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CD19-directed immunotherapies are clinically effective for treating B cell malignancies but also cause a high incidence of neurotoxicity. A subset of patients treated with chimeric antigen receptor (CAR) T cells or bispecific T cell engager (BiTE) antibodies display severe neurotoxicity, including fatal cerebral edema associated with T cell infiltration into the brain. Here, we report that mural cells, which surround the endothelium and are critical for blood-brain-barrier integrity, express CD19. We identify CD19 expression in brain mural cells using single-cell RNA sequencing data and confirm perivascular staining at the protein level. CD19 expression in the brain begins early in development alongside the emergence of mural cell lineages and persists throughout adulthood across brain regions. Mouse mural cells demonstrate lower levels of Cd19 expression, suggesting limitations in preclinical animal models of neurotoxicity. These data suggest an on-target mechanism for neurotoxicity in CD19-directed therapies and highlight the utility of human single-cell atlases for designing immunotherapies.
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Barreira Hematoencefálica/metabolismo , Células Epiteliais/metabolismo , Imunoterapia Adotiva/efeitos adversos , Animais , Anticorpos Biespecíficos/imunologia , Antígenos CD19/imunologia , Linfócitos B/imunologia , Barreira Hematoencefálica/imunologia , Encéfalo/imunologia , Encéfalo/metabolismo , Linhagem Celular Tumoral , Citotoxicidade Imunológica , Humanos , Imunoterapia/efeitos adversos , Imunoterapia/métodos , Imunoterapia Adotiva/métodos , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Músculo Liso Vascular/metabolismo , Neoplasias , Receptores de Antígenos de Linfócitos T/imunologia , Receptores de Antígenos Quiméricos/imunologia , Análise de Célula Única/métodos , Linfócitos T/imunologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The immune system is a well-known vital regulator of tumor growth, and one of the main hallmarks of cancer is evading the immune system. Immune system deregulation can lead to immune surveillance evasion, sustained cancer growth, proliferation, and metastasis. Tumor-mediated disruption of the immune system is accomplished by different mechanisms that involve extensive crosstalk with the immediate microenvironment, which includes endothelial cells, immune cells, and stromal cells, to create a favorable tumor niche that facilitates the development of cancer. The essential role of non-coding RNAs such as microRNAs (miRNAs) in the mechanism of cancer cell immune evasion has been highlighted in recent studies. miRNAs are small non-coding RNAs that regulate a wide range of post-transcriptional gene expression in a cell. Recent studies have focused on the function that miRNAs play in controlling the expression of target proteins linked to immune modulation. Studies show that miRNAs modulate the immune response in cancers by regulating the expression of different immune-modulatory molecules associated with immune effector cells, such as macrophages, dendritic cells, B-cells, and natural killer cells, as well as those present in tumor cells and the tumor microenvironment. This review explores the relationship between miRNAs, their altered patterns of expression in tumors, immune modulation, and the functional control of a wide range of immune cells, thereby offering detailed insights on the crosstalk of tumor-immune cells and their use as prognostic markers or therapeutic agents.
