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Article ; Online: Cell death classification: A new insight based on molecular mechanisms.

Dehghan, Sepehr / Kheshtchin, Nasim / Hassannezhad, Shaghayegh / Soleimani, Maryam

2023 Volume 433, Issue 2, Page(s) 113860

Abstract: Cells tend to disintegrate themselves or are forced to undergo such destructive processes in critical circumstances. This complex cellular function necessitates various mechanisms and molecular pathways in order to be executed. The very nature of cell ... ...

Abstract	Cells tend to disintegrate themselves or are forced to undergo such destructive processes in critical circumstances. This complex cellular function necessitates various mechanisms and molecular pathways in order to be executed. The very nature of cell death is essentially important and vital for maintaining homeostasis, thus any type of disturbing occurrence might lead to different sorts of diseases and dysfunctions. Cell death has various modalities and yet, every now and then, a new type of this elegant procedure gets to be discovered. The diversity of cell death compels the need for a universal organizing system in order to facilitate further studies, therapeutic strategies and the invention of new methods of research. Considering all that, we attempted to review most of the known cell death mechanisms and sort them all into one arranging system that operates under a simple but subtle decision-making (If \ Else) order as a sorting algorithm, in which it decides to place and sort an input data (a type of cell death) into its proper set, then a subset and finally a group of cell death. By proposing this algorithm, the authors hope it may solve the problems regarding newer and/or undiscovered types of cell death and facilitate research and therapeutic applications of cell death.
MeSH term(s)	Cell Death/physiology ; Cell Movement ; Homeostasis
Language	English
Publishing date	2023-11-26
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	1493-x
ISSN	1090-2422 ; 0014-4827
ISSN (online)	1090-2422
ISSN	0014-4827
DOI	10.1016/j.yexcr.2023.113860
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Article ; Online: Targeting hypoxia and hypoxia-inducible factor-1 in the tumor microenvironment for optimal cancer immunotherapy.

Kheshtchin, Nasim / Hadjati, Jamshid

Journal of cellular physiology

2021 Volume 237, Issue 2, Page(s) 1285–1298

Abstract: The development of new strategies of anticancer immunotherapies has provided promising approaches in the treatment of solid tumors. However, despite the improved survival in responders, most of the patients show incomplete responses with a lack of ... ...

Abstract	The development of new strategies of anticancer immunotherapies has provided promising approaches in the treatment of solid tumors. However, despite the improved survival in responders, most of the patients show incomplete responses with a lack of remarkable clinical improvement. Hypoxia has been identified as a common characteristic of solid tumors contributing to different aspects of tumor progression, including invasion, metastasis, and the creation of the immunosuppressive tumor microenvironment. Hypoxia, through its main mediator, hypoxia-inducible factor-1 (HIF-1) is also associated with the limited efficacy of immunotherapies. Therefore, designing new strategies for immunotherapy implicating therapeutic targeting of HIF-1 molecules may enhance the clinical effectiveness of immunotherapy. Here, we discuss the contribution of hypoxia to the development of the immunosuppressive tumor microenvironment. We will also outline different strategies for targeting hypoxia to provide insight into the therapeutic potential of the application of such strategies to improve the clinical benefit of cancer immunotherapy.
MeSH term(s)	Cell Hypoxia ; Humans ; Hypoxia ; Hypoxia-Inducible Factor 1 ; Hypoxia-Inducible Factor 1, alpha Subunit/genetics ; Immunotherapy ; Neoplasms/pathology ; Neoplasms/therapy ; Tumor Microenvironment
Chemical Substances	Hypoxia-Inducible Factor 1 ; Hypoxia-Inducible Factor 1, alpha Subunit
Language	English
Publishing date	2021-11-19
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	3116-1
ISSN	1097-4652 ; 0021-9541
ISSN (online)	1097-4652
ISSN	0021-9541
DOI	10.1002/jcp.30643
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Article ; Online: Immunoediting in SARS-CoV-2: Mutual relationship between the virus and the host.

