scholarly journals Immunoepigenetics Combination Therapies: An Overview of the Role of HDACs in Cancer Immunotherapy

2019 ◽  
Vol 20 (9) ◽  
pp. 2241 ◽  
Author(s):  
Debarati Banik ◽  
Sara Moufarrij ◽  
Alejandro Villagra
Keyword(s):  
Histone Deacetylase Inhibitors ◽  
Critical Role ◽  
Preclinical Studies ◽  
Clinical Use ◽  
Combination Therapies ◽  
Drug Candidates ◽  
Cellular Processes ◽  
Fda Approval

Long-standing efforts to identify the multifaceted roles of histone deacetylase inhibitors (HDACis) have positioned these agents as promising drug candidates in combatting cancer, autoimmune, neurodegenerative, and infectious diseases. The same has also encouraged the evaluation of multiple HDACi candidates in preclinical studies in cancer and other diseases as well as the FDA-approval towards clinical use for specific agents. In this review, we have discussed how the efficacy of immunotherapy can be leveraged by combining it with HDACis. We have also included a brief overview of the classification of HDACis as well as their various roles in physiological and pathophysiological scenarios to target key cellular processes promoting the initiation, establishment, and progression of cancer. Given the critical role of the tumor microenvironment (TME) towards the outcome of anticancer therapies, we have also discussed the effect of HDACis on different components of the TME. We then have gradually progressed into examples of specific pan-HDACis, class I HDACi, and selective HDACis that either have been incorporated into clinical trials or show promising preclinical effects for future consideration. Finally, we have included examples of ongoing trials for each of the above categories of HDACis as standalone agents or in combination with immunotherapeutic approaches.

scholarly journals The Canonical Wnt Pathway as a Key Regulator in Liver Development, Differentiation and Homeostatic Renewal

Genes ◽  
2020 ◽  
Vol 11 (10) ◽  
pp. 1163
Author(s):  
Sebastian L. Wild ◽  
Aya Elghajiji ◽  
Carmen Grimaldos Rodriguez ◽  
Stephen D. Weston ◽  
Zoë D. Burke ◽  
...  
Keyword(s):  
Critical Role ◽  
Hypoxia Inducible Factor ◽  
Signalling Pathway ◽  
Fate Specification ◽  
Cellular Processes ◽  
Recent Developments ◽  
Body Patterning ◽  
Important Regulator ◽  
Canonical Wnt

The canonical Wnt (Wnt/β-catenin) signalling pathway is highly conserved and plays a critical role in regulating cellular processes both during development and in adult tissue homeostasis. The Wnt/β-catenin signalling pathway is vital for correct body patterning and is involved in fate specification of the gut tube, the primitive precursor of liver. In adults, the Wnt/β-catenin pathway is increasingly recognised as an important regulator of metabolic zonation, homeostatic renewal and regeneration in response to injury throughout the liver. Herein, we review recent developments relating to the key role of the pathway in the patterning and fate specification of the liver, in the directed differentiation of pluripotent stem cells into hepatocytes and in governing proliferation and zonation in the adult liver. We pay particular attention to recent contributions to the controversy surrounding homeostatic renewal and proliferation in response to injury. Furthermore, we discuss how crosstalk between the Wnt/β-catenin and Hedgehog (Hh) and hypoxia inducible factor (HIF) pathways works to maintain liver homeostasis. Advancing our understanding of this pathway will benefit our ability to model disease, screen drugs and generate tissue and organ replacements for regenerative medicine.

scholarly journals Positive-strand RNA viruses stimulate host phosphatidylcholine synthesis at viral replication sites

2016 ◽  
Vol 113 (8) ◽  
pp. E1064-E1073 ◽  
Author(s):  
Jiantao Zhang ◽  
Zhenlu Zhang ◽  
Vineela Chukkapalli ◽  
Jules A. Nchoutmboube ◽  
Jianhui Li ◽  
...  
Keyword(s):  
Viral Replication ◽  
Rna Viruses ◽  
Critical Role ◽  
Brome Mosaic Virus ◽  
Alternate Host ◽  
Positive Strand ◽  
Cellular Processes ◽  
Replication Sites ◽  
Positive Strand Rna

