Publications by authors named "Ajaz A Bhat"

40 Publications

Insights Into the Role of CircRNAs: Biogenesis, Characterization, Functional, and Clinical Impact in Human Malignancies.

Front Cell Dev Biol 2021 5;9:617281. Epub 2021 Feb 5.

Functional and Molecular Imaging Laboratory, Cancer Research Department, Sidra Medicine, Doha, Qatar.

Circular RNAs (circRNAs) are an evolutionarily conserved novel class of non-coding endogenous RNAs (ncRNAs) found in the eukaryotic transcriptome, originally believed to be aberrant RNA splicing by-products with decreased functionality. However, recent advances in high-throughput genomic technology have allowed circRNAs to be characterized in detail and revealed their role in controlling various biological and molecular processes, the most essential being gene regulation. Because of the structural stability, high expression, availability of microRNA (miRNA) binding sites and tissue-specific expression, circRNAs have become hot topic of research in RNA biology. Compared to the linear RNA, circRNAs are produced differentially by backsplicing exons or lariat introns from a pre-messenger RNA (mRNA) forming a covalently closed loop structure missing 3' poly-(A) tail or 5' cap, rendering them immune to exonuclease-mediated degradation. Emerging research has identified multifaceted roles of circRNAs as miRNA and RNA binding protein (RBP) sponges and transcription, translation, and splicing event regulators. CircRNAs have been involved in many human illnesses, including cancer and neurodegenerative disorders such as Alzheimer's and Parkinson's disease, due to their aberrant expression in different pathological conditions. The functional versatility exhibited by circRNAs enables them to serve as potential diagnostic or predictive biomarkers for various diseases. This review discusses the properties, characterization, profiling, and the diverse molecular mechanisms of circRNAs and their use as potential therapeutic targets in different human malignancies.
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http://dx.doi.org/10.3389/fcell.2021.617281DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7894079PMC
February 2021

Role of NAD in regulating cellular and metabolic signaling pathways.

Mol Metab 2021 Feb 17;49:101195. Epub 2021 Feb 17.

Department of Diagnostic Imaging, St. Jude Children's Research Hospital, Memphis, TN, USA. Electronic address:

Background: Nicotinamide adenine dinucleotide (NAD), a critical coenzyme present in every living cell, is involved in a myriad of metabolic processes associated with cellular bioenergetics. For this reason, NAD is often studied in the context of aging, cancer, and neurodegenerative and metabolic disorders.

Scope Of Review: Cellular NAD depletion is associated with compromised adaptive cellular stress responses, impaired neuronal plasticity, impaired DNA repair, and cellular senescence. Increasing evidence has shown the efficacy of boosting NAD levels using NAD precursors in various diseases. This review provides a comprehensive understanding into the role of NAD in aging and other pathologies and discusses potential therapeutic targets.

Major Conclusions: An alteration in the NAD/NADH ratio or the NAD pool size can lead to derailment of the biological system and contribute to various neurodegenerative disorders, aging, and tumorigenesis. Due to the varied distribution of NAD/NADH in different locations within cells, the direct role of impaired NAD-dependent processes in humans remains unestablished. In this regard, longitudinal studies are needed to quantify NAD and its related metabolites. Future research should focus on measuring the fluxes through pathways associated with NAD synthesis and degradation.
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http://dx.doi.org/10.1016/j.molmet.2021.101195DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7973386PMC
February 2021

Tumor microenvironment: an evil nexus promoting aggressive head and neck squamous cell carcinoma and avenue for targeted therapy.

Signal Transduct Target Ther 2021 Jan 12;6(1):12. Epub 2021 Jan 12.

Watson-Crick Centre for Molecular Medicine, Islamic University of Science and Technology, Awantipora, Jammu & Kashmir, India.

Head and neck squamous cell carcinoma (HNSCC) is a very aggressive disease with a poor prognosis for advanced-stage tumors. Recent clinical, genomic, and cellular studies have revealed the highly heterogeneous and immunosuppressive nature of HNSCC. Despite significant advances in multimodal therapeutic interventions, failure to cure and recurrence are common and account for most deaths. It is becoming increasingly apparent that tumor microenvironment (TME) plays a critical role in HNSCC tumorigenesis, promotes the evolution of aggressive tumors and resistance to therapy, and thereby adversely affects the prognosis. A complete understanding of the TME factors, together with the highly complex tumor-stromal interactions, can lead to new therapeutic interventions in HNSCC. Interestingly, different molecular and immune landscapes between HPV and HPV (human papillomavirus) HNSCC tumors offer new opportunities for developing individualized, targeted chemoimmunotherapy (CIT) regimen. This review highlights the current understanding of the complexity between HPV and HPV HNSCC TME and various tumor-stromal cross-talk modulating processes, including epithelial-mesenchymal transition (EMT), anoikis resistance, angiogenesis, immune surveillance, metastatic niche, therapeutic resistance, and development of an aggressive tumor phenotype. Furthermore, we summarize the recent developments and the rationale behind CIT strategies and their clinical applications in HPV and HPV HNSCC.
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http://dx.doi.org/10.1038/s41392-020-00419-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7804459PMC
January 2021

Cytokine-chemokine network driven metastasis in esophageal cancer; promising avenue for targeted therapy.

Mol Cancer 2021 01 4;20(1). Epub 2021 Jan 4.

Functional and Molecular Imaging Laboratory, Cancer Research Department, Sidra Medicine, Doha, Qatar.

