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BACKGROUND: With the gradual understanding of glioma development and the immune microenvironment, many immune cells have been discovered. Despite the growing comprehension of immune cell functions and the clinical application of immunotherapy, the precise roles and characteristics of immune cell subtypes, how glioma induces subtype transformation of immune cells and its impact on glioma progression have yet to be understood. AIM OF THE REVIEW: In this review, we comprehensively center on the four major immune cells within the glioma microenvironment, particularly neutrophils, macrophages, lymphocytes, myeloid-derived suppressor cells (MDSCs), and other significant immune cells. We discuss (1) immune cell subtype markers, (2) glioma-induced immune cell subtype transformation, (3) the mechanisms of each subtype influencing chemotherapy resistance, (4) therapies targeting immune cells, and (5) immune cell-associated single-cell sequencing. Eventually, we identified the characteristics of immune cell subtypes in glioma, comprehensively summarized the exact mechanism of glioma-induced immune cell subtype transformation, and concluded the progress of single-cell sequencing in exploring immune cell subtypes in glioma. KEY SCIENTIFIC CONCEPTS OF REVIEW: In conclusion, we have analyzed the mechanism of chemotherapy resistance detailly, and have discovered prospective immunotherapy targets, excavating the potential of novel immunotherapies approach that synergistically combines radiotherapy, chemotherapy, and surgery, thereby paving the way for improved immunotherapeutic strategies against glioma and enhanced patient outcomes.
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Glioblastoma (GBM) presents a daunting challenge due to its resistance to temozolomide (TMZ), a hurdle exacerbated by the proneural-to-mesenchymal transition (PMT) from a proneural (PN) to a mesenchymal (MES) phenotype. TAGLN2 is prominently expressed in GBM, particularly in the MES subtype compared to low-grade glioma (LGG) and the PN subtype. Our research reveals TAGLN2's involvement in PMT and TMZ resistance through a series of in vitro and in vivo experiments. TAGLN2 knockdown can restrain proliferation and invasion, trigger DNA damage and apoptosis, and heighten TMZ sensitivity in GBM cells. Conversely, elevating TAGLN2 levels amplifies resistance to TMZ in cellular and intracranial xenograft mouse models. We demonstrate the interaction relationship between TAGLN2 and ERK1/2 through co-immunoprecipitation (Co-IP) and liquid chromatography-tandem mass spectrometry (LC-MS/MS) spectrometry analysis. Knockdown of TAGLN2 results in a decrease in the expression of p-ERK1/2, whereas overexpression of TAGLN2 leads to an increase in p-ERK1/2 expression within the nucleus. Subsequently, the regulatory role of TAGLN2 in the expression and control of MGMT has been demonstrated. Finally, the regulation of TAGLN2 by NF-κB has been validated through chromatin immunoprecipitation and ChIP-PCR assays. In conclusion, our results confirm that TAGLN2 exerts its biological functions by interacting with the ERK/MGMT axis and being regulated by NF-κB, thereby facilitating the acquisition of promoting PMT and increased resistance to TMZ therapy in glioblastoma. These results provide valuable insights for the advancement of targeted therapeutic approaches to overcome TMZ resistance in clinical treatments.
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Antineoplásicos Alquilantes , Neoplasias Encefálicas , Resistencia a Antineoplásicos , Glioblastoma , Temozolomida , Temozolomida/farmacología , Humanos , Glioblastoma/patología , Glioblastoma/genética , Glioblastoma/tratamiento farmacológico , Glioblastoma/metabolismo , Animales , Línea Celular Tumoral , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/metabolismo , Ratones , Antineoplásicos Alquilantes/farmacología , Proliferación Celular/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto , Apoptosis/efectos de los fármacos , Proteínas de Microfilamentos/genética , Proteínas de Microfilamentos/metabolismo , Transición Epitelial-Mesenquimal/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Ratones Desnudos , Proteínas Supresoras de Tumor/genética , Proteínas Supresoras de Tumor/metabolismo , Enzimas Reparadoras del ADN/genética , Enzimas Reparadoras del ADN/metabolismo , Metilasas de Modificación del ADN/metabolismo , Metilasas de Modificación del ADN/genéticaRESUMEN
BACKGROUND: In this era of rapid technological development, medical schools have had to use modern technology to enhance traditional teaching. Online teaching was preferred by many medical schools. However due to the complexity of intracranial anatomy, it was challenging for the students to study this part online, and the students were likely to be tired of neurosurgery, which is disadvantageous to the development of neurosurgery. Therefore, we developed this database to help students learn better neuroanatomy. MAIN BODY: The data were sourced from Rhoton's Cranial Anatomy and Surgical Approaches and Neurosurgery Tricks of the Trade in this database. Then we designed many hand gesture figures connected with the atlas of anatomy. Our database was divided into three parts: intracranial arteries, intracranial veins, and neurosurgery approaches. Each section below contains an atlas of anatomy, and gestures represent vessels and nerves. Pictures of hand gestures and atlas of anatomy are available to view on GRAVEN ( www.graven.cn ) without restrictions for all teachers and students. We recruited 50 undergraduate students and randomly divided them into two groups: using traditional teaching methods or GRAVEN database combined with above traditional teaching methods. Results revealed a significant improvement in academic performance in using GRAVEN database combined with traditional teaching methods compared to the traditional teaching methods. CONCLUSION: This database was vital to help students learn about intracranial anatomy and neurosurgical approaches. Gesture teaching can effectively simulate the relationship between human organs and tissues through the flexibility of hands and fingers, improving anatomy interest and education.
