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3. Temporal patterns of cancer burden in Asia, 1990–2019: a systematic examination for the Global Burden of Disease 2019 study

Author

Sharma, Rajesh, Abbastabar, Hedayat, Abdulah, Deldar Morad, Abidi, Hassan, Abolhassani, Hassan, Abrehdari-Tafreshi, Zahra, Absalan, Abdorrahim, Ali, Hiwa Abubaker, Abu-Gharbieh, Eman, Acuna, Juan Manuel, Adib, Nasrin, Sakilah Adnani, Qorinah Estiningtyas, Aghaei, Abbas, Ahmad, Aqeel, Ahmad, Sajjad, Ahmadi, Ali, Ahmadi, Sepideh, Ahmed, Luai A., Ajami, Marjan, Al Hamad, Hanadi, Al Hasan, Syed Mahfuz, Alanezi, Fahad Mashhour, Saeed Al-Gheethi, Adel Ali, Al-Hanawi, Mohammed Khaled, Ali, Abid, Ali, Beriwan Abdulqadir, Alimohamadi, Yousef, Aljunid, Syed Mohamed, Ali Al-Maweri, Sadeq Ali, Alqahatni, Saleh A., AlQudah, Mohammad, Al-Raddadi, Rajaa M., Al-Tammemi, Ala'a B., Ansari-Moghaddam, Alireza, Anwar, Sumadi Lukman, Anwer, Razique, Aqeel, Muhammad, Arabloo, Jalal, Arab-Zozani, Morteza, Ariffin, Hany, Artaman, Al, Arulappan, Judie, Ashraf, Tahira, Askari, Elaheh, Athar, Mohammad, Wahbi Atout, Maha Moh'd, Azadnajafabad, Sina, Badar, Muhammad, Badiye, Ashish D., Baghcheghi, Nayereh, Bagherieh, Sara, Bai, Ruhai, Bajbouj, Khuloud, Baliga, Shrikala, Bardhan, Mainak, Bashiri, Azadeh, Baskaran, Pritish, Basu, Saurav, Belgaumi, Uzma Iqbal, Nazer C Bermudez, Amiel, Bhandari, Bharti, Bhardwaj, Nikha, Bhat, Ajay Nagesh, Bitaraf, Saeid, Boloor, Archith, Hashemi, Milad Bonakdar, Butt, Zahid A., Chadwick, Joshua, Kai Chan, Jeffrey Shi, Chattu, Vijay Kumar, Chaturvedi, Pankaj, Cho, William C.S., Darwesh, Aso Mohammad, Dash, Nihar Ranjan, Dehghan, Amin, Dhali, Arkadeep, Dianatinasab, Mostafa, Dibas, Mahmoud, Dixit, Abhinav, Dixit, Shilpi Gupta, Dorostkar, Fariba, Dsouza, Haneil Larson, Elbarazi, Iffat, Elemam, Noha Mousaad, El-Huneidi, Waseem, Elkord, Eyad, Abdou Elmeligy, Omar Abdelsadek, Emamian, Mohammad Hassan, Erkhembayar, Ryenchindorj, Ezzeddini, Rana, Fadoo, Zehra, Faiz, Razana, Fakhradiyev, Ildar Ravisovich, Fallahzadeh, Aida, Faris, MoezAlIslam Ezzat Mahmoud, Farrokhpour, Hossein, Fatehizadeh, Ali, Fattahi, Hamed, Fekadu, Ginenus, Fukumoto, Takeshi, Gaidhane, Abhay Motiramji, Galehdar, Nasrin, Garg, Priyanka, Ghadirian, Fataneh, Ghafourifard, Mansour, Ghasemi, MohammadReza, Nour, Mohammad Ghasemi, Ghassemi, Fariba, Gholamalizadeh, Maryam, Gholamian, Asadollah, Ghotbi, Elena, Golechha, Mahaveer, Goleij, Pouya, Goyal, Sahil, Mohialdeen Gubari, Mohammed Ibrahim, Gunasekera, D Sanjeeva, Gunawardane, Damitha Asanga, Gupta, Sapna, Habibzadeh, Parham, Haeri Boroojeni, Helia Sadat, Halboub, Esam S., Hamadeh, Randah R., Hamoudi, Rifat, Harorani, Mehdi, Hasanian, Mohammad, Hassan, Treska S., Hay, Simon I., Heidari, Mohammad, Heidari-Foroozan, Mahsa, Hessami, Kamran, Hezam, Kamal, Hiraike, Yuta, Holla, Ramesh, Hoseini, Mohammad, Hossain, Md Mahbub, Hossain, Sahadat, Hsieh, Vivian Chia-rong, Huang, Junjie, Hussein, Nawfal R., Hwang, Bing-Fang, Iravanpour, Farideh, Ismail, Nahlah Elkudssiah, Iwagami, Masao, Merin J, Linda, Jadidi-Niaragh, Farhad, Jafarinia, Morteza, Jahani, Mohammad Ali, Jahrami, Haitham, Jaiswal, Abhishek, Jakovljevic, Mihajlo, Jalili, Mahsa, Jamshidi, Elham, Jayarajah, Umesh, Jayaram, Shubha, Jha, Sweety Suman, Jokar, Mohammad, Joseph, Nitin, Kabir, Ali, Kabir, Md. Awal, Kadir, Dler Hussein, Kakodkar, Pradnya Vishal, Kalankesh, Laleh R., Kalankesh, Leila R., Kalhor, Rohollah, Kaliyadan, Feroze, Kamal, Vineet Kumar, Kamal, Zul, Kamath, Ashwin, Kar, Sitanshu Sekhar, Karimi, Hanie, Kaur, Navjot, Keikavoosi-Arani, Leila, Keykhaei, Mohammad, Khader, Yousef Saleh, Khajuria, Himanshu, Khan, Ejaz