Identification of the additional mitochondrial liabilities of 2-hydroxyflutamide when compared to its parent compound, flutamide in HepG2 cells

The androgen receptor antagonist, flutamide, is strongly associated with idiosyncratic drug-induced liver injury (DILI). Following administration, flutamide undergoes extensive first-pass metabolism to its primary metabolite, 2-hydroxyflutamide. Flutamide is a known mitochondrial toxicant; however there has been limited investigation into the potential mitochondrial toxicity of 2-hydroxyflutamide and its contribution to flutamide-induced liver injury. In this study we have used the acute glucose or galactose-conditioning of HepG2 cells to compare the mitochondrial toxicity of flutamide, 2-hydroxyflutamide and the structurally-related, non-hepatotoxic androgen receptor antagonist, bicalutamide. Compound-induced changes in mitochondrial oxygen consumption rate were assessed using Seahorse technology. Permeabilization of cells and delivery of specific substrates and inhibitors of the various respiratory complexes provided more detailed information on the origin of mitochondrial perturbations. These analyses were supported by assessment of downstream impacts including changes in cellular NAD+/NADH ratio. Bicalutamide was not found to be a mitochondrial toxicant, yet flutamide and 2-hydroxyflutamide significantly reduced basal and maximal respiration. Both flutamide and 2-hydroxyflutamide significantly reduced respiratory complex I-linked respiration, though 2-hydroxyflutamide also significantly decreased complex II and V-linked respiration; liabilities not demonstrated by the parent compound. This study has identified for the first time, the additional mitochondrial liabilities of the major metabolite, 2-hydroxyflutamide compared with its parent drug, flutamide. Given the rapid production of this metabolite upon administration of flutamide, but not bicalutamide, we propose that the additional mitochondrial toxicity of 2-hydroxyflutamide may fundamentally contribute to the idiosyncratic DILI seen in flutamide-treated, but not bicalutamide-treated patients

Nonlinear Fourier transform for optical data processing and transmission:advances and perspectives

Fiber-optic communication systems are nowadays facing serious challenges due to the fast growing demand on capacity from various new applications and services. It is now well recognized that nonlinear effects limit the spectral efficiency and transmission reach of modern fiber-optic communications. Nonlinearity compensation is therefore widely believed to be of paramount importance for increasing the capacity of future optical networks. Recently, there has been steadily growing interest in the application of a powerful mathematical tool-the nonlinear Fourier transform (NFT)-in the development of fundamentally novel nonlinearity mitigation tools for fiber-optic channels. It has been recognized that, within this paradigm, the nonlinear crosstalk due to the Kerr effect is effectively absent, and fiber nonlinearity due to the Kerr effect can enter as a constructive element rather than a degrading factor. The novelty and the mathematical complexity of the NFT, the versatility of the proposed system designs, and the lack of a unified vision of an optimal NFT-type communication system, however, constitute significant difficulties for communication researchers. In this paper, we therefore survey the existing approaches in a common framework and review the progress in this area with a focus on practical implementation aspects. First, an overview of existing key algorithms for the efficacious computation of the direct and inverse NFT is given, and the issues of accuracy and numerical complexity are elucidated. We then describe different approaches for the utilization of the NFT in practical transmission schemes. After that we discuss the differences, advantages, and challenges of various recently emerged system designs employing the NFT, as well as the spectral efficiency estimates available up-to-date. With many practical implementation aspects still being open, our mini-review is aimed at helping researchers assess the perspectives, understand the bottlenecks, and envision the development paths in the upcoming NFT-based transmission technologies

Multi-Band Programmable Gain Raman Amplifier

Optical communication systems, operating in C-band, are reaching their theoretically achievable capacity limits. An attractive and economically viable solution to satisfy the future data rate demands is to employ the transmission across the full low-loss spectrum encompassing O, E, S, C, and L band of the single mode fibers (SMF). Utilizing all five bands offers a bandwidth of up to sim53.5 THz (365 nm) with loss below 0.4 dB/km. A key component in realizing multi-band optical communication systems is the optical amplifier. Apart from having an ultra-wide gain profile, the ability of providing arbitrary gain profiles, in a controlled way, will become an essential feature. The latter will allow for signal power spectrum shaping which has a broad range of applications such as the maximization of the achievable information rate × distance product, the elimination of static and lossy gain flattening filters (GFF) enabling a power efficient system design, and the gain equalization of optical frequency combs. In this paper, we experimentally demonstrate a multi-band (S+C+L) programmable gain optical amplifier using only Raman effects and machine learning. The amplifier achieves >1000 programmable gain profiles within the range 3.5 to 30 dB, in an ultra-fast way and a very low maximum error of 1.6 cdot 10{-2} dB/THz over an ultra-wide bandwidth of 17.6-THz (140.7-nm)

The Intracellular Localization of ID2 Expression Has a Predictive Value in Non Small Cell Lung Cancer

