Gastrointestinal stromal tumors (GISTs) are among the most common soft tissue tumors in the digestive system, typically arising from specialized cells known as interstitial cells of Cajal. These tumors are characterized by their formation as a result of genetic mutations, most of which are associated with KIT and PDGFRA genes. There are various therapeutic strategies available for treating GIST, but drug resistance presents a major challenge. In this article, we address the role of immune cells infiltrating tumors, specifically macrophages and their interaction with tumor cells, and how this understanding can serve in developing new treatment strategies. We will also discuss how these immune interactions affect disease progression and recurrence risks. Join us to explore this complex relationship between immune cells and tumors and the potential benefits that can arise from it.
Understanding Gastrointestinal Stromal Tumors
Gastrointestinal stromal tumor, abbreviated as GIST, is a common form of soft tissue tumors in the gastrointestinal tract. This type of tumor develops from specialized cells known as interstitial cells of Cajal that are found in the intestinal wall. The nature of treatment for this tumor heavily depends on its biological characteristics, including genetic mutations. Two of the most common mutations associated with GIST have been identified, namely mutations in the KIT gene (75-80%) and mutations in PDGFRA (5-10%). Gastrointestinal stromal tumors are problematic due to their tendency to have a high recurrence rate post-treatment, necessitating modern treatment strategies.
Risk stratification based on tumor size, location, and mitotic count is considered an important tool to predict the likelihood of disease recurrence. Imatinib, a tyrosine kinase inhibitor, is typically used as the first-line treatment for patients with advanced or recurrent tumors. However, the issue of drug resistance seems to be increasing, necessitating the search for new treatment strategies for GIST. The importance of comprehensive studies on the relationship between infiltrating immune cells and tumor progression has also been highlighted.
Immune Response and Relationship with Infiltrating Cells
The immune response to gastrointestinal tumors involves the unique experience of infiltrating immune cells, particularly macrophages and T cells. Recent studies reveal that a large presence of these cells can play a crucial role in tumor development and the success of therapies. For instance, results from single-cell genomic research have shown that various immune cells influence tumor development through complex interactions within the surrounding microenvironment of cancer cells.
Among the key findings was the focus on the MIF/CXCR4 axis, which represents the most common interaction between immune cells and tumor cells. As the risks of disease recurrence increased, the expression levels of immune markers such as CD68, CD206, MIF, and CXCR4 were found to rise. Practical experiments demonstrated that cancer cells, such as GIST882 cells, could modulate macrophage responses through the secretion of MIF, leading to enhanced phenotypic modifications in macrophages towards an M2 pattern. This opens up possibilities for exploring new immune strategies to enhance therapeutic efficacy.
Modern Techniques Used in Research
The scientific techniques used to study GIST and the interaction between immune cells vary. One of the prominent methods is single-cell RNA sequencing, which allows for the gathering of detailed information about different cell types in the tumor microenvironment. This technique was utilized in the study described, where samples from patients with GIST tumors were examined. The use of specific enzymes, collection of genetic material, and obtaining accurate results were part of the experimental protocol.
Furthermore, tissue array and immunohistochemical techniques were employed to identify and classify cells within the tumor microenvironment. This type of analysis reflects how immune networks are formed and where active cells, such as T-cell macrophages, are located within the tumor tissue. According to experts, this is an important indicator for understanding how the surrounding environment affects tumor behavior.
Implications
Clinical Significance of Results and Future Research
Understanding the role of infiltrating immune cells in GIST is a pivotal step in developing new therapeutic strategies. Studies show that immune cells are not only visible as defenses against tumors but also as factors influencing disease pathways and progression. Researchers now have the opportunity to understand how to enhance immune formation and limit tumor response by targeting complex pathways.
These new research directions require more clinical studies to verify the efficacy of immunotherapies and consider combination strategies, such as combining immunoinhibition with traditional therapies for better outcomes. Scientists emphasize the need to focus on delivering personalized treatments that take into account the complex interaction between tumor cells and the surrounding immunity. This deep understanding is likely to contribute to significant advancements in the management and treatment of gastrointestinal sarcoma tumors.
