Publications by authors named "Shahab Uddin"

152 Publications

Remdesivir for the Treatment of COVID-19: A Need for Combined and Studies to Evaluate the Efficacy.

J Pharm Pract 2021 06 24;34(3):343-346. Epub 2021 Feb 24.

Tıbbi Farmakoloji Anabilim Dalı, 66757Tıp Fakultesi, Cukurova Universitesi, Sarıcam, Adana, Turkey.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/0897190021997001DOI Listing
June 2021

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fcell.2021.617281DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7894079PMC
February 2021

Emerging dynamics pathways of response and resistance to PD-1 and CTLA-4 blockade: tackling uncertainty by confronting complexity.

J Exp Clin Cancer Res 2021 Feb 18;40(1):74. Epub 2021 Feb 18.

Department of Medical Oncology, Translational Research Institute, National Center for Cancer Care and Research, Hamad Medical Corporation, Doha, Qatar.

Immune checkpoint inhibitors provide considerable therapeutic benefit in a range of solid cancers as well as in a subgroup of hematological malignancies. Response rates are however suboptimal, and despite considerable efforts, predicting response to immune checkpoint inhibitors ahead of their administration in a given patient remains elusive. The study of the dynamics of the immune system and of the tumor under immune checkpoint blockade brought insight into the mechanisms of action of these therapeutic agents. Equally relevant are the mechanisms of adaptive resistance to immune checkpoint inhibitors that have been uncovered through this approach. In this review, we discuss the dynamics of the immune system and of the tumor under immune checkpoint blockade emanating from recent studies on animal models and humans. We will focus on mechanisms of action and of resistance conveying information predictive of therapeutic response.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13046-021-01872-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7893879PMC
February 2021

Anticancer Activity of Natural Compounds.

Asian Pac J Cancer Prev 2021 02 1;22(S1):1-2. Epub 2021 Feb 1.

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

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.31557/APJCP.2021.22.S1.1DOI Listing
February 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12943-020-01294-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7780621PMC
January 2021

TRPV2: A Cancer Biomarker and Potential Therapeutic Target.

Dis Markers 2020 10;2020:8892312. Epub 2020 Dec 10.

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

The Transient Receptor Potential Vanilloid type-2 (TRPV2) channel exhibits oncogenicity in different types of cancers. TRPV2 is implicated in signaling pathways that mediate cell survival, proliferation, and metastasis. In leukemia and bladder cancer, the oncogenic activity of TRPV2 was linked to alteration of its expression profile. In multiple myeloma patients, TRPV2 overexpression correlated with bone tissue damage and poor prognosis. In prostate cancer, TRPV2 overexpression was associated with the castration-resistant phenotype and metastasis. Loss or inactivation of TRPV2 promoted glioblastoma cell proliferation and increased resistance to CD95-induced apoptotic cell death. TRPV2 overexpression was associated with high relapse-free survival in triple-negative breast cancer, whereas the opposite was found in patients with esophageal squamous cell carcinoma or gastric cancer. Another link was found between TRPV2 expression and either drug-induced cytotoxicity or stemness of liver cancer. Overall, these findings validate TRPV2 as a prime candidate for cancer biomarker and future therapeutic target.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1155/2020/8892312DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7746447PMC
December 2020

Exosomes: Emerging Diagnostic and Therapeutic Targets in Cutaneous Diseases.

Int J Mol Sci 2020 Dec 4;21(23). Epub 2020 Dec 4.

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

Skin is the largest human organ and is continuously exposed to various exogenous and endogenous trigger factors affecting body homeostasis. A number of mechanisms, including genetic, inflammatory and autoimmune ones, have been implicated in the pathogenesis of cutaneous diseases. Recently, there has been considerable interest in the role that extracellular vesicles, particularly exosomes, play in human diseases, through their modulation of multiple signaling pathways. Exosomes are nano-sized vesicles secreted by all cell types. They function as cargo carriers shuttling proteins, nucleic acids, lipids etc., thus impacting the cell-cell communications and transfer of vital information/moieties critical for skin homeostasis and disease pathogenesis. This review summarizes the available knowledge on how exosomes affect pathogenesis of cutaneous diseases, and highlights their potential as future targets for the therapy of various skin diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms21239264DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7730213PMC
December 2020

Recent developments in unraveling signaling mechanisms underlying drug resistance due to cancer stem-like cells.

