Aberrant protein glycosylation in cancer: implications in targeted therapy

2021 ◽  
Author(s):  
Joana G. Rodrigues ◽  
Henrique O. Duarte ◽  
Celso A. Reis ◽  
Joana Gomes
Keyword(s):  
Targeted Therapy ◽  
Tumour Cell ◽  
Rational Design ◽  
Molecular Mechanisms ◽  
Clinical Performance ◽  
Therapeutic Strategies ◽  
Protein Glycosylation ◽  
Immune Checkpoints ◽  
Immunosuppressive Microenvironment ◽  
The Impact

Aberrant cell surface glycosylation signatures are currently known to actively drive the neoplastic transformation of healthy cells. By disrupting the homeostatic functions of their protein carriers, cancer-associated glycans mechanistically underpin several molecular hallmarks of human malignancy. Furthermore, such aberrant glycan structures play key roles in the acquisition of molecular resistance to targeted therapeutic agents, which compromises their clinical efficacy, by modulating tumour cell aggressiveness and supporting the establishment of an immunosuppressive microenvironment. Recent advances in the study of the tumour cell glycoproteome have unravelled previously elusive molecular mechanisms of therapeutic resistance, guided the rational design of novel personalized therapeutic strategies, and may further improve the clinical performance of currently approved anti-cancer targeted agents. In this review, we highlight the impact of glycosylation in cancer targeted therapy, with particular focus on receptor tyrosine kinase-targeted therapy, immune checkpoints blockade therapy, and current developments on therapeutic strategies directed to glycan-binding proteins and other innovative glycan therapeutic strategies.

scholarly journals Immune Checkpoints Contribute Corneal Immune Privilege: Implications for Dry Eye Associated with Checkpoint Inhibitors

2020 ◽  
Vol 21 (11) ◽  
pp. 3962
Author(s):  
Junko Hori ◽  
Tomoyuki Kunishige ◽  
Yuji Nakano
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Dry Eye ◽  
Molecular Mechanisms ◽  
Checkpoint Inhibitors ◽  
Corneal Transplantation ◽  
Immune Privilege ◽  
Immune Checkpoints ◽  
Corneal Tissue ◽  
Immunosuppressive Microenvironment

The eye is provided with immune protection against pathogens in a manner that greatly reduces the threat of inflammation-induced vision loss. Immune-mediated inflammation and allograft rejection are greatly reduced in the eye, a phenomenon called ‘immune privilege’. Corneal tissue has inherent immune privilege properties with underlying three mechanisms: (1) anatomical, cellular, and molecular barriers in the cornea; (2) an immunosuppressive microenvironment; and (3) tolerance related to regulatory T cells and anterior chamber-associated immune deviation. This review describes the molecular mechanisms of the immunosuppressive microenvironment and regulatory T cells in the cornea that have been elucidated from animal models of ocular inflammation, especially those involving corneal transplantation, it also provides an update on immune checkpoint molecules in corneal and systemic immune regulation, and its relevance for dry eye associated with checkpoint inhibitor therapy.

scholarly journals New development of Immune checkpoints blockade in cancer immunotherapy

2019 ◽  
Vol 131 ◽  
pp. 01022
Author(s):  
Feixuan Wu
Keyword(s):  
Cell Death ◽  
Targeted Therapy ◽  
Programmed Cell Death ◽  
Cancer Treatment ◽  
Molecular Mechanisms ◽  
Nk Cell ◽  
Cytotoxic T Lymphocyte ◽  
Immune Checkpoints ◽  
Main Stream ◽  
Positive Effects

Immunotherapy has become the main stream in cancer treatment nowadays. It includes T cell, NK cell targeted therapy, as well as antibody targeted therapy and its derivatives. Recently immune checkpoints blockade (ICB) has been developed, which are said to be a better method in treatment. The release of negative regulators of immune activation has resulted in unprecedented rates of long-lasting tumor responses in patients with a variety of cancers. This can be achieved by antibodies blocking the cytotoxic T lymphocyte–associated protein 4 (CTLA-4), the programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PDL-1) pathway or the lymphocyte-activated gene-3 (LAG-3) pathway, either alone or in combination. Improvement of treatment benefits from the research in molecular mechanisms of ICB. For example, mechanism of LAG-3 and its valid ligands is unclear, which leads to a misunderstanding that the antibody might be ineffective. After finding these results demonstrating that fibrinogen-like protein 1(FGL1) is an important functional ligand of LAG-3, it reveals the role of this LAG 3-FGL1 pathway in tumor immunity. Although there are some potential side effects, these therapies turn out to have lots of positive effects on most patients. Therefore, this review summarizes the latest advances, hoping that it may have a great contribution to the cancer treatment.