Esophageal cancer (EC) is a disease often marked by aggressive growth and poor prognosis. Lack of targeted therapies, resistance to chemoradiation therapy, and distant metastases among patients with advanced disease account for the high mortality rate. The tumor microenvironment (TME) contains several cell types, including fibroblasts, immune cells, adipocytes, stromal proteins, and growth factors, which play a significant role in supporting the growth and aggressive behavior of cancer cells. The complex and dynamic interactions of the secreted cytokines, chemokines, growth factors, and their receptors mediate chronic inflammation and immunosuppressive TME favoring tumor progression, metastasis, and decreased response to therapy. The molecular changes in the TME are used as biological markers for diagnosis, prognosis, and response to treatment in patients. This review highlighted the novel insights into the understanding and functional impact of deregulated cytokines and chemokines in imparting aggressive EC, stressing the nature and therapeutic consequences of the cytokine-chemokine network. We also discuss cytokine-chemokine oncogenic potential by contributing to the Epithelial-Mesenchymal Transition (EMT), angiogenesis, immunosuppression, metastatic niche, and therapeutic resistance development. In addition, it discusses the wide range of changes and intracellular signaling pathways that occur in the TME. Overall, this is a relatively unexplored field that could provide crucial insights into tumor immunology and encourage the effective application of modulatory cytokine-chemokine therapy to EC.
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http://dx.doi.org/10.1186/s12943-020-01294-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7780621PMC
January 2021

Non-invasive biomarkers for monitoring the immunotherapeutic response to cancer.

J Transl Med 2020 12 9;18(1):471. Epub 2020 Dec 9.

Functional and Molecular Imaging Laboratory, Cancer Research Department, Sidra Medicine, P.O. Box 26999, Doha, Qatar.

Immunotherapy is an efficient way to cure cancer by modulating the patient's immune response. However, the immunotherapy response is heterogeneous and varies between individual patients and cancer subtypes, reinforcing the need for early benefit predictors. Evaluating the infiltration of immune cells in the tumor and changes in cell-intrinsic tumor characteristics provide potential response markers to treatment. However, this approach requires invasive sampling and may not be suitable for real-time monitoring of treatment response. The recent emergence of quantitative imaging biomarkers provides promising opportunities. In vivo imaging technologies that interrogate T cell responses, metabolic activities, and immune microenvironment could offer a powerful tool to monitor the cancer response to immunotherapy. Advances in imaging techniques to identify tumors' immunological characteristics can help stratify patients who are more likely to respond to immunotherapy. This review discusses the metabolic events that occur during T cell activation and differentiation, anti-cancer immunotherapy-induced T cell responses, focusing on non-invasive imaging techniques to monitor T cell metabolism in the search for novel biomarkers of response to cancer immunotherapy.
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http://dx.doi.org/10.1186/s12967-020-02656-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7727217PMC
December 2020

Cytokine-Mediated Dysregulation of Signaling Pathways in the Pathogenesis of Multiple Myeloma.

Int J Mol Sci 2020 Jul 15;21(14). Epub 2020 Jul 15.

Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha 3050, Qatar.

Multiple myeloma (MM) is a hematologic disorder of B lymphocytes characterized by the accumulation of malignant plasma cells (PCs) in the bone marrow. The altered plasma cells overproduce abnormal monoclonal immunoglobulins and also stimulate osteoclasts. The host's immune system and microenvironment are of paramount importance in the growth of PCs and, thus, in the pathogenesis of the disease. The interaction of MM cells with the bone marrow (BM) microenvironment through soluble factors and cell adhesion molecules causes pathogenesis of the disease through activation of multiple signaling pathways, including NF-κβ, PI3K/AKT and JAK/STAT. These activated pathways play a critical role in the inhibition of apoptosis, sustained proliferation, survival and migration of MM cells. Besides, these pathways also participate in developing resistance against the chemotherapeutic drugs in MM. The imbalance between inflammatory and anti-inflammatory cytokines in MM leads to an increased level of pro-inflammatory cytokines, which in turn play a significant role in dysregulation of signaling pathways and proliferation of MM cells; however, the association appears to be inadequate and needs more research. In this review, we are highlighting the recent findings on the roles of various cytokines and growth factors in the pathogenesis of MM and the potential therapeutic utility of aberrantly activated signaling pathways to manage the MM disease.
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http://dx.doi.org/10.3390/ijms21145002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7403981PMC
July 2020

Genetics of structural and functional brain changes in autism spectrum disorder.

Transl Psychiatry 2020 07 13;10(1):229. Epub 2020 Jul 13.

Functional and Molecular Imaging Laboratory, Sidra Medicine, Doha, Qatar.

Autism spectrum disorder (ASD) is a neurological and developmental disorder characterized by social impairment and restricted interactive and communicative behaviors. It may occur as an isolated disorder or in the context of other neurological, psychiatric, developmental, and genetic disorders. Due to rapid developments in genomics and imaging technologies, imaging genetics studies of ASD have evolved in the last few years. Increased risk for ASD diagnosis is found to be related to many specific single-nucleotide polymorphisms, and the study of genetic mechanisms and noninvasive imaging has opened various approaches that can help diagnose ASD at the nascent level. Identifying risk genes related to structural and functional changes in the brain of ASD patients provide a better understanding of the disease's neuropsychiatry and can help identify targets for therapeutic intervention that could be useful for the clinical management of ASD patients.
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http://dx.doi.org/10.1038/s41398-020-00921-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7359361PMC
July 2020

Genetic and Neuroimaging Approaches to Understanding Post-Traumatic Stress Disorder.

Int J Mol Sci 2020 Jun 24;21(12). Epub 2020 Jun 24.

Functional and Molecular Imaging Department, Research Branch, Sidra Medicine, Doha 26999, Qatar.

