Search results for "Harm"
showing 10 items of 13866 documents
Role of AxyZ Transcriptional Regulator in Overproduction of AxyXY-OprZ Multidrug Efflux System in Achromobacter Species Mutants Selected by Tobramycin
2017
ABSTRACT AxyXY-OprZ is an RND-type efflux system that confers innate aminoglycoside resistance to Achromobacter spp. We investigated here a putative TetR family transcriptional regulator encoded by the axyZ gene located upstream of axyXY-oprZ . An in-frame axyZ gene deletion assay led to increased MICs of antibiotic substrates of the efflux system, including aminoglycosides, cefepime, fluoroquinolones, tetracyclines, and erythromycin, indicating that the product of axyZ negatively regulates expression of axyXY-oprZ . Moreover, we identified an amino acid substitution at position 29 of AxyZ (V29G) in a clinical Achromobacter strain that occurred during the course of chronic respiratory tract…
Multifactorial Modes of Action of Arsenic Trioxide in Cancer Cells as Analyzed by Classical and Network Pharmacology
2018
Arsenic trioxide is a traditional remedy in Chinese Medicine since ages. Nowadays, it is clinically used to treat acute promyelocytic leukemia (APL) by targeting PML/RARA. However, the drug’s activity is broader and the mechanisms of action in other tumor types remain unclear. In this study, we investigated molecular modes of action by classical and network pharmacological approaches. CEM/ADR5000 resistance leukemic cells were similar sensitive to As2O3 as their wild-type counterpart CCRF-CEM (resistance ratio: 1.88). Drug-resistant U87.MG ΔEGFR glioblastoma cells harboring mutated epidermal growth factor receptor were even more sensitive (collateral sensitive) than wild-type U87.MG cells (…
Assessment of tumor-infiltrating TCRV γ 9V δ 2 γδ lymphocyte abundance by deconvolution of human cancers microarrays
2017
Most human blood γδ cells are cytolytic TCRVγ9Vδ2+lymphocytes with antitumor activity. They are currently investigated in several clinical trials of cancer immunotherapy but so far, their tumor infiltration has not been systematically explored across human cancers. Novel algorithms allowing the deconvolution of bulk tumor transcriptomes to find the relative proportions of infiltrating leucocytes, such as CIBERSORT, should be appropriate for this aim but in practice they fail to accurately recognize γδ T lymphocytes. Here, by implementing machine learning from microarray data, we first improved the computational identification of blood-derived TCRVγ9Vδ2+γδ lymphocytes and then appl…
Human ectonucleotidase-expressing CD25 high Th17 cells accumulate in breast cancer tumors and exert immunosuppressive functions
2015
IF 7.644; International audience; Th17 cells contribute to the development of some autoimmune and allergic diseases by driving tissue inflammation. However, the function of Th17 cells during cancer progression remains controversial. Here, we show that human memory CD25(high) Th17 cells suppress T cell immunity in breast cancer. Ectonucleotidase-expressing Th17 cells accumulated in breast cancer tumors and suppressed CD4(+) and CD8(+) T cell activation. These cells expressed both Ror gamma t and Foxp3 genes and secreted Th17 related cytokines. We further found that CD39 ectonucleotisase expression on tumor-infiltrating Th17 cells was driven by TGF-beta and IL-6. Finally, immunohistochemical …
New Therapeutic Implications of Endothelial Nitric Oxide Synthase (eNOS) Function/Dysfunction in Cardiovascular Disease
2019
The Global Burden of Disease Study identified cardiovascular risk factors as leading causes of global deaths and life years lost. Endothelial dysfunction represents a pathomechanism that is associated with most of these risk factors and stressors, and represents an early (subclinical) marker/predictor of atherosclerosis. Oxidative stress is a trigger of endothelial dysfunction and it is a hall-mark of cardiovascular diseases and of the risk factors/stressors that are responsible for their initiation. Endothelial function is largely based on endothelial nitric oxide synthase (eNOS) function and activity. Likewise, oxidative stress can lead to the loss of eNOS activity or even “uncoupli…