scholarly journals The Impact of Oxidative Stress in Human Pathology: Focus on Gastrointestinal Disorders

Antioxidants ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 201
Author(s):  
Rosa Vona ◽  
Lucia Pallotta ◽  
Martina Cappelletti ◽  
Carola Severi ◽  
Paola Matarrese
Keyword(s):  
Oxidative Stress ◽  
Molecular Mechanisms ◽  
Gastrointestinal Diseases ◽  
Therapeutic Strategies ◽  
Gastrointestinal Disorders ◽  
Antioxidant Systems ◽  
New Techniques ◽  
Human Pathology ◽  
Substantial Progress ◽  
The Impact

Accumulating evidence shows that oxidative stress plays an essential role in the pathogenesis and progression of many diseases. The imbalance between the production of reactive oxygen species (ROS) and the antioxidant systems has been extensively studied in pulmonary, neurodegenerative cardiovascular disorders; however, its contribution is still debated in gastrointestinal disorders. Evidence suggests that oxidative stress affects gastrointestinal motility in obesity, and post-infectious disorders by favoring the smooth muscle phenotypic switch toward a synthetic phenotype. The aim of this review is to gain insight into the role played by oxidative stress in gastrointestinal pathologies (GIT), and the involvement of ROS in the signaling underlying the muscular alterations of the gastrointestinal tract (GIT). In addition, potential therapeutic strategies based on the use of antioxidants for the treatment of inflammatory gastrointestinal diseases are reviewed and discussed. Although substantial progress has been made in identifying new techniques capable of assessing the presence of oxidative stress in humans, the biochemical-molecular mechanisms underlying GIT mucosal disorders are not yet well defined. Therefore, further studies are needed to clarify the mechanisms through which oxidative stress-related signaling can contribute to the alteration of the GIT mucosa in order to devise effective preventive and curative therapeutic strategies

scholarly journals Molecular Scale Spatio-Chemical Control of the Activating-Inhibitory Signal Integration in NK Cells

2020 ◽  
Author(s):  
Esti Toledo ◽  
Guillaume Le Saux ◽  
Long Li ◽  
Maor Rosenberg ◽  
Yossi Keidar ◽  
...  
Keyword(s):  
Nk Cells ◽  
Rational Design ◽  
Molecular Mechanisms ◽  
Spatial Interaction ◽  
Immune Checkpoints ◽  
Cytotoxic Lymphocytes ◽  
Inhibitory Receptors ◽  
Molecular Scale ◽  
Cell Niche

AbstractThe role of the spatial juxtaposition between activating and inhibitory receptors in cytotoxic lymphocytes has been strongly debated in the context of the inhibition of immune signaling. The challenge in addressing this problem was so far a lack of experimental tools which can simultaneously manipulate different signaling molecules. Here, we circumvent this challenge by introducing a nanoengineered multifunctional cell niche, in which activating and inhibitory ligands are positioned with molecular-scale variability and control, and applied it to elucidate the role of the spatial juxtaposition between ligands for NKG2D and KIR2DL1 – activating and inhibitory receptors in Natural Killer (NK) cells – in KIR2DL1-mediated inhibition of NKG2D signaling. We realized the niche by a nanopatterning of nanodots of different metals with molecular scale registry in one lithographic step, followed by a novel ternary functionalization of the fabricated bi-metallic pattern and its background to with three distinct biochemical moieties. We found, that within the probed range, the 40 nm gap between the activating and inhibitory ligands provided an optimal inhibition condition. Supported by theoretical modeling and simulations we interpret these findings as a consequence of the size and conformational flexibility of the ligands in their spatial interaction. Our findings provide an important insight onto the spatial mechanism of the inhibitory immune checkpoints, whose understanding is both fundamentally important, and essential for the rational design of future immunotherapies. Furthermore, our approach is highly versatile and paves the way to numerous complex molecular platforms aimed at revealing molecular mechanisms through which receptors integrate their signals.

scholarly journals Global Dynamics as Communication Sensors in Peptide Synthetase Cyclization Domains.

