scholarly journals Increased Intrahepatic Expression of Immune Checkpoint Molecules in Autoimmune Liver Disease

Cells ◽  
2021 ◽  
Vol 10 (10) ◽  
pp. 2671
Author(s):  
Zuzana Macek Jilkova ◽  
Marie Noelle Hilleret ◽  
Theophile Gerster ◽  
Nathalie Sturm ◽  
Marion Mercey-Ressejac ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Liver Tissue ◽  
Lymphocyte Subsets ◽  
Normal Liver ◽  
Alanine Transaminase ◽  
Therapeutic Interventions ◽  
General Picture ◽  
Immune Checkpoint Molecules ◽  
Large Panel ◽  
Immune Alterations

Immune checkpoint molecules (ICM) are critical in maintaining immunologic homeostasis and participate in preventing or promoting autoimmune disease development. Exploring a large panel of intrahepatic inhibitory and stimulatory ICM is necessary for drawing a general picture of the immune alterations in autoimmune hepatitis (AIH). Here, we performed a multiparametric analysis of ICM, including PD-1, TIM3, LAG3, CTLA-4, OX40 and 4-1BB, and we determined their expression on intrahepatic lymphocyte subsets in untreated and in treated patients with AIH in comparison to normal liver tissue. AIH patient-derived liver tissue revealed the overexpression of ICM, mainly PD-1 and 4-1BB, as well as the strong correlation between PD-1+ CD8+ T-cell abundance and severity of AIH (alanine transaminase and aspartate transaminase levels). Our results show that the ICM play an important role in the loss of immune homeostasis in the liver, providing an attractive approach to investigate their role as targets for effective therapeutic interventions.

scholarly journals Prognostic values, ceRNA network, and immune regulation function of SDPR in KRAS-mutant lung cancer

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Xiaoqing Luo ◽  
Shunli Peng ◽  
Sijie Ding ◽  
Qin Zeng ◽  
Rong Wang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Immune Checkpoint ◽  
Cox Regression ◽  
Tissue Array ◽  
Lung Cancers ◽  
Cox Regression Analysis ◽  
Immune Checkpoint Molecules ◽  
Cerna Network ◽  
Kaplan Meier ◽  
Infiltration Models

Abstract Background Serum Deprivation Protein Response (SDPR) plays an important role in formation of pulmonary alveoli. However, the functions and values of SDPR in lung cancer remain unknown. We explored prognostic value, expression pattern, and biological function of SDPR in non-small cell lung cancer (NSCLC) and KRAS-mutant lung cancers. Methods SDPR expression was evaluated by quantitative real-time PCR (RT-qPCR), immunohistochemistry (IHC), and Western blot on human NSCLC cells, lung adenocarcinoma tissue array, KRAS-mutant transgenic mice, TCGA and GEO datasets. Prognostic values of SDPR were evaluated by Kaplan–Meier and Cox regression analysis. Bioinformatics implications of SDPR including SDPR-combined transcription factors (TFs) and microRNAs were predicted. In addition, correlations between SDPR, immune checkpoint molecules, and tumor infiltration models were illustrated. Results SDPR expression was downregulated in tumor cells and tissues. Low SDPR expression was an independent factor that correlated with shorter overall survival of patients both in lung cancer and KRAS-mutant subgroups. Meanwhile, ceRNA network was constructed to clarify the regulatory and biological functions of SDPR. Negative correlations were found between SDPR and immune checkpoint molecules (PD-L1, TNFRSF18, TNFRSF9, and TDO2). Moreover, diversity immune infiltration models were observed in NSCLC with different SDPR expression and copy number variation (CNV) patterns. Conclusions This study elucidated regulation network of SDPR in KRAS-mutant NSCLC, and it illustrated correlations between low SDPR expression and suppressed immune system, unfolding a prognostic factor and potential target for the treatment of lung cancer, especially for KRAS-mutant NSCLC.

scholarly journals Combined Inhibition of TGF-β1-Induced EMT and PD-L1 Silencing Re-Sensitizes Hepatocellular Carcinoma to Sorafenib Treatment

2021 ◽  
Vol 10 (9) ◽  
pp. 1889
Author(s):  
Ritu Shrestha ◽  
Prashanth Prithviraj ◽  
Kim R. Bridle ◽  
Darrell H. G. Crawford ◽  
Aparna Jayachandran
Keyword(s):  
Hepatocellular Carcinoma ◽  
Combination Treatment ◽  
Immune Checkpoint ◽  
Post Treatment ◽  
Immune Checkpoints ◽  
Sorafenib Treatment ◽  
Mesenchymal Transition ◽  
Immune Checkpoint Molecules ◽  
Tgf Β1 ◽  
Hcc Cells