Post-traumatic stress disorder (PTSD) is a highly disabling condition, increasingly recognized as both a disorder of mental health and social burden, but also as an anxiety disorder characterized by fear, stress, and negative alterations in mood. PTSD is associated with structural, metabolic, and molecular changes in several brain regions and the neural circuitry. Brain areas implicated in the traumatic stress response include the amygdala, hippocampus, and prefrontal cortex, which play an essential role in memory function. Abnormalities in these brain areas are hypothesized to underlie symptoms of PTSD and other stress-related psychiatric disorders. Conventional methods of studying PTSD have proven to be insufficient for diagnosis, measurement of treatment efficacy, and monitoring disease progression, and currently, there is no diagnostic biomarker available for PTSD. A deep understanding of cutting-edge neuroimaging genetic approaches is necessary for the development of novel therapeutics and biomarkers to better diagnose and treat the disorder. A current goal is to understand the gene pathways that are associated with PTSD, and how those genes act on the fear/stress circuitry to mediate risk vs. resilience for PTSD. This review article explains the rationale and practical utility of neuroimaging genetics in PTSD and how the resulting information can aid the diagnosis and clinical management of patients with PTSD.
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http://dx.doi.org/10.3390/ijms21124503DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352752PMC
June 2020

Therapeutic Effects of Curcumol in Several Diseases; An Overview.

Nutr Cancer 2021 14;73(2):181-195. Epub 2020 Apr 14.

Translational Medicine, Research Branch, Sidra Medical and Research Center, Doha, Qatar.

also known as is a traditional Chinese medicine that has been used for many centuries against several diseases. The rhizome of the plant is composed of curcuminoids (curcumin, demethoxycurcumin, and bisdemethoxycurcumin), and essential volatile oils including curcumol, curdione, and germacrone. While curcuminoids have been extensively studied for their antimicrobial, antioxidant, anti-inflammatory and anticancer properties, the therapeutic efficacy of curcumol is still emerging. Recent studies have shown anticancer properties of curcumol against multiple solid tumors such as breast, colorectal, head and neck, and lung adenocarcinomas. The underlying anti-tumor mechanisms revealed inhibition of several signaling pathways (NF-κB, MAPK, PI-3K/AKT, and GSK-3β) associated with cell proliferation, survival, anti-apoptosis, invasion and metastasis. Besides curcumol, extracts from the roots possess many other terpenoids such as β-elemene, δ-elemene, germacrone, furanodiene and furanodienone with known anticancer properties. In this review, we comprehensively focused on the composition of essential oils, their structure, isolation and therapeutic uses of curcumol to aid in the improvement and development of novel drugs with minimal cytotoxicity, enhanced efficacy, and less cost.
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http://dx.doi.org/10.1080/01635581.2020.1749676DOI Listing
April 2020

Functional In Vivo Imaging of Tumors.

Cancer Treat Res 2020 ;180:3-50

Center for Magnetic Resonance and Optical Imaging, Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

Noninvasive imaging of functional and molecular changes in cancer has become an indispensable tool for studying cancer in vivo. Targeting the functional and molecular changes in cancer imaging provides a platform for the in vivo analysis of the mechanisms such as gene expression, signal transduction, biochemical reactions, regulatory pathways, cell trafficking, and drug action underlying cancer noninvasively. The main focus of imaging in cancer is the development of new contrast methods/molecular probes for the early diagnosis and the precise evaluation of therapy response. In clinical setup, imaging modalities facilitate screening, prediction, staging, biopsy and therapy guidance, therapy response, therapy planning, and prognosis of cancer. In this book chapter, we review different established and emerging in vivo imaging modalities and their applications in monitoring functional, molecular, and metabolic changes in cancer.
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http://dx.doi.org/10.1007/978-3-030-38862-1_1DOI Listing
September 2020

Role of non-coding RNA networks in leukemia progression, metastasis and drug resistance.

Mol Cancer 2020 03 12;19(1):57. Epub 2020 Mar 12.

Translational Research Institute, Academic Health System, Hamad Medical Corporation, P.O. Box 3050, Doha, Qatar.

Early-stage detection of leukemia is a critical determinant for successful treatment of the disease and can increase the survival rate of leukemia patients. The factors limiting the current screening approaches to leukemia include low sensitivity and specificity, high costs, and a low participation rate. An approach based on novel and innovative biomarkers with high accuracy from peripheral blood offers a comfortable and appealing alternative to patients, potentially leading to a higher participation rate.Recently, non-coding RNAs due to their involvement in vital oncogenic processes such as differentiation, proliferation, migration, angiogenesis and apoptosis have attracted much attention as potential diagnostic and prognostic biomarkers in leukemia. Emerging lines of evidence have shown that the mutational spectrum and dysregulated expression of non-coding RNA genes are closely associated with the development and progression of various cancers, including leukemia. In this review, we highlight the expression and functional roles of different types of non-coding RNAs in leukemia and discuss their potential clinical applications as diagnostic or prognostic biomarkers and therapeutic targets.
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http://dx.doi.org/10.1186/s12943-020-01175-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7069174PMC
March 2020

Claudin-1, A Double-Edged Sword in Cancer.

Int J Mol Sci 2020 Jan 15;21(2). Epub 2020 Jan 15.

Division of Translational Medicine, Research Branch, Sidra Medicine, Doha 26999, Qatar.