Analysis of Migratory Cells in Soft Tissue Cancer
The findings derived from single-cell analyses using RNA sequencing highlighted the biological diversity of cells within different tumors. By analyzing two tumor samples, CD8+ T cells, macrophages, and cancer cells were among the prominent cells present. In sample G01, cancer cells constituted 55.1% of the total cell count, while in sample G02, this percentage dropped to 27.5%. These results suggest that variation in cell composition may play a crucial role in determining tumor function and its response to treatment.
The study also showed that the number of infiltrating immune cells in the samples was substantial, with a high concentration of CD8+ in G02, indicating a stronger immune response in lower-risk tumors. On the other hand, G01 results showed a clear increase in the number of macrophages, which could indicate the presence of an inflammatory environment conducive to tumor growth. Overall, these differences underscore the importance of understanding the tumor microenvironment and how it impacts disease progression.
Cell Interaction in Cancer Tissues
Cell interaction analyses such as CellChat were used to determine how cells communicate within cancer tissues. Seven cell types were identified, and the inputs and outputs for each cell type were analyzed through ligand-receptor partnership models. Tumor cells were the most interactive with macrophages, supporting the hypothesis that this interaction may contribute to sustained cancer growth and progression.
It was determined that the MIF/CXCR4 signaling axis represents one of the most important pathways for communication between cancer and macrophage cells. This partnership was studied in both G01 and G02, where it was found that this signaling plays a crucial role in regulating the immune response of the body towards the tumor. Enhancing interactions between cells could facilitate an anti-tumor immune response if the balance is correct, but in cases where macrophages dominate, this may lead to negative outcomes, including facilitating tumor growth.
The Role of Immune Cells in Tumor Progression and Cancer Characteristics
The immune profiling of tumors is a key approach in understanding how immune cells can influence tumor development. In the study, immunohistochemistry was used to identify levels of CD8+ and CD68+ cells. High levels of CD8+ cells were found in low-risk tumors, while macrophage counts increased significantly with rising risk levels.
The results suggest that increased macrophage levels may reflect a replacement mechanism between immune cells, where high-risk tumors show a trend of evading immune response. This is consistent with previous studies indicating that macrophages associated with certain tumors may contribute to the suppression of effective immune mechanisms and enhance the tumor growth environment.
Impact
MIF/CXCR4 Axis in Immune Cell Differentiation
Highlighting the MIF/CXCR4 signaling pathway in cellular changes raises further questions about how these signals operate. In laboratory experiments, GIST-882 cells demonstrated the ability to secrete MIF, and an increase in differentiation components toward M2 cells was observed. This effect was noted to potentially decrease with the use of MIF inhibitors, indicating that balancing the immune environment using these signals may be key to effective treatment.
Questions have been raised about how this understanding can be utilized to improve therapeutic strategies in GIST patients, who face challenges in their treatment, including drug resistance. The use of MIF inhibitors can be viewed as a means to enhance the balance of the immune response and identify the precise characteristics of each type of cancer, which may ultimately lead to increased effectiveness of current therapies.
Conclusion and Future Analysis
The results underscore the importance of detailing and specifying the individual role of each cell type in tumors, as risk classifications and the distribution of macrophages and related immune cells strongly intersect with how the disease progresses. Not only in terms of cell numbers but also regarding how these cells can negatively or positively influence immune responses. A more nuanced understanding of these dynamics may assist in developing new therapeutic strategies based on modifying the tumor microenvironment and tailoring treatments more precisely. This research represents an important step toward understanding the interaction between immunotherapy and the tumor microenvironment, highlighting a significant direction for future research in this field.
Tumor Progression and Cellular Interactions
Tumors are complex diseases that depend on interactions between the tumor microenvironment and immune cells as well as adjacent cells. Tumor progression is highlighted in the context of two types of immune responses: M1 inflammatory state and M2 tumor-promoting state. Studies suggest that the M1 state contributes to an effective immune response against cancer cells, while the M2 state enhances tumor progression. However, the environmental roots of these two states and understanding the supportive mechanisms of progression remain subjects of intensive investigation.
Research has shown that PD-1 expression is present in M2 tumor-associated macrophages, suggesting that these macrophages may contribute to increased tumor progression. Through the analysis of CD206 expression, the highest level was found in high-risk tumors. However, the reason for the increased M2 macrophages in high-risk cases remains unclear, warranting further studies to understand the relationship between macrophage gene expression and tumor progression.
