scholarly journals Five-Lipoxygenase-Activating Protein Mediated CYLD Attenuation is a Candidate Driver in Hepatic Malignant Lesion

2021 ◽  
Author(s):  
Kun-kai Su ◽  
Xue-hua Zheng ◽  
Christian Bréchot ◽  
Xiao-ping Zheng ◽  
Dan-hua Zhu ◽  
...  
Keyword(s):  
Inflammatory Mediators ◽  
Malignant Lesion ◽  
Safety Evaluation ◽  
Ki 67 ◽  
Drug Safety Evaluation ◽  
Pathway Activation ◽  
Early Hcc ◽  
The Impact ◽  
Functional Components ◽  
Hcc Cells

Abstract Background: Hepatocellular carcinoma (HCC) is an inflammation-associated cancer. However, the lipid pro-inflammatory mediators have only been seldom investigated in HCC pathogenesis. Activation of NF-κB and expression of c-Myc are negatively regulated by cylindromatosis (CYLD) in hepatocarcinogenesis. But it remains largely unknown whether lipid pro-inflammatory mediators are involved in CYLD suppression. Here, we aimed to evaluate the significance of hepatic lipid pro-inflammatory metabolites of arachidonate affected CYLD expression via 5-lipoxygenase (5-LO)-pathway.Methods: Resection liver tissues from HCC patients or donors were evaluated for the correlation of 5-LO/cysteinyl leukotrienes (CysLTs)-signaling to expression of CYLD. The impact of functional components in 5-LO/CysLTs cascade on survival of HCC patients was subsequently assessed. Both livers from canines, a routine animal for drug safety evaluation, and genetic-modified human HCC cells treated with hepatocarcinogen aristolochic acid I (AAI) were further used to reveal the possible relevance between 5-LO pathway activation and CYLD depression. Results: 5-LO-activating protein (FLAP), an essential partner of 5-LO, significantly overexpressed and was parallel to CYLD depression, CD34 neovascular localization, and high Ki-67 expression in the resection tissues from HCC patients. Importantly, high hepatic FLAP transcription markedly shortened the median survival time of HCC patients after surgical resection. In the livers of AAI-treated canines, FLAP overexpression was parallel to enhanced CysLTs contents, simultaneous attenuated CYLD expression. Moreover, knock-in FLAP significantly diminished the expression of CYLD in AAI-treated human HCC cells.Conclusions: Hepatic FLAP/CysLTs axis is a crucial suppressor of CYLD in HCC pathogenesis, which highlights a novel mechanism in hepatocarcinogenesis and development. FLAP therefore can be explored for the early HCC detection and a target of anti-HCC therapy.

scholarly journals SLC6A8-mediated intracellular creatine accumulation enhances hypoxic breast cancer cell survival via ameliorating oxidative stress

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Qiao Li ◽  
Manran Liu ◽  
Yan Sun ◽  
Ting Jin ◽  
Pengpeng Zhu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Overall Survival ◽  
Molecular Mechanisms ◽  
Expression Profiles ◽  
Histological Grade ◽  
Metabolic Adaptation ◽  
Mitochondrial Activity ◽  
Cell Viability Assay ◽  
Ki 67 ◽  
The Impact

