A systematic review of platinum and taxane resistance from bench to clinic: an inverse relationship

We undertook a systematic review of the pre-clinical and clinical literature for studies investigating the relationship between platinum and taxane resistance. Medline was searched for 1) cell models of acquired drug resistance reporting platinum and taxane sensitivities and 2) clinical trials of platinum or taxane salvage therapy in ovarian cancer. 137 models of acquired drug resistance were identified. 68.1% of cisplatin-resistant cells were sensitive to paclitaxel and 66.7% of paclitaxel-resistant cells were sensitive to cisplatin. A similar inverse pattern was observed for cisplatin vs docetaxel, carboplatin vs paclitaxel and carboplatin vs docetaxel. These associations were independent of cancer type, agents used to develop resistance and reported mechanisms of resistance. 65 eligible clinical trials of paclitaxel-based salvage after platinum therapy were identified. Studies of single agent paclitaxel in platinum-resistant ovarian cancer where patients had previously recieved paclitaxel had a pooled response rate of 35.3% n=232, compared to 22% in paclitaxel naïve patients n=1918 (p<0.01 Chi-squared). Suggesting that pre-treatment with paclitaxel may improve the response of salvage paclitaxel therapy. The response rate to paclitaxel/platinum combination regimens in platinum-sensitive ovarian cancer was 79.5% n=88 compared to 49.4% n=85 for paclitaxel combined with other agents (p<0.001 Chi-squared), suggesting a positive interaction between taxanes and platinum. Therefore the inverse relationship between platinum and taxanes resistance seen in cell models is mirrored in the clinical response to these agents in ovarian cancer. An understanding of the cellular and molecular mechanisms responsible would be valuable in predicting response to salvage chemotherapy and may identify new therapeutic targets

Sea anemones (Exaiptasia pallida) use a secreted adhesive and complex pedal disc morphology for surface attachment

Background The mechanism by which sea anemones attach to surfaces underwater remains elusive, which is surprising given their ubiquitous distribution in the world’s oceans and tractability for experimental biology. Their adhesion is mechanically interesting, bridging the interface between very hard and soft materials. The Cnidaria are thought to have evolved adhesion to surfaces at least 505 Ma ago implying that, among the Metazoa, only Porifera developed this capability earlier. The purpose of this study was primarily to address an existing hypothesis, that spirocysts (a sticky class of cnidocyst) facilitate adhesion to surfaces, as observed during prey capture. Results We demonstrated conclusively that spirocysts were not involved in the pedal disc adhesion of Exaiptasia pallida. Second, we applied a variety of imaging methods to develop an understanding of the true adhesion mechanism. Morphological studies using scanning electron microscopy identified a meshwork of adhesive material, unique to the pedal disc. Serial block-face SEM highlighted four classes of cells that could secrete the adhesive from the pedal disc ectoderm. A variety of histochemical techniques identified proteins, glycans and quinones in the cell contents and secreted adhesive, with variation in contents of specific cell-types in different areas of the body. Conclusions Spirocysts are not used by Exaiptasia pallida for adhesion to surfaces. Instead, a structurally and compositionally complex secreted glue was observed, firmly attaching the animals underwater. The results of this study provide a basis for further investigations of adhesion in Cnidaria, and establish E. pallida as a new model organism for bioadhesion research

Driving sustainable change in antimicrobial prescribing practice:how can social and behavioural sciences help?