Ahmad, Khan, M Nuruzzaman, Khan, Maseer, Khan, Moien A.B., Khan, Yusra H., Khanmohammadi, Shaghayegh, Khatatbeh, Moawiah Mohammad, Khateri, Sorour, Khayamzadeh, Maryam, Khayat Kashani, Hamid Reza, Kim, Min Seo, Kompani, Farzad, Koohestani, Hamid Reza, Koulmane Laxminarayana, Sindhura Lakshmi, Krishan, Kewal, Kumar, Narinder, Kumar, Naveen, Kutluk, Tezer, Kuttikkattu, Ambily, Ching Lai, Daphne Teck, Lal, Dharmesh Kumar, Lami, Faris Hasan, Lasrado, Savita, Lee, Sang-Woong, Lee, Seung Won, Lee, Yeong Yeh, Lee, Yo Han, Leong, Elvynna, Li, Ming-Chieh, Liu, Jue, Madadizadeh, Farzan, Mafi, Ahmad R., Mahjoub, Soleiman, Malekzadeh, Reza, Malik, Ahmad Azam, Malik, Iram, Mallhi, Tauqeer Hussain, Mansournia, Mohammad Ali, Martini, Santi, Mathews, Elezebeth, Mathur, Manu Raj, Meena, Jitendra Kumar, Menezes, Ritesh G., Mirfakhraie, Reza, Mirinezhad, Seyed Kazem, Mirza-Aghazadeh-Attari, Mohammad, Mithra, Prasanna, Mohamadkhani, Ashraf, Mohammadi, Soheil, Mohammadzadeh, Maryam, Mohan, Syam, Mokdad, Ali H., Al Montasir, Ahmed, Montazeri, Fateme, Moradi, Maryam, Sarabi, Mostafa Moradi, Moradpour, Farhad, Moradzadeh, Maliheh, Moraga, Paula, Mosapour, Abbas, Motaghinejad, Majid, Mubarik, Sumaira, Muhammad, Jibran Sualeh, Murray, Christopher J.L., Nagarajan, Ahamarshan Jayaraman, Naghavi, Mohsen, Nargus, Shumaila, Natto, Zuhair S., Nayak, Biswa Prakash, Nejadghaderi, Seyed Aria, Nguyen, Phuong The, Niazi, Robina Khan, Noroozi, Nafise, Okati-Aliabad, Hassan, Okekunle, Akinkunmi Paul, Ong, Sokking, Oommen, Anu Mary, Padubidri, Jagadish Rao, Pandey, Ashok, Park, Eun-Kee, Park, Seoyeon, Pati, Siddhartha, Patil, Shankargouda, Paudel, Rajan, Paudel, Uttam, Pirestani, Majid, Podder, Indrashis, Pourali, Ghazaleh, Pourjafar, Mona, Pourshams, Akram, Syed, Zahiruddin Quazi, Radhakrishnan, Raghu Anekal, Radhakrishnan, Venkatraman, Rahman, Mosiur, Rahmani, Shayan, Rahmanian, Vahid, Ramesh, Pushkal Sinduvadi, Rana, Juwel, Rao, Indu Ramachandra, Rao, Sowmya J., Rashedi, Sina, Rashidi, Mohammad-Mahdi, Rezaei, Nazila, Rezaei, Negar, Rezaei, Nima, Rezaei, Saeid, Rezaeian, Mohsen, Roshandel, Gholamreza, Chandan, S.N., Saber-Ayad, Maha Mohamed, Sabour, Siamak, Sabzmakan, Leila, Saddik, Basema, Saeed, Umar, Safi, Sher Zaman, Sharif-Askari, Fatemeh Saheb, Sahebkar, Amirhossein, Sahoo, Harihar, Sajedi, Seyed Aidin, Sajid, Mirza Rizwan, Salehi, Mohammad Amin, Farrokhi, Amir Salek, Sarasmita, Made Ary, Sargazi, Saman, Sarode, Gargi Sachin, Sarode, Sachin C., Sathian, Brijesh, Satpathy, Maheswar, Semwal, Prabhakar, Senthilkumaran, Subramanian, Sepanlou, Sadaf G., Shafeghat, Melika, Shahabi, Saeed, Shahbandi, Ataollah, Shahraki-Sanavi, Fariba, Shaikh, Masood Ali, Shannawaz, Mohammed, Sheikhi, Rahim Ali, Shobeiri, Parnian, Shorofi, Seyed Afshin, Shrestha, Sunil, Siabani, Soraya, Singh, Garima, Singh, Paramdeep, Singh, Surjit, Sinha, Dhirendra Narain, Siwal, Samarjeet Singh, Sreeram, Saraswathy, Suleman, Muhammad, Abdulkader, Rizwan Suliankatchi, Sultan, Iyad, Sultana, Abida, Tabish, Mohammad, Tabuchi, Takahiro, Taheri, Majid, Talaat, Iman M., Tehrani-Banihashemi, Arash, Temsah, Mohamad-Hani, Thangaraju, Pugazhenthan, Thomas, Nihal, Thomas, Nikhil Kenny, Tiyuri, Amir, Tobe-Gai, Ruoyan, Toghroli, Razie, Tovani-Palone, Marcos Roberto, Ullah, Sana, Unnikrishnan, Bhaskaran, Upadhyay, Era, Tahbaz, Sahel Valadan, Valizadeh, Rohollah, Varthya, Shoban Babu, Waheed, Yasir, Wang, Song, Wickramasinghe, Dakshitha Praneeth, Wickramasinghe, Nuwan Darshana, Xiao, Hong, Yonemoto, Naohiro, Younis, Mustafa Z., Yu, Chuanhua, Zahir, Mazyar, Zaki, Nazar, Zamanian, Maryam, Zhang, Zhi-Jiang, Zhao, Hanqing, Zitoun, Osama A., and Zoladl, Mohammad

