Plasma D-dimer and FDP are promising biomarkers to predict perioperative fibrinolysis and bleeding following primary total joint arthroplasty: A STROBE compliant article

Perioperative bleeding is associated with postoperative hyperfibrinolysis caused by surgical trauma in the setting of total hip and knee arthroplasty (THA/ TKA). The study aimed to clarify the dynamics of postoperative fibrinolytic activity and the values of fibrin degeneration products and thromboelastography (TEG) to guide precisive antifibrinolytic therapy.Forty three patients undergoing primary unilateral THAs and 40 TKAs were included to the prospective observational cohort study. Venous blood sample at different time points (preoperative, intraoperative, postoperative 6 hours, 12 hours, 24 hours, 48 hours) were drawn to test D-dimer, fibrin (-ogen) degradation products (FDP) and TEG.The TEG parameters associated with coagulation (R, K, α, MA, and CI) and fibrinolysis (estimate percent lysis and Ly30) were all in normal range although had a higher level than preoperative time (P < .05). The postoperative levels of D-dimer and FDP were higher than preoperative level (P < .05). The dynamics of D-dimer and FDP presented a bimodal pattern, which peaked at 6 hours postoperatively, then remained and decreased until 24 hours, but would rebound at 48 hours postoperatively with smaller amplitude. Moreover, FDP_6h (P = .028), D-Dimer_6h (P = .044), FDP_12h (P = .009), D-dimer_12h (P = .007), and FDP_48h (P = .016) were all correlated with total blood loss on POD3.FDP and D-dimer were effective and practical markers for prediction of acute postoperative fibrinolytic activity, which peaked at 6 hours after end of surgery and would maintain for at least 24 hours.     

Comparative assessment of in vitro and in vivo toxicity of azinphos methyl and its commercial formulation

The toxic effects of Gusathion (GUS), which is a commercial organophosphate (OP) pesticide, and also its active ingredient, azinphos methyl (AzM), are evaluated comparatively with in vitro and in vivo studies. Initially, the 96‐h LC₅₀ values of AzM and GUS were estimated for two different life stages of Xenopus laevis, embryos, and tadpoles. The actual AzM concentrations in exposure media were monitored by high‐performance liquid chromatography. Also, the sub‐lethal effects of these compounds to tadpoles were determined 24 h later at exposure concentrations of 0.1 and 1 mg/L using selected biomarker enzymes such as acetylcholinesterase (AChE), carboxylesterase (CaE), glutathione S‐transferase (GST), glutathione reductase, lactate dehydrogenase, and aspartate aminotrasferase. Differences in AChE inhibition capacities of AzM and GUS were evaluated under in vitro conditions between frogs and fish in the second part of this study. The AChE activities in a pure electrical eel AChE solution and in brain homogenates of adult Cyprinus carpio, Pelophylax ridibundus, and X. laevis were assayed after in vitro exposure to 0.05, 0.5, 5, and 50 mg/L concentrations of AzM and GUS. According to in vivo studies AChE, CaE and GST are important biomarkers of the effect of OP exposure while CaE may be more effective in short‐term, low‐concentration exposures. The results of in vitro studies showed that amphibian brain AChEs were relatively more resistant to OP exposure than fish AChEs. The resistance may be the cause of the lower toxicity/lethality of OP compounds to amphibians than to fish. © 2014 Wiley Periodicals, Inc. Environ Toxicol 30: 1091–1101, 2015.     

Effect of trifloxystrobin on hatching,survival, and gene expression of endocrine biomarkers in early life stages of medaka (Oryzias latipes)

Trifloxystrobin is a systemic broad‐spectrum foliar strobilurin fungicides that enters the aquatic environment during agricultural application. It is highly toxic and poses a potential risk to aquatic organisms, whereas the effect on the development of early life stages of fish are unclear. In this study, hatchability, time to hatching, and larval mortality were measured. Additionally, the expression of biomarker genes, including those involved in sex hormone pathways (er, vtg, cyp17, and cyp19a), thyroid hormone pathways (trα and dio2), and aryl hydrocarbon receptor pathways (ahr and cyp1a), was determined after embryos of medaka (Oryzias latipes) were exposed to different levels of trifloxystrobin (0, 0.1, 1, 10, and 100 μg/L) for 28 days. The results showed that there were significant differences between controls and the 100 μg/L treatment group in both hatchability and time to hatching of fertilized eggs (p < 0.05). Larval mortality was significantly increased in the 0.1, 1, and 10 μg/L treatment groups (p < 0.05). These results indicate that embryonic and larval development may be affected by trifloxystrobin exposure. Moreover, the mRNA levels of the er gene were significantly up‐regulated at levels of trifloxystrobin above 1 μg/L treatment groups. Up‐regulation of vtg, cyp17, and cyp19a mRNA levels was observed in the larvae at the lower concentration treatment groups. The mRNA levels of cyp1a genes were significantly up‐regulated at all of the treatment groups. These results suggest that trifloxystrobin is a potential endocrine disruptor through effects on the sex hormone pathway and xenobiotic metabolism. The changes in cyp1a expression can be used as a highly sensitive biomarker to assess trifloxystrobin contamination in the early life stages of fish. © 2013 Wiley Periodicals, Inc. Environ Toxicol 30: 648–655, 2015.     

