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Molecular therapeutics of pancreatic ductal adenocarcinoma:targeted pathways and the role of cancer stem cells
No full textPancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers in humans due to late detection and highly metastatic characteristics. PDAC cells vary in their tumorigenic capabilities with the presence of a subset of PDAC cells known as pancreatic cancer stem cells (CSCs), which are more resistant to currently used therapeutics. Here, we describe the role of CSCs and tumour stroma in developing therapeutic strategies for PDAC and suggest that developmental plasticity could be considered a hallmark of cancers. We provide an overview of the molecular targets in PDAC treatments, including targeted therapies of cellular processes such as proliferation, evasion of growth suppressors, activating metastasis, and metabolic effects. Since PDAC is an inflammation-driven cancer, we also revisit therapeutic strategies targeting inflammation and immunotherapy. Lastly, we suggest that targeting epigenetic mechanisms opens therapeutic routes for heterogeneous cancer cell populations, including CSCs
Gaze behaviour to lateral face stimuli in infants who do and do not gain an ASD diagnosis
No full textCerebral lateralisation of function is common characteristic across vertebrate species and is positively associated with fitness of the organism, in humans we hypothesise that it is associated with cognitive fitness. This investigation evaluated the early development of lateralised gaze behaviour for face stimuli in infants at high and low risk for autism from the British Autism Sibling Infant Study (BASIS). The BASIS cohort includes a low risk group and three high-risk groups who at age 3 were developing (i) typically, (ii) atypically or (iii) had received a diagnosis for ASD. Using eye-tracking data derived from a face pop-out task at 6 and 14 months of age, all non-ASD groups showed a bias for stimuli on the left at both timepoints. At 6 months the ASD group demonstrated a preference for stimuli on the right and were slower than their neurotypical counterparts to look at faces on the left. However, by 14 months these differences disappear. Longitudinal associations between lateral looking behaviour at 6 months and language and motor ability at 14 months were also found. Results suggest that infants who go on to be diagnosed with autism exhibit early differences in gaze behaviour that may be associated with subsequent cognitive outcomes
A matched comparison of revision rates of cemented Oxford Unicompartmental Knee Replacements with Single and Twin Peg femoral components, based on data from the National Joint Registry for England, Wales, Northern Ireland and the Isle of Man
No full textBackground and purpose — Registries report high revision rates after unicompartmental knee replacement (UKR) due, in part, to aseptic loosing. In an attempt to improve Oxford UKR femoral component fixation a new design was introduced with a Twin rather than a Single peg. We used the National Joint Registry (NJR) to compare the 5-year outcomes of the Single and Twin Peg cemented Oxford UKRs.
Patients and methods — We performed a retrospective observational study using NJR data on propensity score matched Single and Twin Peg UKRs (matched for patient, implant and surgical factors). Data on 2,834 Single Peg and 2,834 Twin Peg were analyzed. Cumulative implant survival was calculated using the Kaplan–Meier method and comparisons between groups performed using Cox regression models.
Results — In the matched cohort, the mean follow up for both Single and Twin Peg UKRs was 3.3 (SD 2) and 3.4 years (SD 2) respectively. The 5-year cumulative implant survival rates for Single Peg and Twin Peg were 94.8% (95% CI 93.6–95.8) and 96.2% (CI 95.1–97.1) respectively. Implant revision rates were statistically significantly lower in the Twin Peg (hazard ratio [HR)] = 0.74; p = 0.04). The revision rate for femoral component aseptic loosening decreased significantly (p = 0.03) from 0.4% (n = 11) with the Single Peg to 0.1% (n = 3) with the Twin Peg. The revision rate for pain decreased significantly (p = 0.01) from 0.8% (n = 23) with the Single Peg to 0.3% (n = 9) with the Twin Peg. No other reasons for revision had significant differences in revision rates.
