scholarly journals Oncogenic KRAS-Induced Feedback Inflammatory Signaling in Pancreatic Cancer: An Overview and New Therapeutic Opportunities

Cancers ◽  
2021 ◽  
Vol 13 (21) ◽  
pp. 5481
Author(s):  
Sapana Bansod ◽  
Paarth B. Dodhiawala ◽  
Kian-Huat Lim
Keyword(s):  
Cell Types ◽  
Therapeutic Strategies ◽  
Ductal Adenocarcinoma ◽  
Inflammatory Signaling ◽  
Inflammatory Signals ◽  
Bidirectional Signaling ◽  
Novel Therapeutic Strategies ◽  
Almost All ◽  
The Impact ◽  
Malignant Behavior

Pancreatic ductal adenocarcinoma (PDAC) remains highly refractory to treatment. While the KRAS oncogene is present in almost all PDAC cases and accounts for many of the malignant feats of PDAC, targeting KRAS or its canonical, direct effector cascades remains unsuccessful in patients. The recalcitrant nature of PDAC is also heavily influenced by its highly fibro-inflammatory tumor microenvironment (TME), which comprises an acellular extracellular matrix and various types of non-neoplastic cells including the fibroblasts, immune cells, and adipocytes, underscoring the critical need to delineate the bidirectional signaling interplay between PDAC cells and the TME in order to develop novel therapeutic strategies. The impact of tumor-cell KRAS signaling on various cell types in the TME has been well covered by several reviews. In this article, we critically reviewed evidence, including work from our group, on how the feedback inflammatory signals from the TME impact and synergize with oncogenic KRAS signaling in PDAC cells, ultimately augmenting their malignant behavior. We discussed past and ongoing clinical trials that target key inflammatory pathways in PDAC and highlight lessons to be learned from outcomes. Lastly, we provided our perspective on the future of developing therapeutic strategies for PDAC through understanding the breadth and complexity of KRAS and the inflammatory signaling network.

scholarly journals Deciphering the Role of Innate Immune NF-ĸB Pathway in Pancreatic Cancer

Cancers ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 2675
Author(s):  
Namrata Khurana ◽  
Paarth B. Dodhiawala ◽  
Ashenafi Bulle ◽  
Kian-Huat Lim
Keyword(s):  
Molecular Mechanisms ◽  
Clinical Success ◽  
Cell Types ◽  
Innate Immune ◽  
Ductal Adenocarcinoma ◽  
Effective Treatment Option ◽  
Stromal Fibroblasts ◽  
Major Mechanism ◽  
Cell Type Specific ◽  
Novel Therapeutic Strategies

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers with no effective treatment option. A predominant hallmark of PDAC is the intense fibro-inflammatory stroma which not only physically collapses vasculature but also functionally suppresses anti-tumor immunity. Constitutive and induced activation of the NF-κB transcription factors is a major mechanism that drives inflammation in PDAC. While targeting this pathway is widely supported as a promising therapeutic strategy, clinical success is elusive due to a lack of safe and effective anti-NF-κB pathway therapeutics. Furthermore, the cell type-specific contribution of this pathway, specifically in neoplastic cells, stromal fibroblasts, and immune cells, has not been critically appraised. In this article, we highlighted seminal and recent literature on molecular mechanisms that drive NF-κB activity in each of these major cell types in PDAC, focusing specifically on the innate immune Toll-like/IL-1 receptor pathway. We reviewed recent evidence on the signaling interplay between the NF-κB and oncogenic KRAS signaling pathways in PDAC cells and their collective contribution to cancer inflammation. Lastly, we reviewed clinical trials on agents that target the NF-κB pathway and novel therapeutic strategies that have been proposed in preclinical studies.

scholarly journals Highlights on the Role of KRAS Mutations in Reshaping the Microenvironment of Pancreatic Adenocarcinoma

2021 ◽  
Vol 22 (19) ◽  
pp. 10219
Author(s):  
Shirin Hafezi ◽  
Maha Saber-Ayad ◽  
Wael M. Abdel-Rahman
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Progression ◽  
Human Cancer ◽  
Ductal Adenocarcinoma ◽  
Ras Gene ◽  
Kras Mutations ◽  
Oncogenic Mutations ◽  
History Of ◽  
Novel Therapeutic Strategies ◽  
The Impact

The most frequent mutated oncogene family in the history of human cancer is the RAS gene family, including NRAS, HRAS, and, most importantly, KRAS. A hallmark of pancreatic cancer, recalcitrant cancer with a very low survival rate, is the prevalence of oncogenic mutations in the KRAS gene. Due to this fact, studying the function of KRAS and the impact of its mutations on the tumor microenvironment (TME) is a priority for understanding pancreatic cancer progression and designing novel therapeutic strategies for the treatment of the dismal disease. Despite some recent enlightening studies, there is still a wide gap in our knowledge regarding the impact of KRAS mutations on different components of the pancreatic TME. In this review, we will present an updated summary of mutant KRAS role in the initiation, progression, and modulation of the TME of pancreatic ductal adenocarcinoma (PDAC). This review will highlight the intriguing link between diabetes mellitus and PDAC, as well as vitamin D as an adjuvant effective therapy via TME modulation of PDAC. We will also discuss different ongoing clinical trials that use KRAS oncogene signaling network as therapeutic targets.