Extensive analysis of the molecular biomarkers excision repair cross complementing 1, ribonucleotide reductase M1, β-tubulin III,thymidylate synthetase,and topoisomerase IIα in breast cancer: Association with clinicopathological characteristics

Excision repair cross complementing 1 (ERCC1), ribonucleotide reductase M1 (RRM1), β-tubulin III (TUBB3), thymidylate synthetase (TYMS), and topoisomerase IIα (TOP2A) genes have been shown to be associated with the pathogenesis and prognosis of various types of carcinomas; however, their roles in breast cancer have not been fully validated. In this study, we evaluated the correlations among these biomarkers and the associations between their expression intensity and the clinicopathological characteristics to investigate whether the above genes are underlying biomarkers for patients with breast cancer.Ninety-seven tissue specimens collected from breast cancer patients. The expression levels of these biomarkers were measured by the multiplex branched DNA liquidchip (MBL) technology and clinicopathological characteristics were collected simultaneously.The expression levels of ERCC1, TUBB3, TYMS, and TOP2A were significantly associated with the characteristics of menopausal status, tumor size, lymph node metastasis, hormone receptor status, triple-negative status, Ki-67 index, and epidermal growth factor receptor. The expression intensity of ERCC1 negatively associated with that of TUBB3 and TYMS, and positively associated with that of RRM1. The expression intensity of TOP2A positively associated with that of TYMS. Hierarchical clustering analysis and difference test indicated that breast cancer with higher levels of TUBB3, TYMS, and TOP2A, as well as lower levels of ERCC1 and RRM1 tended to have higher histological grade and Ki-67 index.Our studies showed that ERCC1, TYMS, TUBB3, and TOP2A may be potential biomarkers for prognosis and individualized chemotherapy guidance, while there may be interactions between ERCC1 and RRM1, or TUBB3, or TYMS, as well as between TOP2A and TYMS in pathogenesis and development of breast cancer.     

Evolution of bacterial steroid biosynthesis and its impact on eukaryogenesis

Steroids are components of the eukaryotic cellular membrane and have indispensable roles in the process of eukaryotic endocytosis by regulating membrane fluidity and permeability. In particular, steroids may have been a structural prerequisite for the acquisition of mitochondria via endocytosis during eukaryogenesis. While eukaryotes are inferred to have evolved from an archaeal lineage, there is little similarity between the eukaryotic and archaeal cellular membranes. As such, the evolution of eukaryotic cellular membranes has limited our understanding of eukaryogenesis. Despite evolving from archaea, the eukaryotic cellular membrane is essentially a fatty acid bacterial-type membrane, which implies a substantial bacterial contribution to the evolution of the eukaryotic cellular membrane. Here, we address the evolution of steroid biosynthesis in eukaryotes by combining ancestral sequence reconstruction and comprehensive phylogenetic analyses of steroid biosynthesis genes. Contrary to the traditional assumption that eukaryotic steroid biosynthesis evolved within eukaryotes, most steroid biosynthesis genes are inferred to be derived from bacteria. In particular, aerobic deltaproteobacteria (myxobacteria) seem to have mediated the transfer of key genes for steroid biosynthesis to eukaryotes. Analyses of resurrected steroid biosynthesis enzymes suggest that the steroid biosynthesis pathway in early eukaryotes may have been similar to the pathway seen in modern plants and algae. These resurrected proteins also experimentally demonstrate that molecular oxygen was required to establish the modern eukaryotic cellular membrane during eukaryogenesis. Our study provides unique insight into relationships between early eukaryotes and other bacteria in addition to the well-known endosymbiosis with alphaproteobacteria.