Modern methods such as CellChat analysis have been utilized to understand the cellular communications between tumor cells and macrophages. The results demonstrated that the MIF/CXCR4 axis is a primary communication type, where a high level of MIF is associated with tumor development across various cancer types. It was discovered that MIF can act on cells in an autocrine or paracrine manner, leading to changes in physiological functions.
MIF/CXCR4 Axis and Cancer Progression
The MIF/CXCR4 axis is considered a critical pathway in tumor development, as this axis is associated with numerous negative effects in tumors. Studies have shown that high expression of both MIF and CXCR4 is linked to an increased risk of tumor recurrence. Not only does it contribute to drug resistance, but it also plays a role in the tumor’s invasive capability.
Through laboratory experiments, it was found that GIST882 cells can secrete MIF, enhancing M2 macrophage activity. The findings indicate that high expression levels of both compounds are negative prognostic indicators, highlighting the importance of this axis in the cancer progression process. While the precise mechanism of the MIF/CXCR4 ensemble remains not fully understood, the results suggest the need for further research to comprehend how these components influence tumor development.
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During clinical studies, it has been confirmed that elevated levels of MIF indicate a deterioration of the disease state. As a result, targeting the MIF/CXCR4 axis is being considered as a new therapeutic strategy. This strategy may provide new hope in improving current therapies by offering a deeper understanding of how cancer cells interact with their surrounding immune environment.
Macrophages and the Immune Environment in GIST Tumors
Macrophages are key immune cells that play an important role in shaping the tumor microenvironment. M2-type macrophages are the most prevalent in GIST tumors, where they can modify the immune response in favor of tumor progression. Research has shown that these macrophages contribute to the formation of an immunosuppressive environment, facilitating tumor cell infiltration and progression.
Studies in this field indicate that an increased number of M2 macrophages in the tumor is directly associated with increased disease severity and recurrence. By understanding how M2 macrophages are attracted, ways can be explored to modify this response to make it more beneficial in combating cancer. This knowledge may be crucial for developing new therapeutic strategies that target the balance of immune response in tumors.
Understanding macrophage dynamics and their interaction with tumor cells provides new insights into the cellular mechanisms that support tumor growth and immune responses. This understanding may contribute to offering advanced therapeutic strategies that may target the tumor’s immune microbiome, potentially leading to improved treatment outcomes for patients with complex tumors like GIST.
Gastrointestinal Stromal Tumor: Understanding Genetic and Pathological Factors
Gastrointestinal stromal tumor, also known as GIST, is a type of tumor that arises in the fibrous tissues of the gastrointestinal tract. This type of cancer is characterized by genetic mutations, most notably mutations in the KIT and PDGFRA genes. These mutations are key factors that contribute to tumor development and increase its aggressiveness. In several cases, KIT mutations show increased reactivity, facilitating the growth and spread of cancer cells. By the time diagnosis of GIST occurs, it is often associated with high recurrence rates, making it an important topic for research and the development of treatment strategies.
Although targeted therapy using tyrosine kinase inhibitors like imatinib is the primary treatment, drug resistance poses a significant challenge. Statistics show that up to 50% of patients develop drug resistance over time. Hence, there is an increasing need to develop new treatments that consider the microenvironment of the tumor and its interactions with immune cells.
Interaction Between Tumor Cells and the Immune System
In recent years, studies have increased regarding how tumor cells interact with immune cells, particularly those associated with tumors such as macrophages. Immune checkpoint molecules play a vital role in how tumors respond to therapies, and predictive markers such as PD-1/PD-L1 and T cell diversity are key factors in this. Research has shown a significant quantity of infiltrating immune cells in the tumor microenvironment of GISTs, indicating that immune responses may be compromised in many patients. While cells like CD8+ T cells can activate immune responses, they may become exhausted as the disease progresses, leading to an increase in macrophages that can contribute to tumor progression.
Furthermore, macrophages are believed to participate in regulating the tumor microenvironments, and studies have shown that the M2 macrophage polarization pattern contributes to tumor advancement and adaptation to the responsive immune environment. Therefore, understanding the role of macrophages and their strategies in immune evasion may be key to developing more effective treatments for GIST.
