Epigenetics as a mechanism driving polygenic clinical drug resistance

Aberrant methylation of CpG islands located at or near gene promoters is associated with inactivation of gene expression during tumour development. It is increasingly recognised that such epimutations may occur at a much higher frequency than gene mutation and therefore have a greater impact on selection of subpopulations of cells during tumour progression or acquisition of resistance to anticancer drugs. Although laboratory-based models of acquired resistance to anticancer agents tend to focus on specific genes or biochemical pathways, such 'one gene : one outcome' models may be an oversimplification of acquired resistance to treatment of cancer patients. Instead, clinical drug resistance may be due to changes in expression of a large number of genes that have a cumulative impact on chemosensitivity. Aberrant CpG island methylation of multiple genes occurring in a nonrandom manner during tumour development and during the acquisition of drug resistance provides a mechanism whereby expression of multiple genes could be affected simultaneously resulting in polygenic clinical drug resistance. If simultaneous epigenetic regulation of multiple genes is indeed a major driving force behind acquired resistance of patients' tumour to anticancer agents, this has important implications for biomarker studies of clinical outcome following chemotherapy and for clinical approaches designed to circumvent or modulate drug resistance

Differential livelihood adaptation to social-ecological change in coastal Bangladesh

Social-ecological changes, brought about by the rapid growth of the aquaculture industry and the increased occurrence of climatic stressors, have significantly affected the livelihoods of coastal communities in Asian mega-deltas. This paper explores the livelihood adaptation responses of households of different wealth classes, the heterogeneous adaptation opportunities, barriers and limits (OBLs) faced by these households and the dynamic ways in which these factors interact to enhance or impede adaptive capacities. A mixed methods approach was used to collect empirical evidence from two villages in coastal Bangladesh. Findings reveal that households’ adaptive capacities largely depend on their wealth status, which not only determine their availability of productive resources, but also empower them to navigate social-ecological change in desirable ways. Households operate within a shared response space, which is shaped by the broader socio-economic and political landscape, as well as their previous decisions that can lock them in to particular pathways. While an adaptive response may be effective for one social group, it may cause negative externalities that can undermine the adaptation options and outcomes of another group. Adaptation OBLs interact in complex ways; the extent to which these OBLs affect different households depend on the specific livelihood activities being considered and the differential values and interests they hold. To ensure more equitable and environmentally sustainable livelihoods in future, policies and programs should aim to expand households’ adaptation space by accounting for the heterogeneous needs and complex interdependencies between response processes of different groups

Research into the Health Benefits of Sprint Interval Training Should Focus on Protocols with Fewer and Shorter Sprints

Over the past decade, it has been convincingly shown that regularly performing repeated brief supramaximal cycle sprints (sprint interval training [SIT]) is associated with aerobic adaptations and health benefits similar to or greater than with moderate-intensity continuous training (MICT). SIT is often promoted as a time-efficient exercise strategy, but the most commonly studied SIT protocol (4–6 repeated 30-s Wingate sprints with 4 min recovery, here referred to as ‘classic’ SIT) takes up to approximately 30 min per session. Combined with high associated perceived exertion, this makes classic SIT unsuitable as an alternative/adjunct to current exercise recommendations involving MICT. However, there are no indications that the design of the classic SIT protocol has been based on considerations regarding the lowest number or shortest duration of sprints to optimise time efficiency while retaining the associated health benefits. In recent years, studies have shown that novel SIT protocols with both fewer and shorter sprints are efficacious at improving important risk factors of noncommunicable diseases in sedentary individuals, and provide health benefits that are no worse than those associated with classic SIT. These shorter/easier protocols have the potential to remove many of the common barriers to exercise in the general population. Thus, based on the evidence summarised in this current opinion paper, we propose that there is a need for a fundamental change in focus in SIT research in order to move away from further characterising the classic SIT protocol and towards establishing acceptable and effective protocols that involve minimal sprint durations and repetitions