Published
2024
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11. Designing a broad-spectrum integrative approach for cancer prevention and treatment

Author

Block, Keith I, Gyllenhaal, Charlotte, Lowe, Leroy, Amedei, Amedeo, Amin, ARM Ruhul, Amin, Amr, Aquilano, Katia, Arbiser, Jack, Arreola, Alexandra, Arzumanyan, Alla, Ashraf, S Salman, Azmi, Asfar S, Benencia, Fabian, Bhakta, Dipita, Bilsland, Alan, Bishayee, Anupam, Blain, Stacy W, Block, Penny B, Boosani, Chandra S, Carey, Thomas E, Carnero, Amancio, Carotenuto, Marianeve, Casey, Stephanie C, Chakrabarti, Mrinmay, Chaturvedi, Rupesh, Chen, Georgia Zhuo, Chen, Helen, Chen, Sophie, Chen, Yi Charlie, Choi, Beom K, Ciriolo, Maria Rosa, Coley, Helen M, Collins, Andrew R, Connell, Marisa, Crawford, Sarah, Curran, Colleen S, Dabrosin, Charlotta, Damia, Giovanna, Dasgupta, Santanu, DeBerardinis, Ralph J, Decker, William K, Dhawan, Punita, Diehl, Anna Mae E, Dong, Jin-Tang, Dou, Q Ping, Drew, Janice E, Elkord, Eyad, El-Rayes, Bassel, Feitelson, Mark A, Felsher, Dean W, Ferguson, Lynnette R, Fimognari, Carmela, Firestone, Gary L, Frezza, Christian, Fujii, Hiromasa, Fuster, Mark M, Generali, Daniele, Georgakilas, Alexandros G, Gieseler, Frank, Gilbertson, Michael, Green, Michelle F, Grue, Brendan, Guha, Gunjan, Halicka, Dorota, Helferich, William G, Heneberg, Petr, Hentosh, Patricia, Hirschey, Matthew D, Hofseth, Lorne J, Holcombe, Randall F, Honoki, Kanya, Hsu, Hsue-Yin, Huang, Gloria S, Jensen, Lasse D, Jiang, Wen G, Jones, Lee W, Karpowicz, Phillip A, Keith, W Nicol, Kerkar, Sid P, Khan, Gazala N, Khatami, Mahin, Ko, Young H, Kucuk, Omer, Kulathinal, Rob J, Kumar, Nagi B, Kwon, Byoung S, Le, Anne, Lea, Michael A, Lee, Ho-Young, Lichtor, Terry, Lin, Liang-Tzung, Locasale, Jason W, Lokeshwar, Bal L, Longo, Valter D, Lyssiotis, Costas A, MacKenzie, Karen L, Malhotra, Meenakshi, Marino, Maria, Martinez-Chantar, Maria L, and Matheu, Ander