Claudins, a group of membrane proteins involved in the formation of tight junctions, are mainly found in endothelial or epithelial cells. These proteins have attracted much attention in recent years and have been implicated and studied in a multitude of diseases. Claudins not only regulate paracellular transepithelial/transendothelial transport but are also critical for cell growth and differentiation. Not only tissue-specific but the differential expression in malignant tumors is also the focus of claudin-related research. In addition to up- or down-regulation, claudin proteins also undergo delocalization, which plays a vital role in tumor invasion and aggressiveness. Claudin (CLDN)-1 is the most-studied claudin in cancers and to date, its role as either a tumor promoter or suppressor (or both) is not established. In some cancers, lower expression of CLDN-1 is shown to be associated with cancer progression and invasion, while in others, loss of CLDN-1 improves the patient survival. Another topic of discussion regarding the significance of CLDN-1 is its localization (nuclear or cytoplasmic vs perijunctional) in diseased states. This article reviews the evidence regarding CLDN-1 in cancers either as a tumor promoter or suppressor from the literature and we also review the literature regarding the pattern of CLDN-1 distribution in different cancers, focusing on whether this localization is associated with tumor aggressiveness. Furthermore, we utilized expression data from The Cancer Genome Atlas (TCGA) to investigate the association between CLDN-1 expression and overall survival (OS) in different cancer types. We also used TCGA data to compare CLDN-1 expression in normal and tumor tissues. Additionally, a pathway interaction analysis was performed to investigate the interaction of CLDN-1 with other proteins and as a future therapeutic target.
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http://dx.doi.org/10.3390/ijms21020569DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7013445PMC
January 2020

Exploring Dysregulated Signaling Pathways in Cancer.

Curr Pharm Des 2020 ;26(4):429-445

Translational Medicine, Research Branch, Sidra Medicine, Doha, Qatar.

Cancer cell biology takes advantage of identifying diverse cellular signaling pathways that are disrupted in cancer. Signaling pathways are an important means of communication from the exterior of cell to intracellular mediators, as well as intracellular interactions that govern diverse cellular processes. Oncogenic mutations or abnormal expression of signaling components disrupt the regulatory networks that govern cell function, thus enabling tumor cells to undergo dysregulated mitogenesis, to resist apoptosis, and to promote invasion to neighboring tissues. Unraveling of dysregulated signaling pathways may advance the understanding of tumor pathophysiology and lead to the improvement of targeted tumor therapy. In this review article, different signaling pathways and how their dysregulation contributes to the development of tumors have been discussed.
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http://dx.doi.org/10.2174/1381612826666200115095937DOI Listing
November 2020

Association of genes with phenotype in autism spectrum disorder.

Aging (Albany NY) 2019 11 19;11(22):10742-10770. Epub 2019 Nov 19.

Research Branch, Sidra Medicine, Doha, Qatar.

Autism spectrum disorder (ASD) is a genetic heterogeneous neurodevelopmental disorder that is characterized by impairments in social interaction and speech development and is accompanied by stereotypical behaviors such as body rocking, hand flapping, spinning objects, sniffing and restricted behaviors. The considerable significance of the genetics associated with autism has led to the identification of many risk genes for ASD used for the probing of ASD specificity and shared cognitive features over the past few decades. Identification of ASD risk genes helps to unravel various genetic variants and signaling pathways which are involved in ASD. This review highlights the role of ASD risk genes in gene transcription and translation regulation processes, as well as neuronal activity modulation, synaptic plasticity, disrupted key biological signaling pathways, and the novel candidate genes that play a significant role in the pathophysiology of ASD. The current emphasis on autism spectrum disorders has generated new opportunities in the field of neuroscience, and further advancements in the identification of different biomarkers, risk genes, and genetic pathways can help in the early diagnosis and development of new clinical and pharmacological treatments for ASD.
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http://dx.doi.org/10.18632/aging.102473DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6914398PMC
November 2019

APE1 Upregulates MMP-14 via Redox-Sensitive ARF6-Mediated Recycling to Promote Cell Invasion of Esophageal Adenocarcinoma.

Cancer Res 2019 09 15;79(17):4426-4438. Epub 2019 Jul 15.

Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida.

Esophageal adenocarcinoma (EAC) is an aggressive malignancy with poor clinical outcome. The incidence of EAC has been rising rapidly in the past three decades. Here, we showed that apurinic/apyrimidinic endonuclease (APE1) is overexpressed in EAC cell lines, and patients' samples of dysplasia and EAC. Downregulation of APE1 or inhibition of its redox function significantly repressed invasion. Overexpression of a redox-defective mutant, C65A, abrogated the proinvasive phenotype of APE1. APE1 regulated invasion via upregulation of matrix metalloproteinase 14 (MMP-14), which subsequently activated MMP-2, leading to degradation of the extracellular matrix in a redox-dependent manner. Downregulation of APE1 or inhibition of its redox function decreased the rate of endocytosis and recycling of MMP-14 protein. APE1 interacted with ARF6, a key regulator of MMP-14 recycling, which maintained ARF6 activity in an APE1-redox-dependent manner, promoting its ability to regulate MMP-14 recycling to the cell surface. In summary, these findings identify a novel redox-sensitive APE1-ARF6-MMP-14 signaling axis that mediates cellular invasion in esophageal carcinogenesis. SIGNIFICANCE: This study demonstrates the association between oxidative stress and the development and metastatic behavior of esophageal adenocarcinoma.
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http://dx.doi.org/10.1158/0008-5472.CAN-19-0237DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6726537PMC
September 2019

Activation of STAT3 signaling is mediated by TFF1 silencing in gastric neoplasia.

Nat Commun 2019 07 10;10(1):3039. Epub 2019 Jul 10.

Department of Veterans Affairs, Miami Healthcare System, Miami, FL, USA.