Mild Cognitive Impairment Staging Yields Genetic Susceptibility, Biomarker, and Neuroimaging Differences

INTRODUCTION: While Alzheimer’s disease (AD) is divided into severity stages, mild cognitive impairment (MCI) remains a solitary construct despite clinical and prognostic heterogeneity. This study aimed to characterize differences in genetic, cerebrospinal fluid (CSF), neuroimaging, and neuropsychological markers across clinician-derived MCI stages. METHODS: Vanderbilt Memory & Aging Project participants with MCI were categorized into 3 severity subtypes at screening based on neuropsychological assessment, functional assessment, and Clinical Dementia Rating interview, including mild (n = 18, 75 ± 8 years), moderate (n = 89 72 ± 7 years), and severe subtypes (n = 18, 78 ± 8 years). At enrollment, participants underwent neuropsychological testing, 3T brain magnetic resonance imaging (MRI), and optional fasting lumbar puncture to obtain CSF. Neuropsychological testing and MRI were repeated at 18-months, 3-years, and 5-years with a mean follow-up time of 3.3 years. Ordinary least square regressions examined cross-sectional associations between MCI severity and apolipoprotein E (APOE)-ε4 status, CSF biomarkers of amyloid beta (Aβ), phosphorylated tau, total tau, and synaptic dysfunction (neurogranin), baseline neuroimaging biomarkers, and baseline neuropsychological performance. Longitudinal associations between baseline MCI severity and neuroimaging and neuropsychological trajectory were assessed using linear mixed effects models with random intercepts and slopes and a follow-up time interaction. Analyses adjusted for baseline age, sex, race/ethnicity, education, and intracranial volume for MRI models. RESULTS: Stages differed at baseline on APOE-ε4 status (early middle = late), phosphorylated and total tau (early = middle < late; p-values < 0.05), and neurogranin concentrations (early = middle < late; p-values < 0.05). MCI stage related to greater longitudinal cognitive decline, hippocampal atrophy, and inferior lateral ventricle dilation (early < late; p-values < 0.03). DISCUSSION: Clinician staging of MCI severity yielded longitudinal cognitive trajectory and structural neuroimaging differences in regions susceptible to AD neuropathology and neurodegeneration. As expected, participants with more severe MCI symptoms at study entry had greater cognitive decline and gray matter atrophy over time. Differences are likely attributable to baseline differences in amyloidosis, tau, and synaptic dysfunction. MCI staging may provide insight into underlying pathology, prognosis, and therapeutic targets

Suppression of ABCE1-mediated mRNA translation limits N-MYC-driven cancer progression

The ability of the N-MYC transcription factor to drive cancer progression is well demonstrated in neuroblastoma, the most common extracranial pediatric solid tumor, where MYCN amplification heralds a poor prognosis, with only 11% of high-risk patients surviving past 5 years. However, decades of attempts of direct inhibition of N-MYC or its paralogues has led to the conclusion that this protein is “undruggable.” Therefore, targeting pathways upregulated by N-MYC signaling presents an alternative therapeutic approach. Here, we show that MYCN-amplified neuroblastomas are characterized by elevated rates of protein synthesis and that high expression of ABCE1, a translation factor directly upregulated by N-MYC, is itself a strong predictor of poor clinical outcome. Despite the potent ability of N-MYC in heightening protein synthesis and malignant characteristics in cancer cells, suppression of ABCE1 alone selectively negated this effect, returning the rate of translation to baseline levels and significantly reducing the growth, motility, and invasiveness of MYCN-amplified neuroblastoma cells and patient-derived xenograft tumors in vivo. The growth of nonmalignant cells or MYCN-nonamplified neuroblastoma cells remained unaffected by reduced ABCE1, supporting a therapeutic window associated with targeting ABCE1. Neuroblastoma cells with c-MYC overexpression also required ABCE1 to maintain cell proliferation and translation. Taken together, ABCE1-mediated translation constitutes a critical process in the progression of N-MYC-driven and c-MYC-driven cancers that warrants investigations into methods of its therapeutic inhibition