All positive-strand RNA viruses reorganize host intracellular membranes to assemble their viral replication complexes (VRCs); however, how these viruses modulate host lipid metabolism to accommodate such membrane proliferation and rearrangements is not well defined. We show that a significantly increased phosphatidylcholine (PC) content is associated with brome mosaic virus (BMV) replication in both natural host barley and alternate host yeast based on a lipidomic analysis. Enhanced PC levels are primarily associated with the perinuclear ER membrane, where BMV replication takes place. More specifically, BMV replication protein 1a interacts with and recruits Cho2p (choline requiring 2), a host enzyme involved in PC synthesis, to the site of viral replication. These results suggest that PC synthesized at the site of VRC assembly, not the transport of existing PC, is responsible for the enhanced accumulation. Blocking PC synthesis by deleting theCHO2gene resulted in VRCs with wider diameters than those in wild-type cells; however, BMV replication was significantly inhibited, highlighting the critical role of PC in VRC formation and viral replication. We further show that enhanced PC levels also accumulate at the replication sites of hepatitis C virus and poliovirus, revealing a conserved feature among a group of positive-strand RNA viruses. Our work also highlights a potential broad-spectrum antiviral strategy that would disrupt PC synthesis at the sites of viral replication but would not alter cellular processes.

Ontology Development and the Role of Knowledge in E-Government Project Management

2016 ◽  
pp. 475-496
Author(s):  
Bongani Ngwenya
Keyword(s):  
Developing Countries ◽  
Project Management ◽  
Critical Role ◽  
Ontology Development ◽  
Government Project ◽  
Information And Communication ◽  
Management Approaches ◽  
Services Implementation

The literature suggests that the elaboration of ontology contributes to the standardization and classification of concepts and terminologies, and it has been happening in some sectors, such as software engineering, e-Government services implementation, and project management. In the area of e-Government, knowledge plays a critical role in the development of e-Government transformation project management ontology, which aims at adopting and customizing the existing project management approaches according to the specific challenges encountered in the e-Government environment. It is in this context that this chapter presents an ontological representation of the concepts of e-Government project management in one of the developing countries in southern Africa. The chapter further intends to collaborate in the excellence and productivity of the management of the e-Government project process. This will also enable the interoperability and knowledge reuse between all factors and stakeholders related with the implementation of such types of projects as a lesson for developing countries. The data was collected by use of an interview protocol or schedule, and the researcher interviewed relevant employees of the two ministries, the Ministry of Information Technology and the Ministry of Information and Communication. The data was then analyzed qualitatively to draw a model that the Zimbabwean government is adopting.

Metabolite identification in preclinical and clinical phase of drug development

2021 ◽  
Vol 22 ◽  
Author(s):  
Yali Wu ◽  
Lulu Pan ◽  
Zhendong Chen ◽  
Yuandong Zheng ◽  
Xingxing Diao ◽  
...  
Keyword(s):  
Drug Development ◽  
Kinase Inhibitors ◽  
Critical Role ◽  
Metabolite Identification ◽  
Correct Identification ◽  
Drug Candidates ◽  
Clinical Phase ◽  
Natural Medicines ◽  
Insight Into

: Metabolite identification plays a critical role in the phases during drug development. Drug metabolites can contribute to efficacy, toxicity, and drug-drug interaction. Thus, the correct identification of metabolites is essential to understand the behavior of drugs in humans. Drug administration authorities (e.g., FDA, EMA, and NMPA) emphasize evaluating the safety of human metabolites with exposure higher than 10% of the total drug-related components. Many previous reviews have summarized the various methods, tools, and strategies for the appropriate and comprehensive identification of metabolites. In this review, we focus on summarizing the importance of identifying metabolites in the preclinical and clinical phases of drug development. Summarized scenarios include the role of metabolites in pharmacokinetics/pharmacodynamics (PK/PD) analysis, disproportional exposure of metabolites that contribute to drug toxicity, changes in metabolite exposure in renal-impaired patients, covalent tyrosine kinase inhibitors (anticancer drugs), and metabolite identification of drug candidates from natural medicines. This review is aimed to provide meaningful insight into the significant role of metabolite identification in drug development.