Mineral Profile of Children’s Fast Food Menu Samples
2017
Abstract Children’s fast food menus, including hamburgers served with french fries, dessert, and a soft drink, were analyzed to obtain the mineral profile of trace elements. The developed analytical methodology involved sample digestion under pressure inside a microwave oven with a mixture of HNO3 and H2O2 and inductively coupled plasma-optical emission spectrometry. The method was validated by carrying out the analysis of certified reference materials (NIST 1570a spinach leaves, NCS ZC73016 chicken, and NIST 1568a rice flour) and using recovery experiments. Repeatability was verified by analyzing replicate samples. Twenty-six elements were studied, 12 of which—aluminum, barium, calcium, co…
CCR7 on CD4+ T Cells Plays a Crucial Role in the Induction of Experimental Autoimmune Encephalomyelitis
2018
Abstract Multiple sclerosis (MS) is the most common chronic inflammatory demyelinating disease of the CNS. Myelin-specific CD4+ Th lymphocytes are known to play a major role in both MS and its animal model experimental autoimmune encephalomyelitis (EAE). CCR7 is a critical element for immune cell trafficking and recirculation, that is, lymph node homing, under homeostatic conditions; blocking CCR7+ central memory cells from egress of lymph nodes is a therapeutic approach in MS. To define the effect of CD4+ T cell–specific constitutive deletion of CCR7 in the priming and effector phase in EAE, we used an active EAE approach in T cell reconstituted Rag1−/− mice, as well as adoptive transfer E…
γδ cell-based immunotherapy for cancer.
2019
Introduction: Cancer immunotherapy relies on the development of an efficient and long-lasting anti-tumor response, generally mediated by cytotoxic T cells. gamma delta T cells possess distinctive features that justify their use in cancer immunotherapy. Areas covered: Here we will review our current knowledge on the functions of human gamma delta T cells that may be relevant in tumor immunity and the most recent advances in our understanding of how these functions are regulated in the tumor microenvironment. We will also discuss the major achievements and limitations of gamma delta T cell-based immunotherapy of cancer. Expert opinion: Several small-scale clinical trials have been conducted i…
Anakinra drug retention rate and predictive factors of long-term response in systemic juvenile idiopathic arthritis and adult onset still disease
2019
Background and Objective: Only a few studies have reported long-term efficacy of interleukin (IL)-1 inhibition in systemic juvenile idiopathic arthritis (sJIA) and adult-onset Still disease (AOSD). Herein we report on the effectiveness of anakinra (ANA), expressed in terms of drug retention rate (DRR), and evaluate the predictive factors of drug survival in a cohort of patients with sJIA and AOSD. Patients and Methods: This is a multicenter study reviewing retrospectively the medical records from 61 patients with sJIA and 76 with AOSD, all treated with ANA in 25 Italian tertiary referral centers. Results: The cumulative retention rate of ANA at 12-, 24-, 48-, and 60-month of follow-up was 7…
Phase I Study of the Indoleamine 2,3-Dioxygenase 1 (IDO1) Inhibitor Navoximod (GDC-0919) Administered with PD-L1 Inhibitor (Atezolizumab) in Advanced…
2019
Abstract Purpose: IDO1 induces immune suppression in T cells through l-tryptophan (Trp) depletion and kynurenine (Kyn) accumulation in the local tumor microenvironment, suppressing effector T cells and hyperactivating regulatory T cells (Treg). Navoximod is an investigational small-molecule inhibitor of IDO1. This phase I study evaluated safety, tolerability, pharmacokinetics, and pharmacodynamics of navoximod in combination with atezolizumab, a PD-L1 inhibitor, in patients with advanced cancer. Patients and Methods: The study consisted of a 3+3 dose-escalation stage (n = 66) and a tumor-specific expansion stage (n = 92). Navoximod was given orally every 12 hours continuously for 21 consecu…