Kheshtchin, Nasim / Bakhshi, Parisa / Arab, Samaneh / Nourizadeh, Maryam

International immunopharmacology

2022 Volume 105, Page(s) 108531

Abstract: Immunoediting is a well-known concept that occurs in cancer through three steps of elimination, equilibrium, and escape (3Es), where the immune system first suppresses the growth of tumor cells and then promotes them towards the malignancy. This ... ...

Abstract	Immunoediting is a well-known concept that occurs in cancer through three steps of elimination, equilibrium, and escape (3Es), where the immune system first suppresses the growth of tumor cells and then promotes them towards the malignancy. This phenomenon has been conceptualized in some chronic viral infections such as HTLV-1 and HIV by obtaining the resistance to elimination and making a persistent form of infected cells especially in untreated patients. Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a heterogeneous disease characterizing from mild/asymptomatic to severe/critical courses with some behavioral aspects in an immunoediting setting. In this context, a coordinated effort between innate and adaptive immune system leads to detection and destruction of early infection followed by equilibrium between virus-specific responses and infected cells, which eventually ends up with an uncontrolled inflammatory response in severe/critical patients. Although the SARS-CoV-2 applies several escape strategies such as mutations in viral epitopes, modulating the interferon response and inhibiting the MHC I molecules similar to the cancer cells, the 3Es hallmark may not occur in all clinical conditions. Here, we discuss how the lesson learnt from cancer immunoediting and accurate understanding of these pathophysiological mechanisms helps to develop more effective therapeutic strategies for COVID-19.
MeSH term(s)	Animals ; COVID-19/drug therapy ; COVID-19/immunology ; Host-Pathogen Interactions ; Humans ; Neoplasms/immunology ; SARS-CoV-2
Language	English
Publishing date	2022-01-10
Publishing country	Netherlands
Document type	Journal Article ; Review
ZDB-ID	2043785-7
ISSN	1878-1705 ; 1567-5769
ISSN (online)	1878-1705
ISSN	1567-5769
DOI	10.1016/j.intimp.2022.108531
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Article ; Online: Immune checkpoint molecules in prevention and development of asthma.

Kanannejad, Zahra / Soleimanian, Saeede / Ghahramani, Zahra / Sepahi, Najmeh / Mohkam, Milad / Alyasin, Soheila / Kheshtchin, Nasim

Frontiers in immunology

2023 Volume 14, Page(s) 1070779

Abstract: Allergic asthma is a respiratory disease initiated by type-2 immune responses characterized by secretion of alarmins, interleukin-4 (IL-4), IL-5, and IL-13, eosinophilic inflammation, and airway hyperresponsiveness (AHR). Immune checkpoints (ICPs) are ... ...

Abstract	Allergic asthma is a respiratory disease initiated by type-2 immune responses characterized by secretion of alarmins, interleukin-4 (IL-4), IL-5, and IL-13, eosinophilic inflammation, and airway hyperresponsiveness (AHR). Immune checkpoints (ICPs) are inhibitory or stimulatory molecules expressed on different immune cells, tumor cells, or other cell types that regulate immune system activation and maintain immune homeostasis. Compelling evidence indicates a key role for ICPs in both the progression and prevention of asthma. There is also evidence of asthma development or exacerbation in some cancer patients receiving ICP therapy. The aim of this review is to provide an updated overview of ICPs and their roles in asthma pathogenesis, and to assess their implications as therapeutic targets in asthma.
MeSH term(s)	Humans ; Immune Checkpoint Proteins ; Asthma/prevention & control ; Respiratory Hypersensitivity ; Alarmins ; Homeostasis
Chemical Substances	Immune Checkpoint Proteins ; Alarmins
Language	English
Publishing date	2023-02-14
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2023.1070779
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Article ; Online: Senescent CD153+ T Lymphocytes Increase in the Peripheral Blood of Patients with Thromboangiitis Obliterans.