TFF1, a secreted protein, plays an essential role in keeping the integrity of gastric mucosa and its barrier function. Loss of TFF1 expression in the TFF1-knockout (KO) mouse leads to a pro-inflammatory phenotype with a cascade of gastric lesions that include low-grade dysplasia, high-grade dysplasia, and adenocarcinomas. In this study, we demonstrate nuclear localization of p-STAT, with significant overexpression of several STAT3 target genes in gastric glands from the TFF1-KO mice. We also show frequent loss of TFF1 with nuclear localization of STAT3 in human gastric cancers. The reconstitution of TFF1 protein in human gastric cancer cells and 3D gastric glands organoids from TFF1-KO mice abrogates IL6-induced nuclear p-STAT3 expression. Reconstitution of TFF1 inhibits IL6-induced STAT3 transcription activity, suppressing expression of its target genes. TFF1 blocks IL6Rα-GP130 complex formation through interfering with binding of IL6 to its receptor IL6Rα. These findings demonstrate a functional role of TFF1 in suppressing gastric tumorigenesis by impeding the IL6-STAT3 pro-inflammatory signaling axis.
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http://dx.doi.org/10.1038/s41467-019-11011-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6620282PMC
July 2019

Extracellular vesicles-mediated intercellular communication: roles in the tumor microenvironment and anti-cancer drug resistance.

Mol Cancer 2019 03 30;18(1):55. Epub 2019 Mar 30.

Division of Translational Medicine, Sidra Medicine, PO BOX 26999, Doha, Qatar.

The tumor microenvironment represents a complex network, in which tumor cells not only communicate with each other but also with stromal and immune cells. Current research has demonstrated the vital role of the tumor microenvironment in supporting tumor phenotype via a sophisticated system of intercellular communication through direct cell-to-cell contact or by classical paracrine signaling loops of cytokines or growth factors. Recently, extracellular vesicles have emerged as an important mechanism of cellular interchange of bioactive molecules. Extracellular vesicles isolated from tumor and stromal cells have been implicated in various steps of tumor progression, such as proliferation, angiogenesis, metastasis, and drug resistance. Inhibition of extracellular vesicles secretion, and thus of the transfer of oncogenic molecules, holds promise for preventing tumor growth and drug resistance. This review focuses on the role of extracellular vesicles in modulating the tumor microenvironment by addressing different aspects of the bidirectional interactions among tumor and tumor-associated cells. The contribution of extracellular vesicles to drug resistance will also be discussed as well as therapeutic strategies targeting extracellular vesicles production for the treatment of cancer.
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http://dx.doi.org/10.1186/s12943-019-0965-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6441157PMC
March 2019

Tight Junction Proteins and Signaling Pathways in Cancer and Inflammation: A Functional Crosstalk.

Front Physiol 2018 23;9:1942. Epub 2019 Jan 23.

Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar.

The ability of epithelial cells to organize through cell-cell adhesion into a functioning epithelium serves the purpose of a tight epithelial protective barrier. Contacts between adjacent cells are made up of tight junctions (TJ), adherens junctions (AJ), and desmosomes with unique cellular functions and a complex molecular composition. These proteins mediate firm mechanical stability, serves as a gatekeeper for the paracellular pathway, and helps in preserving tissue homeostasis. TJ proteins are involved in maintaining cell polarity, in establishing organ-specific apical domains and also in recruiting signaling proteins involved in the regulation of various important cellular functions including proliferation, differentiation, and migration. As a vital component of the epithelial barrier, TJs are under a constant threat from proinflammatory mediators, pathogenic viruses and bacteria, aiding inflammation and the development of disease. Inflammatory bowel disease (IBD) patients reveal loss of TJ barrier function, increased levels of proinflammatory cytokines, and immune dysregulation; yet, the relationship between these events is partly understood. Although TJ barrier defects are inadequate to cause experimental IBD, mucosal immune activation is changed in response to augmented epithelial permeability. Thus, the current studies suggest that altered barrier function may predispose or increase disease progression and therapies targeted to specifically restore the barrier function may provide a substitute or supplement to immunologic-based therapies. This review provides a brief introduction about the TJs, AJs, structure and function of TJ proteins. The link between TJ proteins and key signaling pathways in cell proliferation, transformation, and metastasis is discussed thoroughly. We also discuss the compromised intestinal TJ integrity under inflammatory conditions, and the signaling mechanisms involved that bridge inflammation and cancer.
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http://dx.doi.org/10.3389/fphys.2018.01942DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6351700PMC
January 2019

Changes in resting-state functional brain activity are associated with waning cognitive functions in HIV-infected children.

Neuroimage Clin 2018 29;20:1204-1210. Epub 2018 Oct 29.

Division of Translational Medicine, Research Branch, Sidra Medicine, Doha, Qatar; Laboratory Animal Research Center, Qatar University, Doha, Qatar.

Delayed brain development in perinatally HIV-infected children may affect the functional brain activity and subsequently cognitive function. The current study evaluated the functional brain activity in HIV-infected children by quantifying the amplitude of low frequency fluctuations (ALFF) and functional connectivity (FC). Additionally, correlation of ALFF and FC with cognitive measures was performed. Twenty-six HIV-infected children and 20 control children underwent neuropsychological (NP) assessment and resting-state functional magnetic resonance imaging (rs-fMRI). ALFF and FC maps were generated and group differences were analyzed using two-sample t-test. Furthermore, ALFF and FC showing significant group differences were correlated with NP scores using Pearson's correlation. Significantly lower ALFF in the left middle temporal gyrus, precentral and post central gyrus was observed in HIV-infected children compared to controls. FC was significantly reduced in the right inferior parietal, vermis, middle temporal and left postcentral regions, and significantly increased in the right precuneus, superior parietal and left middle frontal regions in HIV-infected children as compared to control. HIV-infected children showed significantly lower NP scores in various domains including closure, exclusion, memory, verbal meaning, quantity and hidden figure than controls. These waning cognitive functions were significantly associated with changes in ALFF and FC in HIV-infected children. The findings suggest that abnormal ALFF and FC may responsible for cognitive deficits in HIV-infected children. ALFF and FC in association with cognitive evaluation may provide a clinical biomarker to evaluate functional brain activity and to plan neurocognitive intervention in HIV-infected children undergoing standard treatment.
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http://dx.doi.org/10.1016/j.nicl.2018.10.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6224323PMC
February 2019

Goal-Directed Reasoning and Cooperation in Robots in Shared Workspaces: an Internal Simulation Based Neural Framework.