Addressing the growing threat of antimicrobial resistance is, in part, reliant on the complex challenge of changing human behaviour—in terms of reducing inappropriate antibiotic use and preventing infection. Whilst there is no ‘one size fits all’ recommended behavioural solution for improving antimicrobial stewardship, the behavioural and social sciences offer a range of theories, frameworks, methods and evidence-based principles that can help inform the design of behaviour change interventions that are context-specific and thus more likely to be effective. However, the state-of-the-art in antimicrobial stewardship research and practice suggests that behavioural and social influences are often not given due consideration in the design and evaluation of interventions to improve antimicrobial prescribing. In this paper, we discuss four potential areas where the behavioural and social sciences can help drive more effective and sustained behaviour change in antimicrobial stewardship: (i) defining the problem in behavioural terms and understanding current behaviour in context; (ii) adopting a theory-driven, systematic approach to intervention design; (iii) investigating implementation and sustainability of interventions in practice; and (iv) maximizing learning through evidence synthesis and detailed intervention reporting

Musical beat influences corticospinal drive to ankle flexor and extensor muscles in man

Abstract Body movements in man are frequently observed in relation to musical rhythms. In this study we have investigated the effect of strongly rhythmic music on corticospinal drive to the ankle extensor and flexor muscles involved in foot tapping. Surface electromyographic (EMG) recordings were made from tibialis anterior (TA) and lateral gastrocnemius (LGN) muscles in 12 normal subjects. Rock music with a strong rhythmic beat or white noise was played. Transcranial magnetic stimulation (TMS) was delivered to the motor cortex in time with the music to produce motor evoked potentials (MEPs) in both muscles while relaxed. During white noise trials nine subjects showed a significant correlation of MEP areas in TA with LGN, compared with only three subjects during music. Overall, there was a significant decrease in the correlation coefficient during music. We conclude that correlated variations in MEP areas between the muscles seen during white noise can be destroyed in the presence of music. This may be due to subthreshold variations in corticospinal excitability to ankle extensors and flexors, which are time-locked to the musical beat but out of phase with one another.

Variation in the SLC23A1 gene does not influence cardiometabolic outcomes to the extent expected given its association with L-ascorbic acid

Background: Observational studies showed that circulating l-ascorbic acid (vitamin C) is inversely associated with cardiometabolic traits. However, these studies were susceptible to confounding and reverse causation. Objectives:We assessed the relation between l-ascorbic acid and 10 cardiometabolic traits by using a single nucleotide polymorphism in the solute carrier family 23 member 1 (SLC23A1) gene (rs33972313) associated with circulating l-ascorbic acid concentrations. The observed association between rs33972313 and cardiometabolic outcomes was compared with that expected given the rs33972313-l-ascorbic acid and l-ascorbic acid–outcome associations. Design: A meta-analysis was performed in the following 5 independent studies: the British Women's Heart and Health Study (n = 1833), the MIDSPAN study (n = 1138), the Ten Towns study (n = 1324), the British Regional Heart Study (n = 2521), and the European Prospective Investigation into Cancer (n = 3737). Results: With the use of a meta-analysis of observational estimates, inverse associations were shown between l-ascorbic acid and systolic blood pressure, triglycerides, and the waist-hip ratio [the strongest of which was the waist-hip ratio (−0.13-SD change; 95% CI: −0.20-, −0.07-SD change; P = 0.0001) per SD increase in l-ascorbic acid], and a positive association was shown with high-density lipoprotein (HDL) cholesterol. The variation at rs33972313 was associated with a 0.18-SD (95% CI: 0.10-, 0.25-SD; P = 3.34 × 10−6) increase in l-ascorbic acid per effect allele. There was no evidence of a relation between the variation at rs33972313 and any cardiometabolic outcome. Although observed estimates were not statistically different from expected associations between rs33972313 and cardiometabolic outcomes, estimates for low-density lipoprotein cholesterol, HDL cholesterol, triglycerides, glucose, and body mass index were in the opposite direction to those expected. Conclusions: The nature of the genetic association exploited in this study led to limited statistical application, but despite this, when all cardiometabolic traits were assessed, there was no evidence of any trend supporting a protective role of l-ascorbic acid. In the context of existing work, these results add to the suggestion that observational relations between l-ascorbic acid and cardiometabolic health may be attributable to confounding and reverse causation

Assessment of two types of passive sampler for the efficient recovery of SARS-CoV-2 and other viruses from wastewater