scholarly journals Nutrients in Alzheimer’s Disease: The Interaction of Diet, Drugs and Disease

2019 ◽  
Vol 46 (1) ◽  
pp. 23-34 ◽  
Author(s):  
S. Imindu Liyanage ◽  
Prachi Vilekar ◽  
Donald F. Weaver
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trials ◽  
Therapeutic Strategies ◽  
Protective Agent ◽  
Dietary Preferences ◽  
Novel Therapeutic Strategies ◽  
The Impact ◽  
Potential Therapeutics ◽  
Novel Therapeutic

AbstractIn recent decades, clinical trials in Alzheimer’s disease (AD) have failed at an unprecedented rate. The etiology of AD has since come under renewed scrutiny, both to elucidate the underlying pathologies and to identify novel therapeutic strategies. Here, diet has emerged as a potential causative/protective agent. A variety of nutrients, including lipids, minerals, vitamins, antioxidants and sugars as well as broader dietary patterns and microbiotal interactions have demonstrated associations with AD. Although clinical trials have yet to definitively implicate any singular dietary element as therapeutic or causative, it is apparent that dietary preferences, likely in complex synergies, may influence the risk, onset and course of AD. This review catalogs the impact of major dietary elements on AD. It further examines an unexplored reciprocal association where AD may modulate diet, as well as how potential therapeutics may complicate these interactions. In doing so, we observe diet may have profound effects on the outcome of a clinical trial, either as a confounder of a drug/disease interaction or as a generally disruptive covariate. We therefore conclude that future clinical trials in AD should endeavor to control for diet, either in study design or subsequent analyses.

scholarly journals Stem Cell Transplantation in Cardiovascular Disease: An Update

2012 ◽  
Vol 40 (3) ◽  
pp. 833-838 ◽  
Author(s):  
M Teng ◽  
Z Geng ◽  
L Huang ◽  
X Zhao
Keyword(s):  
Stem Cell ◽  
Cardiovascular Diseases ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Phase 1 ◽  
Cell Types ◽  
Therapeutic Strategies ◽  
Routes Of Administration ◽  
Novel Therapeutic Strategies ◽  
Novel Therapeutic

Despite the development of novel therapeutic strategies, cardiovascular diseases remain the main cause of morbidity and mortality worldwide. Many phase 1 and 2 clinical trials have reported the safety, feasibility and promising potential of stem cell transplantation, however, the optimal cell types, timing of infusion, cell dosage and routes of administration remain to be determined. This paper reviews the findings of various clinical studies and discusses the challenges facing the delivery of stem cell therapy in cardiovascular diseases.

scholarly journals A glutamine “tug-of-war”: Targets to manipulate glutamine metabolism for cancer immunotherapy

2021 ◽  
Author(s):  
L J Pallett ◽  
S Dimeloe ◽  
L V Sinclair ◽  
A J Byrne ◽  
A Schurich
Keyword(s):  
Individual Cell ◽  
Cell Types ◽  
Tumour Microenvironment ◽  
Therapeutic Strategies ◽  
The Body ◽  
Glutamine Metabolism ◽  
Drug Resistant ◽  
Novel Therapeutic Strategies ◽  
Intense Research ◽  
Abundant Amino Acid

Abstract Within the tumour microenvironment (TME) there is a cellular ‘tug-of-war’ for glutamine, the most abundant amino acid in the body. This competition is most evident when considering the balance between successful anti-tumour immune response and the uncontrolled growth of tumour cells that are addicted to glutamine. The differential effects of manipulating glutamine abundance in individual cell types is an area of intense research and debate. Here, we discuss some of the current strategies in development altering local glutamine availability focusing on inhibition of enzymes involved in the utilisation of glutamine and its uptake by cells in the TME. Further studies are urgently needed to complete our understanding of glutamine metabolism, to provide critical insights into the pathways that represent promising targets and for the development of novel therapeutic strategies for the treatment of advanced or drug resistant cancers.