The emergence of modern eukaryotic cells from their archaeal ancestor requires multiple evolutionary steps, most notably the acquisition of mitochondria, nucleus, endomembrane system, and bacterial-like cellular membranes. The acquisition of mitochondria by early eukaryotes before the last eukaryotic common ancestor (LECA) would have been a key step to exploit new resources within an aerobic environment (1). Similarly, the transformation of the eukaryotic cellular membrane system from an archaeal-type to bacterial-type membrane would have also been crucial to develop the dynamic cellular membrane system observed in modern eukaryotes (2). Such a dynamic membrane may have been the prerequisite for a pre-LECA cell to perform endocytosis and, hence, later acquire organelles such as mitochondria and chloroplasts. While the tetraether monolayer membrane in archaea is more rigid and is advantageous to harsh environments, such as high temperature and low pH conditions, the diester bilayer membrane found in bacteria and eukaryotes has been suggested to be adaptable to more general environments (3). Recent phylogenomic analyses of archaea and eukaryotes suggest that eukaryotes evolved from within the archaeal domain (4, 5). However, there is little similarity between the archaeal and the bacterial/eukaryotic cellular membranes. Both the stereochemistry of lipid molecules (i.e., phospholipids) and their lipid composition (e.g., fatty acid chain versus isoprenoid chain and the presence of sphingolipids and steroids) are fundamentally different between the two types of membranes. As such, the evolutionary history of the eukaryotic cellular membrane is a major gap in our understanding of eukaryogenesis (6).Here, we focus on the evolution of the steroid component of the eukaryotic cellular membrane. Steroids have indispensable roles in the process of eukaryotic endocytosis because they are embedded in the cellular membrane and are known to regulate membrane fluidity and permeability (7–9). Thus, steroids may also have been integral for the endocytic process to acquire mitochondria during eukaryogenesis. Steroids would also function as hormones to control various cellular processes, including differentiation, morphogenesis, and homeostasis to enable multicellularity (10). In addition to the vital biochemical role in modern eukaryotes, steroids also have a geobiological importance. They can serve as unique biological markers (biomarkers) for eukaryotes in the geological record and thus provide clues to trace the evolutionary history of eukaryotes on a geological time scale. Membrane-bound steroids are modified in a unique manner within each eukaryotic taxon. For instance, cholesterol is a major component of cellular membrane in metazoans, whereas stigmasterol is a major component in plants (11, 12). These taxon-specific modifications can be used as taxonomic markers in the geological record (13–15). No analogous steroid biosynthesis pathway has been observed in archaea and thus steroid biosynthesis is generally inferred to have evolved de novo within eukaryotes (16). Despite this inference, some bacteria are known to produce hopanoids that are structurally similar to steroids (17). Indeed, several genes that are involved in hopanoid and steroid biosynthesis are suggested to have been horizontally transferred from bacteria to eukaryotes (18, 19). These recent observations suggest a more complex evolutionary history of steroid biosynthesis in eukaryotes. Ancestral sequence reconstruction (ASR) enables us to experimentally analyze resurrected enzymes (20, 21) and thus infer evolutionary histories of steroid biosynthesis and their impacts on eukaryogenesis.     

MiR-122 and other microRNAs as potential circulating biomarkers of drug-induced liver injury

Introduction: Drug-induced liver injury (DILI) is a severe adverse drug reaction which is of major concern to patients, clinicians and the pharmaceutical industry. Accurate and rapid detection of DILI is important for patient stratification and treatment in the clinic and benefits preclinical drug design and risk assessment. MicroRNAs (miRNAs) offer a potential new and improved class of circulating biomarkers of DILI over the current gold standard biomarkers.

Areas covered: This review highlights the shortcomings of the currently used panel of biomarkers and how miRNAs, primarily miR-122, show an improved level of specificity and sensitivity in the prediction of DILI. Furthermore, the use of miRNAs as potential markers of progression of DILI and specific zonated damage within the liver is discussed.

Expert commentary: MiRNAs offer more sensitive and specific markers over the current biomarkers for DILI. Combinations of different miRNAs may be able to relay the location of DILI and the progression of disease. More studies using different hepatotoxins apart from acetaminophen will ultimately strengthen the case for the clinical introduction of miRNAs as biomarkers of DILI.     

Predictive biomarkers for the treatment of resectable esophageal and esophago-gastric junction adenocarcinoma: from hypothesis generation to clinical validation

Introduction: Esophageal and esophago-gastric junction (EGJ) adenocarcinomas remain a major health problem worldwide with a worryingly increasing incidence. Recent trials indicate survivals benefit for preoperative or perioperative chemoradiotherapy compared to surgery alone. Beside standard chemoradiotherapy regimens, new therapeutic approaches with targeted therapies have been proposed for the treatment of resectable disease. However, clinical outcomes remain extremely poor due to drug resistance phenomena. The failure of these approaches could be partially ascribed to their incorrect application in patients. Therefore, the identification of strong biomarkers for optimal patient management is urgently needed.

Areas covered: This review aims to summarize and critically discuss the most relevant findings regarding predictive biomarker development for neoadjuvant treatment of resectable esophageal and esophago-gastric junction adenocarcinoma patients.

Expert commentary: Optimizing the currently available therapeutic modalities through a more accurate selection of patients may avoid the use of ineffective and potentially toxic treatments. During the last decade, the advent of high-throughput ‘-omics’ technologies has set the basis for a new biomarker discovery approach from ‘molecule by molecule’ screening towards a large-scale systematic screening process with exponential increases in putative biomarkers, which often failed to provide adequate clinical validation.