Hepatocellular carcinoma (HCC) is the most common type of primary hepatic malignancy. HCC is one of the leading causes of cancer deaths worldwide. The oral multi-tyrosine kinase inhibitor Sorafenib is the standard first-line therapy in patients with advanced unresectable HCC. Despite the significant survival benefit in HCC patients post treatment with Sorafenib, many patients had progressive disease as a result of acquiring drug resistance. Circumventing resistance to Sorafenib by exploring and targeting possible molecular mechanisms and pathways is an area of active investigation worldwide. Epithelial-to-mesenchymal transition (EMT) is a cellular process allowing epithelial cells to assume mesenchymal traits. HCC tumour cells undergo EMT to become immune evasive and develop resistance to Sorafenib treatment. Immune checkpoint molecules control immune escape in many tumours, including HCC. The aim of this study is to investigate whether combined inhibition of EMT and immune checkpoints can re-sensitise HCC to Sorafenib treatment. Post treatment with Sorafenib, HCC cells PLC/PRF/5 and Hep3B were monitored for induction of EMT and immune checkpoint molecules using quantitative reverse transcriptase (qRT)- PCR, western blot, immunofluorescence, and motility assays. The effect of combination treatment with SB431542, a specific inhibitor of the transforming growth factor (TGF)-β receptor kinase, and siRNA mediated knockdown of programmed cell death protein ligand-1 (PD-L1) on Sorafenib resistance was examined using a cell viability assay. We found that three days of Sorafenib treatment activated EMT with overexpression of TGF-β1 in both HCC cell lines. Following Sorafenib exposure, increase in the expression of PD-L1 and other immune checkpoints was observed. SB431542 blocked the TGF-β1-mediated EMT in HCC cells and also repressed PD-L1 expression. Likewise, knockdown of PD-L1 inhibited EMT. Moreover, the sensitivity of HCC cells to Sorafenib was enhanced by combining a blockade of EMT with SB431542 and knockdown of PD-L1 expression. Sorafenib-induced motility was attenuated with the combined treatment of SB431542 and PD-L1 knockdown. Our findings indicate that treatment with Sorafenib induces EMT and expression of immune checkpoint molecules, which contributes to Sorafenib resistance in HCC cells. Thus, the combination treatment strategy of inhibiting EMT and immune checkpoint molecules can re-sensitise HCC cells to Sorafenib.

scholarly journals Eight-Color Multiplex Immunohistochemistry for Simultaneous Detection of Multiple Immune Checkpoint Molecules within the Tumor Microenvironment

2017 ◽  
Vol 200 (1) ◽  
pp. 347-354 ◽  
Author(s):  
Mark A. J. Gorris ◽  
Altuna Halilovic ◽  
Katrin Rabold ◽  
Anne van Duffelen ◽  
Iresha N. Wickramasinghe ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Immune Checkpoint ◽  
Simultaneous Detection ◽  
Immune Checkpoint Molecules

scholarly journals Discovering Digital Tumor Signatures—Using Latent Code Representations to Manipulate and Classify Liver Lesions

Cancers ◽  
2021 ◽  
Vol 13 (13) ◽  
pp. 3108
Author(s):  
Jens Kleesiek ◽  
Benedikt Kersjes ◽  
Kai Ueltzhöffer ◽  
Jacob M. Murray ◽  
Carsten Rother ◽  
...  
Keyword(s):  
Unsupervised Learning ◽  
Liver Tissue ◽  
Synthetic Data ◽  
Normal Liver ◽  
Chance Level ◽  
Ct Scans ◽  
Liver Lesions ◽  
Abdominal Ct ◽  
Latent Representations ◽  
Spatial Locations

Modern generative deep learning (DL) architectures allow for unsupervised learning of latent representations that can be exploited in several downstream tasks. Within the field of oncological medical imaging, we term these latent representations “digital tumor signatures” and hypothesize that they can be used, in analogy to radiomics features, to differentiate between lesions and normal liver tissue. Moreover, we conjecture that they can be used for the generation of synthetic data, specifically for the artificial insertion and removal of liver tumor lesions at user-defined spatial locations in CT images. Our approach utilizes an implicit autoencoder, an unsupervised model architecture that combines an autoencoder and two generative adversarial network (GAN)-like components. The model was trained on liver patches from 25 or 57 inhouse abdominal CT scans, depending on the experiment, demonstrating that only minimal data is required for synthetic image generation. The model was evaluated on a publicly available data set of 131 scans. We show that a PCA embedding of the latent representation captures the structure of the data, providing the foundation for the targeted insertion and removal of tumor lesions. To assess the quality of the synthetic images, we conducted two experiments with five radiologists. For experiment 1, only one rater and the ensemble-rater were marginally above the chance level in distinguishing real from synthetic data. For the second experiment, no rater was above the chance level. To illustrate that the “digital signatures” can also be used to differentiate lesion from normal tissue, we employed several machine learning methods. The best performing method, a LinearSVM, obtained 95% (97%) accuracy, 94% (95%) sensitivity, and 97% (99%) specificity, depending on if all data or only normal appearing patches were used for training of the implicit autoencoder. Overall, we demonstrate that the proposed unsupervised learning paradigm can be utilized for the removal and insertion of liver lesions at user defined spatial locations and that the digital signatures can be used to discriminate between lesions and normal liver tissue in abdominal CT scans.