Oxidative and inflammatory signals in obesity-associated vascular abnormalities

2017 ◽  
Vol 131 (14) ◽  
pp. 1689-1700 ◽  
Author(s):  
John J. Reho ◽  
Kamal Rahmouni
Keyword(s):  
Oxidative Stress ◽  
Vascular Function ◽  
Therapeutic Approach ◽  
Inflammatory Signaling ◽  
Perivascular Adipose Tissue ◽  
Arterial Stiffening ◽  
Vascular Abnormalities ◽  
Inflammatory Signals ◽  
Cardiovascular Morbidity And Mortality ◽  
The Impact

Obesity is associated with increased cardiovascular morbidity and mortality in part due to vascular abnormalities such as endothelial dysfunction and arterial stiffening. The hypertension and other health complications that arise from these vascular defects increase the risk of heart diseases and stroke. Prooxidant and proinflammatory signaling pathways as well as adipocyte-derived factors have emerged as critical mediators of obesity-associated vascular abnormalities. Designing treatments aimed specifically at improving the vascular dysfunction caused by obesity may provide an effective therapeutic approach to prevent the cardiovascular sequelae associated with excessive adiposity. In this review, we discuss the recent evidence supporting the role of oxidative stress and cytokines and inflammatory signals within the vasculature as well as the impact of the surrounding perivascular adipose tissue (PVAT) on the regulation of vascular function and arterial stiffening in obesity. In particular, we focus on the highly plastic nature of the vasculature in response to altered oxidant and inflammatory signaling and highlight how weight management can be an effective therapeutic approach to reduce the oxidative stress and inflammatory signaling and improve vascular function.

scholarly journals Integrative Modelling of Signalling Network Dynamics Identifies Cell Type-selective 1 Therapeutic Strategies for FGFR4-driven Cancers

2021 ◽  
Author(s):  
Sungyoung Shin ◽  
Nicole J Chew ◽  
Milad Ghomlaghi ◽  
Anderly C Chueh ◽  
Lan Nguyen ◽  
...  
Keyword(s):  
Protein Expression ◽  
Single Agent ◽  
Cell Types ◽  
Therapeutic Strategies ◽  
Cell Type ◽  
Drug Induced ◽  
Network Modelling ◽  
Combination Treatments ◽  
Signalling Network ◽  
The Impact

Oncogenic FGFR4 signalling represents a potential therapeutic target in many cancer types, including triple negative breast cancer (TNBC) and hepatocellular carcinoma (HCC). However, resistance to single-agent therapy directed at FGFR4 remains a major challenge, prompting the need to identify more effective combinatorial therapeutic strategies. Here, we integrated computational network modelling and experimental validation to characterise dynamic reprogramming of the FGFR4 signalling network in TNBC following FGFR4 kinase inhibition. We found that AKT, which signals downstream of FGFR4, displayed a rapid and potent reactivation following FGFR4 targeting. Through model-based simulation and systematic prediction of the effect of co-targeting specific network nodes, we predicted, and validated experimentally, strong synergism of co-targeting FGFR4 and particular ErbB kinases or AKT, but not the upstream kinase PI3K. Further, incorporation of protein expression data from hundreds of cancer cell types enabled us to adapt our model to other diverse cellular contexts, leading to the prediction that while AKT rebound occurs frequently, it is not a general phenomenon. Instead, ERK is reactivated in a subset of cell types, including the FGFR4-driven HCC cell line Hep3B. This was subsequently corroborated, and moreover, co-targeting FGFR4 and MEK in Hep3B cells markedly enhanced inhibition of cell proliferation. Overall, these findings provide novel insights into the dynamics of drug-induced network remodelling in cancer cells, highlight the impact of protein expression heterogeneity on network response to targeted therapy and identify candidate cell type-selective combination treatments for FGFR4-driven cancer.

Contemporary Qur'anic Studies in Iran and its Relationship with Qur'anic Studies in the West

2012 ◽  
Vol 14 (1) ◽  
pp. 45-72
Author(s):  
Morteza Karimi-Nia
Keyword(s):  
Islamic Law ◽  
Human Sciences ◽  
The West ◽  
Communications Technologies ◽  
Religious Learning ◽  
The Status ◽  
Islamic Republic Of Iran ◽  
Almost All ◽  
The Impact ◽  
The Relationship

The status of tafsīr and Qur'anic studies in the Islamic Republic of Iran has changed significantly during recent decades. The essay provides an overview of the state of Qur'anic studies in Iran today, aiming to examine the extent of the impact of studies by Western scholars on Iranian academic circles during the last three decades and the relationship between them. As in most Islamic countries, the major bulk of academic activity in Iran in this field used to be undertaken by the traditional ʿulamāʾ; however, since the beginning of the twentieth century and the establishment of universities and other academic institutions in the Islamic world, there has been increasing diversity and development. After the Islamic Revolution, many gradual changes in the structure and approach of centres of religious learning and universities have occurred. Contemporary advancements in modern sciences and communications technologies have gradually brought the institutions engaged in the study of human sciences to confront the new context. As a result, the traditional Shīʿī centres of learning, which until 50 years ago devoted themselves exclusively to the study of Islamic law and jurisprudence, today pay attention to the teaching of foreign languages, Qur'anic sciences and exegesis, including Western studies about the Qur'an, to a certain extent, and recognise the importance of almost all of the human sciences of the West.

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