Immune Checkpoints and Autoimmunity

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Immunology and Immunotherapy".

Deadline for manuscript submissions: closed (31 March 2023) | Viewed by 27773

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Guest Editor
Clinical Immunology, Allergy and Advanced Biotechnologies Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy
Interests: autoimmunity; inflammation; immunomodulation; immunotherapy; giant cell arteritis; vasculitis; behcet disease; miRNA; cytokine; high throughput profiling; flow cytometry
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Special Issue Information

This Special Issue, "Immune Checkpoints and Autoimmunity", will mainly focus on the pathogenic role of immune checkpoints in autoimmune and inflammatory diseases and the therapeutic potential of modulating immune checkpoints in the abovementioned diseases.

Immune checkpoint molecules have emerged as key regulators of the immune system. They are crucial for self-tolerance but also for the activation of the immune system. To date, most studies have investigated the role of immune checkpoints in cancers, while fewer data are available in autoimmune and inflammatory diseases. Upregulation of inhibitory checkpoint molecules by cancer cells or in the tumor microenvironment can favor cancer cell escape from immune surveillance. Drugs which are able to block the inhibitory checkpoint molecules have shown efficacy in some types of cancers. On the other hand, they are sometimes coupled with the onset of immune-mediated reactions. Once the role of immune checkpoints in autoimmune and inflammatory diseases is defined, drugs and approaches able to modulate such molecules can be used for therapy.

We invite authors to submit original research (basic, translational, and clinical research) and review articles about the deregulation, biological functions, and therapeutic potential of immune checkpoints in autoimmune and inflammatory diseases. Potential topics include but are not limited to:

• Profiling of inhibitory and stimulatory immune checkpoint molecules in autoimmune and inflammatory diseases;

• Functional studies to dissect the role of immune checkpoint molecules in autoimmune and inflammatory diseases;

• Modulation of immune checkpoints for therapy of autoimmune and inflammatory diseases;

• Association between checkpoint inhibitor therapy in cancer and autoimmunity.

Dr. Stefania Croci
Guest Editor

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • immune checkpoint molecules
  • autoimmune diseases
  • inflammatory diseases
  • checkpoint inhibitor therapy
  • PD-1/PD-L1
  • VISTA
  • TIM-3
  • LAG3
  • CTLA-4
  • IDO

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Published Papers (10 papers)