Interpretation — The revision rate for the cemented Twin Peg Oxford UKR was 26% less than the Single Peg Oxford UKR. This was mainly because the revision rates for femoral loosening and pain more than halved. This suggests that the Twin Peg component should be used in preference to the Single Peg design
Software requirements for the analysis and interpretation of native ion mobility mass spectrometry data
No full textThe past few years have seen a dramatic increase in applications of native mass and ion mobility spectrometry, especially for the study of proteins and protein complexes. This increase has been catalyzed by the availability of commercial instrumentation capable of carrying out such analyses. As in most fields, however, the software to process the data generated from new instrumentation lags behind. Recently, a number of research groups have started addressing this by developing software, but further improvements are still required in order to realize the full potential of the data sets generated. In this perspective, we describe practical aspects as well as challenges in processing native mass spectrometry (MS) and ion mobility-MS data sets and provide a brief overview of currently available tools. We then set out our vision of future developments that would bring the community together and lead to the development of a common platform to expedite future computational developments, provide standardized processing approaches, and serve as a location for the deposition of data for this emerging field. This perspective has been written by members of the European Cooperation in Science and Technology Action on Native MS and Related Methods for Structural Biology (EU COST Action BM1403) as an introduction to the software tools available in this area. It is intended to serve as an overview for newcomers and to stimulate discussions in the community on further developments in this field, rather than being an in-depth review. Our complementary perspective (http://dx.doi.org/10.1021/acs.analchem.9b05791) focuses on computational approaches used in this field
Bias caused by reliance on patient-reported outcome measures in non-blinded randomized trials: an in-depth look at exercise therapy for chronic fatigue syndrome
No full textBackground
Several randomized trials have reported that graded exercise therapy (GET) is an effective treatment for chronic fatigue syndrome (CFS). These trials were not blinded and relied on patient-reported outcome measures (PROMs). We investigate whether bias introduced by this study design influenced the results.
Methods
We extracted standardized mean differences from the most recent meta-analysis on exercise therapy for CFS to analyze their size, consistency over time, and congruence with objective measurements. A narrative review methodology was used to examine mediation analyses, plausible mechanisms of improvement, and risk of response bias.
Results
Patient-reported improvements in exercise trials for CFS tend to be small, transient, and poorly supported by objective measurements. The risk of expectancy effects and response bias was high as patients were actively encouraged to adopt a positive attitude towards exercise therapy. Mediation analyses suggest that self-reported improvements in fatigue and physical function are not mediated by objective measures of fitness.
Conclusions
Treatment effects seen in exercise trials for CFS could be the result of bias associated with the use of PROMs in non-blinded trials. This might explain the discrepancy between positive results reported in randomized trials and views on exercise therapy expressed by patient organizations. We hope that this case study furthers critical assessment of patient-reported improvements in areas of medicine where blinding of therapists and trial participants faces practical limitations
A GIS-based approach to evaluating environmental influences on active and public transport accessibility of university students
No full textMany young adults are susceptible to obesity issues and the increased health risks associated with a lack of physical activity. Those who are prone to gaining weight include university students. An active transport system (walking and cycling), in combination with well-funded public transport, are essential components of a sustainable urban transport network, offering many benefits to the health of the individual, as well as the environment, economy, and society as a whole. The spatial association between active mobility (i.e. the physical activity of a human being for locomotion) of young adults and the environment, however, is poorly understood. This study presents a GIS-based model to determine association of various environmental (natural and built environment) factors with locational accessibility of active and public transport trips taken by university students. A GIS-based ensemble of Frequency Ratio (FR) and the Analytical Hierarchy Process (AHP) model was established. We analysed the characteristics of locations accessed by university students in relation to eight environmental factors including slope, elevation, land use, population density, travel time, building density, intersection density, and public transport service area. The model was applied to the Grenoble metropolitan region of France, an area well-known for policies which promote active transport. The results indicated that intersection density and land use are strongly associated with active and public transport accessibility, with weights of 0.17 and 0.16, respectively. The presence of infrastructure to support active travel, and regulation to limit vehicular speed, also improved accessibility. Approximately 50% of the area of the Grenoble metropolitan region was defined as accessible and suitable (‘moderate’ to ‘very high’ degree) for active mobility. The results of this study could allow city planners to monitor the existing status of active and public transport facilities, and identify areas that require additional work to improve accessibility
