HIF1 and DROSHA are involved in MMACHC repression in hypoxia

The MMACHC gene encodes for an enzyme involved in intracellular vitamin B12 metabolism, and autosomal recessive defects in MMACHC represent the most common disorder of intracellular vitamin B12 metabolism. Recent studies have identified increased levels of reactive oxygen species in cells and tissues with MMACHC dysfunction, suggesting a role for oxidative stress in disease. To investigate the link between oxidative stress and MMACHC, we exposed mice as well as human and mouse cells to hypoxia, and found significant repression of MMACHC in all investigated tissues (retina, eyecup, liver, kidney) and cell lines (HeLa, ARPE-19, human and mouse fibroblasts, 661W). Furthermore, in HeLa cells, we found transcriptional repression already at 5% oxygen, which was stable during prolonged hypoxia up to 5 days, and a return of MMACHC transcripts to normal levels only 24 h after reoxygenation. This hypoxia-induced downregulation of MMACHC was not due to altered function of the known MMACHC controlling transcription factor complex HCFC1/THAP11/ZNF143. Using in vitro RNA interference against hypoxia-induced transcription factors (HIF1A, HIF2A and REST) as well as the microRNA transcription machinery (DROSHA), we observed release of hypoxia-dependent downregulation of MMACHC expression by HIF1A and DROSHA knockdowns, whose combined effect was additive. Together, these results strongly indicate that MMACHC is a hypoxia-regulated gene whose downregulation appears to be partially mediated through both hypoxia-induced transcription factor and microRNA machinery. These findings suggest that oxidative stress could impair vitamin B12 metabolism by repression of MMACHC in healthy as well as in diseased individuals

Monitoring EPR Effect Dynamics during Nanotaxane Treatment with Theranostic Polymeric Micelles

Cancer nanomedicines rely on the enhanced permeability and retention (EPR) effect for efficient target site accumulation. The EPR effect, however, is highly heterogeneous among different tumor types and cancer patients and its extent is expected to dynamically change during the course of nanochemotherapy. Here the authors set out to longitudinally study the dynamics of the EPR effect upon single- and double-dose nanotherapy with fluorophore-labeled and paclitaxel-loaded polymeric micelles. Using computed tomography-fluorescence molecular tomography imaging, it is shown that the extent of nanomedicine tumor accumulation is predictive for therapy outcome. It is also shown that the interindividual heterogeneity in EPR-based tumor accumulation significantly increases during treatment, especially for more efficient double-dose nanotaxane therapy. Furthermore, for double-dose micelle therapy, tumor accumulation significantly increased over time, from 7% injected dose per gram (ID g–1) upon the first administration to 15% ID g–1 upon the fifth administration, contributing to more efficient inhibition of tumor growth. These findings shed light on the dynamics of the EPR effect during nanomedicine treatment and they exemplify the importance of using imaging in nanomedicine treatment prediction and clinical translation

Cardiac rehabilitation availability and delivery in Europe: How does it differ by region and compare with other high-income countries?: Endorsed by the European Association of Preventive Cardiology

Aims: The aims of this study were to establish cardiac rehabilitation availability and density, as well as the nature ofprogrammes, and to compare these by European region (geoscheme) and with other high-income countries.Methods: A survey was administered to cardiac rehabilitation programmes globally. Cardiac associations were engagedto facilitate programme identification. Density was computed using global burden of disease study ischaemic heartdisease incidence estimates. Four high-income countries were selected for comparison (N¼790 programmes) toEuropean data, and multilevel analyses were performed.Results: Cardiac rehabilitation was available in 40/44 (90.9%) European countries. Data were collected in 37 (94.8%country response rate). A total of 455/1538 (29.6% response rate) programme respondents initiated the survey.Programme volumes (median 300) were greatest in western European countries, but overall were higher than inother high-income countries (

Nature of Cardiac Rehabilitation Around the Globe

BackgroundCardiac rehabilitation (CR) is a clinically-effective but complex model of care. The purpose of this study was to characterize the nature of CR programs around the world, in relation to guideline recommendations, and compare this by World Health Organization (WHO) region.MethodsIn this cross-sectional study, a piloted survey was administered online to CR programs globally. Cardiac associations and local champions facilitated program identification. Quality (benchmark of ≥ 75% of programs in a given country meeting each of 20 indicators) was ranked. Results were compared by WHO region using generalized linear mixed models.Findings111/203 (54.7%) countries in the world offer CR; data were collected in 93 (83.8%; N = 1082 surveys, 32.1% program response rate). The most commonly-accepted indications were: myocardial infarction (n = 832, 97.4%), percutaneous coronary intervention (n = 820, 96.1%; 0.10), and coronary artery bypass surgery (n = 817, 95.8%). Most programs were led by physicians (n = 680; 69.1%). The most common CR providers (mean = 5.9 ± 2.8/program) were: nurses (n = 816, 88.1%; low in Africa, p

Cardiac Rehabilitation Availability and Density around the Globe

BackgroundDespite the epidemic of cardiovascular disease and the benefits of cardiac rehabilitation (CR), availability is known to be insufficient, although this is not quantified. This study ascertained CR availability, volumes and its drivers, and density.MethodsA survey was administered to CR programs globally. Cardiac associations and local champions facilitated program identification. Factors associated with volumes were assessed using generalized linear mixed models, and compared by World Health Organization region. Density (i.e. annual ischemic heart disease [IHD] incidence estimate from Global Burden of Disease study divided by national CR capacity) was computed.FindingsCR was available in 111/203 (54.7%) countries; data were collected in 93 (83.8% country response; N?=?1082 surveys, 32.1% program response rate). Availability by region ranged from 80.7% of countries in Europe, to 17.0% in Africa (p

Classification of current anticancer immunotherapies

During the past decades, anticancer immunotherapy has evolved from a promising therapeutic option to a robust clinical reality. Many immunotherapeutic regimens are now approved by the US Food and Drug Administration and the European Medicines Agency for use in cancer patients, and many others are being investigated as standalone therapeutic interventions or combined with conventional treatments in clinical studies. Immunotherapies may be subdivided into “passive” and “active” based on their ability to engage the host immune system against cancer. Since the anticancer activity of most passive immunotherapeutics (including tumor-targeting monoclonal antibodies) also relies on the host immune system, this classification does not properly reflect the complexity of the drug-host-tumor interaction. Alternatively, anticancer immunotherapeutics can be classified according to their antigen specificity. While some immunotherapies specifically target one (or a few) defined tumor-associated antigen(s), others operate in a relatively non-specific manner and boost natural or therapy-elicited anticancer immune responses of unknown and often broad specificity. Here, we propose a critical, integrated classification of anticancer immunotherapies and discuss the clinical relevance of these approaches