Abstract Background Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, with poor prognosis and limited treatment options. Hypoxia is a key hallmark of TNBC. Metabolic adaptation promotes progression of TNBC cells that are located within the hypoxic tumor regions. However, it is not well understood regarding the precise molecular mechanisms underlying the regulation of metabolic adaptions by hypoxia. Methods RNA sequencing was performed to analyze the gene expression profiles in MDA-MB-231 cell line (20% O2 and 1% O2). Expressions of Slc6a8, which encodes the creatine transporter protein, were detected in breast cancer cells and tissues by quantitative real-time PCR. Immunohistochemistry was performed to detect SLC6A8 protein abundances in tumor tissues. Clinicopathologic correlation and overall survival were evaluated by chi-square test and Kaplan-Meier analysis, respectively. Cell viability assay and flow cytometry analysis with Annexin V/PI double staining were performed to investigate the impact of SLC6A8-mediated uptake of creatine on viability of hypoxic TNBC cells. TNBC orthotopic mouse model was used to evaluate the effects of creatine in vivo. Results SLC6A8 was aberrantly upregulated in TNBC cells in hypoxia. SLC6A8 was drastically overexpressed in TNBC tissues and its level was tightly associated with advanced TNM stage, higher histological grade and worse overall survival of TNBC patients. We found that SLC6A8 was transcriptionally upregulated by p65/NF-κB and mediated accumulation of intracellular creatine in hypoxia. SLC6A8-mediated accumulation of creatine promoted survival and suppressed apoptosis via maintaining redox homeostasis in hypoxic TNBC cells. Furthermore, creatine was required to facilitate tumor growth in xenograft mouse models. Mechanistically, intracellular creatine bolstered cell antioxidant defense by reducing mitochondrial activity and oxygen consumption rates to reduce accumulation of intracellular reactive oxygen species, ultimately activating AKT-ERK signaling, the activation of which protected the viability of hypoxic TNBC cells via mediating the upregulation of Ki-67 and Bcl-2, and the downregulation of Bax and cleaved Caspase-3. Conclusions Our study indicates that SLC6A8-mediated creatine accumulation plays an important role in promoting TNBC progression, and may provide a potential therapeutic strategy option for treatment of SLC6A8 high expressed TNBC.

scholarly journals Understanding Surgical Decision Making in Early Hepatocellular Carcinoma

2011 ◽  
Vol 29 (6) ◽  
pp. 619-625 ◽  
Author(s):  
Hari Nathan ◽  
John F.P. Bridges ◽  
Richard D. Schulick ◽  
Andrew M. Cameron ◽  
Kenzo Hirose ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Decision Making ◽  
Independent Effect ◽  
Clinical Factors ◽  
Surgical Decision ◽  
Early Hepatocellular Carcinoma ◽  
Early Hcc ◽  
The Impact ◽  
Surgical Decision Making ◽  
Choice Of Therapy

Purpose The choice between liver transplantation (LT), liver resection (LR), and radiofrequency ablation (RFA) as initial therapy for early hepatocellular carcinoma (HCC) is controversial, yet little is known about how surgeons choose therapy for individual patients. We sought to quantify the impact of both clinical factors and surgeon specialty on surgical decision making in early HCC by using conjoint analysis. Methods Surgeons with an interest in liver surgery were invited to complete a Web-based survey including 10 case scenarios. Choice of therapy was then analyzed by using regression models that included both clinical factors and surgeon specialty (non-LT v LT). Results When assessing early HCC occurrences, non-LT surgeons (50% LR; 41% LT; 9% RFA) made significantly different recommendations compared with LT surgeons (63% LT; 31% LR; 6% RFA; P < .001). Clinical factors, including tumor number and size, type of resection required, and platelet count, had significant effects on the choice between LR, LT, and RFA. After adjusting for clinical factors, non-LT surgeons remained more likely than LT surgeons to choose LR compared with LT (relative risk ratio [RRR], 2.67). When the weight of each clinical factor was allowed to vary by surgeon specialty, the residual independent effect of surgeon specialty on the decision between LR and LT was negligible (RRR, 0.93). Conclusion The impact of surgeon specialty on choice of therapy for early HCC is stronger than that of some clinical factors. However, the influence of surgeon specialty does not merely reflect an across-the-board preference for one therapy over another. Rather, certain clinical factors are weighed differently by surgeons in different specialties.

scholarly journals Inflammatory responses of C57BL/6NKorl mice to dextran sulfate sodium-induced colitis: comparison between three C57BL/6 N sub-strains

2021 ◽  
Vol 37 (1) ◽  
Author(s):  
Sou Hyun Kim ◽  
Doyoung Kwon ◽  
Seung Won Son ◽  
Tae Bin Jeong ◽  
Seunghyun Lee ◽  
...  
Keyword(s):  
Animal Model ◽  
Dextran Sulfate ◽  
Dextran Sulfate Sodium ◽  
Inflammatory Responses ◽  
Inbred Mouse ◽  
Clinical Signs ◽  
Safety Evaluation ◽  
Inbred Mouse Strain ◽  
Drug Safety Evaluation ◽  
Factor Α