Cognit Comput 2018 14;10(4):558-576. Epub 2018 Apr 14.

2CSEE Department, University of Essex, Colchester, UK.

From social dining in households to product assembly in manufacturing lines, goal-directed reasoning and cooperation with other agents in shared workspaces is a ubiquitous aspect of our day-to-day activities. Critical for such behaviours is the ability to spontaneously anticipate what is doable by oneself as well as the interacting partner based on the evolving environmental context and thereby exploit such information to engage in goal-oriented action sequences. In the setting of an industrial task where two robots are jointly assembling objects in a shared workspace, we describe a bioinspired neural architecture for goal-directed action planning based on coupled interactions between multiple internal models, primarily of the robot's body and its peripersonal space. The internal models (of each robot's body and peripersonal space) are learnt through a process of sensorimotor exploration and then employed in a range of anticipations related to the feasibility and consequence of potential actions of two industrial robots in the context of a joint goal. The ensuing behaviours are demonstrated in a real-world industrial scenario where two robots are assembling industrial fuse-boxes from multiple constituent objects (fuses, fuse-stands) scattered randomly in their workspace. In a spatially unstructured and temporally evolving assembly scenario, the robots employ reward-based dynamics to plan and anticipate which objects to act on at what time instances so as to successfully complete as many assemblies as possible. The existing spatial setting fundamentally necessitates planning collision-free trajectories and avoiding potential collisions between the robots. Furthermore, an interesting scenario where the assembly goal is not realizable by either of the robots individually but only realizable if they meaningfully cooperate is used to demonstrate the interplay between perception, simulation of multiple internal models and the resulting complementary goal-directed actions of both robots. Finally, the proposed neural framework is benchmarked against a typically engineered solution to evaluate its performance in the assembly task. The framework provides a computational outlook to the emerging results from neurosciences related to the learning and use of body schema and peripersonal space for embodied simulation of action and prediction. While experiments reported here engage the architecture in a complex planning task specifically, the internal model based framework is domain-agnostic facilitating portability to several other tasks and platforms.
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http://dx.doi.org/10.1007/s12559-018-9553-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6096944PMC
April 2018

TFF1 antagonizes TIMP-1 mediated proliferative functions in gastric cancer.

Mol Carcinog 2018 11 14;57(11):1577-1587. Epub 2018 Aug 14.

Department of Veterans Affairs, Miami Healthcare System, Miami, Florida.

Tissue inhibitor matrix metalloproteinase-1 (TIMP1) is one of four identified members of the TIMP family. We evaluated the role of TIMP1 in gastric cancer using human and mouse tissues along with gastric organoids and in vitro cell models. Using quantitative real-time RT-PCR, we detected significant overexpression of TIMP1 in the human gastric cancer samples, as compared to normal stomach samples (P < 0.01). We also detected overexpression of Timp1 in neoplastic gastric lesions of the Tff1-knockout (KO) mice, as compared to normal stomach tissues. Reconstitution of TFF1 in human gastric cancer cell lines led to a significant decrease in the mRNA expression level of TIMP1 (P < 0.05). In vitro analysis demonstrated that TIMP1 mRNA expression is induced by TNF-α and activation of NF-κB whereas inhibition of NF-κB using BAY11-7082 led to inhibition of NF-κB and downregulation of TIMP1. Western blot analysis confirmed the decrease in TIMP1 protein level following reconstitution of TFF1. By using immunofluorescence, we showed nuclear localization of NF-κB and expression of TIMP1 in gastric organoids established from the Tff1-KO stomach where reconstitution of Tff1 using recombinant protein led to a notable reduction in the expression of both NF-κB and TIMP1. Using EDU assay, as a measure of proliferating cells, we found that TIMP1 promotes cellular proliferation whereas TFF1 reconstitution leads to a significant decrease in cellular proliferation (P < 0.05). In summary, our findings demonstrate overexpression of TIMP1 in mouse and human gastric cancers through NF-kB-dependent mechanism. We also show that TFF1 suppresses NF-κB and inhibits TIMP1-mediated proliferative potential in gastric cancer.
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http://dx.doi.org/10.1002/mc.22880DOI Listing
November 2018

Exposure of Barrett's and esophageal adenocarcinoma cells to bile acids activates EGFR-STAT3 signaling axis via induction of APE1.

Oncogene 2018 11 10;37(46):6011-6024. Epub 2018 Jul 10.

Department of Surgery, Miller School of Medicine, University of Miami, Miami, FL, USA.

