A Role for ATF2 in Regulating MITF and Melanoma Development

The transcription factor ATF2 has been shown to attenuate melanoma susceptibility to apoptosis and to promote its ability to form tumors in xenograft models. To directly assess ATF2's role in melanoma development, we crossed a mouse melanoma model (Nras(Q61K)::Ink4a⁻/⁻) with mice expressing a transcriptionally inactive form of ATF2 in melanocytes. In contrast to 7/21 of the Nras(Q61K)::Ink4a⁻/⁻ mice, only 1/21 mice expressing mutant ATF2 in melanocytes developed melanoma. Gene expression profiling identified higher MITF expression in primary melanocytes expressing transcriptionally inactive ATF2. MITF downregulation by ATF2 was confirmed in the skin of Atf2⁻/⁻ mice, in primary human melanocytes, and in 50% of human melanoma cell lines. Inhibition of MITF transcription by MITF was shown to be mediated by ATF2-JunB-dependent suppression of SOX10 transcription. Remarkably, oncogenic BRAF (V600E)-dependent focus formation of melanocytes on soft agar was inhibited by ATF2 knockdown and partially rescued upon shMITF co-expression. On melanoma tissue microarrays, a high nuclear ATF2 to MITF ratio in primary specimens was associated with metastatic disease and poor prognosis. Our findings establish the importance of transcriptionally active ATF2 in melanoma development through fine-tuning of MITF expression

Spinal involvement in mucopolysaccharidosis IVA (Morquio-Brailsford or Morquio A syndrome): presentation, diagnosis and management.

Mucopolysaccharidosis IVA (MPS IVA), also known as Morquio-Brailsford or Morquio A syndrome, is a lysosomal storage disorder caused by a deficiency of the enzyme N-acetyl-galactosamine-6-sulphate sulphatase (GALNS). MPS IVA is multisystemic but manifests primarily as a progressive skeletal dysplasia. Spinal involvement is a major cause of morbidity and mortality in MPS IVA. Early diagnosis and timely treatment of problems involving the spine are critical in preventing or arresting neurological deterioration and loss of function. This review details the spinal manifestations of MPS IVA and describes the tools used to diagnose and monitor spinal involvement. The relative utility of radiography, computed tomography (CT) and magnetic resonance imaging (MRI) for the evaluation of cervical spine instability, stenosis, and cord compression is discussed. Surgical interventions, anaesthetic considerations, and the use of neurophysiological monitoring during procedures performed under general anaesthesia are reviewed. Recommendations for regular radiological imaging and neurologic assessments are presented, and the need for a more standardized approach for evaluating and managing spinal involvement in MPS IVA is addressed

Virtual reality surgery simulation: A survey on patient specific solution

For surgeons, the precise anatomy structure and its dynamics are important in the surgery interaction, which is critical for generating the immersive experience in VR based surgical training applications. Presently, a normal therapeutic scheme might not be able to be straightforwardly applied to a specific patient, because the diagnostic results are based on averages, which result in a rough solution. Patient Specific Modeling (PSM), using patient-specific medical image data (e.g. CT, MRI, or Ultrasound), could deliver a computational anatomical model. It provides the potential for surgeons to practice the operation procedures for a particular patient, which will improve the accuracy of diagnosis and treatment, thus enhance the prophetic ability of VR simulation framework and raise the patient care. This paper presents a general review based on existing literature of patient specific surgical simulation on data acquisition, medical image segmentation, computational mesh generation, and soft tissue real time simulation

Is Cardiorespiratory Fitness Related to Cardiometabolic Health and All-Cause Mortality Risk in Patients with Coronary Heart Disease? A CARE CR Study

Background: Higher cardiorespiratory fitness (CRF) is associated with lower morbidity and mortality in patients with coronary heart disease (CHD). The mechanisms for this are not fully understood. A more favourable cardiometabolic risk factor profile may be responsible, however few studies have comprehensively evaluated cardiometabolic risk factors in relation to CRF, among patients with CHD. Objective: To explore differences in cardiometabolic risk and 5-year all-cause mortality risk in patients with CHD who have low, moderate, and high levels of CRF. Methods: Patients with CHD underwent maximal cardiopulmonary exercise testing (CPET), echocardiogram, carotid intima-media thickness measurement, spirometry, and dual X-ray absorptiometry assessment. Full blood count, biochemical lipid pro-files, high sensitivity (hs)- C-reactive protein and NT-proBNP were analysed. Pa-tients were defined as having low, moderate, or high CRF based on established prognostic thresholds. Results: 70 patients with CHD (age 63.1 ± 10.0 years, 86% male) were recruited. Patients with low CRF had a lower ventilatory anaerobic threshold, peak oxygen pulse, post-exercise heart rate recovery and poor ventilatory efficiency. The low CRF group also had higher NT pro-BNP, hs-CRP, non-fasting glucose concentrations and lower haemoglobin and haematocrit. Five-year mortality risk (CALIBER risk score) was also greatest in the lowest CRF group (14.9%). Conclusion: Practitioners should interpret low CRF as an important clinical risk factor associated with adverse cardiometabolic health and poor prognosis. Study registry; researchregistry.com (researchregistry3548). Key Words: Coronary Heart Disease, Cardiac Rehabilitation, Cardiometabolic Health, Exercise Training, Atherosclerosis, VO2peak, Maximal Cardiopulmonary Exercise Testing, Caliber 5-year ris

Exploring synergies and trade-offs among the sustainable development goals: collective action and adaptive capacity in marginal mountainous areas of India