Current advances in lymphoedema management
No full textLymphoedema is the accumulation of protein-rich interstitial fluid within subcutaneous tissue and skin as a result of dysfunction of the lymphatic system. It is an underestimated, widely neglected and debilitating chronic condition. This article presents an overview of lymphoedema and recent advances in its management
Harnessing employment-based social assistance programmes to scale up nature-based climate action
No full textAs the severity of the triple challenges of global inequality, climate change and biodiversity loss becomes clearer, governments and international development institutions must find effective policy instruments to respond. We examine the potential of social assistance policies in this context. Social assistance refers to transfers to poor, vulnerable and marginalized groups to reduce their vulnerability and livelihood risks, and to enhance their rights and status. Substantial public funds support social assistance programmes globally. Collectively, lower- and middle-income countries spend approximately 1.5% of their GDP on social assistance annually. We focus on the potential of paid employment schemes to promote effective ecosystem stewardship. Available evidence suggests such programmes can offer multiple benefits in terms of improvements in local ecosystems and natural capital, carbon sequestration and local biodiversity conservation. We review evidence from three key case studies: in India (the Mahatma Gandhi National Rural Employment Guarantee Scheme), Ethiopia (the Productive Safety Nets Programme) and Mexico (the Temporary Employment Programme). We conclude that, to realize the potential of employment-based social assistance for ecosystem benefits it will be necessary to address two challenges: first, the weak design and maintenance of local public works outputs in many schemes, and second, the concern that social protection schemes may become less effective if they are overburdened with additional objectives. Overcoming these challenges requires an evolution of institutional systems for delivering social assistance to enable a more effective combination of social and environmental objectives
Molecular characterization of Plasmodium falciparum antifolate resistance markers in Thailand between 2008 and 2016
No full textBackground
Resistance to anti-malarials is a major threat to the control and elimination of malaria. Sulfadoxine–pyrimethamine (SP) anti-malarial treatment was used as a national policy for treatment of uncomplicated falciparum malaria in Thailand from 1973 to 1990. In order to determine whether withdrawal of this antifolate drug has led to restoration of SP sensitivity, the prevalence of genetic markers of SP resistance was assessed in historical Thai samples.
Methods
Plasmodium falciparum DNA was collected from the Thailand–Myanmar, Thailand–Malaysia and Thailand–Cambodia borders during 2008–2016 (N = 233). Semi-nested PCR and nucleotide sequencing were used to assess mutations in Plasmodium falciparum dihydrofolate reductase (pfdhfr), P. falciparum dihydropteroate synthase (pfdhps). Gene amplification of Plasmodium falcipaurm GTP cyclohydrolase-1 (pfgch1) was assessed by quantitative real-time PCR. The association between pfdhfr/pfdhps mutations and pfgch1 copy numbers were evaluated.
Results
Mutations in pfdhfr/pfdhsp and pfgch1 copy number fluctuated overtime through the study period. Altogether, 14 unique pfdhfr–pdfhps haplotypes collectively containing quadruple to octuple mutations were identified. High variation in pfdhfr–pfdhps haplotypes and a high proportion of pfgch1 multiple copy number (51% (73/146)) were observed on the Thailand–Myanmar border compared to other parts of Thailand. Overall, the prevalence of septuple mutations was observed for pfdhfr–pfdhps haplotypes. In particular, the prevalence of pfdhfr–pfdhps, septuple mutation was observed in the Thailand–Myanmar (50%, 73/146) and Thailand–Cambodia (65%, 26/40) border. In Thailand–Malaysia border, majority of the pfdhfr–pfdhps haplotypes transaction from quadruple (90%, 9/10) to quintuple (65%, 24/37) during 2008–2016. Within the pfdhfr–pfdhps haplotypes, during 2008–2013 the pfdhps A/S436F mutation was observed only in Thailand–Myanmar border (9%, 10/107), while it was not identified later. In general, significant correlation was observed between the prevalence of pfdhfr I164L (ϕ = 0.213, p-value = 0.001) or pfdhps K540E/N (ϕ = 0.399, p-value ≤ 0.001) mutations and pfgch1 gene amplification.
Conclusions
Despite withdrawal of SP as anti-malarial treatment for 17 years, the border regions of Thailand continue to display high prevalence of antifolate and anti-sulfonamide resistance markers in falciparum malaria. Significant association between pfgch1 amplification and pfdhfr (I164L) or pfdhps (K540E) resistance markers were observed, suggesting a compensatory mutation