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Cancer, Rare Diseases, Precision Medicine, Aetiology, 5.1 Pharmaceuticals, Development of treatments and therapeutic interventions, 2.1 Biological and endogenous factors, Good Health and Well Being, Antineoplastic Agents, Phytogenic, Drug Resistance, Neoplasm, Genetic Heterogeneity, Humans, Molecular Targeted Therapy, Neoplasms, Signal Transduction, Tumor Microenvironment, Multi-targeted, Cancer hallmarks, Phytochemicals, Targeted therapy, Integrative medicine, Oncology & Carcinogenesis, Biochemistry and cell biology, Oncology and carcinogenesis
Abstract

Targeted therapies and the consequent adoption of "personalized" oncology have achieved notable successes in some cancers; however, significant problems remain with this approach. Many targeted therapies are highly toxic, costs are extremely high, and most patients experience relapse after a few disease-free months. Relapses arise from genetic heterogeneity in tumors, which harbor therapy-resistant immortalized cells that have adopted alternate and compensatory pathways (i.e., pathways that are not reliant upon the same mechanisms as those which have been targeted). To address these limitations, an international task force of 180 scientists was assembled to explore the concept of a low-toxicity "broad-spectrum" therapeutic approach that could simultaneously target many key pathways and mechanisms. Using cancer hallmark phenotypes and the tumor microenvironment to account for the various aspects of relevant cancer biology, interdisciplinary teams reviewed each hallmark area and nominated a wide range of high-priority targets (74 in total) that could be modified to improve patient outcomes. For these targets, corresponding low-toxicity therapeutic approaches were then suggested, many of which were phytochemicals. Proposed actions on each target and all of the approaches were further reviewed for known effects on other hallmark areas and the tumor microenvironment. Potential contrary or procarcinogenic effects were found for 3.9% of the relationships between targets and hallmarks, and mixed evidence of complementary and contrary relationships was found for 7.1%. Approximately 67% of the relationships revealed potentially complementary effects, and the remainder had no known relationship. Among the approaches, 1.1% had contrary, 2.8% had mixed and 62.1% had complementary relationships. These results suggest that a broad-spectrum approach should be feasible from a safety standpoint. This novel approach has potential to be relatively inexpensive, it should help us address stages and types of cancer that lack conventional treatment, and it may reduce relapse risks. A proposed agenda for future research is offered.

Published
2015

16. Editorial: Novel biomarkers in tumor immunity and immunotherapy.

Author

Takaji Matsutani, Akbay, Esra, and Elkord, Eyad

Subjects
TUMOR markers, IMMUNOTHERAPY, PLATELET lymphocyte ratio, THYROID cancer, IMMUNITY, PROGNOSIS
Abstract

This document provides an overview of various studies conducted to identify novel biomarkers and predictive methods for cancer immunotherapy across different types of cancer. The research utilizes advanced technologies and techniques to uncover promising biomarkers that can help predict treatment response and prognosis in cancer patients. The role of the gut microbiota in modulating the tumor microenvironment and response to immunotherapy is also explored. The document highlights the value of serological methods and technological advancements in immunohistochemical methods for identifying biomarkers. Overall, this body of work contributes to the advancement of cancer diagnosis, prognosis, and treatment. [Extracted from the article]

Published
2024
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20. Structure-based small inhibitors search combined with molecular dynamics driven energies for human programmed cell death-1 (PD-1) protein

Author

Waqas, Muhammad, Halim, Sobia Ahsan, Alsalman, Alhasan, Khan, Ajmal, Elkord, Eyad, and Al-Harrasi, Ahmed

Subjects
Structural Biology, General Medicine, Molecular Biology
Abstract

Human immune system is specialized in distinguishing normal cells from foreign particles mainly through proteins expressed on immune cells called ‘checkpoints’. Immune checkpoints work as a switch to activate and deactivate immune responses. T cells express one of the immune checkpoint, human programmed cell death-1 (PD-1), which normally operates as an off-switch function to protect the normal cell from T-cell attack. Binding of PD-1 to its ligand, the programmed cell death ligand (PD-L1/2) expressed on myeloid/cancer cells, induce downstream inhibitory signals, leading to tumor immune evasion. Targeting PD-1 or PD-L1 can boost the immune response against cancer cells. To design novel small molecule inhibitors for the PD-1, in silico structure-based screening on pharmacophoric points and molecular docking were performed. Based on the docking score and significant binding interaction with the crucial residues of PD-1 (Thr59, Glu61, Ser62, Glu84, Arg86 and Ala132), compounds were selected from the ZINC20 database, and their dynamic behavior and conformational stability were examined through molecular dynamic simulations. Besides, the Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) method was used to calculate the binding strength of each selected inhibitor complexed with PD-1. The binding energy calculations revealed that these selected inhibitors show a considerable affinity for PD-1. The selected novel inhibitors exhibit excellent drug-like and pharmacokinetic properties (absorption, distribution, metabolism, excretion and toxicity). In conclusion, the identified novel compounds (ZINC1443480030, ZINC1002854123, ZINC988238128, ZINC1481242350, ZINC1001739421, ZINC1220816434 and ZINC1167786692) from the current study can be validated in-vitro as potential PD-1 inhibitors and for discovery of novel drugs against PD-1 in the future. Communicated by Ramaswamy H. Sarma