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Research

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13 pages, 2127 KiB  
Article
The High-Resolution Structure Reveals Remarkable Similarity in PD-1 Binding of Cemiplimab and Dostarlimab, the FDA-Approved Antibodies for Cancer Immunotherapy
by Tae-Jun Jeong, Hyun-Tae Lee, Nahyeon Gu, Yu-Jeong Jang, Seung-Beom Choi, Ui-Beom Park, Sang-Hyung Lee and Yong-Seok Heo
Biomedicines 2022, 10(12), 3154; https://doi.org/10.3390/biomedicines10123154 - 06 Dec 2022
Cited by 4 | Viewed by 2269
Abstract
Multiple tumors have responded well to immunotherapies, which use monoclonal antibodies to block the immune checkpoint proteins and reactivate the T-cell immune response to cancer cells. Significantly, the anti-PD-1 antibodies pembrolizumab and nivolumab, which were approved in 2014, have revolutionized cancer therapy, demonstrating [...] Read more.
Multiple tumors have responded well to immunotherapies, which use monoclonal antibodies to block the immune checkpoint proteins and reactivate the T-cell immune response to cancer cells. Significantly, the anti-PD-1 antibodies pembrolizumab and nivolumab, which were approved in 2014, have revolutionized cancer therapy, demonstrating dramatic improvement and longer duration. The US FDA authorized the third anti-PD-1 medication, cemiplimab, in 2018 for use in patients with cutaneous squamous cell carcinoma. To further understand the molecular mechanism of the antibody drug, we now reveal the intricate structure of PD-1 in complex with the cemiplimab Fab at a resolution of 1.98 Å. The cemiplimab–PD-1 interaction preoccupies the space for PD-L1 binding with a greater binding affinity than the PD-1/PD-L1 interaction, which is the basis for the PD-1 blocking mechanism. The structure reveals that cemiplimab and dostarlimab are significantly similar in PD-1 binding, although the precise interactions differ. A comparative investigation of PD-1 interactions with the four FDA-approved antibodies reveals that the BC, C’D, and FG loops of PD-1 adopt distinct conformations for optimal interaction with the antibodies. The structural characteristics in this work could be helpful information for developing more potent anti-PD-1 biologics against cancer. Full article
(This article belongs to the Special Issue Immune Checkpoints and Autoimmunity)
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15 pages, 2184 KiB  
Article
Pilot Study: Immune Checkpoints Polymorphisms in Greek Primary Breast Cancer Patients
by Nyanbol Kuol, Xu Yan, Vanessa Barriga, Jimsheena Karakkat, Stamatis Vassilaros, Ioannis Fyssas, Anastasios Tsimpanis, Sarah Fraser, Kulmira Nurgali and Vasso Apostolopoulos
Biomedicines 2022, 10(8), 1827; https://doi.org/10.3390/biomedicines10081827 - 29 Jul 2022
Cited by 3 | Viewed by 1618
Abstract
Background: Breast cancer is the most prevalent and second leading cause of cancer-related death in women worldwide. Despite early detection and better treatment therapies, 30% of early-stage breast cancer patients still develop recurrent disease. Breast cancer is a heterogeneous disease comprising several molecular [...] Read more.
Background: Breast cancer is the most prevalent and second leading cause of cancer-related death in women worldwide. Despite early detection and better treatment therapies, 30% of early-stage breast cancer patients still develop recurrent disease. Breast cancer is a heterogeneous disease comprising several molecular subtypes, commonly classified into clinical subtypes based on the hormone receptor status. These subtypes included luminal A and luminal B, which have different prognoses. Breast cancer development and progression involve many factors. Polymorphisms of PD-1, PD-L1, and PD-L2 genes have been previously associated with high risk and prognosis of cancer. However, no studies have associated PD-1, PD-L1, and PD-L2 polymorphisms with primary breast cancer subtypes. Hence, this study evaluated functional single nucleotide polymorphisms of PD-1, PD-L1, and PD-L2 with primary breast cancer subtypes, luminal A, and luminal B. In addition, we evaluated the PD-L1 protein expression in relation to primary breast cancer subtypes and stages. Results: There were no significant differences in the allele frequencies of PD-1 polymorphisms (rs2227981 G>A, rs7421861 A>G, and rs11568821 C>T) and PD-L1 polymorphisms (rs10815225 C>T and rs2282055 T>G) when compared with the general European population. However, a significant difference was detected in one of the PD-L2 polymorphisms (rs1009759 A>G), with the G allele higher in breast cancer patients than in the general European population. A higher prevalence of the T allele of PD-L1 polymorphism rs2282055 T>G was observed in luminal B breast cancer patients compared with luminal A. No significant difference was detected in other polymorphisms. We also observed that the PD-L1 rs2282055 TT genotype was more prevalent in luminal B breast cancer patients compared with luminal A. Our results found no association of the selected SNPs in the PDCD1 gene with breast cancer risk. Similarly, the protein expression data showed that PD-L1 and PD-L2 are associated with an aggressive phenotype, Luminal B, and advanced breast cancer stage. Conclusion: These findings suggest that immune checkpoint polymorphisms are associated with the risk and subtypes of breast cancer. Full article
(This article belongs to the Special Issue Immune Checkpoints and Autoimmunity)