Abstract Background Inflammatory bowel disease (IBD), including both Crohn’s disease and ulcerative colitis, are chronic human diseases that are challenging to cure and are often unable to be resolved. The inbred mouse strain C57BL/6 N has been used in investigations of IBD as an experimental animal model. The purpose of the current study was to compare the inflammatory responsiveness of C57BL/6NKorl mice, a sub-strain recently established by the National Institute of Food and Drug Safety Evaluation (NIFDS), with those of C57BL/6 N mice from two different sources using a dextran sulfate sodium (DSS)-induced colitis model. Results Male mice (8 weeks old) were administered DSS (0, 1, 2, or 3%) in drinking water for 7 days. DSS significantly decreased body weight and colon length and increased the colon weight-to-length ratio. Moreover, severe colitis-related clinical signs including diarrhea and rectal bleeding were observed beginning on day 4 in mice administered DSS at a concentration of 3%. DSS led to edema, epithelial layer disruption, inflammatory cell infiltration, and cytokine induction (tumor necrosis factor-α, interleukin-6, and interleukin-1β) in the colon tissues. However, no significant differences in DSS-promoted abnormal symptoms or their severity were found between the three sub-strains. Conclusions These results indicate that C57BL/6NKorl mice responded to DSS-induced colitis similar to the generally used C57BL6/N mice, thus this newly developed mouse sub-strain provides a useful animal model of IBD.

scholarly journals Variability of Pathologists' Utilization of p16 and Ki-67 Immunostaining in the Diagnosis of Cervical Biopsies in Routine Pathology Practice and Its Impact on the Frequencies of Cervical Intraepithelial Neoplasia Diagnoses and Cytohistologic Correlations

2014 ◽  
Vol 138 (1) ◽  
pp. 76-87 ◽  
Author(s):  
Charanjeet Singh ◽  
J. Carlos Manivel ◽  
Alexander M. Truskinovsky ◽  
Kay Savik ◽  
Samy Amirouche ◽  
...  
Keyword(s):  
Cervical Intraepithelial Neoplasia ◽  
Intraepithelial Neoplasia ◽  
Lower Range ◽  
Ki 67 ◽  
Detection Rates ◽  
Cervical Biopsy ◽  
Biopsy Specimens ◽  
Frequency Of Use ◽  
Lower Variability ◽  
The Impact

Context.—The use of p16 in cervical biopsies improves the accuracy of cervical intraepithelial neoplasia (CIN) diagnosis and grading and decreases its interpathologist variability. Objective.—To determine the impact of the frequency of use of p16 immunostains in cervical biopsies on pathologists' diagnoses of CIN grade 1 and grade 2 or above (CIN1 and CIN2+) and on cytohistologic correlations. Design.—We identified all cervical biopsy specimens with cytologic correlations subjected or not to p16 staining from January 1, 2005, to September 30, 2010; calculated each pathologist's percentage of p16 use; and correlated it with their major cytohistologic discrepancy rates, CIN2+ diagnoses, and CIN1/CIN2+ ratios. Results.—During the study period, each of the 23 pathologists interpreted 59 to 1811 (mean, 518) of 11 850 cervical biopsy specimens, used p16 for 0% to 21.31% (mean, 10.14%) of these, had CIN2+ detection rates of 9.5% to 24.1% (mean, 18.9%), and CIN1/CIN2+ ratios of 0.7 to 4.5 (mean, 1.5). Compared to the 12 “low users” of p16, who used p16 fewer times than the institution's mean for p16 use, the 11 “high users” of p16 diagnosed more biopsies (8391 versus 3459), had a lower rate of major cytohistologic discrepancies (12.62% versus 14.92%, P &lt; .001), a higher rate of CIN2+ diagnoses (19.9% versus 16.4%, P &lt; .001), a lower range of CIN2+ rates (15.0%–23.1% versus 9.5%–24.1%), and lower CIN1/CIN2+ ratios (1.2 versus 2.3). Conclusions.—We found a high intrainstitutional variability of p16 use in cervical biopsies, CIN2+ rates, and CIN1/CIN2+ ratios. Use of p16 for greater than 10% of cervical biopsies was associated with improved cytohistologic correlation rates and with lower variability in the frequencies of histologic diagnoses.