Curr Opin Pharmacol 2020 10 6;54:130-141. Epub 2020 Nov 6.

Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar; Dermatology Institute, Academic Health System, Hamad Medical Corporation, Doha 3050, Qatar; Department of Dermatology and Venereology, Rumailah Hospital, Hamad Medical Corporation, Doha 3050, Qatar. Electronic address:

Resistance in cancer cells to therapeutic measures is challenging and requires a rigorous delineation of the underlying mechanisms. Emerging findings reflect the characteristics of tumor cells to do the reprogramming of signaling machinery in order to overturn the therapeutic responses. Recent evidence shows that the tumor acquires drug resistance due to the presence of cancer stem cells (CSCs). Hence the understanding that how tumor cells reprogram their signaling mechanisms converging towards the stemness of CSCs is imperative for novel and effective therapy. This review outlines the current updates on how CSC-associated signaling pathways and its enhanced stemness trigger the development of drug resistance. Furthermore, we also discussed the strategies with a combinational approach that can simultaneously target both CSC-induced stemness and the resistance-related signaling pathways, which may provide an optimal outcome to overcome the problem of drug resistance in cancer therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.coph.2020.09.012DOI Listing
October 2020

Dysregulated Phosphorylation of p53, Autophagy and Stemness Attributes the Mutant p53 Harboring Colon Cancer Cells Impaired Sensitivity to Oxaliplatin.

Front Oncol 2020 28;10:1744. Epub 2020 Aug 28.

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

Colorectal cancer (CRC) forms one of the highest ranked cancer types in the world with its increasing incidence and mortality rates despite the advancement in cancer therapeutics. About 50% of human CRCs are reported to have defective p53 expression resultant of gene mutation often contributing to drug resistance. The current study was aimed to investigate the response of wild-type harboring HCT 116 and mutant harboring HT 29 colon cancer cells to chemotherapeutic drug oxaliplatin (OX) and to elucidate the underlying molecular mechanisms of sensitivity/resistance in correlation to their p53 status. OX inhibited growth of wild-type p53-harboring colon cancer cells via p53/p21-Bax mediated apoptosis. Our study revealed that dysregulated phosphorylation of p53, autophagy as well as cancer stemness attributes the mutant p53-harboring colon cancer cells impaired sensitivity to OX.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fonc.2020.01744DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7485421PMC
August 2020

Inositol-requiring enzyme 1 (IRE1) plays for AvrRpt2-triggered immunity and RIN4 cleavage in Arabidopsis under endoplasmic reticulum (ER) stress.

Plant Physiol Biochem 2020 Nov 5;156:105-114. Epub 2020 Sep 5.

College of Pharmacy and Research Institute of Pharmaceutical Science, PMBBRC, Gyeongsang National University, Jinju, 660-701, Republic of Korea. Electronic address:

Many stresses induce the accumulation of unfolded and misfolded proteins in the endoplasmic reticulum, a phenomenon known as ER stress. In response to ER stress, cells initiate a protective response, known as unfolded protein response (UPR), to maintain cellular homeostasis. The UPR sensor, inositol-requiring enzyme 1 (IRE1), catalyzes the cytoplasmic splicing of bZIP transcription factor-encoding mRNAs to activate the UPR signaling pathway. Recently, we reported that pretreatment of Arabidopsis thaliana plants with tunicamycin, an ER stress inducer, increased their susceptibility to bacterial pathogens; on the other hand, IRE1 deficient mutants were susceptible to Pseudomonas syringae pv. maculicola (Psm) and failed to induce salicylic acid (SA)-mediated systemic acquired resistance. However, the functional relationship of IRE1 with the pathogen and TM treatment remains unknown. In the present study, we showed that bacterial pathogen-associated molecular patterns (PAMPs) induced IRE1 expression; however, PAMP-triggered immunity (PTI) response such as callose deposition, PR1 protein accumulation, or Pst DC3000 hrcC growth was not altered in ire1 mutants. We observed that IRE1 enhanced plant immunity against the bacterial pathogen P. syringae pv. tomato DC3000 (Pst DC3000) under ER stress. Moreover, TM-pretreated ire1 mutants were more susceptible to the avirulent strain Pst DC3000 (AvrRpt2) and showed greater cell death than wild-type plants during effector-triggered immunity (ETI). Additionally, Pst DC3000 (AvrRpt2)-mediated RIN4 degradation was reduced in ire1 mutants under TM-induced ER stress. Collectively, our results reveal that IRE1 plays a pivotal role in the immune signaling pathway to activate plant immunity against virulent and avirulent bacterial strains under ER stress.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.plaphy.2020.09.002DOI Listing
November 2020

Persistent anti-NY-ESO-1-specific T cells and expression of differential biomarkers in a patient with metastatic gastric cancer benefiting from combined radioimmunotherapy treatment: a case report.

