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Cancer is a worldwide pandemic. The burden it imposes grows steadily on a global scale causing emotional, physical, and financial strains on individuals, families, and health care systems. Despite being the second leading cause of death worldwide, many cancers do not have screening programs and many people with a high risk of developing cancer fail to follow the advised medical screening regime due to the nature of the available screening tests and other challenges with compliance. Moreover, many liquid biopsy strategies being developed for early detection of cancer lack the sensitivity required to detect early-stage cancers. Early detection is key for improved quality of life, survival, and to reduce the financial burden of cancer treatments which are greater at later stage detection. This review examines the current liquid biopsy market, focusing in particular on the strengths and drawbacks of techniques in achieving early cancer detection. We explore the clinical utility of liquid biopsy technologies for the earlier detection of solid cancers, with a focus on how a combination of various spectroscopic and -omic methodologies may pave the way for more efficient cancer diagnostics.

When trying to identify new potential therapeutic protein targets, access to data and knowledge is increasingly important. In a field where new resources and data sources become available every day, it is crucial to be able to take a step back and look at the wider picture in order to identify potential drug targets. While this task is routinely performed by bespoke literature searches, it is often time-consuming and lacks uniformity when comparing multiple targets at one time. To address this challenge, we developed TargetDB, a tool that aggregates public information available on given target(s) (links to disease, safety, 3D structures, ligandability, novelty, etc.) and assembles it in an easy to read output ready for the researcher to analyze. In addition, we developed a target scoring system based on the desirable attributes of good therapeutic targets and machine learning classification system to categorize novel targets as having promising or challenging tractrability. In this manuscript, we present the methodology used to develop TargetDB as well as test cases.

Protein schematics are valuable for research, teaching and knowledge communication. However, the tools used to automate the process are challenging. The purpose of the drawProteins package is to enable the generation of schematics of proteins in an automated fashion that can integrate with the Bioconductor/R suite of tools for bioinformatics and statistical analysis. Using UniProt accession numbers, the package uses the UniProt API to get the features of the protein from the UniProt database. The features are assembled into a data frame and visualized using adaptations of the ggplot2 package. Visualizations can be customised in many ways including adding additional protein features information from other data frames, altering colors and protein names and adding extra layers using other ggplot2 functions. This can be completed within a script that makes the workflow reproducible and sharable.

Small-ring cage hydrocarbons are popular bioisosteres (molecular replacements) for commonly found para -substituted benzene rings in drug design 1 . The utility of these cage structures derives from their superior pharmacokinetic properties compared with their parent aromatics, including improved solubility and reduced susceptibility to metabolism 2 , 3 . A prime example is the bicyclo[1.1.1]pentane motif, which is mainly synthesized by ring-opening of the interbridgehead bond of the strained hydrocarbon [1.1.1]propellane with radicals or anions 4 . By contrast, scaffolds mimicking meta -substituted arenes are lacking because of the challenge of synthesizing saturated isosteres that accurately reproduce substituent vectors 5 . Here we show that bicyclo[3.1.1]heptanes (BCHeps), which are hydrocarbons for which the bridgehead substituents map precisely onto the geometry of meta- substituted benzenes, can be conveniently accessed from [3.1.1]propellane. We found that [3.1.1]propellane can be synthesized on a multigram scale, and readily undergoes a range of radical-based transformations to generate medicinally relevant carbon- and heteroatom-substituted BCHeps, including pharmaceutical analogues. Comparison of the absorption, distribution, metabolism and excretion (ADME) properties of these analogues reveals enhanced metabolic stability relative to their parent arene-containing drugs, validating the potential of this meta- arene analogue as an sp 3 -rich motif in drug design. Collectively, our results show that BCHeps can be prepared on useful scales using a variety of methods, offering a new surrogate for meta- substituted benzene rings for implementation in drug discovery programmes. The potential power of the saturated carbocycle bicyclo[3.1.1]heptane as a beneficial motif for improving the pharmacokinetic and physicochemical properties of drug candidates is demonstrated.

Non-specific symptoms, as well as the lack of a cost-effective test to triage patients in primary care, has resulted in increased time-to-diagnosis and a poor prognosis for brain cancer patients. A rapid, cost-effective, triage test could significantly improve this patient pathway. A blood test using attenuated total reflection (ATR)-Fourier transform infrared (FTIR) spectroscopy for the detection of brain cancer, alongside machine learning technology, is advancing towards clinical translation. However, whilst the methodology is simple and does not require extensive sample preparation, the throughput of such an approach is limited. Here we describe the development of instrumentation for the analysis of serum that is able to differentiate cancer and control patients at a sensitivity and specificity of 93.2% and 92.8%. Furthermore, preliminary data from the first prospective clinical validation study of its kind are presented, demonstrating how this innovative technology can triage patients and allow rapid access to imaging. Diagnosing brain cancer is frequently difficult and requires specialist equipment. Here, the authors develop their previous attenuated total reflectance-Fourier transform infrared spectroscopy method and incoporate the use of disposable silicon wafers for diagnosing brain cancer using serum samples.

