Causes of genome instability: the effect of low dose chemical exposures in modern society.

Genome instability is a prerequisite for the development of cancer. It occurs when genome maintenance systems fail to safeguard the genome's integrity, whether as a consequence of inherited defects or induced via exposure to environmental agents (chemicals, biological agents and radiation). Thus, genome instability can be defined as an enhanced tendency for the genome to acquire mutations; ranging from changes to the nucleotide sequence to chromosomal gain, rearrangements or loss. This review raises the hypothesis that in addition to known human carcinogens, exposure to low dose of other chemicals present in our modern society could contribute to carcinogenesis by indirectly affecting genome stability. The selected chemicals with their mechanisms of action proposed to indirectly contribute to genome instability are: heavy metals (DNA repair, epigenetic modification, DNA damage signaling, telomere length), acrylamide (DNA repair, chromosome segregation), bisphenol A (epigenetic modification, DNA damage signaling, mitochondrial function, chromosome segregation), benomyl (chromosome segregation), quinones (epigenetic modification) and nano-sized particles (epigenetic pathways, mitochondrial function, chromosome segregation, telomere length). The purpose of this review is to describe the crucial aspects of genome instability, to outline the ways in which environmental chemicals can affect this cancer hallmark and to identify candidate chemicals for further study. The overall aim is to make scientists aware of the increasing need to unravel the underlying mechanisms via which chemicals at low doses can induce genome instability and thus promote carcinogenesis

Association Between Plasma Levels of Fibrinogen and the Presence and Severity of Coronary Artery Ectasia

Objective The aim of this study was to investigate the plasma fibrinogen levels in patients with isolated coronary artery ectasia (CAE).Materialsand MethodsThe study population included 154 patients, of whom 52 had isolated CAE, 52 had stable coronary artery disease (CAD) and 50 had normal coronary arteries (NCA). Theseverity of isolated CAE was determined using the Markis classification. All the subjects underwent complete physical examinations, including a detailed medical history,complete blood count and biochemical parameters. Plasma fibrinogen levels also were measured in all subjects.Results The baseline characteristics of the three groups were similar. Plasma fibrinogen levels were significantly higher in the CAE group and CAD group than in the NCA group(383.3 ± 53.0 mg/dl and 400.8 ± 50.6 mg/dl vs 324.0 ± 56.4 respectively, p 325 mg/dl identified patientswith isolated CAE.Conclusions Plasma fibrinogen is an easily measurable systemic inflammatory biomarker that is independently associated with CAE presence and severity. This suggests that fibrinogenmay be involved in the pathophysiology of CAE.Amaç Bu çalışmanın amacı izole koroner arter ektazisi (KAE) olan hastalarda plazma fibrinojen düzeylerini araştırmaktı. Gereç ve Yöntemler Çalışma popülasyonunda 52’si izole KAE, 52’sinde koroner arter hastalığı (KAH) ve 50’sinde normal koroner arter (NKA) bulunan 154 hasta vardı. İzole KAE ciddiyeti Markis sınıflandırması kullanılarak belirlendi. Tüm hastalardan ayrıntılı tıbbi öykü alındı ve eksiksiz fizik muayene yapıldı. Tam kan sayımı ve biyokimyasal parametreler değerlendirildi. Tüm hastaların plazma fibrinojen düzeyleri de ölçüldü. Bulgular Üç grubun temel özellikleri benzerdi. Plazma fibrinojen düzeyleri KAE grubunda ve KAH grubunda NKA grubuna göre anlamlı derecede yüksekti (sırasıyla 383.3 ± 53.0 mg / dl ve 400.8 ± 50.6 mg / dl vs 324.0 ± 56.4, p 325 mg / dl olmasının KAE hastalarını tanımladığı saptandı. Sonuç Plazma fibrinojeni; KAE varlığı ve şiddeti ile bağımsız bir şekilde ilişkili olan, kolayca ölçülebilen sistemik inflamatuar bir biyobelirteçtir. Bu sonuçlar, fibrinojenin KAE patofizyolojisinde rol oynayabileceğini göstermektedir

Protein O-GlcNAcylation Promotes Trophoblast Differentiation at Implantation

Embryo implantation begins with blastocyst trophectoderm (TE) attachment to the endometrial epithelium, followed by the breaching of this barrier by TE-derived trophoblast. Dynamic protein modification with O-linked β-N-acetylglucosamine (O-GlcNAcylation) is mediated by O-GlcNAc transferase and O-GlcNAcase (OGA), and couples cellular metabolism to stress adaptation. O-GlcNAcylation is essential for blastocyst formation, but whether there is a role for this system at implantation remains unexplored. Here, we used OGA inhibitor thiamet g (TMG) to induce raised levels of O-GlcNAcylation in mouse blastocysts and human trophoblast cells. In an in vitro embryo implantation model, TMG promoted mouse blastocyst breaching of the endometrial epithelium. TMG reduced expression of TE transcription factors Cdx2, Gata2 and Gata3, suggesting that O-GlcNAcylation stimulated TE differentiation to invasive trophoblast. TMG upregulated transcription factors OVOL1 and GCM1, and cell fusion gene ERVFRD1, in a cell line model of syncytiotrophoblast differentiation from human TE at implantation. Therefore O-GlcNAcylation is a conserved pathway capable of driving trophoblast differentiation. TE and trophoblast are sensitive to physical, chemical and nutritive stress, which can occur as a consequence of maternal pathophysiology or during assisted reproduction, and may lead to adverse neonatal outcomes and associated adult health risks. Further investigation of how O-GlcNAcylation regulates trophoblast populations arising at implantation is required to understand how peri-implantation stress affects reproductive outcomes

Don’t abandon RCTs in IVF. We don’t even understand them

The conclusion of the Human Fertilisation and Embryology Authority that 'add-on' therapies in IVF are not supported by high-quality evidence has prompted new questions regarding the role of the randomized controlled trial (RCT) in evaluating infertility treatments. Critics argue that trials are cumbersome tools that provide irrelevant answers. Instead, they argue that greater emphasis should be placed on large observational databases, which can be analysed using powerful algorithms to determine which treatments work and for whom. Although the validity of these arguments rests upon the sciences of statistics and epidemiology, the discussion to date has largely been conducted without reference to these fields. We aim to remedy this omission, by evaluating the arguments against RCTs in IVF from a primarily methodological perspective. We suggest that, while criticism of the status quo is warranted, a retreat from RCTs is more likely to make things worse for patients and clinicians