Mashhadi, Niloofar / Kasraian, Leila / Ghoddusi Johari, Hamed / Hosseinzadeh, Ahmad / Kheshtchin, Nasim / Doroudchi, Mehrnoosh

Iranian journal of immunology : IJI

2023 Volume 20, Issue 3, Page(s) 262–275

Abstract: Background: Buerger's disease, also known as Thromboangiitis Obliterans (TAO), is a progressive, inflammatory vascular disease with unknown etiology.: Objective: To address the degree of T cell immunosenescence in this inflammatory disease, the ... ...

Abstract	Background: Buerger's disease, also known as Thromboangiitis Obliterans (TAO), is a progressive, inflammatory vascular disease with unknown etiology. Objective: To address the degree of T cell immunosenescence in this inflammatory disease, the frequency of senescent T cells expressing CD57 and/or CD153 (CD30L) in patients with TAO. Methods: In this study, nine male cigarette smoker patients with TAO, nine male healthy cigarette smokers, and nine male healthy non-smoker blood donors were enrolled. PBMCs were extracted from the blood of all participants and stored in liquid nitrogen before use. The percentages of senescent T cells were detected by flow cytometry. The results were analyzed using non-parametric statistical tests. Results: The frequencies of senescent CD3+CD4+CD57+CD153+ and CD3+CD4+CD57-CD153+ T cells significantly increased in patients compared with the non-smoker controls (p=0.01 and p=0.04, respectively). The frequency of senescent CD3+CD4-CD57-CD153+ T cells was higher in patients compared with the smoker controls (p=0.02). In patients with TAO, CD57+CD153- cells were more frequent in CD3hiCD4- and CD3hiCD4+ T cells compared with the CD3loCD4- and CD3loCD4+ T cells (p=0.008 and p=0.0002, respectively). Conversely, the frequency of CD57-CD153+ T cells was significantly higher in CD3loCD4- T cells compared with the CD3hiCD4- T cells (p=0.004). The percentage of CD3+CD4+CD57+CD153- T cells correlated negatively with smoking level in smoker controls (p=0.02, Spearman r=-0.80). Conclusion: Elevated frequencies of senescent CD4+CD57+CD153+ and CD4+CD57-CD153+ T cells in patients compared with non-smoker and smoker controls suggest the contribution of immunosenescence in TAO.
Language	English
Publishing date	2023-08-28
Publishing country	Iran
Document type	Journal Article
ZDB-ID	2616647-1
ISSN	1735-367X ; 1735-367X
ISSN (online)	1735-367X
ISSN	1735-367X
DOI	10.22034/iji.2023.99188.2622
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Article ; Online: Identification of the Optimal Pattern of the Injection and Dosage of DC Immunotherapy Using the Mathematical Models Based on Ordinary Differential Equations.

Zand, Bahareh / Arab, Samaneh / Kheshtchin, Nasim / Arabameri, Abazar / Ashourpour, Mahboubeh / Asemani, Davoud / Sharif-Paghaleh, Ehsan / Nourbakhsh, Farshid / Hadjati, Jamshid

Iranian journal of immunology : IJI

2022 Volume 19, Issue 1, Page(s) 1

Abstract: Background: Mathematical modeling offers the possibility to select the optimal dose of a drug or vaccine. Considerable evidence show that many bacterial components can activate dendritic cells (DCs). Our previous report showed that multiple doses of DCs ...