J Immunother Cancer 2020 09;8(2)

Medical Oncology, National Center for Cancer Care and Research, Doha, Qatar

Combined radioimmunotherapy is currently being investigated to treat patients with cancer. Anti-programmed cell death-1 (PD-1) immunotherapy offers the prospect of long-term disease control in solid tumors. Radiotherapy has the ability to promote immunogenic cell death leading to the release of tumor antigens, increasing infiltration and activation of T cells. New York esophageal squamous cell carcinoma-1 (NY-ESO-1) is a cancer-testis antigen expressed in 20% of advanced gastric cancers and known to induce humoral and cellular immune responses in patients with cancer. We report on the dynamic immune response to the NY-ESO-1 antigen and important immune-related biomarkers in a patient with metastatic gastric cancer treated with radiotherapy combined with anti-PD-1 pembrolizumab antibody.Our patient was an 81-year-old man diagnosed with locally advanced unresectable mismatch repair-deficient gastric cancer having progressed to a metastatic state under a second line of systemic treatment consisting of an anti-PD-1 pembrolizumab antibody. The patient was subsequently treated with local radiotherapy administered concomitantly with anti-PD-1, with a complete response on follow-up radiologic assessment. Disease control was sustained with no further therapy for a period of 12 months before relapse. We have identified an NY-ESO-1-specific interferon-γ (IFN-γ) secretion from the patients' T cells that was significantly increased at response (****p˂0.0001). A novel promiscuous immunogenic NY-ESO-1 peptide P39 (P) restricted to the four patient's HLA-DQ and HLA-DP alleles was identified. Interestingly, this peptide contained the known NY-ESO-1-derived HLA-A2-02:01(P) immunogenic epitope. We have also identified a CD107 cytotoxic T cell subset within a specific CD8/HLA-A2-NY-ESO-1 T cell population that was low at disease progression, markedly increased at disease resolution and significantly decreased again at disease re-progression. Finally, we identified two groups of cytokines/chemokines. Group 1 contains five cytokines (IFN-γ, tumor necrosis factor-α, interleukin-2 (IL-2), IL-5 and IL-6) that were present at disease progression, significantly downregulated at disease resolution and dramatically upregulated again at disease re-progression. Group 2 contains four biomarkers (perforin, soluble FAS, macrophage inflammatory protein-3α and C-X-C motif chemokine 11/Interferon-inducible T Cell Alpha Chemoattractant that were present at disease progression, significantly upregulated at disease resolution and dramatically downregulated again at disease re-progression. Combined radioimmunotherapy can enhance specific T cell responses to the NY-ESO-1 antigen that correlates with beneficial clinical outcome of the patient.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/jitc-2020-001278DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7484873PMC
September 2020

Epigenetic Regulation of Cancer Stem Cells by the Aryl Hydrocarbon Receptor Pathway.

Semin Cancer Biol 2020 Aug 30. Epub 2020 Aug 30.

Department of Pharmaceutical Sciences, College of Pharmacy, QU Health, Qatar University, Doha, Qatar. Electronic address:

Compelling evidence has demonstrated that tumor bulk comprises distinctive subset of cells generally referred as cancer stem cells (CSCs) that have been proposed as a strong sustainer and promoter of tumorigenesis and therapeutic resistance. These distinguished properties of CSCs have raised interest in understanding the molecular mechanisms that govern the maintenance of these cells. Numerous experimental and epidemiological studies have demonstrated that exposure to environmental toxins such as the polycyclic aromatic hydrocarbons (PAHs) is strongly involved in cancer initiation and progression. The PAH-induced carcinogenesis is shown to be mediated through the activation of a cytosolic receptor, aryl hydrocarbon receptor (AhR)/Cytochrome P4501A pathway, suggesting a possible direct link between AhR and CSCs. Several recent studies have investigated the role of AhR in CSCs self-renewal and maintenance, however the molecular mechanisms and particularly the epigenetic regulations of CSCs by the AhR/CYP1A pathway have not been reviewed before. In this review, we first summarize the crosstalk between AhR and cancer genetics, with a particular emphasis on the mechanisms relevant to CSCs such as Wnt/β-catenin, Notch, NF-κB, and PTEN-PI3K/Akt signaling pathways. The second part of this review discusses the recent advances and studies highlighting the epigenetic mechanisms mediated by the AhR/CYP1A pathway that control CSC gene expression, self-renewal, and chemoresistance in various human cancers. Furthermore, the review also sheds light on the importance of targeting the epigenetic pathways as a novel therapeutic approach against CSCs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.semcancer.2020.08.014DOI Listing
August 2020