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24 pages, 5514 KiB  
Article
Reclassification of Kidney Clear Cell Carcinoma Based on Immune Cell Gene-Related DNA CpG Pairs
by Qizhan Luo and Thomas-Alexander Vögeli
Biomedicines 2021, 9(2), 215; https://doi.org/10.3390/biomedicines9020215 - 20 Feb 2021
Cited by 1 | Viewed by 1943
Abstract
Background: A new method was developed based on the relative ranking of gene expression level, overcoming the flaw of the batch effect, and having reliable results in various studies. In the current study, we defined the two methylation sites as a pair. The [...] Read more.
Background: A new method was developed based on the relative ranking of gene expression level, overcoming the flaw of the batch effect, and having reliable results in various studies. In the current study, we defined the two methylation sites as a pair. The methylation level in a specific sample was subject to pairwise comparison to calculate a score for each CpGs-pair. The score was defined as a CpGs-pair score. If the first immune-related CpG value was higher than the second one in a specific CpGs-pair, the output score of this immune-related CpGs-pair was 1; otherwise, the output score was 0. This study aimed to construct a new classification of Kidney Clear Cell Carcinoma (KIRC) based on DNA CpGs (methylation sites) pairs. Methods: In this study, the biomarkers of 28 kinds of immune infiltration cells and corresponding methylation sites were acquired. The methylation data were compared between KIRC and normal tissue samples, and differentially methylated sites (DMSs) were obtained. Then, DNA CpGs-pairs were obtained according to the pairs of DMSs. In total, 441 DNA CpGs-pairs were utilized to construct a classification using unsupervised clustering analysis. We also analyzed the potential mechanism and therapy of different subtypes, and validated them in a testing set. Results: The classification of KIRC contained three subgroups. The clinicopathological features were different across three subgroups. The distribution of immune cells, immune checkpoints and immune-related mechanisms were significantly different across the three clusters. The mutation and copy number variation (CNV) were also different. The clinicopathological features and potential mechanism in the testing dataset were consistent with those in the training set. Conclusions: Our findings provide a new accurate and stable classification for developing personalized treatments for the new specific subtypes. Full article
(This article belongs to the Special Issue Immune Checkpoints and Autoimmunity)
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14 pages, 2242 KiB  
Article
Lectin-Like Transcript 1 (LLT1) Checkpoint: A Novel Independent Prognostic Factor in HPV-Negative Oropharyngeal Squamous Cell Carcinoma
by Mario Sanchez-Canteli, Francisco Hermida-Prado, Christian Sordo-Bahamonde, Irene Montoro-Jiménez, Esperanza Pozo-Agundo, Eva Allonca, Aitana Vallina-Álvarez, César Álvarez-Marcos, Segundo Gonzalez, Juana M. García-Pedrero and Juan P. Rodrigo
Biomedicines 2020, 8(12), 535; https://doi.org/10.3390/biomedicines8120535 - 25 Nov 2020
Cited by 7 | Viewed by 2407
Abstract
Lectin-like transcript 1 (LLT1) expression by tumor cells contributes to immune evasion, thereby emerging as a natural killer (NK) cell-mediated immunotherapeutic target. This study is the first to investigate LLT1 expression (encoded by CLEC2D gene) in head and neck cancers to ascertain its [...] Read more.
Lectin-like transcript 1 (LLT1) expression by tumor cells contributes to immune evasion, thereby emerging as a natural killer (NK) cell-mediated immunotherapeutic target. This study is the first to investigate LLT1 expression (encoded by CLEC2D gene) in head and neck cancers to ascertain its impact on patient prognosis. LLT1 expression was analyzed by immunohistochemistry in a homogeneous cohort of human papillomavirus (HPV)-negative oropharyngeal squamous cell carcinomas (OPSCC), and correlated with clinical data. Results were further validated using transcriptomic data from the TCGA database. Tumoral LLT1 expression was detected in 190/221 (86%) OPSCC specimens, whereas normal pharyngeal epithelium was negative. Patients harboring LLT1-positive tumors showed significantly lower disease-specific (DSS) and overall survival (OS) (p = 0.049 and p = 0.036, respectively, log-rank test). High density of LLT1-positive tumor-infiltrating lymphocytes (TIL) was also frequently detected in 160 (73%) OPSCC samples, and significantly associated with better DSS and OS (p < 0.001 and p = 0.007, respectively). Multivariate Cox analysis further revealed that tumoral LLT1 expression and infiltration of LLT1-positive TIL were independent prognostic factors for DSS and OS. CLEC2D mRNA levels are also significantly increased in primary tumors compared to normal tissue. Strikingly, the prognostic impact of CLEC2D mRNA levels varied depending on HPV status in OPSCC, and among distinct cancer types. CLEC2D expression was significantly correlated with NK cell infiltration using the MCP-counter model. These findings uncover LLT1/CLEC2D as an independent prognostic factor in HPV-negative OPSCC, and a potential novel target for immunotherapy. Full article
(This article belongs to the Special Issue Immune Checkpoints and Autoimmunity)
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Review