Abstract	Background: Mathematical modeling offers the possibility to select the optimal dose of a drug or vaccine. Considerable evidence show that many bacterial components can activate dendritic cells (DCs). Our previous report showed that multiple doses of DCs matured with Listeria monocytogenes led to tumor regression whereas multiple doses of CpG-matured DCs affected tumor reversely. Objective: To assess a combined pattern of DC vaccination proposed by a mathematical model for tumor regression. Method: WEHI164 cells were inoculated subcutaneously in the right flank of BALB/c mice. Bone marrow-derived DCs were matured by Listeria monocytogenes and CpG motifs. DCs were injected using specific patterns and doses predicted by mathematical modeling. Effector cell-mediated cytotoxicity, gene expression of T cell-related transcription factors, as well as tumor growth and survival rate, were assessed in different groups. Results: Our study indicated that the proposed mathematical model could simulate the tumor and immune system interaction, and it was verified by decreasing tumor size in the List+CpG group. However, comparing the effect of different treatment modalities on Th1/Treg transcription factor expression or cytotoxic responses revealed no advantage for combined therapy over other treatment modalities. Conclusions: These results suggest that finding new combinations of DC vaccines for the treatment of tumors will be promising in the future. The results of this study support the mathematical modelling for DC vaccine design. However, some parameters in this model must be modified to provide a more optimized therapy approach.
MeSH term(s)	Animals ; Cytotoxicity, Immunologic ; Dendritic Cells ; Immunotherapy ; Listeria monocytogenes ; Mice ; Models, Theoretical
Language	English
Publishing date	2022-03-17
Publishing country	Iran
Document type	Journal Article
ISSN	1735-367X
ISSN (online)	1735-367X
DOI	10.22034/IJI.2022.91617.2092
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Article ; Online: Identification of the Optimal Pattern of the Injection and Dosage of DC Immunotherapy Using the Mathematical Models Based on Ordinary Differential Equations

Bahareh Zand / Samaneh Arab / Nasim Kheshtchin / Abazar Arabameri / Mahboubeh Ashourpour / Davoud Asemani / Ehsan Sharif-Paghaleh / Farshid Noorbakhsh / Jamshid Hadjati

Iranian Journal of Immunology, Vol 19, Iss 1, Pp 1-

2022 Volume 17

Abstract	Background: Mathematical modeling offers the possibility to select the optimal dose of a drug or vaccine. Considerable evidence show that many bacterial components can activate dendritic cells (DCs). Our previous report showed that multiple doses of DCs matured with Listeria monocytogenes led to tumor regression whereas multiple doses of CpG-matured DCs affected tumor reversely. Objective: To assess a combined pattern of DC vaccination proposed by a mathematical model for tumor regression. Method: WEHI164 cells were inoculated subcutaneously in the right flank of BALB/c mice. Bone marrow-derived DCs were matured by Listeria monocytogenes and CpG motifs. DCs were injected using specific patterns and doses predicted by mathematical modeling. Effector cell-mediated cytotoxicity, gene expression of T cell-related transcription factors, as well as tumor growth and survival rate, were assessed in different groups. Results: Our study indicated that the proposed mathematical model could simulate the tumor and immune system interaction, and it was verified by decreasing tumor size in the List+CpG group. However, comparing the effect of different treatment modalities on Th1/Treg transcription factor expression or cytotoxic responses revealed no advantage for combined therapy over other treatment modalities. Conclusions: These results suggest that finding new combinations of DC vaccines for the treatment of tumors will be promising in the future. The results of this study support the mathematical modelling for DC vaccine design. However, some parameters in this model must be modified to provide a more optimized therapy approach.
Keywords	cancer vaccines ; cpg ; dendritic cells ; listeria monocytogenes ; mathematical model ; Biology (General) ; QH301-705.5
Subject code	610
Language	English
Publishing date	2022-03-01T00:00:00Z
Publisher	Shiraz University of Medical Sciences
Document type	Article ; Online
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Article ; Online: Agent-based Modeling of Tumor and Immune System Interactions in Combinational Therapy with Low-dose 5-fluorouracil and Dendritic Cell Vaccine in Melanoma B16F10.