scholarly journals Role of mTOR Signaling in Tumor Microenvironment: An Overview

2018 ◽  
Vol 19 (8) ◽  
pp. 2453 ◽  
Author(s):  
Fabiana Conciatori ◽  
Chiara Bazzichetto ◽  
Italia Falcone ◽  
Sara Pilotto ◽  
Emilio Bria ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Mammalian Target Of Rapamycin ◽  
Mtor Pathway ◽  
Mtor Signaling ◽  
New Combination ◽  
Combination Therapies ◽  
Cellular Processes ◽  
Promising Target ◽  
Exogenous Cues

The mammalian target of rapamycin (mTOR) pathway regulates major processes by integrating a variety of exogenous cues, including diverse environmental inputs in the tumor microenvironment (TME). In recent years, it has been well recognized that cancer cells co-exist and co-evolve with their TME, which is often involved in drug resistance. The mTOR pathway modulates the interactions between the stroma and the tumor, thereby affecting both the tumor immunity and angiogenesis. The activation of mTOR signaling is associated with these pro-oncogenic cellular processes, making mTOR a promising target for new combination therapies. This review highlights the role of mTOR signaling in the characterization and the activity of the TME’s elements and their implications in cancer immunotherapy.

Protein Chimera-based Ca2+ Rewiring as a Treatment Modality for Neurodegeneration

2019 ◽  
Vol 8 (1) ◽  
pp. 27-40
Author(s):  
Netra Unni Rajesh ◽  
Anam Qudrat
Keyword(s):  
Neurological Disease ◽  
Signal Transmission ◽  
Critical Role ◽  
Disease Development ◽  
Targeted Therapeutics ◽  
Cellular Processes ◽  
Symptom Alleviation ◽  
Modular Proteins ◽  
Neuronal Signal

Calcium is a versatile signaling molecule; a key regulator of an array of diverse cellular processes ranging from transcription to motility to apoptosis. It plays a critical role in neuronal signal transmission and energy metabolism through specialized mechanisms. Dysregulation of the Ca2+ signaling pathways has been linked to major psychiatric diseases. Here, we focus on molecular psychiatry, exploring the role of calcium signaling in neurological disease development and aggravation, specifically in Alzheimer’s and Huntington’s diseases. Understanding the molecular underpinnings helps us first to identify common mechanistic patterns, and second to develop targeted therapeutics for symptom alleviation. Specifically, we propose potential protein-level hallmarks of dysregulation that can be targeted using calcium-based chimeras (synthetic fusions of unrelated modular proteins) for localized pharmacotherapy.

scholarly journals Pathobiology of pulmonary arterial hypertension: understanding the roads less travelled

2017 ◽  
Vol 26 (146) ◽  
pp. 170093 ◽  
Author(s):  
Anna R. Hemnes ◽  
Marc Humbert
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Critical Role ◽  
Fatal Disease ◽  
Treatment Regimens ◽  
Cellular Processes ◽  
Considerable Research ◽  
Pulmonary Arterial ◽  
Target Alternative

The pathobiology of pulmonary arterial hypertension (PAH) is complex and incompletely understood. Although three pathogenic pathways have been relatively well characterised, it is widely accepted that dysfunction in a multitude of other cellular processes is likely to play a critical role in driving the development of PAH. Currently available therapies, which all target one of the three well-characterised pathways, provide significant benefits for patients; however, PAH remains a progressive and ultimately fatal disease. The development of drugs to target alternative pathogenic pathways is, therefore, an attractive proposition and one that may complement existing treatment regimens to improve outcomes for patients. Considerable research has been undertaken to identify the role of the less well-understood pathways and in this review we will highlight some of the key discoveries and the potential for utility as therapeutic targets.

scholarly journals SIRT7: a sentinel of genome stability

Open Biology ◽  
2021 ◽  
Vol 11 (6) ◽  
pp. 210047
Author(s):  
Ming Tang ◽  
Huangqi Tang ◽  
Bo Tu ◽  
Wei-Guo Zhu
Keyword(s):  
Dna Damage ◽  
Genome Stability ◽  
Biological Function ◽  
Critical Role ◽  
Class Iii ◽  
Cellular Processes ◽  
The Past ◽  
Damage Response ◽  
Normal Gene