Published
2023
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33. T‐cell responses and therapies against SARS‐CoV‐2 infection

Author

Toor, Salman M., Saleh, Reem, Sasidharan Nair, Varun, Taha, Rowaida Z., and Elkord, Eyad

Subjects
Immunity, Cellular, COVID-19 Vaccines, SARS-CoV-2, T-Lymphocytes, Immunology, coronavirus, T cells, COVID-19, Review Article, Adoptive Transfer, Antiviral Agents, immune responses, SARS‐CoV‐2, COVID-19 Drug Treatment, COVID‐19, Host-Pathogen Interactions, Immunology and Allergy, Animals, Humans, Immunologic Factors, Immunotherapy, Review Articles, Lung
Abstract

Coronavirus disease 2019 (COVID‐19) is caused by SARS‐CoV‐2, a novel coronavirus strain. Some studies suggest that COVID‐19 could be an immune‐related disease, and failure of effective immune responses in initial stages of viral infection could contribute to systemic inflammation and tissue damage, leading to worse disease outcomes. T cells can act as a double‐edge sword with both pro‐ and anti‐roles in the progression of COVID‐19. Thus, better understanding of their roles in immune responses to SARS‐CoV‐2 infection is crucial. T cells primarily react to the spike protein on the coronavirus to initiate antiviral immunity; however, T‐cell responses can be suboptimal, impaired or excessive in severe COVID‐19 patients. This review focuses on the multifaceted roles of T cells in COVID‐19 pathogenesis and rationalizes their significance in eliciting appropriate antiviral immune responses in COVID‐19 patients and unexposed individuals. In addition, we summarize the potential therapeutic approaches related to T cells to treat COVID‐19 patients. These include adoptive T‐cell therapies, vaccines activating T‐cell responses, recombinant cytokines, Th1 activators and Th17 blockers, and potential utilization of immune checkpoint inhibitors alone or in combination with anti‐inflammatory drugs to improve antiviral T‐cell responses against SARS‐CoV‐2., This review focuses on the multi‐faceted roles of T cells in COVID‐19 pathogenesis and rationalizes their significance in eliciting appropriate antiviral immune responses in COVID‐19 patients and unexposed individuals. In addition, wesummarize the potential therapeutic approaches related to T cells to treat COVID‐19 patients.

Published
2020

34. Expression of immune checkpoints and T cell exhaustion markers in early and advanced stages of colorectal cancer

Author

Saleh, Reem, Taha, Rowaida Z., Toor, Salman M., Sasidharan Nair, Varun, Murshed, Khaled, Khawar, Mahwish, Al-Dhaheri, Mahmood, Petkar, Mahir Abdulla, Abu Nada, Mohamed, and Elkord, Eyad

Subjects
Adult, Male, Prognostic biomarker, Therapeutic target, T-Lymphocytes, Programmed Cell Death 1 Receptor, Young Adult, Lymphocytes, Tumor-Infiltrating, Biomarkers, Tumor, Humans, CTLA-4 Antigen, Receptors, Immunologic, Aged, Neoplasm Staging, T cell exhaustion, Aged, 80 and over, Oncology and carcinogenesis, Middle Aged, Colorectal cancer, Gene Expression Regulation, Neoplastic, Case-Control Studies, Immune checkpoints, Original Article, Female, Colorectal Neoplasms, Follow-Up Studies
Abstract

Despite recent advances in colorectal cancer (CRC) treatment, a large proportion of patients show limited responses to therapies, especially in advanced stages. There is an urgent need to identify prognostic biomarkers and/or therapeutic targets in advanced stages, aiming to improve the efficacy of current treatments. We aimed to determine prognostic biomarkers in tumor tissue and circulation of CRC patients, with a special focus on T cell exhaustion markers. We found that mRNA levels of PD-1, TIM-3, CTLA-4, TIGIT, CD160, CD244, KLRG1, TOX2, TOX3, Ki-67, and PRDM1 were elevated in CRC tumor tissues. We also investigated differences in gene expression between early and advanced disease stages. We found that TOX and potentially TIM-3, CTLA-4, VISTA, TIGIT, KLRG1, TOX2, SIRT1, Ki-67, and Helios mRNA levels in tumor tissue were elevated in advanced disease stages, suggesting their potential roles in CRC progression. In contrast, PD-1 and CD160 levels in tumor tissue were downregulated in advanced stages. In the circulation of CRC patients, mRNA levels of PD-1, VISTA and LAG-3 were higher than those of healthy individuals. Moreover, in circulation, PD-1, CTLA-4 and TIGIT mRNA levels were reduced in advanced stages. Interestingly, levels of PD-1 in both tumor tissue and circulation were reduced in advanced stages, suggesting that targeting PD-1 in patients with advanced stages could be less effective. Altogether, these findings suggest some potential T cell exhaustion markers that could be utilized as prognostic biomarkers and/or therapeutic targets for CRC. However, further investigations and validations in larger cohorts are required to confirm these findings.Other Information Published in: Cancer Immunology, Immunotherapy License: https://creativecommons.org/licenses/by/4.0See article on publisher's website: http://dx.doi.org/10.1007/s00262-020-02593-w