Rahbar, Sarah / Shafiekhani, Sajad / Allahverdi, Armin / Jamali, Arezoo / Kheshtchin, Nasim / Ajami, Maryam / Mirsanei, Zahra / Habibi, Sima / Makkiabadi, Bahador / Hadjati, Jamshid / Jafari, Amir Homayoun

Iranian journal of allergy, asthma, and immunology

2022 Volume 21, Issue 2, Page(s) 151–166

Abstract: This study is designed to present an agent-based model (ABM) to simulate the interactions between tumor cells and the immune system in the melanoma model. The Myeloid-derived Suppressor Cells (MDSCs) and dendritic cells (DCs) are considered in this model ...

Abstract	This study is designed to present an agent-based model (ABM) to simulate the interactions between tumor cells and the immune system in the melanoma model. The Myeloid-derived Suppressor Cells (MDSCs) and dendritic cells (DCs) are considered in this model as immunosuppressive and antigen-presenting agents respectively. The animal experiment was performed on 68 B16F10 melanoma tumor-bearing C57BL/6 female mice to collect dynamic data for ABM implementation and validation. Animals were divided into 4 groups; group 1 was control (no treatment) while groups 2 and 3 were treated with DC vaccine and low-dose 5- fluorouracil (5-FU) respectively and group 4 was treated with both DC Vaccine and low-dose of 5-FU. The tumor growth rate, number of MDSC, and presence of CD8+/CD107a+ T cells in the tumor microenvironment were evaluated in each group. Firstly, the tumor cells, the effector immune cells, DCs, and the MDSCs have been considered as the agents of the ABM model and their interaction methods have been extracted from the literature and implemented in the model. Then, the model parameters were estimated by the dynamic data collected from animal experiments. To validate the ABM model, the simulation results were compared with the real data. The results show that the dynamics of the model agents can mimic the relations among considered immune system components to an emergent outcome compatible with real data. The simplicity of the proposed model can help to understand the results of the combinational therapy and make this model a useful tool for studying different scenarios and assessing the combinational results. Determining the role of each component helps to find critical times during tumor progression and change the tumor and immune system balance in favor of the immune system.
MeSH term(s)	Animals ; CD8-Positive T-Lymphocytes ; Dendritic Cells ; Female ; Fluorouracil/pharmacology ; Fluorouracil/therapeutic use ; Male ; Melanoma ; Mice ; Mice, Inbred C57BL ; Systems Analysis ; Tumor Microenvironment
Chemical Substances	Fluorouracil (U3P01618RT)
Language	English
Publishing date	2022-04-11
Publishing country	Iran
Document type	Journal Article
ZDB-ID	2488724-9
ISSN	1735-5249 ; 1735-1502
ISSN (online)	1735-5249
ISSN	1735-1502
DOI	10.18502/ijaai.v21i2.9223
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Article ; Online: Agent-based Modeling of Tumor and Immune System Interactions in Combinational Therapy with Low-dose 5-fluorouracil and Dendritic Cell Vaccine in Melanoma B16F10

Sarah Rahbar / Sajad Shafiekhani / Armin Allahverdi / Arezoo Jamali / Nasim Kheshtchin / Maryam Ajami / Zahra Mirsanei / Sima Habibi / Bahador Makkiabadi / Jamshid Hadjati / Amir Homayoun Jafari