The development of Barrett's esophagus (BE) and its progression to esophageal adenocarcinoma (EAC) is highly linked to exposure to acidic bile salts due to chronic gastroesophageal reflux disease (GERD). In this study, we investigated the role of Apurinic/apyrimidinic endonuclease 1/redox effector factor-1 (APE1/REF-1) in STAT3 activation in response to acidic bile salts. Our results indicate that APE1 is constitutively overexpressed in EAC, whereas its expression is transiently induced in response to acidic bile salts in non-neoplastic BE. Using overexpression or shRNA knockdown of APE1, we found that APE1 is required for phosphorylation, nuclear localization, and transcriptional activation of STAT3. By using an APE1 redox-specific mutant (C65A) and APE1 redox inhibitor (E3330), we demonstrate that APE1 activates STAT3 in a redox-dependent manner. By using pharmacologic inhibitors and genetic knockdown systems, we found that EGFR is a required link between APE1 and STAT3. EGFR phosphorylation (Y1068) was directly associated with APE1 levels and redox function. Co-immunoprecipitation and proximity ligation assays indicated that APE1 coexists and interacts with the EGFR-STAT3 protein complex. Consistent with these findings, we demonstrated a significant induction in mRNA expression levels of STAT3 target genes (IL-6, IL-17A, BCL-xL, Survivin, and c-MYC) in BE and EAC cells, following acidic bile salts treatment. ChIP assays indicated that acidic bile salts treatment enhances binding of STAT3 to the promoter of its target genes, Survivin and BCL-xL. Inhibition of APE1/REF-1 redox activity using E3330 abrogated STAT3 DNA binding and transcriptional activity. The induction of APE1-STAT3 axis in acidic bile salts conditions provided a survival advantage and promoted cellular proliferation. In summary, our study provides multiple pieces of evidence supporting a critical role for APE1 induction in activating the EGFR-STAT3 signaling axis in response to acidic bile salts, the main risk factor for Barrett's carcinogenesis.
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http://dx.doi.org/10.1038/s41388-018-0388-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6328352PMC
November 2018

Ovarian development and histological observations of threatened dwarf snakehead fish, (Hamilton, 1822).

Saudi J Biol Sci 2018 Jan 16;25(1):149-153. Epub 2017 Mar 16.

Zoology Department, College of Science, King Saud University, PO Box 2455, Riyadh 11451, Saudi Arabia.

were monthly sampled throughout a year and the histological analysis of their ovaries was done to determine the changes occurring in ovarian development. Based on histological examination of the ovaries, the oogenic process of undergoes distinct cyclic and seasonal morphological changes. Five different developmental stages were identified under three major categories: pre-spawning (immature, maturing, mature), spawning (ripe-running) and post-spawning (spent). The peak spawning period of was noticed during December - February. The gonadosomatic index (GSI) and ova diameter ranged from 0.79 to 3.61% and 543-1123 μm respectively. The highest mean GSI (3.61 ± 0.16) and oocyte diameter (1123 ± 55 μm) were observed in December indicating that during this month the gonadal development reached maturity.
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http://dx.doi.org/10.1016/j.sjbs.2017.03.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5775079PMC
January 2018

Potential therapeutic targets of Guggulsterone in cancer.

Nutr Metab (Lond) 2017 28;14:23. Epub 2017 Feb 28.

Translational Research Institute, Hamad Medical Corporation, PO Box 3050, Doha, Qatar.

Natural compounds capable of inducing apoptosis in cancer cells have always been of considerable interest as potential anti-cancer agents. Many such compounds are under screening and development with their potential evolution as a clinical drug benefiting many of the cancer patients. Guggulsterone (GS), a phytosterol isolated gum resin of the tree has been widely used in Indian traditional medicine as a remedy for various diseses. GS has been shown to possess cancer chemopreventive and therapeutic potential as established by in vitro and in vivo studies. GS has been shown to target constitutively activated survival pathways such as PI3-kinase/AKT, JAK/STAT, and NFκB signaling pathways that are involved in the regulation of growth and inflammatory responses regulation of antiapoptotic and inflammatory genes. The current review focuses on the molecular targets of GS, cellular responses, and the animal model studies in various cancers. The mechanistic action of GS in different types of cancers also forms a part of this review. The perspective of translating this natural compound into a clinically approved drug with its pros and cons is also discussed.
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http://dx.doi.org/10.1186/s12986-017-0180-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5331628PMC
February 2017

Claudin-1 promotes TNF-α-induced epithelial-mesenchymal transition and migration in colorectal adenocarcinoma cells.

Exp Cell Res 2016 Nov 11;349(1):119-127. Epub 2016 Oct 11.

From the Department of Veterans Affairs, University of Nebraska Medical Center, Omaha, NE 68022, United States; Departments of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68022, United States; Buffet Cancer Center, University of Nebraska Medical Center, Omaha, NE 68022, United States. Electronic address:

Epithelial-mesenchymal transition (EMT) is an important mechanism in cancer progression and malignancy including colorectal cancer (CRC). Importantly, inflammatory mediators are critical constituents of the local tumor environment and an intimate link between CRC progression and inflammation is now validated. We and others have reported key role of the deregulated claudin-1 expression in colon carcinogenesis including colitis-associated colon cancer (CAC). However, the causal association between claudin-1 expression and inflammation-induced colon cancer progression remains unclear. Here we demonstrate, TNF-α, a pro-inflammatory cytokine, regulates claudin-1 to modulate epithelial to mesenchymal transition (EMT) and migration in colon adenocarcinoma cells. Importantly, colon cancer cells cultured in the presence of TNF-α (10ng/ml), demonstrated a sharp decrease in E-cadherin expression and an increase in vimentin expression (versus control cells). Interestingly, TNF-α treatment also upregulated (and delocalized) claudin-1 expression in a time-dependent manner accompanied by increase in proliferation and wound healing. Furthermore, similar to our previous observation that claudin-1 overexpression in CRC cells induces ERK1/2 and Src- activation, signaling associated with colon cancer cell survival and transformation, TNF-α-treatment induced upregulation of phospho-ERK1/2 and -Src expression. The shRNA-mediated inhibition of claudin-1 expression largely abrogated the TNF-α-induced changes in EMT, proliferation, migration, p-Erk and p-Src expression. Taken together, our data demonstrate TNF-α mediated regulation of claudin-1 and tumorigenic abilities of colon cancer cells and highlights a key role of deregulated claudin-1 expression in inflammation-induced colorectal cancer growth and progression, through the regulation of the ERK and Src-signaling.
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http://dx.doi.org/10.1016/j.yexcr.2016.10.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6166648PMC
November 2016

Therapeutic Potential of Resveratrol in Lymphoid Malignancies.