Published
2022
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37. DNA methylation in the promoters of PD-L1, MMP9, ARG1, galectin-9, TIM-3, VISTA and TGF-β genes in HLA-DR– myeloid cells, compared with HLA-DR+ antigen-presenting cells

Author

Saleh, Reem, Toor, Salman M., Taha, Rowaida Z., Al-Ali, Dana, Sasidharan Nair, Varun, and Elkord, Eyad

Subjects
DNA methylation, immunosuppression, B7 Antigens, epigenetics, Arginase, MDSC, Sialic Acid Binding Ig-like Lectin 3, Antigen-Presenting Cells, HLA-DR Antigens, B7-H1 Antigen, Epigenesis, Genetic, Matrix Metalloproteinase 9, Genetic Loci, Transforming Growth Factor beta, Humans, Myeloid Cells, Promoter Regions, Genetic, Hepatitis A Virus Cellular Receptor 2, Research Article, Research Paper
Abstract

Myeloid cells, including antigen-presenting cells (APCs) and myeloid-derived suppressor cells (MDSCs) play opposing roles to orchestrate innate and adaptive immune responses during physiological and pathological conditions. We investigated the role of DNA methylation in regulating the transcription of inhibitory/suppressive molecules in myeloid suppressive cells (identified as CD33+HLA-DR–) in comparison to APCs. We selected a number of immune checkpoints (ICs), IC ligands, and immunosuppressive molecules that have been implicated in MDSC function, including PD-L1, TIM-3, VISTA, galectin-9, TGF-β, ARG1 and MMP9. We examined their mRNA expression levels, and investigated whether DNA methylation regulates their transcription in sorted myeloid cell subpopulations. We found that mRNA levels of PD-L1, TIM-3, TGF-β, ARG1 and MMP9 in CD33+HLA-DR– cells were higher than APCs. However, VISTA and galectin-9 mRNA levels were relatively similar in both myeloid subpopulations. CpG islands in the promoter regions of TGF-β1, TIM-3 and ARG1 were highly unmethylated in CD33+HLA-DR–cells, compared with APCs, suggesting that DNA methylation is one of the key mechanisms, which regulate their expression. However, we did not find differences in the methylation status of PD-L1 and MMP9 between CD33+HLA-DR– and APCs, suggesting that their transcription could be regulated via other genetic and epigenetic mechanisms. The promoter methylation status of VISTA was relatively similar in both myeloid subpopulations. This study provides novel insights into the epigenetic mechanisms, which control the expression of inhibitory/suppressive molecules in circulating CD33+HLA-DR– cells in a steady-state condition, possibly to maintain immune tolerance and haemostasis.

Published
2020

38. Complement C5a and Clinical Markers as Predictors of COVID-19 Disease Severity and Mortality in a Multi-Ethnic Population

Author

Cyprian, Farhan S., primary, Suleman, Muhammad, additional, Abdelhafez, Ibrahim, additional, Doudin, Asmma, additional, Masud Danjuma, Ibn Mohammed, additional, Mir, Fayaz Ahmad, additional, Parray, Aijaz, additional, Yousaf, Zohaib, additional, Siddiqui, Mohammed Yaseen Ahmed, additional, Abdelmajid, Alaaedin, additional, Mulhim, Mohammad, additional, Al-Shokri, Shaikha, additional, Abukhattab, Mohammad, additional, Shaheen, Ranad, additional, Elkord, Eyad, additional, Al-khal, Abdul Latif, additional, Elzouki, Abdel-Naser, additional, and Girardi, Guillermina, additional

Published
2021
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41. SnoRNAs and miRNAs Networks Underlying COVID-19 Disease Severity

Author

Parray, Aijaz, primary, Mir, Fayaz Ahmad, additional, Doudin, Asmma, additional, Iskandarani, Ahmad, additional, Danjuma, Ibn Mohammed Masud, additional, Kuni, Rahim Ayadathil Thazhhe, additional, Abdelmajid, Alaaedin, additional, Abdelhafez, Ibrahim, additional, Arif, Rida, additional, Mulhim, Mohammad, additional, Abukhattab, Mohammad, additional, Dar, Shoukat Rashhid, additional, Moustafa, Ala-Eddin Al, additional, Elkord, Eyad, additional, Al Khal, Abdul Latif, additional, Elzouki, Abdel-Naser, additional, and Cyprian, Farhan, additional

Published
2021
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43. Correlations between Circulating and Tumor-Infiltrating CD4 + Treg Subsets with Immune Checkpoints in Colorectal Cancer Patients with Early and Advanced Stages.