SIRT7 is a class III histone deacetylase that belongs to the sirtuin family. The past two decades have seen numerous breakthroughs in terms of understanding SIRT7 biological function. We now know that this enzyme is involved in diverse cellular processes, ranging from gene regulation to genome stability, ageing and tumorigenesis. Genomic instability is one hallmark of cancer and ageing; it occurs as a result of excessive DNA damage. To counteract such instability, cells have evolved a sophisticated regulated DNA damage response mechanism that restores normal gene function. SIRT7 seems to have a critical role in this response, and it is recruited to sites of DNA damage where it recruits downstream repair factors and directs chromatin regulation. In this review, we provide an overview of the role of SIRT7 in DNA repair and maintaining genome stability. We pay particular attention to the implications of SIRT7 function in cancer and ageing.

scholarly journals Structural basis of the differential binding of engineered knottins 2.5F and 2.5D to integrins αVβ3 and α5β1

2019 ◽  
Author(s):  
Johannes F. Van Agthoven ◽  
Hengameh Shams ◽  
Frank V. Cochran ◽  
José L. Alonso ◽  
James R. Kintzing ◽  
...  
Keyword(s):  
Cancer Therapy ◽  
Critical Role ◽  
Md Simulations ◽  
Structural Basis ◽  
Conformational Selection ◽  
Drug Candidates ◽  
Tumor Survival ◽  
Differential Binding ◽  
Integrin Ligand

AbstractIntegrins αVβ3 and α5β1 play critical roles in tumor survival, invasion, metastasis, and angiogenesis and are validated targets for cancer therapy and molecular imaging. Increasing evidence suggests that targeting both integrins simultaneously with antagonists is more effective in cancer therapy because of concerns about resistance and paradoxical promotion of tumor growth with use of agents highly selective for a single integrin. Engineered Arg-Gly-Asp (RGD)-containing 3.5 kDa cysteine-knot proteins (knottins 2.5F and 2.5D) are attractive drug candidates due to their exceptional structural stability and high affinity binding to certain integrins. 2.5F binds both αVβ3 and α5β1, whereas 2.5D is αVβ3-selective. To elucidate the structural basis of integrin selection, we determined the structures of 2.5F and 2.5D both as apo-proteins and in complex with αVβ3. These data, combined with MD simulations and mutational studies, revealed a critical role of two αVβ3-specific residues in the vicinity of the metal ion dependent adhesion site (MIDAS) in promoting an αVβ3-induced fit of 2.5D. In contrast, conformational selection accounted for the specificity of 2.5F to both integrins. These data provide new insights into the structural basis of integrin-ligand binding specificity, and could help in development of integrin-targeted therapeutics.

Ontology Development and the Role of Knowledge in E-Government Project Management

2015 ◽  
pp. 289-310
Author(s):  
Bongani Ngwenya
Keyword(s):  
Developing Countries ◽  
Project Management ◽  
Critical Role ◽  
Ontology Development ◽  
Government Project ◽  
Information And Communication ◽  
Management Approaches ◽  
Services Implementation

The literature suggests that the elaboration of ontology contributes to the standardization and classification of concepts and terminologies, and it has been happening in some sectors, such as software engineering, e-Government services implementation, and project management. In the area of e-Government, knowledge plays a critical role in the development of e-Government transformation project management ontology, which aims at adopting and customizing the existing project management approaches according to the specific challenges encountered in the e-Government environment. It is in this context that this chapter presents an ontological representation of the concepts of e-Government project management in one of the developing countries in southern Africa. The chapter further intends to collaborate in the excellence and productivity of the management of the e-Government project process. This will also enable the interoperability and knowledge reuse between all factors and stakeholders related with the implementation of such types of projects as a lesson for developing countries. The data was collected by use of an interview protocol or schedule, and the researcher interviewed relevant employees of the two ministries, the Ministry of Information Technology and the Ministry of Information and Communication. The data was then analyzed qualitatively to draw a model that the Zimbabwean government is adopting.

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