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MicroRNAs , Neoplasias , Células Endoteliais/metabolismo , Humanos , Macrófagos/patologia , MicroRNAs/genética , MicroRNAs/metabolismo , Neoplasias/patologia , Microambiente Tumoral/genéticaRESUMO
BACKGROUND: Skeletal muscle mitochondrial oxidative phosphorylation (mtOXPHOS) is important for ATP generation and its dysfunction leads to exercise intolerance. Phosphorus magnetic resonance spectroscopy (31P-MRS) is a useful, noninvasive technique for mtOXPHOS assessment but has limitations. Creatine-weighted chemical exchange saturation transfer (CrCEST) MRI is a potential alternative to assess muscle bioenergetics. PURPOSE: To evaluate the interscan repeatability, intra- and interobserver reproducibility of CrCEST during mild plantar flexion exercise. STUDY TYPE: Retrospective. SUBJECTS: Twenty healthy volunteers (age 37.6 ± 12.4 years, 11 females). FIELD STRENGTH/SEQUENCE: 3 T/CEST imaging using gradient echo readout. ASSESSMENT: τCrCEST (postexercise Cr recovery time) was assessed in two scans for each participant, following mild plantar flexion exercises targeting the medial gastrocnemius (MG), lateral gastrocnemius (LG), and soleus (Sol) muscles. Three observers measured τCrCEST for interobserver reproducibility. Three readings by one observer were used to measure intraobserver reproducibility. Two scans were used for within-participant interscan repeatability. STATISTICAL TESTS: Paired t tests, intraclass correlation coefficient (ICC), and Pearson correlation were conducted. Bland-Altman plots were used to analyze the interobserver variability. A P-value of 0.05 was considered statistically significant. RESULTS: There was excellent intra- (ICC ∈ 0.94 - 0.98 $$ \in \left[0.94-0.98\right] $$ ) and interobserver (ICC ∈ 0.9 - 0.98 $$ \in \left[0.9-0.98\right] $$ ) reproducibility, with moderate interscan repeatability for τCrCEST in LG and MG (ICC ∈ 0.54 - 0.74 $$ \in \left[0.54-0.74\right] $$ ) and poor-to-moderate interscan repeatability in Sol (ICC ∈ 0.24 - 0.53 $$ \in \left[0.24-0.53\right] $$ ). Excellent interobserver reproducibility was confirmed by Bland-Altman plots (fixed bias P-value ∈ 0.08 - 0.87 $$ \in \left[0.08-0.87\right] $$ ). DATA CONCLUSION: CrCEST MRI shows promise in assessing muscle bioenergetics by evaluating τCrCEST during mild plantar flexion exercise with reasonable reliability, particularly in LG and MG. LEVEL OF EVIDENCE: 4 TECHNICAL EFFICACY: Stage 1.
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Traditional cancer treatments use nonspecific drugs and monoclonal antibodies to target tumor cells. Chimeric antigen receptor (CAR)-T cell therapy, however, leverages the immune system's T-cells to recognize and attack tumor cells. T-cells are isolated from patients and modified to target tumor-associated antigens. CAR-T therapy has achieved FDA approval for treating blood cancers like B-cell acute lymphoblastic leukemia, large B-cell lymphoma, and multiple myeloma by targeting CD-19 and B-cell maturation antigens. Bi-specific chimeric antigen receptors may contribute to mitigating tumor antigen escape, but their efficacy could be limited in cases where certain tumor cells do not express the targeted antigens. Despite success in blood cancers, CAR-T technology faces challenges in solid tumors, including lack of reliable tumor-associated antigens, hypoxic cores, immunosuppressive tumor environments, enhanced reactive oxygen species, and decreased T-cell infiltration. To overcome these challenges, current research aims to identify reliable tumor-associated antigens and develop cost-effective, tumor microenvironment-specific CAR-T cells. This review covers the evolution of CAR-T therapy against various tumors, including hematological and solid tumors, highlights challenges faced by CAR-T cell therapy, and suggests strategies to overcome these obstacles, such as utilizing single-cell RNA sequencing and artificial intelligence to optimize clinical-grade CAR-T cells.
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Neoplasias Hematológicas , Mieloma Múltiplo , Neoplasias , Receptores de Antígenos Quiméricos , Humanos , Inteligência Artificial , Neoplasias/terapia , Imunoterapia Adotiva , Antígenos de Neoplasias , Microambiente Tumoral , Terapia Baseada em Transplante de Células e TecidosRESUMO
Autism spectrum disorder (ASD) is a neurodevelopmental impairment characterized by deficits in social interaction skills, impaired communication, and repetitive and restricted behaviors that are thought to be due to altered neurotransmission processes. The amino acid glutamate is an essential excitatory neurotransmitter in the human brain that regulates cognitive functions such as learning and memory, which are usually impaired in ASD. Over the last several years, increasing evidence from genetics, neuroimaging, protein expression, and animal model studies supporting the notion of altered glutamate metabolism has heightened the interest in evaluating glutamatergic dysfunction in ASD. Numerous pharmacological, behavioral, and imaging studies have demonstrated the imbalance in excitatory and inhibitory neurotransmitters, thus revealing the involvement of the glutamatergic system in ASD pathology. Here, we review the effects of genetic alterations on glutamate and its receptors in ASD and the role of non-invasive imaging modalities in detecting these changes. We also highlight the potential therapeutic targets associated with impaired glutamatergic pathways.