Author

Al-Mterin, Mohammad A., Murshed, Khaled, and Elkord, Eyad

Subjects
IMMUNE checkpoint proteins, REGULATORY T cells, CANCER patients, COLORECTAL cancer, T cells
Abstract

The existence of various T regulatory cell (Treg) subsets in colorectal cancer (CRC) could play a variety of functions in the regulation of anti-cancer immunity. We studied correlations between CD4+ Treg subsets with the expression of immunological checkpoints on CD4+ T cells, including PD-1, TIM-3, LAG-3, and CTLA-4 in CRC patients with early and advanced TNM staging. Strong positive correlations were found between frequencies of FoxP3+ Tregs and FoxP3+Helios+ Tregs with frequencies of various immune checkpoint-expressing CD4+ T cells in the tumor microenvironment (TME). However, there were strong negative correlations between frequencies of FoxP3−Helios− T cells and these immune checkpoint-expressing CD4+ T cells. Specifically, in the TME, we found that the correlations between FoxP3+ Tregs, FoxP3+Helios+ Tregs, FoxP3+Helios− Tregs, and FoxP3−Helios− T cells with CD4+LAG-3+ T cells and CD4+CTLA-4+ T cells were higher in patients with early stages, suggesting the potential of these highly immunosuppressive cells in inhibiting inflammatory responses in the TME. However, the correlations between FoxP3+ Tregs, FoxP3+Helios+ Tregs, and FoxP3−Helios− T cells with CD4+TIM-3+ T cells were higher in patients with advanced stages. This is the first study to explore correlations of Treg subpopulations with immune checkpoint-expressing CD4+ T cells in CRC based on clinicopathological features of CRC patients. The findings of our study provide a justification for focusing on these cells that possess highly immunosuppressive features. Understanding the correlations between different immune checkpoints and Treg subsets in CRC patients has the potential to enhance our understanding of core mechanisms of Treg-mediated immunosuppression in cancer. [ABSTRACT FROM AUTHOR]

Published
2022
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44. Circulating and Tumor-Infiltrating Immune Checkpoint-Expressing CD8 + Treg/T Cell Subsets and Their Associations with Disease-Free Survival in Colorectal Cancer Patients.

Author

Alsalman, Alhasan, Al-Mterin, Mohammad A., Murshed, Khaled, Alloush, Ferial, Al-Shouli, Samia T., Toor, Salman M., and Elkord, Eyad

Subjects
FLOW cytometry, KRUSKAL-Wallis Test, STATISTICS, CONFIDENCE intervals, LOG-rank test, MANN Whitney U Test, COLORECTAL cancer, CANCER patients, T-test (Statistics), DESCRIPTIVE statistics, KAPLAN-Meier estimator, PROGRESSION-free survival, T cells, TUMOR markers, DATA analysis software, DATA analysis
Abstract

Simple Summary: Colorectal cancer is one of the leading causes of global cancer-related mortality. Tumor-infiltrating effector immune cells play critical roles in tumor control, and their activity can dictate disease outcomes. In this study, we provide evidence of the associations between different CD8+ T cell subpopulations with disease-free survival (DFS) in CRC patients. We report associations between higher levels of certain circulating and tumor-infiltrating CD8+ T cell subsets and improved clinical outcomes in CRC patients. T cells in the tumor microenvironment (TME) have diverse roles in anti-tumor immunity, including orchestration of immune responses and anti-tumor cytotoxic attack. However, different T cell subsets may have opposing roles in tumor progression, especially in inflammation-related cancers such as colorectal cancer (CRC). In this study, we phenotypically characterized CD3+CD4- (CD8+) T cells in colorectal tumor tissues (TT), normal colon tissues (NT) and in circulation of CRC patients. We investigated the expression levels of key immune checkpoints (ICs) and Treg-related markers in CD8+ T cells. Importantly, we investigated associations between different tumor-infiltrating CD8+ T cell subpopulations and disease-free survival (DFS) in CRC patients. We found that FoxP3 expression and ICs including PD-1, CTLA-4, TIM-3, and LAG-3 were significantly increased in tumor-infiltrating CD8+ T cells compared with NT and peripheral blood. In the TME, we found that TIM-3 expression was significantly increased in patients with early stages and absent lymphovascular invasion (LVI) compared to patients with advanced stages and LVI. Importantly, we report that high levels of certain circulating CD8+ T cell subsets (TIM-3-expressing, FoxP3−Helios−TIM-3+ and FoxP3−Helios+TIM-3+ cells) in CRC patients were associated with better DFS. Moreover, in the TME, we report that elevated levels of CD25+ and TIM-3+ T cells, and FoxP3+Helios−TIM-3+ Tregs were associated with better DFS. [ABSTRACT FROM AUTHOR]

Published
2022
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45. Transcriptome of Tumor-Infiltrating T Cells in Colorectal Cancer Patients Uncovered a Unique Gene Signature in CD4+ T Cells Associated with Poor Disease-Specific Survival

Author

Toor, Salman M., primary, Sasidharan Nair, Varun, additional, Saleh, Reem, additional, Taha, Rowaida Z., additional, Murshed, Khaled, additional, Al-Dhaheri, Mahmood, additional, Khawar, Mahwish, additional, Ahmed, Ayman A., additional, Kurer, Mohamed A., additional, Abu Nada, Mohamed, additional, and Elkord, Eyad, additional

Published
2021
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49. Associations of different immune checkpoints-expressing CD4+ Treg/ T cell subsets with disease-free survival in colorectal cancer patients.