scholarly journals Sex Differences in Drug-Induced Arrhythmogenesis

2021 ◽  
Vol 12 ◽  
Author(s):  
Mathias Peirlinck ◽  
Francisco Sahli Costabal ◽  
Ellen Kuhl
Keyword(s):  
Sex Differences ◽  
Safety Evaluation ◽  
New Drugs ◽  
Specific Response ◽  
Drug Induced ◽  
Tissue Conductivity ◽  
Male And Female ◽  
Drug Safety Evaluation ◽  
Qt Intervals ◽  
Drug Concentrations

The electrical activity in the heart varies significantly between men and women and results in a sex-specific response to drugs. Recent evidence suggests that women are more than twice as likely as men to develop drug-induced arrhythmia with potentially fatal consequences. Yet, the sex-specific differences in drug-induced arrhythmogenesis remain poorly understood. Here we integrate multiscale modeling and machine learning to gain mechanistic insight into the sex-specific origin of drug-induced cardiac arrhythmia at differing drug concentrations. To quantify critical drug concentrations in male and female hearts, we identify the most important ion channels that trigger male and female arrhythmogenesis, and create and train a sex-specific multi-fidelity arrhythmogenic risk classifier. Our study reveals that sex differences in ion channel activity, tissue conductivity, and heart dimensions trigger longer QT-intervals in women than in men. We quantify the critical drug concentration for dofetilide, a high risk drug, to be seven times lower for women than for men. Our results emphasize the importance of including sex as an independent biological variable in risk assessment during drug development. Acknowledging and understanding sex differences in drug safety evaluation is critical when developing novel therapeutic treatments on a personalized basis. The general trends of this study have significant implications on the development of safe and efficacious new drugs and the prescription of existing drugs in combination with other drugs.

scholarly journals 322 Melanoma-intrinsic hypoxia-inducible factor-1α results in diminished T cell accumulation within the tumor microenvironment

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A347-A347
Author(s):  
Emily Higgs ◽  
Thomas Gajewski ◽  
Jonathan Trujillo
Keyword(s):  
T Cell ◽  
Tumor Microenvironment ◽  
Cancer Cell ◽  
Gene Expression Analysis ◽  
Hypoxia Inducible Factor ◽  
Gene Signature ◽  
T Cell Response ◽  
Pathway Activation ◽  
Cell Accumulation ◽  
The Impact

BackgroundThe hypoxia-inducible factor (HIF) system, consisting of the transcription factors HIF-1α and HIF-2α, mediates cellular adaptation to hypoxia, and can promote cancer progression, invasion, and metastasis. HIF pathway activation in the tumor microenvironment has been implicated in cancer immune evasion; however, a direct causal role for tumor cell-intrinsic HIF-1α and HIF-2α activation in mediating T cell exclusion and cancer cell resistance to immune checkpoint inhibitor therapy has not been demonstrated.MethodsWe performed gene expression analysis of melanoma tumors in the Cancer Genome Atlas (TCGA) data set to determine whether increased HIF-1α pathway activation correlated with reduced T cell-based inflammation. The magnitude of HIF-1α pathway activation across melanoma samples was determined by applying a quantitative scoring system on the expression of a melanocyte-specific hypoxia-induced, HIF-1α-target gene signature consisting of 81 genes. The Pearson correlation test was used to compare the HIF-1α activation score and our 160-gene T-cell-inflamed gene signature. To determine the impact of cancer cell-intrinsic HIF-1α or HIF-2α activation on the endogenous anti-tumor T cell response, we developed an inducible autochthonous mouse melanoma model driven by BRAFV600E expression and PTEN-deletion, with or without inducible expression of either a stabilized variant of HIF-1α or HIF-2α. These murine tumor models are being used to determine the impact of cancer cell-intrinsic HIF-1α or HIF-2α activation on tumor sensitivity to anti-PD-1/PD-L1 and anti-CTLA-4 treatment.ResultsGene expression analysis of human melanomas in the TCGA demonstrated a statistically significant inverse correlation between the HIF-1α activation score and T cell-inflammation score. Braf/PTEN murine melanomas with and without stabilized HIF-1α expression developed with comparable tumor onset and growth kinetics. Multiparameter immunofluorescence staining of melanoma tissue revealed a significant decrease in tumor-infiltrating T cells within Braf/PTEN melanoma tumors expressing stabilized HIF-1α compared to control Braf/PTEN melanomas.ConclusionsOur data demonstrate that tumor-cell intrinsic HIF-1α activation leads to diminished T cell accumulation within the tumor microenvironment, which has implications for cancer immunotherapy. The mechanism of this effect is being elucidated. These novel murine models will help elucidate the roles of cancer cell-intrinsic HIF-1α and HIF-2α activation in modulating the anti-tumor T cell response, providing mechanistic insight that will inform the evaluation of novel selective HIF inhibitors, which are showing promising anti-tumor activity in clinical trials in patients with advanced solid tumors.