Strategies
New Treatments: Combining Antibodies and Immunotherapy
In parallel with research on targeted therapy, uncombined antibodies, such as those targeting immune checkpoints PD-1 and CTLA-4, have begun to gain interest as potential treatments for various tumors. The use of these therapies has led to improved survival rates in some cases, but not all patients respond to them. Factors such as the tumor mutational burden and deviations in the immune system may help enhance treatment options for patients.
It is worth noting that integrating immunotherapies with targeted therapy could represent a step toward improving outcomes in patients with GIST. It is necessary to expand the knowledge base about patient responses to treatment, how the immune system interacts with tumors, and how therapies can be effectively integrated.
Future Research and Treatment Delivery
The rapid changes in research aspects regarding GIST treatment and genetics signal the beginning of a new chapter in clinical medicine. Research is focusing on new strategies, such as using single-cell RNA sequencing technology to determine how immune cells interact with tumor cells. This helps in understanding the fine dynamics of the relationship between them and provides new opportunities to develop treatments.
The shift towards personalizing treatment based on the patient’s genetic makeup and identifying individual patterns of treatment response marks a turning point in how GIST and immunotherapy are managed. The focus of research on improving health outcomes for patients demonstrates positive steps toward achieving better results. Therefore, investment in research and developing new strategies will help improve cure rates and reduce recurrence rates.
Re-excision of Benign Intestinal Tumors and the Importance of Immunological Test Results
Case G02 underwent laparoscopic tumor removal, where the results of immunohistochemical tests showed that CD117, DOG-1, and CD34 were positive. These antigens are known as key indicators of the presence of intestinal tumors known as gastrointestinal stromal tumors (GIST). On the other hand, case G01 experienced a tumor with a maximum diameter of 10 cm, resulting in a high cellular mitotic rate of 12 per 50 field of vision, indicating the severity of the case. We can conclude based on the information that the tumor size and the nature of the mitotic index help doctors classify tumors and understand the potential risks for patients. In comparison, the tumor size in case G02 was small at only 2 cm, with a relatively low mitotic rate, which was classified as very low risk, opening the door for more hopeful and effective therapeutic strategies.
Laboratory Methods in Analyzing GIST Tumors
Tumor tissues were obtained from resection samples and were cut into small pieces. These pieces were digested using collagenase IV, an enzyme used in tissue processing to release the cells. Subsequently, a cell sieve was used to sort the cells, with viability measured using the Countess II Automated Cell Counter. These steps are crucial for generating genomic libraries from single cells as each cell is processed individually, providing an accurate picture of cellular diversity.
The complete process involves using the 10X Chromium Single Cell Platform, which facilitates cell sequencing and access to accurate genetic information. Here are key stages in this process: generation of gel beads in emulsion, barcode design, and cleaning GEM-RT. The sequencing library is then prepared, and the library concentration is measured using Qubit before performing it on the Illumina NovaSeq 6000 for gene sequencing analysis.
Data quality analysis was strictly applied, with any data not meeting specific criteria, such as an RNA count less than 500 or higher than 98% of sample cells, being excluded. This meticulous selection ensures that reliable gene expression data are presented, making the results practical and applicable in clinical studies. The resulting data reflect the cellular composition in tumor tissues and provide a comprehensive insight into patient characteristics and the impact of tumors on the immune system.
Analysis
Cell Expression Using Miniature Tissues
A miniature tissue array was created with a thickness of 5 microns from paraffin-embedded tumor tissues, collected over nine years. The established criteria included patients diagnosed with GIST tumors only, making it a tightly studied group. Patients treated with targeted therapies or those whose tumors were located outside the stomach or intestine were excluded. Ultimately, the study included 80 patients, and various immunohistochemical analyses were performed to allow researchers to understand how different cell types interact in GIST tumors.
Techniques such as immunohistochemistry and immunofluorescence were used, relying on various antibodies to detect the expression of different antigens. Software such as ImageJ was used to scan the stained slides and count the stained cells to reveal results. These results enhance the understanding of the role of different immune cells in tumor development and how proteins such as CD8, CD68, and CD206 contribute to the identification of different tumor types and their stages of progression.
Data analysis showed a clear variation in cell expression among different risk groups, indicating that immune cell interactions play a vital role in the tumor response and the body’s reaction to treatment. Understanding these dynamics is important for the potential development of better treatment strategies.