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14 pages, 1253 KiB  
Review
Association between Immunosuppressive Therapy Utilized in the Treatment of Autoimmune Disease or Transplant and Cancer Progression
by Amanda Reyes, Atish Mohanty, Rebecca Pharaon and Erminia Massarelli
Biomedicines 2023, 11(1), 99; https://doi.org/10.3390/biomedicines11010099 - 30 Dec 2022
Cited by 3 | Viewed by 3248
Abstract
Autoimmunity and cancer rates have both been on the rise in Western civilization prompting many to investigate the link between the two entities. This review will investigate the complex interactions between the activation and deactivation of the immune system and the development of [...] Read more.
Autoimmunity and cancer rates have both been on the rise in Western civilization prompting many to investigate the link between the two entities. This review will investigate the complex interactions between the activation and deactivation of the immune system and the development of malignancy. Additional focus will be placed on the main classes of immune inhibitor therapy utilized in transplant patients and in autoimmune disease including TNF-alpha, Calcineurin, mTOR, purine synthesis antagonists and IMPDH inhibitors. Full article
(This article belongs to the Special Issue Immune Checkpoints and Autoimmunity)
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13 pages, 3967 KiB  
Review
Where Do We Stand with Immunotherapy for Advanced Pancreatic Ductal Adenocarcinoma: A Synopsis of Clinical Outcomes
by Liia Akhuba, Zhanna Tigai and Dmitrii Shek
Biomedicines 2022, 10(12), 3196; https://doi.org/10.3390/biomedicines10123196 - 09 Dec 2022
Cited by 6 | Viewed by 2122
Abstract
Pancreatic cancer is the seventh leading cause of cancer-related mortality in both sexes across the globe. It is associated with extremely poor prognosis and remains a critical burden worldwide due to its low survival rates. Histologically, pancreatic ductal adenocarcinoma (PDAC) accounts for 80% [...] Read more.
Pancreatic cancer is the seventh leading cause of cancer-related mortality in both sexes across the globe. It is associated with extremely poor prognosis and remains a critical burden worldwide due to its low survival rates. Histologically, pancreatic ductal adenocarcinoma (PDAC) accounts for 80% of all pancreatic cancers; the majority of which are diagnosed at advanced stages, which makes them ineligible for curative surgery. Conventional chemotherapy provides a five-year overall survival rate of less than 8% forcing scientists and clinicians to search for better treatment strategies. Recent discoveries in cancer immunology have resulted in the incorporation of immunotherapeutic strategies for cancer treatment. Particularly, immune-checkpoint inhibitors, adoptive cell therapies and cancer vaccines have already shifted guidelines for some malignancies, although their efficacy in PDAC has yet to be elucidated. In this review, we summarize the existing clinical data on immunotherapy clinical outcomes in patients with advanced or metastatic PDAC. Full article
(This article belongs to the Special Issue Immune Checkpoints and Autoimmunity)
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31 pages, 1015 KiB  
Review
Immune Checkpoint Inhibitors and Other Immune Therapies in Breast Cancer: A New Paradigm for Prolonged Adjuvant Immunotherapy
by Andrea Nicolini, Paola Ferrari and Angelo Carpi
Biomedicines 2022, 10(10), 2511; https://doi.org/10.3390/biomedicines10102511 - 08 Oct 2022
Cited by 10 | Viewed by 4517
Abstract
Background: Breast cancer is the most common form of cancer in women worldwide. Advances in the early diagnosis and treatment of cancer in the last decade have progressively decreased the cancer mortality rate, and in recent years, immunotherapy has emerged as a relevant [...] Read more.
Background: Breast cancer is the most common form of cancer in women worldwide. Advances in the early diagnosis and treatment of cancer in the last decade have progressively decreased the cancer mortality rate, and in recent years, immunotherapy has emerged as a relevant tool against cancer. HER2+ and triple-negative breast cancers (TNBCs) are considered more immunogenic and suitable for this kind of treatment due to the higher rate of tumor-infiltrating lymphocytes (TILs) and programmed death ligand 1 (PD-L1) expression. In TNBC, genetic aberrations further favor immunogenicity due to more neo-antigens in cancer cells. Methods: This review summarizes the principal ongoing conventional and investigational immunotherapies in breast cancer. Particularly, immune checkpoint inhibitors (ICIs) and their use alone or combined with DNA damage repair inhibitors (DDRis) are described. Then, the issue on immunotherapy with monoclonal antibodies against HER-2 family receptors is updated. Other investigational immunotherapies include a new schedule based on the interferon beta-interleukin-2 sequence that was given in ER+ metastatic breast cancer patients concomitant with anti-estrogen therapy, which surprisingly showed promising results. Results: Based on the scientific literature and our own findings, the current evaluation of tumor immunogenicity and the conventional model of adjuvant chemotherapy (CT) are questioned. Conclusions: A novel strategy based on additional prolonged adjuvant immunotherapy combined with hormone therapy or alternated with CT is proposed. Full article