Author

Al-Mterin, Mohammad A., Murshed, Khaled, Alsalman, Alhasan, Abu-Dayeh, Ala, and Elkord, Eyad

Abstract

There are different subsets of T regulatory cells (Tregs), orchestrating critical roles in the regulation of anti-tumor immunity in colorectal cancer (CRC). In this study, we report that a high frequency of circulating CD4+FoxP3+ Tregs was associated with poorer disease-free survival (DFS), while their higher frequencies in tumor-infiltrating CD4+ Tregs was associated with better DFS. We further investigated such associations with four Tregs/T cells expressing or lacking FoxP3 and Helios (FoxP3±Helios±). For the first time, we report that a high frequency of circulating CD4+FoxP3+Helios+ Tregs was associated with poorer DFS, while a high frequency of tumor-infiltrating CD4+FoxP3-Helios- T cells was associated with poorer DFS. In the four FoxP3±Helios± T cell subsets expressing any of the immune checkpoints (ICs) investigated, we found that a high frequency of CD4+FoxP3+Helios-PD-1+ Tregs in circulation was associated with worse DFS. We also found that high frequencies of FoxP3+Helios+CTLA-4+ Tregs, FoxP3+Helios-CTLA-4+ Tregs, and FoxP3-Helios+CTLA-4+ CD4+ T cells in circulation were associated with worse DFS. In contrast, high frequencies of CD4+TIM-3+ T cells, FoxP3+Helios+TIM-3+ Tregs, and FoxP3-Helios+TIM-3+ CD4+ T cells in circulation were associated with longer DFS. Our data show that certain CD4+ Treg/T cell subsets could serve as independent predictive biomarkers in CRC patients. Identification of the exact subpopulations contributing to clinical outcomes is critical for prognoses and therapeutic targeting. [ABSTRACT FROM AUTHOR]

Published
2022
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50. Correlations between Circulating and Tumor-Infiltrating CD4 + T Cell Subsets with Immune Checkpoints in Colorectal Cancer.

Author

Al-Mterin, Mohammad A., Murshed, Khaled, and Elkord, Eyad

Subjects
T cells, MONONUCLEAR leukocytes, IMMUNE checkpoint proteins, REGULATORY T cells, COLORECTAL cancer
Abstract

T regulatory cells (Tregs) play different roles in the regulation of anti-tumor immunity in colorectal cancer (CRC), depending on the presence of different Treg subsets. We investigated correlations between different CD4+ Treg/T cell subsets in CRC patients with immune checkpoint-expressing CD4+ T cells. Positive correlations were observed between levels of different immune checkpoint-expressing CD4+ T cells, including PD-1, TIM-3, LAG-3, and CTLA-4 with FoxP3+ Tregs, Helios+ T cells, FoxP3+Helios+ Tregs, and FoxP3+Helios− Tregs in the tumor microenvironment (TME). However, negative correlations were observed between levels of these immune checkpoint-expressing CD4+ T with FoxP3−Helios− T cells in the TME. These correlations in the TME highlight the role of cancer cells in the upregulation of IC-expressing Tregs. Additionally, positive correlations were observed between levels of FoxP3+ Tregs, Helios+ T cells, FoxP3+Helios+ Tregs, and FoxP3+Helios− Tregs and levels of CD4+CTLA-4+ T cells and CD4+PD-1+ T cells in peripheral blood mononuclear cells (PBMCs) and normal tissue-infiltrating lymphocytes (NILs). These observations suggest that CTLA-4 and PD-1 expressions on CD4+ T cell subsets are not induced only by the TME. This is the first study to investigate the correlations of different FoxP3+/−Helios+/− T cell subsets with immune checkpoint-expressing CD4+ T cells in CRC patients. Our data demonstrated strong correlations between FoxP3+/Helios+/− Tregs but not FoxP3−Helios+/− non-Tregs and multiple immune checkpoints, especially in the TME, providing a rationale for targeting these cells with highly immunosuppressive characteristics. Understanding the correlations between different immune checkpoints and Treg/T cell subsets in cancer patients could improve our knowledge of the underlying mechanisms of Treg-mediated immunosuppression in cancer. [ABSTRACT FROM AUTHOR]

Published
2022
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