Cellular Networks and Cell Communication in Tumor Environments
Cellular inflammation and relationships among cells are fundamental topics in the context of tumors. Seven cell types were identified through analysis, and the use of the CellChat tool contributed to providing quantitative analyses of cell interactions in depth. The results showed that interactions between tumor cells and macrophages were the most common, indicating the importance of these relationships in the tumor environment. The cellular networks among different cells contribute to enhancing the microbial environment surrounding the tumor and influence tumor development and growth.
The analysis showed that the MIF/CXCR4 axis was the most frequent among tumor cells and macrophages in both G01 and G02 samples. This highlights an important model of interaction between cells, where immune cells enhance the response of GIST tumors, underscoring the importance of a partnership between immune and cancerous cells. As the patient’s body responds, enhancing the understanding of these relationships opens new avenues for tumor treatment by targeting these axes.
Additionally, these complex communication networks among cells represent an opportunity to explore potential therapies aimed at disrupting or enhancing these interactions, thereby improving tumor management and future treatments.
Gene Expression and Its Impact on Tumor Progression
Gene and receptor expression among tumor cells plays a pivotal role in tumor growth and spread. The MIF/CXCR4 signaling axis was chosen as the main subject for further research in the study, involving interactions between tumor cells and immune cells. The data showed that tumors with higher levels of this signaling were associated with an increased risk of tumor progression.
Through immune assays, the expression of CD8, CD68, and CD206 was analyzed in different risk groups. The results showed that CD8+ T cells were the most abundant in the low-risk group, while CD68+ macrophages were the most prevalent in the high-risk group. This indicates that the surrounding immune environment can vary based on the tumor’s different characteristics, underscoring the necessity of understanding these dynamics to enhance treatment strategies.
This information is highly valuable for developing immunotherapies, as targeted drugs can be tailored to manage the interaction of immune cells with tumors based on the unique differences between these two cell types. Focusing on the balance between immune activation and inhibiting cancer growth might be the key to developing more effective treatments.
Expression
About MIF and CXCR4 in Tumor Growth
The expression levels of MIF and CXCR4 are important factors in the study of tumor growth, as results show that the expression of both proteins is significantly correlated with disease progression. In the case of GIST, the highest expression levels were identified in high-risk tumor categories, indicating that increased expression of these proteins corresponds with deterioration of health and disease exacerbation. Quantitative analyses have revealed statistically significant differences between various groups, where the expression levels of MIF and CXCR4 reflect the progression of cases from low to high risk. These findings are particularly significant as they provide evidence of the clear role these proteins play in the diagnosis and assessment of tumor severity. This phenomenon supports the idea that high expression of CXCR4 and MIF may reflect increased cancer activity and thus could be considered a biomarker in treatment decision-making.
The Role of Immune Cells in Gastrointestinal Tumors
Immune cells, such as CD8+ T cells and CD68+ macrophages, are an integral part of the tumor-associated microbiome, playing a crucial role in tumor surveillance and progression. Studies have shown that an increase in the number of macrophages is associated with cancer severity, due to changes in the immune response that lead to a loss of immune effectiveness against tumors. As the tumor progresses, we observed that the relative quantity of CD8+ cells begins to decrease while the number of macrophages increases, which may indicate a tumor strategy to evade the immune response. The relationship between M1 and M2 macrophage representation has also been discussed, as the balance between these states can significantly influence tumor behavior. For instance, an M2 state may suggest a favorable environment for tumor progression and disease exacerbation, highlighting the importance of understanding how the immune system responds in accelerating tumor growth.
Mechanism of Action of the MIF/CXCR4 Axis and Its Impact on Immune Response
The mechanism of action of the MIF/CXCR4 axis is a significant topic in research for new cancer treatment methods. This mechanism shows how tumor cells can influence immune cells, particularly macrophages. Current data suggest that MIF can modify macrophage responses, thereby facilitating tumor progression by promoting the M2 state that leads to immune suppression. An ELISA test was used to measure MIF secretion from tumor cell lines, providing evidence that GIST882 cells secrete MIF at concentrations that increase over time. This secretion has helped create an immunosuppressive environment around the tumor. Furthermore, the application of inhibitors like ISO-1 and WZ811 has demonstrated how these chemical interventions affect M2 macrophage levels, reflecting the critical role of the MIF/CXCR4 axis in immune response modulation. These discoveries represent an important step toward understanding how this axis can be targeted in cancer immunotherapy.