Feed-borne exposure to deoxynivalenol leads to acute and chronic effects on liver enzymes and histology in carp

2015 ◽  
Vol 8 (5) ◽  
pp. 619-627 ◽  
Author(s):  
C. Pietsch ◽  
P. Burkhardt-Holm
Keyword(s):  
Liver Enzyme ◽  
Enzyme Activities ◽  
Liver Tissue ◽  
Time Course ◽  
Normal Liver ◽  
Fish Feed ◽  
Acute Response ◽  
Biotransformation Enzymes ◽  
Chronic Effects ◽  
Acute And Chronic Effects

Deoxynivalenol (DON) is a frequent contaminant of feeds in aquaculture, but the consequences of this contamination have rarely been evaluated. Previous studies on carp indicated effects of DON on liver function and histology after four weeks of feeding. The present study aimed to unravel the time course of liver responses of carp to orally applied DON. Therefore, liver enzyme activities and histology have been investigated after 7, 14, 26 and 56 days of DON feeding. The acute response comprises down-regulation of biotransformation enzymes, whereas the chronic response to DON is characterised by activation of alanine aminotransferase which indicates damage to liver tissue. Examination of histological sections of liver tissue revealed that changes such as fat aggregation, vacuolisation and hyperaemia were present after 14 and 26 days of exposure to DON but not thereafter. Several enzymes involved in glutathione cycling and reduction of oxidative stress were found to be reduced after 26 and 56 days of DON feeding. The results suggest that supporting the antioxidative system, e.g. by using glutathione-enriched yeast extracts as a food additive, might be successful in preventing the effects of DON in carp. This is the basis of a fundamental hypothesis since DON contamination of fish feed leads to pronounced effects on liver histology and liver enzyme activities which may also cause changes in the normal liver metabolism of endogenous and xenobiotic compounds.

scholarly journals Effect of Intrahepatic Arterial Delivery of Sorafenib on Normal Liver Tissue of Rabbit: An Experimental Study

2020 ◽  
Vol 3 (1) ◽  
pp. 1
Author(s):  
Eerdunbagena Ning ◽  
Zhijun Wang
Keyword(s):  
Heart Rate ◽  
Rectal Temperature ◽  
Liver Tissue ◽  
High Performance ◽  
Arterial Embolization ◽  
Hepatic Arterial Infusion ◽  
Normal Liver ◽  
Normal Liver Tissue ◽  
Breathing Rate ◽  
Local Necrosis

Objective: To assess the safety, feasibility and eluting efficiency of intrahepatic arterial delivery of sorafenib on normal liver tissue of rabbit. Methods: 24 New Zealand rabbits were randomly divided into three groups: group Ⅰ (Lipiodol-sorafenid), group Ⅱ (Lipiodol) and group Ⅲ (Sorafenib). Group Ⅰ and Ⅱ were treated by transcatheter selective hepatic arterial embolization with emulsions of lipiodol and sorafenib or with only lipiodol, while group Ⅲ was given hepatic arterial infusion with sorafenib. Sorafenib concentration in plasma was determined by HPLC (high performance liquid chromatography) in 0 min, 20 min, 1h, 2h, 4h, 8h, 16h, 32h and 48h respectively. The breathing rate, heart rate, rectal temperature and body weight were measured, as well the blood routine test and the function of liver, kidney, and heart. Two animals of each group were respectively killed in the 3rd day, 1st, 3rd and 6th week after treatment. Histopathologic study was done to liver, heart, kinney, lung, brain, gall bladder and intestine. Result: ① The peak sorafenib concentration (Cmax)and AUC(Area under curve) in plasma in groupⅠwas 2.46±0.101μg/ml and 945.72 ± 52.3 μg/mL.min respectively, while in group Ⅲ which was 3.78±0.180 ug/ml and 546.98±21.1μg/mL.min. Compared with groupⅢ, the Cmax and AUC of groupⅠhad a significant statistics difference (p<0.05). ② The breathing rate, heart rate, rectal temperature and AST/ALT,WBC,NEU% of group Ⅰand groupⅢhas a significant statistics difference(p<0.05) in the 3rd day. ③CK ,CK-MB, DB, Cr，BUN,RBC,PLT in plasma did not change in all group.④Local necrosis was seen in group Ⅰand group Ⅱin the 3rd day and 1st week, but they did not seem to be different. Group Ⅲ showed no necrosis. Granulation tissue with bile duty, portal vein and microfossils hyperplasia were seen in local necrosis area in the 3rd week. No pathological changes were found in brain, heart, kidney, intestine and gallbladder. Conclusion: TAE with emulsions of lipiodol and sorafenib is feasible, safe and has some slow-release effect.

Immune Checkpoint Molecules, Personalized Immunotherapy, and Autoimmune Diabetes

2018 ◽  
Vol 24 (11) ◽  
pp. 931-941 ◽  
Author(s):  
Ciriana Orabona ◽  
Giada Mondanelli ◽  
Paolo Puccetti ◽  
Ursula Grohmann
Keyword(s):  
Immune Checkpoint ◽  
Autoimmune Diabetes ◽  
Immune Checkpoint Molecules
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