Nutr Cancer 2016 30;68(3):365-73. Epub 2016 Mar 30.

b Translational Research Institute, Academic Health System, Hamad Medical Corporation , Doha , Qatar.

Natural products have always been sought as a dependable source for the cure of many fatal diseases including cancer. Resveratrol (RSV), a naturally occurring plant polyphenol, has been of recent research interest and is being investigated for its beneficial biological properties that include antioxidant, anti-inflammatory, proapoptotic, and growth inhibitory activities. These effects are mainly mediated by cell cycle arrest, upregulation of proapoptotic proteins, loss of mitochondrial potential, and generation of reactive oxygen species. Among the beneficial properties of RSV, the anticancer property has been of the prime focus and extensively explored during the last few years. Although reports exist on the chemopreventive role of RSV in many solid tumors, limited information is available on the antiproliferative activity of RSV in human lymphoma cells and experimental models. Potential mechanisms for its antiproliferative effect include induction of cell differentiation, apoptosis, and inhibition of DNA synthesis. In this review, the different kinds of lymphoid malignancies and the main mechanisms of cell death induced by resveratrol are discussed. The challenges are limiting in vivo experimental studies involving resveratrol. An attempt for the translation of this compound into a clinical drug also forms a part of this review.
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http://dx.doi.org/10.1080/01635581.2016.1152386DOI Listing
January 2017

Bortezomib-mediated downregulation of S-phase kinase protein-2 (SKP2) causes apoptotic cell death in chronic myelogenous leukemia cells.

J Transl Med 2016 Mar 9;14:69. Epub 2016 Mar 9.

Translational Research Institute, Academic Health System, Hamad Medical Corporation, PO Box 3050, Doha, State of Qatar.

Background: Proteasome inhibitors are attractive cancer therapeutic agents because they can regulate apoptosis-related proteins. Bortezomib also known as Velcade(®), a proteasome inhibitor that has been approved by the food and drug administration for treatment of patients with multiple myeloma, and many clinical trials are ongoing to examine to the efficacy of bortezomib for the treatment of other malignancies. Bortezomib has been shown to induce apoptosis and inhibit cell growth of many cancer cells. In current study, we determine whether bortezomib induces cell death/apoptosis in CML.

Methods: Cell viability was measured using MTT assays. Apoptosis was measured by annexin V/PI dual staining and DNA fragmentation assays. Immunoblotting was performed to examine the expression of proteins. Colony assays were performed using methylcellulose.

Results: Treatment of CML cells with bortezomib results in downregulation of S-phase kinase protein 2 (SKP2) and concomitant stabilization of the expression of p27Kip1. Furthermore, knockdown of SKP2 with small interference RNA specific for SKP2 caused accumulation of p27Kip1. CML cells exposed to bortezomib leads to conformational changes in Bax protein, resulting in loss of mitochondrial membrane potential and leakage of cytochrome c to the cytosol. In the cytosol, cytochrome c causes sequential activation of caspase-9, caspase-3, PARP cleavage and apoptosis. Pretreatment of CML cells with a universal inhibitor of caspases, z-VAD-fmk, prevents bortezomib-mediated apoptosis. Our data also demonstrated that bortezomib treatment of CML downregulates the expression of inhibitor of apoptosis proteins. Finally, inhibition of proteasome pathways by bortezomib suppresses colony formation ability of CML cells.

Conclusions: Altogether, these findings suggest that bortezomib suppresses the cell proliferation via induction of apoptosis in CML cells by downregulation of SKP2 with concomitant accumulation of p27Kip1, suggesting that proteasomal pathway may form novel therapeutic targets for better management of CML.
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http://dx.doi.org/10.1186/s12967-016-0823-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4784454PMC
March 2016

Involvement of F-BOX proteins in progression and development of human malignancies.

Semin Cancer Biol 2016 Feb 26;36:18-32. Epub 2015 Sep 26.

Academic Health System, Translational Research Institute, Hamad Medical Corporation, Doha, Qatar. Electronic address:

The Ubiquitin Proteasome System (UPS) is a core regulator with various protein components (ubiquitin-activating E1 enzymes, ubiquitin-conjugating E2 enzymes, ubiquitin-protein E3 ligases, and the 26S proteasome) which work together in a coordinated fashion to ensure the appropriate and efficient proteolysis of target substrates. E3 ubiquitin ligases are essential components of the UPS machinery, working with E1 and E2 enzymes to bind substrates and assist the transport of ubiquitin molecules onto the target protein. As the UPS controls the degradation of several oncogenes and tumor suppressors, dysregulation of this pathway leads to several human malignancies. A major category of E3 Ub ligases, the SCF (Skp-Cullin-F-box) complex, is composed of four principal components: Skp1, Cul1/Cdc53, Roc1/Rbx1/Hrt1, and an F-box protein (FBP). FBPs are the substrate recognition components of SCF complexes and function as adaptors that bring substrates into physical proximity with the rest of the SCF. Besides acting as a component of SCF complexes, FBPs are involved in DNA replication, transcription, cell differentiation and cell death. This review will highlight the recent literature on three well characterized FBPs SKP2, Fbw7, and beta-TRCP. In particular, we will focus on the involvement of these deregulated FBPs in the progression and development of various human cancers. We will also highlight some novel substrates recently identified for these FBPs.
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http://dx.doi.org/10.1016/j.semcancer.2015.09.008DOI Listing
February 2016