Since the first cloning of BRCA1 in 1994, many of its cellular interactions have been elucidated. However, its highly specific role in tumorigenesis in the breast tissue—carriers of BRCA1 mutations are predisposed to life-time risks of up to 80%—relative to many other tissues that remain unaffected, has not yet been fully enlightened. In this article, we have applied a universal model of tissue-specificity of cancer genes to BRCA1 and present a systematic review of proposed concepts classified into 4 categories. Firstly, tissue-specific differences in levels of BRCA1 expression and secondly differences in expression of proteins with redundant functions are outlined. Thirdly, cell-type specific interactions of BRCA1 are presented: its regulation of aromatase, its interaction with Progesterone- and receptor activator of nuclear factor-κB ligand-signaling that controls proliferation of luminal progenitor cells, and its influence on cell differentiation via modulation of the key regulators jagged 1-NOTCH and snail family transcriptional repressor 2. Fourthly, factors specific to the cell-type as well as the environment of the breast tissue are elucidated: distinct frequency of losses of heterozygosity, interaction with X inactivation specific transcript RNA, estrogen-dependent induction of genotoxic metabolites and nuclear factor (erythroid-derived 2)-like 2, and regulation of sirtuin 1. In conclusion, the impact of these concepts on the formation of hormone-sensitive and -insensitive breast tumors is outlined.
Mutation of the isocitrate-dehydrogenase (IDH) enzymes is one of the central research topics regarding gliomagenesis. Indeed, 70% of gliomas are associated with a gain-of-function IDH mutation and consequently synthesize the oncometabolite, 2-hydroxyglutarate (2-HG). This review aims to elucidate the effects of 2-HG on gliomagenesis. 2-HG promotes tumorigenesis by impacting metabolism, vascularization and altering the epigenome of glioma cells. Glioma metabolism and vascularization is altered by 2-HG’s effect on the stability of hypoxia-inducible factor (HIF) and inhibition of endostatin. However, 2-HG’s impacts on epigenetic mechanisms are more profound to gliomagenesis. Through competitive inhibition of JHDMs and TET proteins, 2-HG orchestrates histone and DNA hypermethylation, which is associated with gene silencing and dedifferentiation of cells. The hypermethylator phenotype induced by 2-HG also results in alterations of the interaction of the immune system with the tumour. Additionally, this study reviews 2-HG promotion of tumorigenesis by inhibiting repair of DNA alkylation damage through competitive inhibition of AlkB proteins.
Purpose of Review The high burden of cardiovascular disease and the simultaneous obesity pandemic is placing an extraordinary strain on the health care system. In the current siloed care model, patients with cardiometabolic disease receive only fractionated care from multiple specialists, leading to insufficient treatment, higher costs, and worse outcomes. Recent Findings The imminent need for a new care model calls for the creation of a distinct cardiometabolic specialty in conjunction with a cardiometabolic outpatient clinic dedicated to the comprehensive cardiometabolic care. The cardiometabolic clinic would consist of a diverse range of professionals relevant to comprehensive treatment. Summary The outpatient clinic we envision here would facilitate an interdisciplinary collaboration between specialists and deliver prevention-focused treatment to patients at risk/established cardiometabolic disease.
Cardiovascular disease (CVD) remains the leading cause of mortality in the United States, and the population of patients with cardiometabolic conditions, including obesity, metabolic syndrome and diabetes mellitus, continues to grow. There is a need for physicians with specific training in cardiometabolic medicine to provide a ‘medical home’ for patients with cardiometabolic disease, rather than the fractured care that currently exists in the United States. Cardiometabolic specialists will head multidisciplinary clinics, develop practice guidelines, and lead through research. Proposals for US training in cardiometabolic medicine include: maintain the current training model, a dedicated 2–3 year fellowship following internal medicine residency, a 1-year fellowship following either internal medicine residency or fellowship in cardiology or endocrinology, and certification available to any interested clinician. This review discusses the pros and cons of these approaches. The authors believe that a dedicated cardiometabolic training fellowship has significant advantages over the other options.
The high prevalence of cardiovascular disease and worldwide diabetes epidemic has created an ever-increasing burden on the healthcare system. This calls for the creation of a new medicine subspecialty: cardiometabolic medicine. Using information from review articles listed on PubMed and professional society guidelines, the authors advocate for a cardiometabolic medicine specialization training program. The curriculum would integrate relevant knowledge and skills of cardiology and endocrinology as well as content of other disciplines essential to the optimal care of cardiometabolic patients, such as epidemiology, biostatistics, behavioral science and psychology. Cardiometabolic medicine should be seen as an opportunity for life-long learning, with core concepts introduced in medical school and continuing through CME courses for practicing physicians. To improve care for complex patients with multiple co-morbidities, a paradigm shift must occur, transforming siloed education, and treatment and training to interdisciplinary and collaborative work.
Context The worldwide rise in the prevalence of cardiometabolic disease, and the introduction of therapeutic options for treating metabolic disease that also lower cardiovascular risk, calls for a restructuring of how we care for patients with cardiometabolic disease. We propose establishment of a new medicine subspecialty, Cardiometabolic Medicine. Evidence Acquisition This summary is based on a synthesis of published original and review articles identified through PubMed, professional society guidelines, and the authors’ knowledge of the fields of metabolism, diabetes, and cardiology. Evidence Synthesis The growing prevalence of cardiometabolic disease will continue to be perhaps the greatest challenge in the United States and throughout the world. We have entered an era where a large set of clinical tools are available that help prevent and treat cardiometabolic disease; however, our old models of clinical training and siloed care are barriers to rapid uptake and efficient healthcare delivery and are in need of change. Conclusions Establishing the field of Cardiometabolic Medicine would be a small step in the right direction towards providing the best possible comprehensive care for those with complex cardiometabolic disease.
Background The relation between cardiorespiratory fitness (CRF) and prostate cancer is not well established. The objective of this study was to determine whether CRF is associated with prostate cancer screening, incidence, or mortality. Methods The Henry Ford Exercise Testing Project is a retrospective cohort study of men aged 40 to 70 years without cancer who underwent physician‐referred exercise stress testing from 1995 to 2009. CRF was quantified in metabolic equivalents of task (METs) (<6 [reference], 6‐9, 10‐11, and ≥12 METs), estimated from the peak workload achieved during a symptom‐limited, maximal exercise stress test. Prostate‐specific antigen (PSA) testing, incident prostate cancer, and all‐cause mortality were analyzed with multivariable adjusted Poisson regression and Cox proportional hazard models. Results In total, 22,827 men were included, of whom 739 developed prostate cancer, with a median follow‐up of 7.5 years. Men who had high fitness (≥12 METs) had an 28% higher risk of PSA screening (95% CI, 1.2‐1.3) compared with those who had low fitness (<6 METs. After adjusting for PSA screening, fitness was associated with higher prostate cancer incidence (men aged <55 years, P = .02; men aged >55 years, P ≤ .01), but not with advanced prostate cancer. Among the men who were diagnosed with prostate cancer, high fitness was associated with a 60% lower risk of all‐cause mortality (95% CI, 0.2‐0.9). Conclusions Although men with high fitness are more likely to undergo PSA screening, this does not fully account for the increased incidence of prostate cancer seen among these individuals. However, men with high fitness have a lower risk of death after a prostate cancer diagnosis, suggesting that the cancers identified may be low‐risk with little impact on long‐term outcomes.
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