Global environmental change (GEC) threatens to undermine the sustainable development goals (SDGs). Smallholders in marginal mountainous areas (MMA) are particularly vulnerable due to precarious livelihoods in challenging environments. Acting collectively can enable and constrain the ability of smallholders to adapt to GEC. The objectives of this paper are: (i) identify collective actions in four MMA of the central Indian Himalaya Region, each with differing institutional contexts; (ii) assess the adaptive capacity of each village by measuring livelihood capital assets, diversity, and sustainable land management practices. Engaging with adaptive capacity and collective action literatures, we identify three broad approaches to adaptive capacity relating to the SDGs: natural hazard mitigation (SDG 13), social vulnerability (SDG 1, 2 and 5), and social–ecological resilience (SDG 15). We then develop a conceptual framework to understand the institutional context and identify SDG synergies and trade-offs. Adopting a mixed method approach, we analyse the relationships between collective action and the adaptive capacity of each village, the sites where apparent trade-offs and synergies among SDGs occur. Results illustrate each village has unique socio-environmental characteristics, implying distinct development challenges, vulnerabilities and adaptive capacities exist. Subsequently, specific SDG synergies and trade-offs occur even within MMA, and it is therefore crucial that institutions facilitate locally appropriate collective actions in order to achieve the SDGs. We suggest that co-production in the identification, prioritisation and potential solutions to the distinct challenges facing MMA can increase understandings of the specific dynamics and feedbacks necessary to achieve the SDGs in the context of GEC

A principal component meta-analysis on multiple anthropometric traits identifies novel loci for body shape

This is the final version of the article. Available from the publisher via the DOI in this record.Large consortia have revealed hundreds of genetic loci associated with anthropometric traits, one trait at a time. We examined whether genetic variants affect body shape as a composite phenotype that is represented by a combination of anthropometric traits. We developed an approach that calculates averaged PCs (AvPCs) representing body shape derived from six anthropometric traits (body mass index, height, weight, waist and hip circumference, waist-to-hip ratio). The first four AvPCs explain >99% of the variability, are heritable, and associate with cardiometabolic outcomes. We performed genome-wide association analyses for each body shape composite phenotype across 65 studies and meta-analysed summary statistics. We identify six novel loci: LEMD2 and CD47 for AvPC1, RPS6KA5/C14orf159 and GANAB for AvPC3, and ARL15 and ANP32 for AvPC4. Our findings highlight the value of using multiple traits to define complex phenotypes for discovery, which are not captured by single-trait analyses, and may shed light onto new pathways

WNT/β-catenin signaling regulates mitochondrial activity to alter the oncogenic potential of melanoma in a PTEN-dependent manner

Aberrant regulation of WNT/β-catenin signaling has a crucial role in the onset and progression of cancers, where the effects are not always predictable depending on tumor context. In melanoma, for example, models of the disease predict differing effects of the WNT/β-catenin pathway on metastatic progression. Understanding the processes that underpin the highly context-dependent nature of WNT/β-catenin signaling in tumors is essential to achieve maximal therapeutic benefit from WNT inhibitory compounds. In this study, we have found that expression of the tumor suppressor, phosphatase and tensin homolog deleted on chromosome 10 (PTEN), alters the invasive potential of melanoma cells in response to WNT/β-catenin signaling, correlating with differing metabolic profiles. This alters the bioenergetic potential and mitochondrial activity of melanoma cells, triggered through regulation of pro-survival autophagy. Thus, WNT/β-catenin signaling is a regulator of catabolic processes in cancer cells, which varies depending on the metabolic requirements of tumors

Feasibility study of multidisciplinary oncology rounds by videoconference for surgeons in remote locales

BACKGROUND: This study was undertaken to assess the feasibility of using videoconferencing to involve community-based surgeons in interactive, multidisciplinary oncology rounds so they may benefit from the type of community of practice that is usually only available in academic cancer centres. METHODS: An existing videoconference service provider with sites across Ontario was chosen and the series was accredited. Indirect needs assessment involved examining responses to a previously conducted survey of provincial surgeons; interviewing three cancer surgeons from different regions of Ontario; and by analyzing an online portfolio of self-directed learning projects. Direct needs assessment involved a survey of surgeons at videoconference-enabled sites. A surgical, medical and radiation oncologist plus a facilitator were scheduled to guide discussion for each session. A patient scenario developed by the discussants was distributed to participants one week prior to each session. RESULTS: Direct and indirect needs assessment confirmed that breast cancer and colorectal cancer topics were of greatest importance to community surgeons. Six one-hour sessions were offered (two breast, two colorectal, one gynecologic and one lung cancer). A median of 22 physicians and a median of eight sites participated in each session. The majority of respondents were satisfied with the videoconference format, presenters and content. Many noted that discussion prompted reflection on practice and that current practice would change. CONCLUSIONS: This pilot study demonstrated that it is possible to engage remote surgeons in multidisciplinary oncology rounds by videoconference. Continued assessment of videoconferencing is warranted but further research is required to develop frameworks by which to evaluate the benefits of telehealth initiatives

Estimating Design Effect and Calculating Sample Size for Respondent-Driven Sampling Studies of Injection Drug Users in the United States

Respondent-driven sampling (RDS) has become increasingly popular for sampling hidden populations, including injecting drug users (IDU). However, RDS data are unique and require specialized analysis techniques, many of which remain underdeveloped. RDS sample size estimation requires knowing design effect (DE), which can only be calculated post hoc. Few studies have analyzed RDS DE using real world empirical data. We analyze estimated DE from 43 samples of IDU collected using a standardized protocol. We find the previous recommendation that sample size be at least doubled, consistent with DE = 2, underestimates true DE and recommend researchers use DE = 4 as an alternate estimate when calculating sample size. A formula for calculating sample size for RDS studies among IDU is presented. Researchers faced with limited resources may wish to accept slightly higher standard errors to keep sample size requirements low. Our results highlight dangers of ignoring sampling design in analysis