(This article belongs to the Special Issue Immune Checkpoints and Autoimmunity)
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15 pages, 830 KiB  
Review
Pharmacological Treatments Available for Immune-Checkpoint-Inhibitor-Induced Colitis
by Sae Ohwada, Keisuke Ishigami, Noriyuki Akutsu and Hiroshi Nakase
Biomedicines 2022, 10(6), 1334; https://doi.org/10.3390/biomedicines10061334 - 06 Jun 2022
Cited by 5 | Viewed by 2689
Abstract
Immune checkpoint inhibitor treatment has shown revolutionary therapeutic effects in various carcinomas. However, immune-related adverse events (irAE) following this treatment can sometimes lead to treatment discontinuation. One such frequently encountered adverse event is immune-related colitis (irAE colitis). Corticosteroids (CS) are the first-line treatment [...] Read more.
Immune checkpoint inhibitor treatment has shown revolutionary therapeutic effects in various carcinomas. However, immune-related adverse events (irAE) following this treatment can sometimes lead to treatment discontinuation. One such frequently encountered adverse event is immune-related colitis (irAE colitis). Corticosteroids (CS) are the first-line treatment for irAE colitis, but we often encounter CS-refractory or -resistant cases. The application of multiple biologics has been proposed as a therapy to be administered after CS treatment; however, the efficacy and safety of biologics for patients with irAE colitis who do not respond to CS have not been established. This review summarizes the treatment regimens available for irAE colitis, focusing on the mechanism of action of corticosteroids, infliximab, vedolizumab, and other drugs. Full article
(This article belongs to the Special Issue Immune Checkpoints and Autoimmunity)
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20 pages, 341 KiB  
Review
Review of Immune-Related Adverse Events (irAEs) in Non-Small-Cell Lung Cancer (NSCLC)—Their Incidence, Management, Multiorgan irAEs, and Rechallenge
by Raju Vaddepally, Rajiv Doddamani, Soujanya Sodavarapu, Narasa Raju Madam, Rujuta Katkar, Anupama P. Kutadi, Nibu Mathew, Rohan Garje and Abhinav B. Chandra
Biomedicines 2022, 10(4), 790; https://doi.org/10.3390/biomedicines10040790 - 28 Mar 2022
Cited by 18 | Viewed by 3896
Abstract
Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of advanced malignancies, including non-small cell lung cancer (NSCLC). These agents have improved clinical outcomes and have become quite an attractive alternative alone or combined with other treatments. Although ICIs are tolerated better, they also [...] Read more.
Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of advanced malignancies, including non-small cell lung cancer (NSCLC). These agents have improved clinical outcomes and have become quite an attractive alternative alone or combined with other treatments. Although ICIs are tolerated better, they also lead to unique toxicities, termed immune-related adverse events (irAEs). A reconstituted immune system may lead to dysregulation in normal immune self-tolerance and cause inflammatory side effects (irAEs). Although any organ system can be affected, immune-related adverse events most commonly involve the gastrointestinal tract, endocrine glands, skin, and liver. They can occur anytime during the treatment course and rarely even after completion. Owen and colleagues showed that approximately 30% of patients with NSCLC treated with ICIs develop irAEs. Kichenadasse et al. conducted a thorough evaluation of multiorgan irAEs, which is of particular interest because information regarding these types of irAEs is currently sparse. It is important to delineate between infectious etiologies and symptom progression during the management of irAEs. Close consultation with disease-specific subspecialties is encouraged. Corticosteroids are the mainstay of treatment of most irAEs. Early intervention with corticosteroids is crucial in the general management of immune-mediated toxicity. Grade 1–2 irAEs can be closely monitored; hypothyroidism and other endocrine irAEs may be treated with hormone supplementation without the need for corticosteroid therapy. Moderate- to high-dose steroids and other additional immunosuppressants such as tocilizumab and cyclophosphamide might be required in severe, grade 3–4 cases. Recently, increasing research on irAEs after immunotherapy rechallenge has garnered much attention. Dolladille and colleagues assessed the safety in patients with cancer who resumed therapy with the same ICIs and found that rechallenge was associated with about 25–30% of the same irAEs experienced previously (4). However, such data should be carefully considered. Further pooled analyses may be required before we conclude about ICIs’ safety in rechallenge. Full article
(This article belongs to the Special Issue Immune Checkpoints and Autoimmunity)

