The Emergent Landscape of Detecting EGFR Mutations Using Circulating Tumor DNA in Lung Cancer.

The advances in targeted therapies for lung cancer are based on the evaluation of specific gene mutations especially the epidermal growth factor receptor (EGFR). The assays largely depend on the acquisition of tumor tissue via biopsy before the initiation of therapy or after the onset of acquired resistance. However, the limitations of tissue biopsy including tumor heterogeneity and insufficient tissues for molecular testing are impotent clinical obstacles for mutation analysis and lung cancer treatment. Due to the invasive procedure of tissue biopsy and the progressive development of drug-resistant EGFR mutations, the effective initial detection and continuous monitoring of EGFR mutations are still unmet requirements. Circulating tumor DNA (ctDNA) detection is a promising biomarker for noninvasive assessment of cancer burden. Recent advancement of sensitive techniques in detecting EGFR mutations using ctDNA enables a broad range of clinical applications, including early detection of disease, prediction of treatment responses, and disease progression. This review not only introduces the biology and clinical implementations of ctDNA but also includes the updating information of recent advancement of techniques for detecting EGFR mutation using ctDNA in lung cancer

Coronary artery disease in dialysis patients: What is the optimal therapy?

AbstractCoronary artery disease (CAD) carries a high risk of mortality in dialysis patients. End-stage renal disease is considered to increase the vulnerability of patients with atherosclerosis superimposed on artery calcification. Recently, an increasing prevalence of CAD in dialysis patients has been attributed to a lack of effective prevention and treatment. Further studies have shown that optimal therapies for CAD in dialysis patients remain neglected and unclarified. These therapies include correction of anemia, control of blood pressure, and antiplatelet therapy. Because of bleeding tendencies in dialysis patients, the benefits of antiplatelet therapy and platelet glycoprotein IIb/IIIa inhibitors for treating CAD require more research. In addition, a meta-analysis of retrospective studies in 2012 showed that dialysis patients with CAD receiving coronary artery bypass surgery had a lower long-term mortality rate and fewer postoperative cardiac complications than those receiving percutaneous coronary angioplasty. A large randomized, long-term cohort study is necessary to confirm these issues

Insights into the Mutation-Induced HHH Syndrome from Modeling Human Mitochondrial Ornithine Transporter-1

Human mitochondrial ornithine transporter-1 is reported in coupling with the hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome, which is a rare autosomal recessive disorder. For in-depth understanding of the molecular mechanism of the disease, it is crucially important to acquire the 3D structure of human mitochondrial ornithine transporter-1. Since no such structure is available in the current protein structure database, we have developed it via computational approaches based on the recent NMR structure of human mitochondrial uncoupling protein (Berardi MJ, Chou JJ, et al. Nature 2011, 476:109–113). Subsequently, we docked the ligand L-ornithine into the computational structure to search for the favorable binding mode. It was observed that the binding interaction for the most favorable binding mode is featured by six remarkable hydrogen bonds between the receptor and ligand, and that the most favorable binding mode shared the same ligand-binding site with most of the homologous mitochondrial carriers from different organisms, implying that the ligand-binding sites are quite conservative in the mitochondrial carriers family although their sequences similarity is very low with 20% or so. Moreover, according to our structural analysis, the relationship between the disease-causing mutations of human mitochondrial ornithine transporter-1 and the HHH syndrome can be classified into the following three categories: (i) the mutation occurs in the pseudo-repeat regions so as to change the region of the protein closer to the mitochondrial matrix; (ii) the mutation is directly affecting the substrate binding pocket so as to reduce the substrate binding affinity; (iii) the mutation is located in the structural region closer to the intermembrane space that can significantly break the salt bridge networks of the protein. These findings may provide useful insights for in-depth understanding of the molecular mechanism of the HHH syndrome and developing effective drugs against the disease

Urban-Rural Disparity of Generics Prescription in Taiwan: The Example of Dihydropyridine Derivatives

The aim of the current study was to investigate the urban-rural disparity of prescribing generics, which were usually cheaper than branded drugs, within the universal health insurance system in Taiwan. Data sources were the cohort datasets of National Health Insurance Research Database with claims data in 2010. The generic prescribing ratios of dihydropyridine (DHP) derivatives (the proportion of DHP prescribed as generics to all prescribed DHP) of medical facilities were examined against the urbanization levels of the clinic location. Among the total 21,606,914 defined daily doses of DHP, 35.7% belonged to generics. The aggregate generic prescribing ratio rose from 6.7% at academic medical centers to 15.3% at regional hospitals, 29.4% at community hospital, and 66.1% at physician clinics. Among physician clinics, the generic prescribing ratio in urban areas was 63.9 ± 41.0% (mean ± standard deviation), lower than that in suburban (69.6 ± 38.7%) and in rural (74.1% ± 35.3%). After adjusting the related factors in the linear regression model, generic prescribing ratios of suburban and rural clinics were significantly higher than those of urban clinics (β=0.043 and 0.077; P=0.024 and 0.008, resp.). The generic prescribing ratio of the most popular antihypertensive agents at a clinic was reversely associated with the urbanization level

Lysosomal sulfate transport: inhibitor studies

AbstractSulfate derived from the degradation of macromolecules is released from lysosomes via a carrier mediated process. In order to further characterize this process, recognized inhibitors of the erythrocyte band 3 anion transporter were examined for their effects on the lysosomal system. Studies with band 3 transport site inhibitors such as DIDS, SITS and phenylglyoxal indicated that, similar to the case for the band 3 protein, the llysosomal transporter has critical lysine and arginine residues. Band 3 translocation pathway or channel blocking inhibitors had mixed effects on the lysosomal system. 1,2-Cyclohexanedione, which covalently modifies a band 3 arginine residue distinct from that modified by phenylglyoxal, inhibited lysosomal sulfate transport. In contrast, the potent band 3 inhibitor dipyridamole had no effect on lysosomal sulfate transport indicating that there are some structural differences between the erythrocyte and lysosomal anion transporters. The band 3 translocation inhibitors niflumic acid and dinitrofluorobenzene were both effective inhibitors of the lysosomal system. Cupric ion inhibited sulfate transport while Ca2+, Co2+, Mg2+, Mn2+, and Zn2+ had no inhibitory effects. Exposure of intact lysosomes to trypsin largely ablated transport of sulfate. This information should be useful in efforts to further elucidate the structure and function of the lysosomal sulfate transporter

Improper Ferroelectric Polarisation in a Perovskite driven by Inter-site Charge Transfer and Ordering

It is of great interest to design and make materials in which ferroelectric polarisation is coupled to other order parameters such as lattice, magnetic and electronic instabilities. Such materials will be invaluable in next-generation data storage devices. Recently, remarkable progress has been made in understanding improper ferroelectric coupling mechanisms that arise from lattice and magnetic instabilities. However, although theoretically predicted, a compact lattice coupling between electronic and ferroelectric (polar) instabilities has yet to be realised. Here we report detailed crystallographic studies of a novel perovskite Hg$^{\textbf{A}}$Mn$^{\textbf{A'}}_{3}$Mn$^{\textbf{B}}_{4}$O$_{12}$ that is found to exhibit a polar ground state on account of such couplings that arise from charge and orbital ordering on both the A' and B-sites, which are themselves driven by a highly unusual Mn$^{A'}$-Mn$^B$ inter-site charge transfer. The inherent coupling of polar, charge, orbital and hence magnetic degrees of freedom, make this a system of great fundamental interest, and demonstrating ferroelectric switching in this and a host of recently reported hybrid improper ferroelectrics remains a substantial challenge.Comment: 9 pages, 7 figure