Epigenetic and breast cancer therapy: Promising diagnostic and therapeutic applications.

Semin Cancer Biol 2020 Aug 25. Epub 2020 Aug 25.

Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, P.O. Box 3050, Qatar; Dermatology Institute, Academic Health System, Hamad Medical Corporation, Doha, P.O. Box 3050, Qatar. Electronic address:

The global burden of breast cancer (BC) is increasing significantly. This trend is caused by several factors such as late diagnosis, limited treatment options for certain BC subtypes, drug resistance which all lead to poor clinical outcomes. Recent research has reported the role of epigenetic alterations in the mechanism of BC pathogenesis and its hallmarks include drug resistance and stemness features. The understanding of these modifications and their significance in the management of BC carcinogenesis is challenging and requires further attention. Nevertheless, it promises to provide novel insight needed for utilizing these alterations as potential diagnostic, prognostic markers, predict treatment efficacy, as well as therapeutic agents. This highlights the importance of continuing research development to further advance the existing knowledge on epigenetics and BC carcinogenesis to overcome the current challenges. Hence, this review aims to shed light and discuss the current state of epigenetics research in the diagnosis and management of BC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.semcancer.2020.08.009DOI Listing
August 2020

Anti-hypertrophic effect of Na/H exchanger-1 inhibition is mediated by reduced cathepsin B.

Eur J Pharmacol 2020 Dec 8;888:173420. Epub 2020 Aug 8.

College of Pharmacy, QU Health, Qatar University, Doha, Qatar. Electronic address:

Previous studies have established the role of Na/H exchanger isoform-1 (NHE1) and cathepsin B (Cat B) in the development of cardiomyocyte hypertrophy (CH). Both NHE1 and Cat B are activated under acidic conditions suggesting that their activities might be interrelated. The inhibition of NHE1 has been demonstrated to reduce cardiac hypertrophy but the mechanism that contributes to the anti-hypertrophic effect of NHE1 inhibition still remains unclear. H9c2 cardiomyoblasts were stimulated with Angiotensin (Ang) II in the presence and absence of N-[2-methyl-4,5-bis(methylsulphonyl)-benzoyl]-guanidine, hydrochloride (EMD, EMD 87580), an NHE1 inhibitor or CA-074Me, a Cat B inhibitor, and various cardiac hypertrophic parameters, namely cell surface area, protein content and atrial natriuretic peptide (ANP) mRNA were analyzed. EMD significantly suppressed markers of cardiomyocyte hypertrophy and inhibited Ang II stimulated Cat B protein and gene expression. Cat B is located within the acidic environment of lysosomes. Cat B proteases are released into the cytoplasm upon disintegration of the lysosomes. EMD or CA-074Me prevented the dispersal of the lysosomes induced by Ang II and reduced the ratio of LC3-II to LC3-I, a marker of autophagy. Moreover, Cat B protein expression and MMP-9 activity in the extracellular space were significantly attenuated in the presence of EMD or CA-074Me. Our study demonstrates a novel mechanism for attenuation of the hypertrophic phenotype by NHE1 inhibition that is mediated by a regression in Cat B. The inhibition of Cat B via EMD or CA-074Me attenuates the autosomal-lysosomal pathway and MMP-9 activation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejphar.2020.173420DOI Listing
December 2020

Role of non-coding RNAs in the progression and resistance of cutaneous malignancies and autoimmune diseases.

Semin Cancer Biol 2020 Jul 25. Epub 2020 Jul 25.

Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar; Dermatology Institute, Academic Health System, Hamad Medical Corporation, Doha 3050, Qatar; Department of Dermatology and Venereology, Rumailah Hospital, Hamad Medical Corporation, Doha 3050, Qatar; Department of Medicine, Weill Cornell Medicine Qatar, Qatar Foundation-Education City, Doha 24144, Qatar; Department of Medicine, Weill Cornell Medicine, 1300 York Avenue, New York, NY 10065, USA; College of Medicine, Qatar University, Doha 2713, Qatar.

Skin, the largest organ of human body, is vital for the existence and survival of human beings. Further, developmental and physiological mechanisms associated with cutaneous biology are vital for homeostasis as their deregulations converge towards pathogenesis of a number of skin diseases, including cancer. It has now been well accepted that most of the transcribed human genome lacks protein translational potential and has been termed as non-coding RNAs (nc-RNAs), which includes circular RNA (circRNA), small nuclear RNA (snRNA), small nucleolar RNA (snoRNA), micro RNA (miRNA), long noncoding RNA (lncRNA), and piwi-interacting RNA (piRNAs). These nc-RNAs have gained great attention in both preclinical and clinical research as they are critical in most of the regulatory mechanisms of biological homeostasis and disease development by controlling the gene expression at transcriptional, post-transcriptional and epigenetic level. In this review we have illustrated how nc-RNAs are critical in the development and maintenance of cutaneous homeostasis and functioning and also, most importantly, how the dysregulated expression and functioning of nc-RNAs play critical role in the pathogenesis of cutaneous diseases including cancer and the autoimmune skin diseases. Considering the vital role of nc-RNAs in cancer resistance, metastasis and autoimmune diseases, we have also highlighted their role as promising prognostic and therapeutic targets for the cutaneous diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.semcancer.2020.07.003DOI Listing
July 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms21145002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7403981PMC
July 2020

Inhibition of p90 ribosomal S6 kinase potentiates cisplatin activity in A549 human lung adenocarcinoma cells.

J Pharm Pharmacol 2020 Nov 15;72(11):1536-1545. Epub 2020 Jul 15.

College of Pharmacy, QU Health, Qatar University, Doha, Qatar.

Objective: Cisplatin is a standard treatment approach against lung adenocarcinoma. Resistance to cisplatin and the toxic side effects of cisplatin continue to remain a challenge. Combining drugs with different mechanisms is being investigated as a means to overcome these challenges. In ovarian cancer cells, the knockdown of RSK2 increased the sensitivity of cisplatin. RSK is a downstream mediator of the MAPK pathway that is responsible for cell survival, proliferation and migration.

Methods: Our study examined the effect of cisplatin, BI-D1870 (RSK inhibitor) or their combination on cell migration, apoptosis, autophagy and cell cycle in A549 human lung adenocarcinoma cells.

Key Findings: The combination of cisplatin and BI-D1870 potentiated the antimigration rate, the activation of caspases-3 and was associated with a significant decrease in RSK1 and ERK expression when compared to cisplatin alone. The combination of cisplatin and BI-D1870 also resulted in the inhibition of LC3 II to LC3 I expression when compared to BI-D1870. The combination of cisplatin and BI-D1870 increased the number of cells in the G2/M-phase when compared to cisplatin alone.

Conclusions: These findings suggest that combining cisplatin with agents that target the RSK mediated cell survival pathway, may potentiate the cisplatin effect in lung adenocarcinoma.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/jphp.13335DOI Listing
November 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms21124503DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352752PMC
June 2020

Prevalence and Type Distribution of High-Risk Human Papillomavirus (HPV) in Breast Cancer: A Qatar Based Study.

Cancers (Basel) 2020 Jun 10;12(6). Epub 2020 Jun 10.

Breast Cancer Unit, Hamad General Hospital, Hamad Medical Corporation, Doha P.O. Box 3050, Qatar.

Human papillomavirus (HPV) has been implicated in the etiology of a variety of human cancers. Studies investigating the presence of high-risk (HR) HPV in breast tissue have generated considerable controversy over its role as a potential risk factor for breast cancer (BC). This is the first investigation reporting the prevalence and type distribution of high-risk HPV infection in breast tissue in the population of Qatar. A prospective comparison blind research study herein reconnoitered the presence of twelve HR-HPV types' DNA using multiplex PCR by screening a total of 150 fresh breast tissue specimens. Data obtained shows that HR-HPV types were found in 10% of subjects with breast cancer; of which the presence of HPV was confirmed in 4/33 (12.12%) of invasive carcinomas. These findings, the first reported from the population of Qatar, suggest that the selective presence of HPV in breast tissue is likely to be a related factor in the progression of certain cases of breast cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers12061528DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352582PMC
June 2020

CAR-T Cell Therapies: An Overview of Clinical Studies Supporting Their Approved Use against Acute Lymphoblastic Leukemia and Large B-Cell Lymphomas.