Wastewater-based epidemiology (WBE) has proven to be a useful surveillance tool during the ongoing SARS-CoV-2 pandemic, and has driven research into evaluating the most reliable and cost-effective techniques for obtaining a representative sample of wastewater. When liquid samples cannot be taken efficiently, passive sampling approaches have been used, however, insufficient data exists on their usefulness for multi-virus capture and recovery. In this study, we compared the virus-binding capacity of two passive samplers (cotton-based tampons and ion exchange filter papers) in two different water types (deionised water and wastewater). Here we focused on the capture of wastewater-associated viruses including Influenza A and B (Flu-A & B), SARS-CoV-2, human adenovirus (AdV), norovirus GII (NoVGII), measles virus (MeV), pepper mild mottle virus (PMMoV), the faecal marker crAssphage and the process control virus Pseudomonas virus phi6. After deployment, we evaluated four different methods to recover viruses from the passive samplers namely, (i) phosphate buffered saline (PBS) elution followed by polyethylene glycol (PEG) precipitation, (ii) beef extract (BE) elution followed by PEG precipitation, (iii) no-elution into PEG precipitation, and (iv) direct extraction. We found that the tampon-based passive samplers had higher viral recoveries in comparison to the filter paper. Overall, the preferred viral recovery method from the tampon passive samplers was the no-elution/PEG precipitation method. Furthermore, we evidenced that non-enveloped viruses had higher percent recoveries from the passive samplers than enveloped viruses. This is the first study of its kind to assess passive sampler and viral recovery methods amongst a plethora of viruses commonly found in wastewater or used as a viral surrogate in wastewater studies

Predicting El Niño in 2014 and 2015.

Early in 2014 several forecast systems were suggesting a strong 1997/98-like El Niño event for the following northern hemisphere winter 2014/15. However the eventual outcome was a modest warming. In contrast, winter 2015/16 saw one of the strongest El Niño events on record. Here we assess the ability of two operational seasonal prediction systems to forecast these events, using the forecast ensembles to try to understand the reasons underlying the very different development and outcomes for these two years. We test three hypotheses. First we find that the continuation of neutral ENSO conditions in 2014 is associated with the maintenance of the observed cold southeast Pacific sea surface temperature anomaly; secondly that, in our forecasts at least, warm west equatorial Pacific sea surface temperature anomalies do not appear to hinder El Niño development; and finally that stronger westerly wind burst activity in 2015 compared to 2014 is a key difference between the two years. Interestingly, in these years at least, this interannual variability in wind burst activity is predictable. ECMWF System 4 tends to produce more westerly wind bursts than Met Office GloSea5 and this likely contributes to the larger SST anomalies predicted in this model in both years

MAGNETIC BRAIN STIMULATION MODULATES NEURONAL PLASTICITY IN SPINAL CORD INJURY PATIENTS

Patients can often recover good motor function in muscles below an incomplete spinal cord injury. Within a few days of injury natural processes lead to down-regulation of inhibitory pathways within the motor cortex than can be demonstrated electrophysiologically. We believe that this natural change might encourage motor recovery by allowing an increased excitability of surviving descending corticospinal neurones. Repetitive transcranial magnetic stimulation (rTMS) can produce similar changes in corticospinal inhibition in normal uninjured individuals, albeit rather short-lasting. In this preliminary study we have delivered a sham rTMS over one week followed by another week of real treatment to four stable incomplete spinal cord injury patients who already showed reduced inhibition compared with controls. Intracortical inhibition was further reduced during the week of treatment but recovered basal levels within the three-week follow-up period. Longer-term improvements were seen in the clinical scores for both motor and sensory function, perceptual threshold to electrical stimulation of the skin and the time taken to complete a standard peg-board test. Although the measurable electrophysiological effects of rTMS are short-lived it would appear that functional recovery persists for at least three weeks after the treatment. Spinal cord injury patients might be more susceptible to the plastic cortical changes evoked by rTMS than non-injured individuals. This preliminary study provides promising data on which to base a larger investigation with the aim of substantiating the use of rTMS as a tool for routine use in rehabilitation