2021 ◽  
Author(s):  
Subrata H Mishra ◽  
Aswani K Kancherla ◽  
Kenneth A Marincin ◽  
Guillaume Bouvignies ◽  
Santrupti Nerli ◽  
...  
Keyword(s):  
Structural Biology ◽  
Structural Dynamics ◽  
Rational Design ◽  
Solution Structure ◽  
Molecular Mechanisms ◽  
Global Dynamics ◽  
Site Mutation ◽  
Molecular Events ◽  
Domain Dynamics ◽  
The Impact

Structural biology is the foundation for deriving molecular mechanisms, where snapshots of macromolecules and binding partners inform on mutations that test or modify function. However, frequently, the impact of mutations violates the underpinnings of structural models, and mechanisms become cryptic. This conundrum applies to multidomain enzymatic systems called nonribosomal peptide synthetases (NRPSs), which assemble simple substrates into complex metabolites often with pharmaceutical properties. Engineering NRPSs can generate new pharmaceuticals, but a dynamic domain organization challenges rational design. Using nuclear magnetic resonance (NMR), we determined the solution structure of a 52 kDa cyclization domain and demonstrate that global intra-domain dynamics enable sensing of substrates tethered to partner domains and draw an allosteric response encompassing the enzyme′s buried active site and two binding sites 40 Å apart. We show that a point-site mutation that impedes the domain dynamics globally hampers the allosteric response. We demonstrate this mechanism through NMR experiments that provide atomic-level read-outs of allosteric responses during biochemical transformations in situ. Our results establish global structural dynamics as sensors of molecular events that can remodel domain interactions and illustrate the need for integrating structural dynamics explicitly when deriving molecular mechanisms through mutagenesis and structural biology.

scholarly journals Mutational patterns in oncogenes and tumour suppressors

2016 ◽  
Vol 44 (3) ◽  
pp. 925-931 ◽  
Author(s):  
Hanadi M. Baeissa ◽  
Graeme Benstead-Hume ◽  
Christopher J. Richardson ◽  
Frances M.G. Pearl
Keyword(s):  
Tumour Cell ◽  
Selective Advantage ◽  
Therapeutic Strategies ◽  
Human Proteome ◽  
Driver Mutations ◽  
Disease Progress ◽  
Tumour Suppressors ◽  
Cancer Initiation ◽  
The Impact ◽  
Automatic Pipeline

All cancers depend upon mutations in critical genes, which confer a selective advantage to the tumour cell. Knowledge of these mutations is crucial to understanding the biology of cancer initiation and progression, and to the development of targeted therapeutic strategies. The key to understanding the contribution of a disease-associated mutation to the development and progression of cancer, comes from an understanding of the consequences of that mutation on the function of the affected protein, and the impact on the pathways in which that protein is involved. In this paper we examine the mutation patterns observed in oncogenes and tumour suppressors, and discuss different approaches that have been developed to identify driver mutations within cancers that contribute to the disease progress. We also discuss the MOKCa database where we have developed an automatic pipeline that structurally and functionally annotates all proteins from the human proteome that are mutated in cancer.

scholarly journals Immuno-profiling and cellular spatial analysis using five immune oncology multiplex immunofluorescence panels for paraffin tumor tissue

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Edwin Roger Parra ◽  
Maria C. Ferrufino-Schmidt ◽  
Auriole Tamegnon ◽  
Jiexin Zhang ◽  
Luisa Solis ◽  
...  
Keyword(s):  
Spatial Relationship ◽  
Suppressor Cells ◽  
Immune Checkpoints ◽  
Formalin Fixed Paraffin ◽  
Tumor Tissues ◽  
Formalin Fixed Paraffin Embedded ◽  
Amplification System ◽  
New Ideas ◽  
Immunosuppressive Microenvironment ◽  
The Impact

AbstractMultiplex immunofluorescence (mIF) has arisen as an important tool for immuno-profiling tumor tissues. We updated our manual protocol into an automated protocol that allows the use of up to seven markers in five mIF panels to apply to formalin-fixed paraffin-embedded tumor tissues. Using a tyramide signal amplification system, we optimized five mIF panels that included cytokeratin to characterize malignant cells (MCs), immune checkpoint markers (i.e., PD-L1, B7-H3, B7-H4, IDO-1, VISTA, LAG3, ICOS, TIM3, and OX40), tumor-infiltrating lymphocytic markers (i.e., CD3, CD8, CD45RO, granzyme B, PD-1, and FOXP3), and markers to characterize myeloid-derived suppressor cells (i.e., CD68, CD66b, CD14, CD33, Arg-1, and CD11b). To determine analytical reproducibility and the impact of those panels for immuno-profiling tumor tissues, we performed an exploratory analysis in a set of non–small cell lung cancer (NSCLC) samples. The slides were scanned, and the different cell phenotypes were quantified by simultaneous co-localizations with the markers using image analysis software. Comparison between the time points of staining showed high analytical reproducibility. The analysis of NSCLC cases showed an immunosuppressive microenvironment with PD-L1/PD-1 expression as a predominant axis. Interestingly, high density of MCs expressing B7-H4 was correlated with recurrence. Unexpectedly, MCs expressing OX40 were also detected, and those cells were a closer distance to CD3+T-cells than were MCs expressing other immune checkpoints. Two different cellular patterns of spatial distribution were determined according the CD3 distribution, and the predominant pattern was related with active immunosuppressive interaction with MCs. Our study shows that these five mIF panels can identify multiple targets in a single cell with high reproducibility. The study of different cell populations and their spatial relationship can open new ideas for therapeutic approaches.