Int J Mol Sci 2020 May 30;21(11). Epub 2020 May 30.

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

Chimeric Antigen Receptor (CAR)-T cell therapy is an exciting development in the field of cancer immunology, wherein immune T-cells from patients are collected, engineered to create 'CAR'-T cells, and infused back into the same patient. Currently, two CAR-T-cell-based therapies, Tisagenlecleucel and Axicabtagene ciloleucel, are approved by FDA for the treatment of hematological malignancies, acute lymphoblastic leukemia and large B-cell lymphomas. Their approval has been a culmination of several phase I and II clinical studies, which are the subject of discussion in this review article. Over the years, CAR-T cells have evolved to be significantly more persistent in patients' blood, resulting in a much-improved clinical response and disease remission. This is particularly significant given that the target patient populations of these therapies are those with relapsed and refractory disease who have often progressed on multiple therapies. Despite the promising clinical results, there are still several challenges that need to be addressed. Of particular note are the associated toxicities exemplified by cytokine release syndrome (CRS) and the neurotoxicity. CRS has been addressed by an FDA-approved therapy of its own-tocilizumab. This article focuses on the progress related to CAR-T therapy: the pertinent clinical studies and their major findings, their associated adverse effects, and future perspective.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms21113906DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7312930PMC
May 2020

Inducing Angiogenesis, a Key Step in Cancer Vascularization, and Treatment Approaches.

Cancers (Basel) 2020 May 6;12(5). Epub 2020 May 6.

National Cancer Care and Research, Hamad Medical Corporation, Doha 3050, Qatar.

Angiogenesis is a term that describes the formation of new blood and lymphatic vessels from a pre-existing vasculature. This allows tumour cells to acquire sustenance in the form of nutrients and oxygen and the ability to evacuate metabolic waste. As one of the hallmarks of cancer, angiogenesis has been studied extensively in animal and human models to enable better understanding of cancer biology and the development of new anti-cancer treatments. Angiogenesis plays a crucial role in the process of tumour genesis, because solid tumour need a blood supply if they are to grow beyond a few millimeters in size. On the other hand, there is growing evidence that some solid tumour exploit existing normal blood supply and do not require a new vessel formation to grow and to undergo metastasis. This review of the literature will present the current understanding of this intricate process and the latest advances in the use of angiogenesis-targeting therapies in the fight against cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers12051172DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7281705PMC
May 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/01635581.2020.1749676DOI Listing
April 2020

Unleashing the immune response to NY-ESO-1 cancer testis antigen as a potential target for cancer immunotherapy.

J Transl Med 2020 03 27;18(1):140. Epub 2020 Mar 27.

National Center for Cancer Care and Research, Hamad Medical Corporation, Doha, Qatar.

Introduction: Cancer Immunotherapy has recently emerged as a promising and effective modality to treat different malignancies. Antigenic profiling of cancer tissues and determination of any pre-existing immune responses to cancer antigens may help predict responses to immune intervention in cancer. NY-ESO-1, a cancer testis antigen is the most immunogenic antigen to date. The promise of NY-ESO-1 as a candidate for specific immune recognition of cancer comes from its restricted expression in normal adult tissue but frequent occurrence in multiple tumors including melanoma and carcinomas of lung, esophageal, liver, gastric, prostrate, ovarian, and bladder.

Main Body: This review summarizes current knowledge of NY-ESO-1 as efficient biomarker and target of immunotherapy. It also addresses limitations and challenges preventing a robust immune response to NY-ESO-1 expressing cancers, and describes pre-clinical and clinical observations relevant to NY-ESO-1 immunity, holding potential therapeutic relevance for cancer treatment.

Conclusion: NY-ESO-1 induces strong immune responses in cancer patients but has limited objective clinical responses to NY-ESO-1 expressing tumors due to effect of competitive negative signaling from immune-checkpoints and immune-suppressive tumor microenvironment. We propose that combination therapy to increase the efficacy of NY-ESO-1 specific immunotherapeutic interventions should be explored to unleash the immune response against NY-ESO-1 expressing tumors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12967-020-02306-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7102435PMC
March 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/978-3-030-38862-1_1DOI Listing
September 2020

Sanguinarine Induces Apoptosis in Papillary Thyroid Cancer Cells via Generation of Reactive Oxygen Species.