scholarly journals Benchmark dose-response analyses for multiple endpoints in drug safety evaluation

2021 ◽  
pp. 115732
Author(s):  
Antero Vieira Silva ◽  
Joakim Ringblom ◽  
Peter Moldeus ◽  
Elin Törnqvist ◽  
Mattias Öberg
Keyword(s):  
Drug Safety ◽  
Dose Response ◽  
Safety Evaluation ◽  
Benchmark Dose ◽  
Multiple Endpoints ◽  
Drug Safety Evaluation

scholarly journals Oxidative stress-induced inflammation in susceptible airways by anthropogenic aerosol

PLoS ONE ◽  
2020 ◽  
Vol 15 (11) ◽  
pp. e0233425 ◽  
Author(s):  
Zaira Leni ◽  
Laure Estelle Cassagnes ◽  
Kaspar R. Daellenbach ◽  
Imad El Haddad ◽  
Athanasia Vlachou ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Inflammatory Mediators ◽  
Apical Cell ◽  
Ambient Air ◽  
Water Soluble ◽  
Ambient Air Pollution ◽  
Anthropogenic Aerosol ◽  
Bronchial Epithelia ◽  
Clear Dose Response ◽  
The Impact

Ambient air pollution is one of the leading five health risks worldwide. One of the most harmful air pollutants is particulate matter (PM), which has different physical characteristics (particle size and number, surface area and morphology) and a highly complex and variable chemical composition. Our goal was first to comparatively assess the effects of exposure to PM regarding cytotoxicity, release of pro-inflammatory mediators and gene expression in human bronchial epithelia (HBE) reflecting normal and compromised health status. Second, we aimed at evaluating the impact of various PM components from anthropogenic and biogenic sources on the cellular responses. Air-liquid interface (ALI) cultures of fully differentiated HBE derived from normal and cystic fibrosis (CF) donor lungs were exposed at the apical cell surface to water-soluble PM filter extracts for 4 h. The particle dose deposited on cells was 0.9–2.5 and 8.8–25.4 μg per cm2 of cell culture area for low and high PM doses, respectively. Both normal and CF HBE show a clear dose-response relationship with increasing cytotoxicity at higher PM concentrations. The concurrently enhanced release of pro-inflammatory mediators at higher PM exposure levels links cytotoxicity to inflammatory processes. Further, the PM exposure deregulates genes involved in oxidative stress and inflammatory pathways leading to an imbalance of the antioxidant system. Moreover, we identify compromised defense against PM in CF epithelia promoting exacerbation and aggravation of disease. We also demonstrate that the adverse health outcome induced by PM exposure in normal and particularly in susceptible bronchial epithelia is magnified by anthropogenic PM components. Thus, including health-relevant PM components in regulatory guidelines will result in substantial human health benefits and improve protection of the vulnerable population.

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