The Impact of Ultraviolet Radiation on Barrier Function in Human Skin: Molecular Mechanisms and Topical Therapeutics

2019 ◽  
Vol 25 (40) ◽  
pp. 5503-5511 ◽  
Author(s):  
Abdulaziz Alhasaniah ◽  
Michael J. Sherratt ◽  
Catherine A. O'Neill
Keyword(s):  
Ultraviolet Radiation ◽  
Barrier Function ◽  
Molecular Mechanisms ◽  
Transepidermal Water Loss ◽  
Protective Effects ◽  
Barrier Dysfunction ◽  
Epidermal Barrier ◽  
Positive Effects ◽  
Terrestrial Mammals ◽  
The Impact

A competent epidermal barrier is crucial for terrestrial mammals. This barrier must keep in water and prevent entry of noxious stimuli. Most importantly, the epidermis must also be a barrier to ultraviolet radiation (UVR) from the sunlight. Currently, the effects of ultraviolet radiation on epidermal barrier function are poorly understood. However, studies in mice and more limited work in humans suggest that the epidermal barrier becomes more permeable, as measured by increased transepidermal water loss, in response UVR, at doses sufficiently high to induce erythema. The mechanisms may include disturbance in the organisation of lipids in the stratum corneum (the outermost layer of the epidermis) and reduction in tight junction function in the granular layer (the first living layer of the skin). By contrast, suberythemal doses of UVR appear to have positive effects on epidermal barrier function. Topical sunscreens have direct and indirect protective effects on the barrier through their ability to block UV and also due to their moisturising or occlusive effects, which trap water in the skin, respectively. Some topical agents such as specific botanical extracts have been shown to prevent the loss of water associated with high doses of UVR. In this review, we discuss the current literature and suggest that the biology of UVR-induced barrier dysfunction, and the use of topical products to protect the barrier, are areas worthy of further investigation.

The Role of Vascular Aging in Atherosclerotic Plaque Development and Vulnerability

2019 ◽  
Vol 25 (29) ◽  
pp. 3098-3111 ◽  
Author(s):  
Luca Liberale ◽  
Giovanni G. Camici
Keyword(s):  
Atherosclerotic Plaque ◽  
Molecular Mechanisms ◽  
Driving Forces ◽  
Plaque Burden ◽  
Vascular Aging ◽  
Age Related ◽  
Plaque Development ◽  
Increased Risk ◽  
The Impact ◽  
Over Time

Background: The ongoing demographical shift is leading to an unprecedented aging of the population. As a consequence, the prevalence of age-related diseases, such as atherosclerosis and its thrombotic complications is set to increase in the near future. Endothelial dysfunction and vascular stiffening characterize arterial aging and set the stage for the development of cardiovascular diseases. Atherosclerotic plaques evolve over time, the extent to which these changes might affect their stability and predispose to sudden complications remains to be determined. Recent advances in imaging technology will allow for longitudinal prospective studies following the progression of plaque burden aimed at better characterizing changes over time associated with plaque stability or rupture. Oxidative stress and inflammation, firmly established driving forces of age-related CV dysfunction, also play an important role in atherosclerotic plaque destabilization and rupture. Several genes involved in lifespan determination are known regulator of redox cellular balance and pre-clinical evidence underlines their pathophysiological roles in age-related cardiovascular dysfunction and atherosclerosis. Objective: The aim of this narrative review is to examine the impact of aging on arterial function and atherosclerotic plaque development. Furthermore, we report how molecular mechanisms of vascular aging might regulate age-related plaque modifications and how this may help to identify novel therapeutic targets to attenuate the increased risk of CV disease in elderly people.

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