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Transtorno do Espectro Autista , Animais , Transtorno do Espectro Autista/metabolismo , Encéfalo/metabolismo , Modelos Animais de Doenças , Ácido Glutâmico/metabolismo , Transmissão SinápticaRESUMO
In the technique presented here, dubbed 'qMRS', we quantify the change in 1H MRS signal following administration of 2H-labeled glucose. As in recent human DMRS studies, we administer [6,6'-2H2]-glucose orally to healthy subjects. Since 2H is not detectable by 1H MRS, the transfer of the 2H label from glucose to a downstream metabolite leads to a reduction in the corresponding 1H MRS resonance of the metabolite, even if the total concentration of both isoforms remains constant. Moreover, introduction of the deuterium label alters the splitting pattern of the proton resonances, making indirect detection of the deuterated forms- as well as the direct detection of the decrease in unlabeled form- possible even without a 2H coil. Because qMRS requires only standard 1H MRS acquisition methods, it can be performed using commonly implemented single voxel spectroscopy (SVS) and chemical shift imaging (CSI) sequences. In this work, we implement qMRS in semi-LASER based CSI, generating dynamic maps arising from the fitted spectra, and demonstrating the feasibility of using qMRS and qCSI to monitor dynamic metabolism in the human brain using a 7T scanner with no auxiliary hardware.
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Glucose , Imageamento por Ressonância Magnética , Deutério , Glucose/metabolismo , Humanos , Imageamento por Ressonância Magnética/métodos , Espectroscopia de Ressonância Magnética/métodos , Espectroscopia de Prótons por Ressonância MagnéticaRESUMO
BACKGROUND: Pantothenate kinase (PANK) is the first and rate-controlling enzymatic step in the only pathway for cellular coenzyme A (CoA) biosynthesis. PANK-associated neurodegeneration (PKAN), formerly known as Hallervorden-Spatz disease, is a rare, life-threatening neurologic disorder that affects the CNS and arises from mutations in the human PANK2 gene. Pantazines, a class of small molecules containing the pantazine moiety, yield promising therapeutic effects in an animal model of brain CoA deficiency. A reliable technique to identify the neurometabolic effects of PANK dysfunction and to monitor therapeutic responses is needed. METHODS: We applied 1H magnetic resonance spectroscopy as a noninvasive technique to evaluate the therapeutic effects of the newly developed Pantazine BBP-671. RESULTS: 1H MRS reliably quantified changes in cerebral metabolites, including glutamate/glutamine, lactate, and N-acetyl aspartate in a neuronal Pank1 and Pank2 double-knockout (SynCre+ Pank1,2 dKO) mouse model of brain CoA deficiency. The neuronal SynCre+ Pank1,2 dKO mice had distinct decreases in Glx/tCr, NAA/tCr, and lactate/tCr ratios compared to the wildtype matched control mice that increased in response to BBP-671 treatment. CONCLUSIONS: BBP-671 treatment completely restored glutamate/glutamine levels in the brains of the mouse model, suggesting that these metabolites are promising clinically translatable biomarkers for future therapeutic trials.