Reshaping the brain's genetic circuits Mobilization of retrotransposons, genetic elements able to move around in the genome where they can become incorporated and start to amplify themselves, is normally suppressed in somatic cells. However, recent reports indicate that L1 retrotransposons can be mobilized in the human brain; this has important consequences for intercellular variation. Using a high-throughput approach, Baillie et al . identify numerous germ-line mutations and putative somatic insertions in the human hippocampus and caudate nucleus, including those of Alu elements. The implication is that retrotransposition-driven somatic mosaicism may reshape the genetic circuitry that underpins normal and abnormal neurobiological processes. Retrotransposons are mobile genetic elements that use a germline ‘copy-and-paste’ mechanism to spread throughout metazoan genomes 1 . At least 50 per cent of the human genome is derived from retrotransposons, with three active families (L1, Alu and SVA) associated with insertional mutagenesis and disease 2 , 3 . Epigenetic and post-transcriptional suppression block retrotransposition in somatic cells 4 , 5 , excluding early embryo development and some malignancies 6 , 7 . Recent reports of L1 expression 8 , 9 and copy number variation 10 , 11 in the human brain suggest that L1 mobilization may also occur during later development. However, the corresponding integration sites have not been mapped. Here we apply a high-throughput method to identify numerous L1, Alu and SVA germline mutations, as well as 7,743 putative somatic L1 insertions, in the hippocampus and caudate nucleus of three individuals. Surprisingly, we also found 13,692 somatic Alu insertions and 1,350 SVA insertions. Our results demonstrate that retrotransposons mobilize to protein-coding genes differentially expressed and active in the brain. Thus, somatic genome mosaicism driven by retrotransposition may reshape the genetic circuitry that underpins normal and abnormal neurobiological processes.

Brain tumours affect 7 per 100,000 people in the UK, glioma being most prevalent, with only 12% five-year survival rates and devastating impacts. Primary care triage tools could facilitate earlier detection of glioma. One option for triage is cognitive function testing. The aim of this systematic review was to determine if cognitive function tests can discriminate between patients with glioma and healthy controls, and their potential suitability for primary care use. Studies were included that conducted cognitive function tests with adult patients with glioma, prior to treatment, compared to healthy controls. Two independent researchers performed screening and data extraction. The primary outcome explored test discrimination between people with glioma and healthy controls. Seventeen studies were identified. Findings indicated multiple cognitive function and language function have potential discriminatory capacity between patients with glioma and healthy controls. Over half of cognitive function tests measuring multiple cognitive functions (59%, n = 17) and language function (54%, n = 30) found significant differences between patients with glioma and healthy controls with medium or large effect size. The Montreal Cognitive Assessment has short test duration, high feasibility and acceptability, suggesting potential primary care suitability. Further acceptability and feasibility studies are needed for other potential tests. Acknowledging high heterogeneity of included studies, this review suggests tests of multiple cognitive functions or language could support primary care practitioners with decision-making for urgent neuroimaging referral. However, interpretations should be treated with caution and the applicability to primary care requires further exploration. Prospero registration number: CRD42023408671.

Traumatic brain injury Toxins—Such as drugs or alcohol, medication overdose, carbon monoxide Shock—Hypovolaemic, septic, cardiogenic and anaphylactic Cardiovascular—Such as arrhythmias, ischaemia, tamponade Respiratory—Such as hypoxia, hypercapnia Neurological—Such as stroke, seizure Metabolic—Diabetic emergency, hepatic or renal failure, electrolyte abnormality Other—Infective, delirium, hypothermia or hyperthermia, neoplastic Evolution of the GCS The GCS Aid is an adjunct to the GCS and provides a check sheet with a structured approach to making a GCS assessment.7 It was devised to provide a framework for standardised examination and to support consistent, reliable GCS assessment but is not a replacement for the GCS. Box 2 Example of how to apply the GCS Aid tool in clinical practice A 56 year old pedestrian hit by a vehicle is brought into the emergency department. The patient is assessed using the Advanced Trauma Life Support (ATLS) Protocol.10 Assessment of airway and cervical spine, breathing, and circulation is unremarkable. Check—Check for patient factors that could interfere with assessment, such as language differences, effects of drugs or alcohol, intubation, or injuries such as spinal cord damage.

In a trial that compared a 2-week course of dexamethasone with placebo in patients with a chronic subdural hematoma, a favorable outcome on the modified Rankin scale at 6 months was more common in the placebo group than in the dexamethasone group, but repeat surgery to evacuate a hematoma was performed more frequently in the placebo group.