Iranian Journal of Allergy, Asthma and Immunology, Vol 21, Iss

2022 Volume 2

Abstract	This study is designed to present an agent-based model (ABM) to simulate the interactions between tumor cells and the immune system in the melanoma model. The Myeloid-derived Suppressor Cells (MDSCs) and dendritic cells (DCs) are considered in this model as immunosuppressive and antigen-presenting agents respectively. The animal experiment was performed on 68 B16F10 melanoma tumor-bearing C57BL/6 female mice to collect dynamic data for ABM implementation and validation. Animals were divided into 4 groups; group 1 was control (no treatment) while groups 2 and 3 were treated with DC vaccine and low-dose 5- fluorouracil (5-FU) respectively and group 4 was treated with both DC Vaccine and low-dose of 5-FU. The tumor growth rate, number of MDSC, and presence of CD8+/CD107a+ T cells in the tumor microenvironment were evaluated in each group. Firstly, the tumor cells, the effector immune cells, DCs, and the MDSCs have been considered as the agents of the ABM model and their interaction methods have been extracted from the literature and implemented in the model. Then, the model parameters were estimated by the dynamic data collected from animal experiments. To validate the ABM model, the simulation results were compared with the real data. The results show that the dynamics of the model agents can mimic the relations among considered immune system components to an emergent outcome compatible with real data. The simplicity of the proposed model can help to understand the results of the combinational therapy and make this model a useful tool for studying different scenarios and assessing the combinational results. Determining the role of each component helps to find critical times during tumor progression and change the tumor and immune system balance in favor of the immune system.
Keywords	Fluorouracil ; Melanoma ; Myeloid-derived suppressor cells ; Tumor microenvironment ; Medicine ; R
Subject code	570
Language	English
Publishing date	2022-04-01T00:00:00Z
Publisher	Tehran University of Medical Sciences
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Optimized Dose of Dendritic Cell-based Vaccination in Experimental Model of Tumor Using Artificial Neural Network.

Mirsanei, Zahra / Habibi, Sima / Kheshtchin, Nasim / Mirzaei, Reza / Arab, Samaneh / Zand, Bahareh / Jadidi-Niaragh, Farhad / Safvati, Aida / Sharif-Paghaleh, Ehsan / Arabameri, Abazar / Asemani, Davud / Hajati, Jamshid

Iranian journal of allergy, asthma, and immunology

2020 Volume 19, Issue 2, Page(s) 172–182

Abstract: Previous studies have demonstrated that maturation of dendritic cells (DCs) by pathogenic components through pathogen-associated molecular patterns (PAMPs) such as Listeria monocytogenes lysate (LML) or CpG DNA can improve cancer vaccination in ... ...

Abstract	Previous studies have demonstrated that maturation of dendritic cells (DCs) by pathogenic components through pathogen-associated molecular patterns (PAMPs) such as Listeria monocytogenes lysate (LML) or CpG DNA can improve cancer vaccination in experimental models. In this study, a mathematical model based on an artificial neural network (ANN) was used to predict several patterns and dosage of matured DC administration for improved vaccination. The ANN model predicted that repeated co-injection of tumor antigen (TA)-loaded DCs matured with CpG (CpG-DC) and LML (List-DC) results in improved antitumor immune response as well as a reduction of immunosuppression in the tumor microenvironment. In the present study, we evaluated the ANN prediction accuracy about DC-based cancer vaccines pattern in the treatment of Wehi164 fibrosarcoma cancer-bearing mice. Our results showed that the administration of the DC vaccine according to ANN predicted pattern, leads to a decrease in the rate of tumor growth and size and augments CTL effector function. Furthermore, gene expression analysis confirmed an augmented immune response in the tumor microenvironment. Experimentations justified the validity of the ANN model forecast in the tumor growth and novel optimal dosage that led to more effective treatment.
MeSH term(s)	Animals ; Cancer Vaccines/immunology ; Cell Line, Tumor ; Cell Proliferation ; Dendritic Cells/immunology ; Dendritic Cells/transplantation ; Fibrosarcoma/immunology ; Fibrosarcoma/therapy ; Gene Expression Regulation, Neoplastic ; Humans ; Immunity/genetics ; Immunotherapy, Adoptive ; Mice ; Mice, Inbred BALB C ; Models, Animal ; Models, Theoretical ; Neoplasm Transplantation ; Neural Networks, Computer ; T-Lymphocytes, Cytotoxic/immunology ; Tumor Burden ; Vaccination
Chemical Substances	Cancer Vaccines
Language	English
Publishing date	2020-04-16
Publishing country	Iran
Document type	Journal Article
ZDB-ID	2488724-9
ISSN	1735-5249 ; 1735-1502
ISSN (online)	1735-5249
ISSN	1735-1502
DOI	10.18502/ijaai.v19i2.2770
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