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Coenzima A , Neurodegeneração Associada a Pantotenato-Quinase , Animais , Encéfalo/patologia , Coenzima A/metabolismo , Modelos Animais de Doenças , Camundongos , Neurodegeneração Associada a Pantotenato-Quinase/genética , Neurodegeneração Associada a Pantotenato-Quinase/patologia , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Espectroscopia de Prótons por Ressonância MagnéticaRESUMO
Gene editing has great potential in treating diseases caused by well-characterized molecular alterations. The introduction of clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9)-based gene-editing tools has substantially improved the precision and efficiency of gene editing. The CRISPR/Cas9 system offers several advantages over the existing gene-editing approaches, such as its ability to target practically any genomic sequence, enabling the rapid development and deployment of novel CRISPR-mediated knock-out/knock-in methods. CRISPR/Cas9 has been widely used to develop cancer models, validate essential genes as druggable targets, study drug-resistance mechanisms, explore gene non-coding areas, and develop biomarkers. CRISPR gene editing can create more-effective chimeric antigen receptor (CAR)-T cells that are durable, cost-effective, and more readily available. However, further research is needed to define the CRISPR/Cas9 system's pros and cons, establish best practices, and determine social and ethical implications. This review summarizes recent CRISPR/Cas9 developments, particularly in cancer research and immunotherapy, and the potential of CRISPR/Cas9-based screening in developing cancer precision medicine and engineering models for targeted cancer therapy, highlighting the existing challenges and future directions. Lastly, we highlight the role of artificial intelligence in refining the CRISPR system's on-target and off-target effects, a critical factor for the broader application in cancer therapeutics.
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Sistemas CRISPR-Cas , Neoplasias , Humanos , Sistemas CRISPR-Cas/genética , Inteligência Artificial , Edição de Genes/métodos , Imunoterapia , Neoplasias/genética , Neoplasias/terapiaRESUMO
Esophageal cancer (EC) is a disease often marked by aggressive growth and poor prognosis. Lack of targeted therapies, resistance to chemoradiation therapy, and distant metastases among patients with advanced disease account for the high mortality rate. The tumor microenvironment (TME) contains several cell types, including fibroblasts, immune cells, adipocytes, stromal proteins, and growth factors, which play a significant role in supporting the growth and aggressive behavior of cancer cells. The complex and dynamic interactions of the secreted cytokines, chemokines, growth factors, and their receptors mediate chronic inflammation and immunosuppressive TME favoring tumor progression, metastasis, and decreased response to therapy. The molecular changes in the TME are used as biological markers for diagnosis, prognosis, and response to treatment in patients. This review highlighted the novel insights into the understanding and functional impact of deregulated cytokines and chemokines in imparting aggressive EC, stressing the nature and therapeutic consequences of the cytokine-chemokine network. We also discuss cytokine-chemokine oncogenic potential by contributing to the Epithelial-Mesenchymal Transition (EMT), angiogenesis, immunosuppression, metastatic niche, and therapeutic resistance development. In addition, it discusses the wide range of changes and intracellular signaling pathways that occur in the TME. Overall, this is a relatively unexplored field that could provide crucial insights into tumor immunology and encourage the effective application of modulatory cytokine-chemokine therapy to EC.
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Quimiocinas/genética , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/patologia , Terapia de Alvo Molecular , Animais , Quimiocinas/metabolismo , Transição Epitelial-Mesenquimal/genética , Humanos , Metástase Neoplásica , Microambiente Tumoral/genéticaRESUMO
Immunotherapy is an efficient way to cure cancer by modulating the patient's immune response. However, the immunotherapy response is heterogeneous and varies between individual patients and cancer subtypes, reinforcing the need for early benefit predictors. Evaluating the infiltration of immune cells in the tumor and changes in cell-intrinsic tumor characteristics provide potential response markers to treatment. However, this approach requires invasive sampling and may not be suitable for real-time monitoring of treatment response. The recent emergence of quantitative imaging biomarkers provides promising opportunities. In vivo imaging technologies that interrogate T cell responses, metabolic activities, and immune microenvironment could offer a powerful tool to monitor the cancer response to immunotherapy. Advances in imaging techniques to identify tumors' immunological characteristics can help stratify patients who are more likely to respond to immunotherapy. This review discusses the metabolic events that occur during T cell activation and differentiation, anti-cancer immunotherapy-induced T cell responses, focusing on non-invasive imaging techniques to monitor T cell metabolism in the search for novel biomarkers of response to cancer immunotherapy.