School Effects on the Wellbeing of Children and Adolescents

Well-being is a multidimensional construct, with psychological, physical and social components. As theoretical basis to help understand this concept and how it relates to school, we propose the Self-Determination Theory, which contends that self-determined motivation and personality integration, growth and well-being are dependent on a healthy balance of three innate psychological needs of autonomy, relatedness and competence. Thus, current indicators involve school effects on children’s well-being, in many diverse modalities which have been explored. Some are described in this chapter, mainly: the importance of peer relationships; the benefits of friendship; the effects of schools in conjunction with some forms of family influence; the school climate in terms of safety and physical ecology; the relevance of the teacher input; the school goal structure and the implementation of cooperative learning. All these parameters have an influence in promoting optimal functioning among children and increasing their well-being by meeting the above mentioned needs. The empirical support for the importance of schools indicates significant small effects, which often translate into important real-life effects as it is admitted at present. The conclusion is that schools do make a difference in children’s peer relationships and well-being

A decision analytical cost analysis of offering ECV in a UK district general hospital

OBJECTIVE: To determine the care pathways and implications of offering mothers the choice of external cephalic version (ECV) at term for singleton babies who present with an uncomplicated breech pregnancy versus assisted breech delivery or elective caesarean. DESIGN: A prospective observational audit to construct a decision analysis of uncomplicated full term breech presentations. SETTING: The North Staffordshire NHS Trust. SUBJECTS: All women (n = 176) who presented at full term with a breech baby without complications during July 1995 and June 1997. MAIN OUTCOME MEASURES: The study determined to compare the outcome in terms of the costs and cost consequences for the care pathways that resulted from whether a women chose to accept the offer of ECV or not. All the associated events were then mapped for the two possible pathways. The costs were considered only within the hospital setting, from the perspective of the health care provider up to the point of delivery. RESULTS: The additional costs for ECV, assisted breech delivery and elective caesarean over and above a normal birth were £186.70, £425.36 and £1,955.22 respectively. The total expected cost of the respective care pathways for "ECV accepted" and "ECV not accepted" (including the probability of adverse events) were £1,452 and £1,828 respectively, that is the cost of delivery through the ECV care pathways is less costly than the non ECV delivery care pathway. CONCLUSIONS: Implementing an ECV service may yield cost savings in secondary care over and above the traditional delivery methods for breech birth of assisted delivery or caesarean section. The scale of these expected cost savings are in the range of £248 to £376 per patient. This converts to a total expected cost saving of between £43,616 and £44,544 for the patient cohort considered in this study

Effectiveness, safety and acceptability of ‘see and treat' with cryotherapy by nurses in a cervical screening study in India

We evaluated a ‘see and treat' procedure involving screening, colposcopy, biopsy and cryotherapy by trained nurses in one-visit in field clinics in a cervical screening study in South India for its acceptability, safety and effectiveness in curing cervical intraepithelial neoplasia (CIN). Women positive on visual inspection with acetic acid (VIA) were advised colposcopy, directed biopsies and cryotherapy if they had colposcopic impression of CIN in one visit by nurses in field clinics supervised by a doctor. Side effects and complications were assessed and cure rates were evaluated with VIA, colposcopy and biopsy if colposcopic abnormalities were suspected. Cure was defined as no clinical or histological evidence of CIN at ⩾6 months from treatment. Of the 2513 women offered ‘see and treat' procedure, 1879 (74.8%) accepted. Of the 1397 women with histologically proved CIN treated with cryotherapy, 1026 reported for follow-up evaluation. Cure rates were 81.4% (752 out of 924) for women with CIN 1; 71.4% (55 out of 77) for CIN 2 and 68.0% (17 out of 25) for CIN 3. Minor side effects and complications were documented in less than 3% of women. ‘See and treat' with cryotherapy by nurses under medical supervision is acceptable, safe and effective for cervical cancer prevention in low-resource settings