ID2 is a member of a subclass of transcription regulators belonging to the general bHLH (basic-helix-loophelix) family of transcription factors. In normal cells, ID2 is responsible for regulating the balance between proliferation and differentiation. More recent studies have demonstrated that ID2 is involved in tumor progression in several cancer types such as prostate or breast

Mechanistic evaluation of primary human hepatocyte culture using global proteomic analysis reveals a selective dedifferentiation profile

© 2016 The Author(s)The application of primary human hepatocytes following isolation from human tissue is well accepted to be compromised by the process of dedifferentiation. This phenomenon reduces many unique hepatocyte functions, limiting their use in drug disposition and toxicity assessment. The aetiology of dedifferentiation has not been well defined, and further understanding of the process would allow the development of novel strategies for sustaining the hepatocyte phenotype in culture or for improving protocols for maturation of hepatocytes generated from stem cells. We have therefore carried out the first proteomic comparison of primary human hepatocyte differentiation. Cells were cultured for 0, 24, 72 and 168 h as a monolayer in order to permit unrestricted hepatocyte dedifferentiation, so as to reveal the causative signalling pathways and factors in this process, by pathway analysis. A total of 3430 proteins were identified with a false detection rate of <1 %, of which 1117 were quantified at every time point. Increasing numbers of significantly differentially expressed proteins compared with the freshly isolated cells were observed at 24 h (40 proteins), 72 h (118 proteins) and 168 h (272 proteins) (p < 0.05). In particular, cytochromes P450 and mitochondrial proteins underwent major changes, confirmed by functional studies and investigated by pathway analysis. We report the key factors and pathways which underlie the loss of hepatic phenotype in vitro, particularly those driving the large-scale and selective remodelling of the mitochondrial and metabolic proteomes. In summary, these findings expand the current understanding of dedifferentiation should facilitate further development of simple and complex hepatic culture systems

Non-puerperal uterine inversion: A case report

A rare case of non-puerperal uterine inversion caused by a large fundal leiomyoma in a 39-year nulliparous, infertile woman resulting in intractable hemorrhage was reported after a myomectomy. Attempts to reduce the inversion vaginally by transecting the anterior and posterior cervix were unsuccessful and a laparotomy was performed. The inversion was not successfully corrected and hysterectomy was done

Data from: Identification of the additional mitochondrial liabilities of 2-hydroxyflutamide when compared to its parent compound, flutamide in HepG2 cells

The androgen receptor antagonist, flutamide, is strongly associated with idiosyncratic drug-induced liver injury (DILI). Following administration, flutamide undergoes extensive first-pass metabolism to its primary metabolite, 2-hydroxyflutamide. Flutamide is a known mitochondrial toxicant; however there has been limited investigation into the potential mitochondrial toxicity of 2-hydroxyflutamide and its contribution to flutamide-induced liver injury. In this study we have used the acute glucose or galactose-conditioning of HepG2 cells to compare the mitochondrial toxicity of flutamide, 2-hydroxyflutamide and the structurally-related, non-hepatotoxic androgen receptor antagonist, bicalutamide. Compound-induced changes in mitochondrial oxygen consumption rate were assessed using Seahorse technology. Permeabilization of cells and delivery of specific substrates and inhibitors of the various respiratory complexes provided more detailed information on the origin of mitochondrial perturbations. These analyses were supported by assessment of downstream impacts including changes in cellular NAD+/NADH ratio. Bicalutamide was not found to be a mitochondrial toxicant, yet flutamide and 2-hydroxyflutamide significantly reduced basal and maximal respiration. Both flutamide and 2-hydroxyflutamide significantly reduced respiratory complex I-linked respiration, though 2-hydroxyflutamide also significantly decreased complex II and V-linked respiration; liabilities not demonstrated by the parent compound. This study has identified for the first time, the additional mitochondrial liabilities of the major metabolite, 2-hydroxyflutamide compared with its parent drug, flutamide. Given the rapid production of this metabolite upon administration of flutamide, but not bicalutamide, we propose that the additional mitochondrial toxicity of 2-hydroxyflutamide may fundamentally contribute to the idiosyncratic DILI seen in flutamide-treated, but not bicalutamide-treated patients

Imaging Biomarkers for Intra-arterial Stroke Therapy

Despite high rates of early revascularization with intra-arterial stroke therapy, the clinical efficacy of this approach has not been clearly demonstrated. Neuroimaging biomarkers will be useful in future trials for patient selection and for outcomes evaluation. To identify patients who are likely to benefit from intra-arterial therapy, the combination of vessel imaging, infarct size quantification and degree of neurologic deficit appears critical. Perfusion imaging may be useful in specific circumstances, but requires further validation. For measuring treatment outcomes, surrogate biomarkers that appear suitable are angiographic reperfusion as measured by the modified Thrombolysis in Cerebral Infarction scale and final infarct volum