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Imunoterapia , Neoplasias , Biomarcadores , Biomarcadores Tumorais , Humanos , Fatores Imunológicos , Neoplasias/terapia , Linfócitos T , Microambiente TumoralRESUMO
PURPOSE: Reliable monitoring of tissue nicotinamide adenine dinucleotide (NAD+ ) concentration may provide insights on its roles in normal and pathological aging. In the present study, we report a 1 H MRS pulse sequence for the in vivo, localized 1 H MRS detection of NAD+ from the human brain. METHODS: Studies were carried out on a 7T Siemens MRI scanner using a 32-channel product volume coil. The pulse sequence consisted of a spectrally selective low bandwidth E-BURP-1 90° pulse. PRESS localization was achieved using optimized Shinnar-Le Roux 180° pulses and overlapping gradients were used to minimize the TE. The reproducibility of NAD+ quantification was measured in 11 healthy volunteers. The association of cerebral NAD+ with age was assessed in 16 healthy subjects 26-78 years old. RESULTS: Spectra acquired from a voxel placed in subjects' occipital lobe consisted of downfield peaks from the H2 , H4 , and H6 protons of the nicotinamide moiety of NAD+ between 8.9-9.35 ppm. The mean ± SD within-session and between-session coefficients of variation were found to be 6.14 ± 2.03% and 6.09 ± 3.20%, respectively. In healthy volunteers, an age-dependent decline of the NAD+ levels in the brain was also observed (ß = -1.24 µM/y, SE = 0.21, P < 0.001). CONCLUSION: We demonstrated the feasibility and robustness of a newly developed 1 H MRS technique to measure localized cerebral NAD+ at 7T MRI using a commercially available RF head coil. This technique may be further applied to detect and quantify NAD+ from different regions of the brain as well as from other tissues.
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Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Imageamento por Ressonância Magnética , Espectroscopia de Ressonância Magnética , NAD/química , Adulto , Fatores Etários , Idoso , Algoritmos , Líquido Cefalorraquidiano/diagnóstico por imagem , Feminino , Lobo Frontal/diagnóstico por imagem , Substância Cinzenta/diagnóstico por imagem , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Lobo Occipital/diagnóstico por imagem , Prótons , Reprodutibilidade dos Testes , Substância Branca/diagnóstico por imagemRESUMO
Noninvasive imaging of functional and molecular changes in cancer has become an indispensable tool for studying cancer in vivo. Targeting the functional and molecular changes in cancer imaging provides a platform for the in vivo analysis of the mechanisms such as gene expression, signal transduction, biochemical reactions, regulatory pathways, cell trafficking, and drug action underlying cancer noninvasively. The main focus of imaging in cancer is the development of new contrast methods/molecular probes for the early diagnosis and the precise evaluation of therapy response. In clinical setup, imaging modalities facilitate screening, prediction, staging, biopsy and therapy guidance, therapy response, therapy planning, and prognosis of cancer. In this book chapter, we review different established and emerging in vivo imaging modalities and their applications in monitoring functional, molecular, and metabolic changes in cancer.
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Neoplasias/diagnóstico por imagem , Meios de Contraste , Detecção Precoce de Câncer , Humanos , Sondas MolecularesRESUMO
Post-traumatic stress disorder (PTSD) is a highly disabling condition, increasingly recognized as both a disorder of mental health and social burden, but also as an anxiety disorder characterized by fear, stress, and negative alterations in mood. PTSD is associated with structural, metabolic, and molecular changes in several brain regions and the neural circuitry. Brain areas implicated in the traumatic stress response include the amygdala, hippocampus, and prefrontal cortex, which play an essential role in memory function. Abnormalities in these brain areas are hypothesized to underlie symptoms of PTSD and other stress-related psychiatric disorders. Conventional methods of studying PTSD have proven to be insufficient for diagnosis, measurement of treatment efficacy, and monitoring disease progression, and currently, there is no diagnostic biomarker available for PTSD. A deep understanding of cutting-edge neuroimaging genetic approaches is necessary for the development of novel therapeutics and biomarkers to better diagnose and treat the disorder. A current goal is to understand the gene pathways that are associated with PTSD, and how those genes act on the fear/stress circuitry to mediate risk vs. resilience for PTSD. This review article explains the rationale and practical utility of neuroimaging genetics in PTSD and how the resulting information can aid the diagnosis and clinical management of patients with PTSD.