Molecules 2020 Mar 9;25(5). Epub 2020 Mar 9.

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

Sanguinarine (SNG), a natural compound with an array of pharmacological activities, has promising therapeutic potential against a number of pathological conditions, including malignancies. In the present study, we have investigated the antiproliferative potential of SNG against two well-characterized papillary thyroid cancer (PTC) cell lines, BCPAP and TPC-1. SNG significantly inhibited cell proliferation of PTC cells in a dose and time-dependent manner. Western blot analysis revealed that SNG markedly attenuated deregulated expression of p-STAT3, without affecting total STAT3, and inhibited growth of PTC via activation of apoptotic and autophagy signaling cascade, as SNG treatment of PTC cells led to the activation of caspase-3 and caspase-8; cleavage of PARP and activation of autophagy markers. Further, SNG-mediated anticancer effects in PTC cells involved the generation of reactive oxygen species (ROS) as N-acetyl cysteine (NAC), an inhibitor of ROS, prevented SNG-mediated antiproliferative, apoptosis and autophagy inducing action. Interestingly, SNG also sensitized PTC cells to chemotherapeutic drug cisplatin, which was inhibited by NAC. Finally, SNG suppressed the growth of PTC thyrospheres and downregulated stemness markers ALDH2 and SOX2. Altogether, the findings of the current study suggest that SNG has anticancer potential against PTC cells as well its derived cancer stem-like cells, most likely via inactivation of STAT3 and its associated signaling molecules.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/molecules25051229DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7179475PMC
March 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12943-020-01175-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7069174PMC
March 2020

Urine as a Main Effector in Urological Tissue Engineering-A Double-Edged Sword.

Cells 2020 02 26;9(3). Epub 2020 Feb 26.

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

In order to reconstruct injured urinary tract tissues, biodegradable scaffolds with autologous seeded cells are explored in this work. However, when cells are obtained via biopsy from individuals who have damaged organs due to infection, congenital disorders, or cancer, this can result in unhealthy engineered cells and donor site morbidity. Thus, neo-organ construction through an alternative cell source might be useful. Significant advancements in the isolation and utilization of urine-derived stem cells have provided opportunities for this less invasive, limitless, and versatile source of cells to be employed in urologic tissue-engineered replacement. These cells have a high potential to differentiate into urothelial and smooth muscle cells. However, urinary tract reconstruction via tissue engineering is peculiar as it takes place in a milieu of urine that imposes certain risks on the implanted cells and scaffolds as a result of the highly cytotoxic nature of urine and its detrimental effect on both growth and differentiation of these cells. Both of these projections should be tackled thoughtfully when designing a suitable approach for repairing urinary tract defects and applying the needful precautions is vital.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cells9030538DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7140397PMC
February 2020

Non-Coding RNAs as Regulators and Markers for Targeting of Breast Cancer and Cancer Stem Cells.

Cancers (Basel) 2020 Feb 4;12(2). Epub 2020 Feb 4.

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

Breast cancer is regarded as a heterogeneous and complicated disease that remains the prime focus in the domain of public health concern. Next-generation sequencing technologies provided a new perspective dimension to non-coding RNAs, which were initially considered to be transcriptional noise or a product generated from erroneous transcription. Even though understanding of biological and molecular functions of noncoding RNA remains enigmatic, researchers have established the pivotal role of these RNAs in governing a plethora of biological phenomena that includes cancer-associated cellular processes such as proliferation, invasion, migration, apoptosis, and stemness. In addition to this, the transmission of microRNAs and long non-coding RNAs was identified as a source of communication to breast cancer cells either locally or systemically. The present review provides in-depth information with an aim at discovering the fundamental potential of non-coding RNAs, by providing knowledge of biogenesis and functional roles of micro RNA and long non-coding RNAs in breast cancer and breast cancer stem cells, as either oncogenic drivers or tumor suppressors. Furthermore, non-coding RNAs and their potential role as diagnostic and therapeutic moieties have also been summarized.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers12020351DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7072613PMC
February 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms21020569DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7013445PMC
January 2020