Future Directions in Cancer Treatment via Targeting Immune Axes
Findings related to the MIF/CXCR4 axis open new horizons in the treatment of GIST tumors. With the increasing focus on immunotherapy, targeting this axis represents a promising strategy to enhance immune response. By improving our understanding of the relationship between tumor cells and immunity, we can develop new drugs that target these axes to inhibit cancer growth mechanisms. Additionally, it is crucial to conduct in-depth studies on drugs that enhance the efficacy of immune cells or those that reduce the impact of the tumor environment, which will lead to improved clinical outcomes. Current data already show how targeted drug therapies may face resistance risks, necessitating further exploration of the possibilities of combining targeted therapies with immunotherapies. Future directions inspire hope for designing integrative treatment protocols that focus on immune and molecular effects to improve outcomes for GIST patients.
Tumors
Sarcoma and Clinical Patterns
Sarcoma tumors are a group of tumors that affect fibrous tissues, such as muscles, bones, and fats. These tumors differ from cancer-like tumors in their causes and clinical patterns. For example, gastrointestinal sarcoma tumors, such as gastrointestinal stromal tumors, are considered a specific type of tumor that occurs in the digestive system and poses unique treatment challenges. The early symptoms of these tumors are often vague and resemble other intestinal diseases, leading to delays in diagnosis.
Differentiating the clinical patterns of sarcoma tumors contributes to a better understanding of how to treat patients. In this context, targeted therapies, such as “Imatinib,” are emphasized, which is widely used to treat gastrointestinal stromal tumors. Studies have shown that Imatinib can help reduce tumor size and improve patients’ quality of life. However, examining the progression of these tumors and assessing their genetic characteristics is crucial for understanding treatment response.
Early Diagnosis and Treatment of Sarcoma Tumors
Early diagnosis of sarcoma tumors is vital in improving health outcomes for patients. Diagnosis requires the use of advanced imaging techniques, such as X-rays, MRI, and CT scans, which provide accurate insight into the location and size of the tumor. For example, X-ray examination can help identify abnormal masses in the patient’s bones, while MRI contributes to the evaluation of surrounding soft tissues.
In addition to imaging techniques, cytological and biological examinations play a crucial role in diagnosing these tumors. Analyzing tissue samples is linked to examining molecular symptoms, such as mutations in the “KIT” and “PDGFRA” genes, as the presence of these mutations can provide critical indicators of tumor type and its treatment response. For example, the presence of mutations in the “KIT” gene is an indicator of Imatinib’s effectiveness as a first-line treatment, helping to guide appropriate treatment pathways.
Research and Recent Developments in Immunotherapy for Sarcoma Tumors
Research on immunotherapy for sarcoma tumors has gained increasing attention in recent years. One of the new aspects is targeting immune checkpoints, such as “PD-1” and “PD-L1,” which play an important role in inhibiting the immune response against cancer cells. Various studies show that using inhibitors of these checkpoints may help restore the activity of exhausted T cells and improve immune defense against tumors.
Immunotherapies are particularly effective in cases of advanced sarcoma tumors, where they can lead to long-term responses in patients who do not respond to traditional treatments. For example, recent studies have shown that combining “PD-1” inhibitors with treatments like “Imatinib” may significantly improve patient outcomes, highlighting the importance of combination therapy strategies.
Future Challenges in Managing Sarcoma Tumors
Despite significant advances in understanding and treating sarcoma tumors, there are still ongoing challenges. Among these challenges is the development of drug resistance, where the tumor may lose its response to treatment over time. Ongoing research aims to understand the molecular mechanisms behind this resistance, contributing to the development of new strategies to prevent negative drug turnover. Additionally, a better understanding of the role of the tumor microenvironment, including immune cells, is essential for achieving effective targeted therapies.
Sustainable management of sarcoma tumors also requires collaboration among various medical specialties, including oncologists, immunotherapy specialists, and radiologists, to create comprehensive treatment protocols tailored to different cases. Research indicates that personalized treatment plans that consider the patient’s genetic characteristics can contribute to improving the overall success rate of treatment.
Link
The source: https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2024.1431535/full
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