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Redes Reguladoras de Genes , Marcadores Genéticos , Estudo de Associação Genômica Ampla , Neuroimagem/métodos , Transtornos de Estresse Pós-Traumáticos/patologia , Animais , Humanos , Transtornos de Estresse Pós-Traumáticos/diagnóstico por imagem , Transtornos de Estresse Pós-Traumáticos/genéticaRESUMO
Claudins, a group of membrane proteins involved in the formation of tight junctions, are mainly found in endothelial or epithelial cells. These proteins have attracted much attention in recent years and have been implicated and studied in a multitude of diseases. Claudins not only regulate paracellular transepithelial/transendothelial transport but are also critical for cell growth and differentiation. Not only tissue-specific but the differential expression in malignant tumors is also the focus of claudin-related research. In addition to up- or down-regulation, claudin proteins also undergo delocalization, which plays a vital role in tumor invasion and aggressiveness. Claudin (CLDN)-1 is the most-studied claudin in cancers and to date, its role as either a tumor promoter or suppressor (or both) is not established. In some cancers, lower expression of CLDN-1 is shown to be associated with cancer progression and invasion, while in others, loss of CLDN-1 improves the patient survival. Another topic of discussion regarding the significance of CLDN-1 is its localization (nuclear or cytoplasmic vs perijunctional) in diseased states. This article reviews the evidence regarding CLDN-1 in cancers either as a tumor promoter or suppressor from the literature and we also review the literature regarding the pattern of CLDN-1 distribution in different cancers, focusing on whether this localization is associated with tumor aggressiveness. Furthermore, we utilized expression data from The Cancer Genome Atlas (TCGA) to investigate the association between CLDN-1 expression and overall survival (OS) in different cancer types. We also used TCGA data to compare CLDN-1 expression in normal and tumor tissues. Additionally, a pathway interaction analysis was performed to investigate the interaction of CLDN-1 with other proteins and as a future therapeutic target.
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Carcinogênese/genética , Claudina-1/genética , Células Epiteliais/metabolismo , Neoplasias/genética , Junções Íntimas/genética , Proteínas Supressoras de Tumor/genética , Proliferação de Células/genética , Claudina-1/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias/metabolismo , Análise de Sobrevida , Junções Íntimas/metabolismo , Proteínas Supressoras de Tumor/metabolismoRESUMO
The current study aims to evaluate the feasibility of creatine (Cr) chemical exchange saturation transfer (CEST)-weighted MRI at 7 T in the human brain by optimizing the saturation pulse parameters and computing contrast using a Z-spectral fitting approach. The Cr-weighted (Cr-w) CEST contrast was computed from phantoms data. Simulations were carried out to obtain the optimum saturation parameters for Cr-w CEST with lower contribution from other brain metabolites. CEST-w images were acquired from the brains of four human subjects at different saturation parameters. The Cr-w CEST contrast was computed using both asymmetry analysis and Z-spectra fitting approaches (models 1 and 2, respectively) based on Lorentzian functions. For broad magnetization transfer (MT) effect, Gaussian and Super-Lorentzian line shapes were also evaluated. In the phantom study, the Cr-w CEST contrast showed a linear dependence on concentration in physiological range and a nonlinear dependence on saturation parameters. The in vivo Cr-w CEST map generated using asymmetry analysis from the brain represents mixed contrast with contribution from other metabolites as well and relayed nuclear Overhauser effect (rNOE). Simulations provided an estimate for the optimum range of saturation parameters to be used for acquiring brain CEST data. The optimum saturation parameters for Cr-w CEST to be used for brain data were around B1rms = 1.45 µT and duration = 2 seconds. The Z-spectral fitting approach enabled computation of individual components. This also resulted in mitigating the contribution from MT and rNOE to Cr-w CEST contrast, which is a major source of underestimation in asymmetry analysis. The proposed modified z-spectra fitting approach (model 2) is more stable to noise compared with model 1. Cr-w CEST contrast obtained using fitting was 6.98 ± 0.31% in gray matter and 5.45 ± 0.16% in white matter. Optimal saturation parameters reduced the contribution from other CEST effects to Cr-w CEST contrast, and the proposed Z-spectral fitting approach enabled computation of individual components in Z-spectra of the brain. Therefore, it is feasible to compute Cr-w CEST contrast with a lower contribution from other CEST and rNOE.
