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.

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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.

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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.

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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.

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The mechanistic target of rapamycin (mTOR) is a major regulator of cell growth and is frequently dysregulated in cancer. While mTOR complex-1 (mTORC1) is a validated cancer target, the role of mTOR complex-2 (mTORC2) remains less defined. Here, we reveal mTORC2 as a critical regulator of breast cancer metabolism. We showed that hyperphosphorylation in ATP citrate lyase (ACL) occurs frequently in human breast tumors and correlates well with HER2+ and/or PIK3CA-mutant (HER2+/PIK3CAmut) status in breast tumor cell lines. In HER2+/PIK3CAmut cells, mTORC2 controls Ser-455 phosphorylation of ACL thereby promoting acetyl-CoA production, de novo lipogenesis and mitochondrial physiology, all of which were inhibited by an mTORC1/mTORC2 kinase inhibitor (mTOR-KI) or cellular depletion of mTORC2 or ACL. mTOR-KI but not rapamycin blocked the IGF-1-induced ACL phosphorylation and glucose to lipid conversion. Depletion of mTORC2 but not mTORC1 specifically inhibited the ACL-dependent acetyl-CoA production. In the HER2+/PIK3CAmut MDA361, MDA453, BT-474 and T47D cells, depletion of mTORC2 or ACL led to growth inhibition and mitochondrial hyperpolarization, which were partially rescued by an alternate source of acetyl-CoA. These same changes were not apparent in mTORC2- or ACL-depleted HER2-/PIK3CAwt MDA231 and HCC1806 cells, highlighting a differential dependence of mTORC2-ACL for survival in these two cell types. Moreover, ACL Ser-455 mutants S455E (phosphomimetic) and S455A (non-phosphorylatable) each increased or decreased, respectively, the acetyl-CoA production, mitochondrial homeostasis and survival in ACL-depleted MDA453 cells. These studies define a new and rapamycin-resistant mechanism of mTORC2-ACL in lipogenesis and acetyl-CoA biology and provide a rationale for targeting of mTORC1 and mTORC2 in HER2+/PIK3CAmut breast cancer.

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