Other

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8 pages, 537 KiB  
Perspective
Dermatological Autoimmune Considerations of Immune Checkpoint Therapy
by Lauren S. Fane, Jimmy T. Efird, Charulata Jindal and Tithi Biswas
Biomedicines 2022, 10(10), 2339; https://doi.org/10.3390/biomedicines10102339 - 20 Sep 2022
Cited by 1 | Viewed by 1277
Abstract
The most common immune-related adverse events (irAEs) involve the skin, and several serve as predictors of response to immune checkpoint inhibitor (ICI) therapy, especially in melanoma. Patients with pre-existing skin autoimmune diseases (ADs) have been excluded from ICI studies for safety concerns, yet [...] Read more.
The most common immune-related adverse events (irAEs) involve the skin, and several serve as predictors of response to immune checkpoint inhibitor (ICI) therapy, especially in melanoma. Patients with pre-existing skin autoimmune diseases (ADs) have been excluded from ICI studies for safety concerns, yet recent research has shown that dermatological ADs can be managed without discontinuing ICI therapy. Patients with ADs respond as well or better to ICIs and can be included as candidates in clinical trials. Frequently taken during ICI therapy, steroids impair immunotherapy efficacy in certain anatomical sites of tumors but not others, including the brain. ICI efficacy can be enhanced by radiotherapy without increasing adverse events, as neoadjuvant radiotherapy is thought to sensitize tumors to ICIs. This perspective highlights clinical autoimmune considerations of ICI therapy in melanoma and discusses important areas for future exploration. Full article
(This article belongs to the Special Issue Immune Checkpoints and Autoimmunity)
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