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Encéfalo/diagnóstico por imagem , Creatina/metabolismo , Imageamento por Ressonância Magnética , Adulto , Simulação por Computador , Estudos de Viabilidade , Substância Cinzenta/diagnóstico por imagem , Humanos , Método de Monte Carlo , Adulto JovemRESUMO
While many decades of scientific research studies have gone into harnessing the power of the immune system to fight cancer, only recently have cancer immunotherapeutic approaches begun to show robust clinical responses in patients with a variety of cancers. These treatments are adding to the current arsenal of cancer treatments; surgery, radiation and chemotherapy, and increasing the therapeutic options for cancer patients. Despite these advances, issues associated with these therapies include that not all patients respond to these therapies, and some patients who respond experience varying degrees of toxicities. One of the major issues affecting immunotherapy is the inability to evaluate trafficking of activated T-cells into sites of tumor. The current diagnostic imaging based on conventional anatomic imaging, which is the mainstay to monitor response to cytotoxic chemotherapy or radiation, is not adequate to assess initial response to immunotherapy or disease evolution. Patients' prognosis by histological analysis has limited use in regards to immunotherapy. Thus, there is a crucial need for noninvasive biomarkers for screening patients that show long term response to therapy. Here, we provide a brief account of emerging molecular magnetic resonance imaging biomarkers that have potential to exploit the metabolism and metabolic products of activated T cells.
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Biomarcadores/metabolismo , Terapia Baseada em Transplante de Células e Tecidos , Imunoterapia , Imagem Molecular/métodos , Humanos , Metaboloma , Neoplasias/imunologia , Neoplasias/terapia , Linfócitos T/metabolismoRESUMO
BACKGROUND: Image contrast enhanced by exogenous contrast agents plays a crucial role in the early detection, characterization, and determination of the precise location of cancers. Here, we investigate the feasibility of using a non-nutritive sweetener, sucralose (commercial name, Splenda), as magnetic resonance imaging (MRI) contrast agent for cancer studies. METHODS: High-resolution nuclear-magnetic-resonance spectroscopy and MR studies on sucralose solution phantom were performed to detect the chemical exchange saturation transfer (CEST) property of sucralose hydroxyl protons with bulk water (sucCEST). For the animal experiments, female Fisher rats (F344/NCR) were used to generate 9L-gliosarcoma model. MRI with CEST experiments were performed on anesthetized rats at 9.4 T MR scanner. Following the baseline CEST scans, sucralose solution was intravenously administered in control and tumor bearing rats. CEST acquisitions were continued during and following the administration of sucralose. Following the sucCEST, Gadolinium-diethylenetriamine pentaacetic acid was injected to perform Gd-enhanced imaging for visualizing the tumor. RESULTS: The sucCEST contrast in vitro was found to correlate positively with the sucralose concentration and negatively with the pH, indicating the potential of this technique in cancer imaging. In a control animal, the CEST contrast from the brain was found to be unaffected following the administration of sucralose, demonstrating its blood-brain barrier impermeability. In a 9L glioma model, enhanced localized sucCEST contrast in the tumor region was detected while the unaffected brain region showed unaltered CEST effect implying the specificity of sucralose toward the tumorous tissue. The CEST asymmetry plots acquired from the tumor region before and after the sucralose infusion showed elevation of asymmetry at 1 ppm, pointing towards the role of sucralose in increased contrast. CONCLUSIONS: We show the feasibility of using sucralose and sucCEST in study of preclinical models of cancer. This study paves the way for the potential development of sucralose and other sucrose derivatives as contrast agents for clinical MRI applications.
