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Iron Overload in Hereditary Tyrosinemia Type 1 Induces Liver Injury through the Sp1/Tfr2/Hepcidin Axis.

Iron is an essential metal for fundamental metabolic processes, but little is known regarding the involvement of iron in other nutritional disorders. In the present study, we investigated disordered iron metabolism in a murine model of hereditary tyrosinemia type I (HT1), a disease of the tyrosine degradation pathway.
We analysed the status of iron accumulation following NTBC withdrawal from fah-/- mice, a murine model for HT1. Liver histology and serum parameters were used to assess the extent of liver injury and iron deposition. To determine the physiological significance of iron accumulation, mice were subjected to a low-iron food intake to reduce the iron accumulation. Mechanistic studies were performed on tissues and cells using immunoblotting, qRT-PCR, adenovirus transfection and other assays.
Severe iron overload was observed in the murine model of HT1 with dramatically elevated hepatic and serum iron levels. Mechanistic studies revealed that downregulation and dysfunction of Tfr2 decreased hepcidin, leading to iron overload. The fah-/- hepatocytes lost the ability of transferrin-sensitive induction of hepcidin. Forced expression of Tfr2 in the murine liver reduced the iron accumulation. Moreover, transcription factor Sp1 was downregulated and identified as a new regulator of Tfr2 here. Additionally, low-iron food intake effectively reduced the iron deposits, protected the liver and prolonged the survival in these mice.
Iron was severely overloaded in the HT1 mice via the Sp1/Tfr2/Hepcidin axis. The iron overload induced liver injury in the HT1 mice, and reduction of the iron accumulation ameliorated liver injury.
Primary and secondary iron overload is an abnormal status affecting millions of people worldwide. Here, we reported severe iron overload in a murine model of HT1, a disease of the tyrosine degradation pathway, and elucidated the mechanistic basis and the physiological significance of iron overload in HT1. These studies are of general interest not only with respect to secondary iron-induced liver injury in HT1 but also are important to elucidate the crosstalk between the two metabolic pathways.
Copyright © 2016. Published by Elsevier B.V.

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Negative influence of programmed death-1-ligands on the survival of esophageal cancer patients treated with chemotherapy.

The programmed death-1/programmed death-1ligands (PD-1/PD-Ls) pathway plays an important role in immunological tumor evasion. However, clinical significance of the PD-Ls (L1 and L2) expression in esophageal cancer treated with chemotherapy has not been fully investigated. We examined the expression of PD-Ls of the primary tumors obtained from 180 esophageal cancer patients who underwent radical resection with or without neoadjuvant chemotherapy (NAC) using immunohistochemical staining. The relationship between the expression patterns and clinico-pathological characteristics were examined. The 53 patients (29.4%) and 88 patients (48.3%) were classified into positive for PD-L1 and PD-L2 expression, respectively. In all the patients examined in this study, overall survival rates of the patients with tumors positive for PD-L1 or PD-L2 were significantly worse than those with tumors negative for PD-L1 or PD-L2 (p=0.0010 and p=0.0237, respectively). However, subgroup analysis showed that these tendencies are only found in the patients treated with NAC, but not in the ones without NAC. The patients with positive PD-L1 expression had significantly higher rate of NAC history (p=0.0139), but those with positive PD-L2 expression did not (p=0.6127). There is no significant relationship between PD-L1 expression and response to chemotherapy (p=0.3118), but the patient with positive PD-L2 expression had significantly inferior responses to chemotherapy (p=0.0034). The PD-1/PD-Ls pathway might be an immunological mechanism associated with the long-term effectiveness of the chemotherapy in esophageal cancer patients. Further investigations on the roles of PD-1 pathway in chemotherapy would lead to the development of better treatments for this disease. This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.

Inactivation of ANGPTL3 reduces hepatic VLDL-triglyceride secretion.

Humans and mice lacking angiopoietin-like protein 3 (ANGPTL3) have pan-hypolipidemia. ANGPTL3 inhibits two intravascular lipases, LPL and endothelial lipase, and the low plasma TG and HDL-cholesterol levels in ANGPTL3 deficiency reflect increased activity of these enzymes. The mechanism responsible for the low LDL-cholesterol levels associated with ANGPTL3 deficiency is not known. Here we used an anti-ANGPTL3 monoclonal antibody (REGN1500) to inactivate ANGPTL3 in mice with genetic deficiencies in key proteins involved in clearance of ApoB-containing lipoproteins. REGN1500 treatment consistently reduced plasma cholesterol levels in mice in which Apoe, Ldlr, Lrp1, and Sdc1 were inactivated singly or in combination, but did not alter clearance of rabbit (125)I-βVLDL or mouse (125)I-LDL. Despite a 61% reduction in VLDL-TG production, VLDL-ApoB-100 production was unchanged in REGN1500-treated animals. Hepatic TG content, fatty acid synthesis, and fatty acid oxidation were similar in REGN1500 and control antibody-treated animals. Taken together, our findings indicate that inactivation of ANGPTL3 does not affect the number of ApoB-containing lipoproteins secreted by the liver but alters the particles that are made such that they are cleared more rapidly from the circulation via a noncanonical pathway(s). The increased clearance of lipolytic remnants results in decreased production of LDL in ANGPTL3-deficient animals.
Copyright © 2015 by the American Society for Biochemistry and Molecular Biology, Inc.

DNA Methylation Analysis of ChIP Products at Single Nucleotide Resolution by Pyrosequencing®.

Interaction and co-occurrence of protein and DNA-based epigenetic modifications have become a topic of interest for many fundamental and biomedical questions. We describe within this chapter a protocol that combines two techniques in order to determine the methylation status of the DNA specifically associated with a protein of interest. First, DNA that directly interacts with the selected protein (such as a specific histone modification, a transcription factor, or any other DNA-associated protein) is purified by standard chromatin immunoprecipitation (ChIP). Second, the level of DNA methylation of this immunoprecipitated DNA is measured by bisulfite conversion and Pyrosequencing, a quantitative sequencing-by-synthesis method. This procedure allows determining the methylation status of genomic DNA associated to a specific protein at single nucleotide resolution.

The state of lung cancer research: a global analysis.

Lung cancer is the leading cause of cancer years of life lost and is associated with the highest economic burden relative to other tumour types. Research remains at the cornerstone of achieving improved outcomes from lung cancer. We present the results of a comprehensive analysis of global lung cancer research between 2004 and 2013 (10 years) METHODS: The study used bibliometrics to undertake a quantitative analysis of research outputs in the 24 leading cancer research countries internationally, based on articles and reviews in the Web of Science (WoS) database.
A total of 32,161 lung cancer research papers from 2,085 different journals were analysed. Lung cancer research represented only 5.6% of overall cancer research in 2013, a 1.2% increase since 2004. The commitment to lung cancer research has fallen in most countries, apart from China, and shows no correlation with lung cancer burden. A review of key research types demonstrated that diagnostics, screening and quality of life research represent 4.3%, 1.8% and 0.3% of total lung cancer research respectively. The leading research types were genetics (20%), systemic therapies (17%) and prognostic biomarkers (16%). Research outputs are increasingly basic science with a fall in clinical translational research output over this time period.
Our findings have established that relative to the huge health, social and economic burden associated with lung cancer, the level of world research output lags significantly behind that of other malignancies. Commitment to diagnostics, screening and quality of life research is much lower compared to basic science and medicines research. The study findings are expected to provide the requisite intelligence to guide future cancer research programs in lung cancer.
Copyright © 2016 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.