 1976 theorem is their incompatibility with the single property of Local Causality. This is contrary to Bell's own later assertions, that his 1964 theorem began with the assumption of Local Causality, even if not by that name. Although the two Bell's theorems are logically equivalent, their assumptions are not. Hence, the earlier and later theorems suggest quite different conclusions, embraced by operationalists and realists, respectively. The key issue is whether Locality or Local Causality is the appropriate notion emanating from Relativistic Causality, and this rests on one's basic notion of causation. For operationalists the appropriate notion is what is here called the Principle of Agent-Causation, while for realists it is Reichenbach's Principle of common cause. By breaking down the latter into even more basic Postulates, it is possible to obtain a version of Bell's theorem in which each camp could reject one assumption, happy that the remaining assumptions reflect its weltanschauung. Formulating Bell's theorem in terms of causation is fruitful not just for attempting to reconcile the two camps, but also for better describing the ontology of different quantum interpretations and for more deeply understanding the implications of Bell's marvellous work.Comment: 24 pages. Prepared for proceedings of the "Quantum [Un]speakables II" conference (Vienna, 2014), to be published by Springe

Human C4orf14 interacts with the mitochondrial nucleoid and is involved in the biogenesis of the small mitochondrial ribosomal subunit.

The bacterial homologue of C4orf14, YqeH, has been linked to assembly of the small ribosomal subunit. Here, recombinant C4orf14 isolated from human cells, co-purified with the small, 28S subunit of the mitochondrial ribosome and the endogenous protein co-fractionated with the 28S subunit in sucrose gradients. Gene silencing of C4orf14 specifically affected components of the small subunit, leading to decreased protein synthesis in the organelle. The GTPase of C4orf14 was critical to its interaction with the 28S subunit, as was GTP. Therefore, we propose that C4orf14, with bound GTP, binds to components of the 28S subunit facilitating its assembly, and GTP hydrolysis acts as the release mechanism. C4orf14 was also found to be associated with human mitochondrial nucleoids, and C4orf14 gene silencing caused mitochondrial DNA depletion. In vitro C4orf14 is capable of binding to DNA. The association of C4orf14 with mitochondrial translation factors and the mitochondrial nucleoid suggests that the 28S subunit is assembled at the mitochondrial nucleoid, enabling the direct transfer of messenger RNA from the nucleoid to the ribosome in the organelle.Medical Research Council (MRC); Biotechnology and Biological Sciences Research Council (BBSRC); European Union; Academy of Finland (to H.M.C.). Funding for open access charge: MRC

Logarithmic rate dependence in deforming granular materials

Rate-independence for stresses within a granular material is a basic tenet of many models for slow dense granular flows. By contrast, logarithmic rate dependence of stresses is found in solid-on-solid friction, in geological settings, and elsewhere. In this work, we show that logarithmic rate-dependence occurs in granular materials for plastic (irreversible) deformations that occur during shearing but not for elastic (reversible) deformations, such as those that occur under moderate repetitive compression. Increasing the shearing rate, \Omega, leads to an increase in the stress and the stress fluctuations that at least qualitatively resemble what occurs due to an increase in the density. Increases in \Omega also lead to qualitative changes in the distributions of stress build-up and relaxation events. If shearing is stopped at t=0, stress relaxations occur with \sigma(t)/ \sigma(t=0) \simeq A \log(t/t_0). This collective relaxation of the stress network over logarithmically long times provides a mechanism for rate-dependent strengthening.Comment: 4 pages, 5 figures. RevTeX

Assessing the impact of key Marine Invasive Non-Native Species on Welsh MPA habitat features, fisheries and aquaculture

Marine Invasive Non-Native Species (INNS) are a significant threat to global biodiversity and can have detrimental socio-economic impacts on activities such as fishing, shipping and aquaculture. Biosecurity measures can prevent the spread of INNS and limit the likelihood of a species entering an area in the first place; such measures are particularly important for marine ecosystems, where eradication and control techniques have been shown to be less effective. A previous study (Macleod et al. 2016) assessed the environmental (with a particular focus on MPA features) and socioeconomic impacts of 8 key marine INNS

Pragmatic Randomised Evaluation of Stable Thoracolumbar fracture treatment Outcomes (PRESTO): Study Protocol for a Randomised Controlled Feasibility Trial combined with a qualitative study and survey

Background A thoracolumbar fracture is the most common fracture of the spinal column. Where the fracture is not obviously stable or unstable, the optimal management is uncertain. There are variations between surgeons, treating centres and within the evidence base as to whether surgical or non-surgical approaches should be used. In addition, the boundaries of this zone of uncertainty for stability are unclear. This study has been designed in response to a NIHR HTA commissioning brief to assess the feasibility of undertaking a large-scale trial to evaluate the effectiveness of surgical and non-surgical treatments for thoracolumbar fractures without neurological deficit. Methods Assessment of feasibility will be addressed through three elements: a randomised external feasibility study, a national survey of surgeons and a qualitative study. The external feasibility study is a pragmatic, parallel group, randomised controlled trial comparing surgical fixation (intervention) versus non-surgical management (control). Recruitment will take place in three secondary care centres in the United Kingdom. The primary outcome is recruitment rate, defined as the proportion of eligible participants who are randomised. Further outcomes related to recruitment, randomisation, drop-out, cross-over, loss to follow-up, completeness of outcome data, study processes and details of the interventions delivered will be collected. The survey of surgeons and qualitative study of clinicians, recruiting staff and patients will enhance the feasibility study, enabling a broad overview of current practice in the field in addition to perceived facilitators and barriers to running a full-scale trial. Discussion PRESTO is a feasibility study which aims to inform methodology for a definitive trial comparing surgical fixation with non-surgical management for patients with stable thoracolumbar fractures. Trial registration The trial is registered with the International Standard Randomised Controlled Trial Register (ISRCTN 12094890). Date of registration was 22/02/2018 (http://www.isrctn.com/ISRCTN12094890). Keywords Thoracolumbar, fracture, surgical fixation, randomised controlled trial, qualitative, survey, feasibility, pilot