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Meios de Contraste/química , Imageamento por Ressonância Magnética/métodos , Neoplasias/diagnóstico por imagem , Adoçantes não Calóricos/química , Animais , Barreira Hematoencefálica/patologia , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Feminino , Gadolínio DTPA/química , Glioma/diagnóstico por imagem , Glioma/patologia , Humanos , Concentração de Íons de Hidrogênio , Imagem Molecular , Imagens de Fantasmas , Ratos , Ratos Endogâmicos F344RESUMO
PURPOSE: To develop a new faster and higher quality three-dimensional (3D) gagCEST MRI technique for reliable quantification of glycosaminoglycan (GAG) present in the human knee cartilages. METHODS: A new magnetization-prepared 3D gradient echo-based MRI pulse sequence has been designed to obtain the B0 inhomogeneity, B1 inhomogeneity, and CEST Z-spectra images. RESULTS: The gagCEST values of different compartments of knee cartilage are calculated using a newly developed technique for healthy subjects and a symptomatic knee cartilage degenerated subject. The effect of the acquired CEST saturation frequency offset step-size was investigated to establish the optimal step-size to obtain reproducible gagCEST maps. Our novel 3D gagCEST technique demonstrates markedly higher gagCEST contrast value than the previously reported 3D gagCEST studies. This study demonstrates the need for separate B0 and B1 inhomogeneity estimation and correction. CONCLUSION: The new technique provided high quality gagCEST maps with clearer visualization of different layers of knee cartilage with reproducible results. Magn Reson Med 77:1866-1873, 2017. © 2016 International Society for Magnetic Resonance in Medicine.
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Cartilagem Articular/diagnóstico por imagem , Glicosaminoglicanos/química , Articulação do Joelho/diagnóstico por imagem , Joelho/diagnóstico por imagem , Imageamento por Ressonância Magnética/métodos , Adulto , Fatores Etários , Idoso , Animais , Humanos , Processamento de Imagem Assistida por Computador , Imageamento Tridimensional , Articulação do Joelho/patologia , Magnetismo , Masculino , Movimento (Física) , Ratos , Reprodutibilidade dos Testes , Adulto JovemRESUMO
Glutamate chemical exchange saturation transfer (GluCEST) MRI was used to measure metabolic changes in mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) by mapping regional cerebral glutamate. The GluCEST contrast following MPTP treatment was correlated with 1 H-MR spectroscopy, motor function, and immunohistochemical measures. The GluCEST contrast was found to be significantly higher in the striatum and motor cortex of mice treated with MPTP than in controls (p < 0.001), which was confirmed by localized 1 H-MR spectroscopy. Elevated striatal GluCEST was positively associated with local astrogliosis measured by immunohistochemistry for glial fibrillary acidic protein. Additionally, a negative correlation was found between motor function, measured by the four-limb grip strength test, and GluCEST of the striatum (R = -0.705, p < 0.001) and the motor cortex (R = -0.617, p < 0.01), suggesting a role of elevated glutamate in the abnormal cerebral motor function regulation. The GluCEST contrast and glial fibrillary acidic protein immunostaining were unaltered in the thalamus indicating glutamate elevation was localized to the striatum and the motor cortex. These findings suggest that in addition to measuring spatial changes in glutamate, GluCEST may serve as an in vivo biomarker of metabolic and functional changes that may be applied to the assessment of a broad range of neuropathologies. Read the Editorial Highlight for this article on page 346.