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Bases de Datos Factuales , Educación de Pregrado en Medicina , Gestos , Neurocirugia , Humanos , Neurocirugia/educación , Educación de Pregrado en Medicina/métodos , Estudiantes de Medicina , Neuroanatomía/educación , Enseñanza , Femenino , MasculinoRESUMEN
INTRODUCTION: Empathy is considered the ability to understand or feel others emotions or experiences. As an important part of medical education, empathy can affect medical students in many ways. It is still lacking a comprehensive evaluation of the existing articles on empathy's impact on medical students, despite the existence of many articles on the topic. OBJECTIVES: To summarize the impact of empathy on medical students during medical education from four perspectives: mental health, academic performance, clinical competence, and specialty preference. METHODS: The search terms used for retrieval were "empathy", "medical student", "mental health", "depression", "anxiety", "burnout", "examinations", "academic performance", "clinical competence", "specialty preference" on PubMed, EBSCO, and Web of Science before January 2024. The search was carried out by two reviewers. Titles and abstracts were screened independently and reviewed based on inclusion/exclusion criteria. A consensus was drawn on which articles were included. RESULTS: Our results indicated that high empathy was a positive factor for mental health, However, students with high affective empathy were more likely to suffer from depression, anxiety, and burnout. Empathy was found to be unrelated to academic performance, but positively correlated with clinical competence, particularly in terms of communication skills. Medical students with high levels of empathy tended to prefer people-oriented majors. CONCLUSIONS: Medical students who score higher on the self-reported empathy scales often have better mental health, better communication skills, and tend to choose people-oriented specialties. But empathy is not related to academic performance. Additionally, the different dimensions of empathy have different impacts on medical students. It is necessary to design targeted courses and training for medical students to enhance their empathy.
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Competencia Clínica , Empatía , Estudiantes de Medicina , Estudiantes de Medicina/psicología , Humanos , Salud Mental , Rendimiento Académico , Ansiedad , DepresiónRESUMEN
Neurospagioma, arising from different glial cells such as astrocytes, oligodendrocytes, and ependymal cells, stands as the prevalent intracranial tumor within the central nervous system. Among its variants, glioblastoma (GBM) represents the most aggressive form, characterized by a notably high occurrence rate and a discouragingly low survival prognosis. The formidable challenge posed by glioblastoma underscores its critical importance as a life-threatening ailment. Currently, clinical approaches often involve surgical excision along with a combination of radiotherapy and chemotherapy. However, these treatments frequently result in a notable recurrence rate, accompanied by substantial adverse effects that significantly compromise the overall prognosis. Hence, there is a crucial need to investigate novel and dependable treatment strategies. Dendritic cells (DCs), being specialized antigen-presenting cells (APCs), hold a significant position in both innate and adaptive immune responses. Presently, DC vaccines have gained widespread application in the treatment of various tumors, including neurospoagioma. In this review, we summarize the immunomodulatory effects and related mechanisms of DC vaccines in neurospoagioma as well as the progress of clinical trials to propose possible challenges of DC vaccines and new development directions.
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Gliomas are the most prevalent and aggressive brain tumors, exhibiting high proliferation, abnormal glycolysis, and poor prognosis. LncRNAs act as regulatory molecules and play crucial roles in the malignant behaviors of GBM cells, including cell self-renewal. However, the regulatory mechanisms involved are largely unknown. In this study, we performed bioinformatics analysis to explore NF-κB pathway-related lncRNAs. ECAR and qRT-PCR were used to measure the relationship between glycolytic activity and lncRNA expression. Assays such as RIP-PCR and ChIP-PCR were employed to reveal the regulatory mechanisms of the lncRNA. Neurosphere formation and limiting dilution assays were performed to evaluate the self-renewal capacity of GBM cells. In our study, we identified an NF-κB pathway-related lncRNA named LINC01127 in GBM, which was found to be associated with poor progression of GBM. Functionally, the NF-κB pathway promoted warburg effect, which, in turn, induced the lactylation of H3 histone and increased the expression of LINC01127. Consequently, this enhancement of LINC01127 expression led to the promotion of self-renewal in GBM cells. Furthermore, LINC01127 regulated MAP4K4 expression in cis by directly guiding POLR2A to the MAP4K4 promoter regions, thereby leading to JNK pathway activation, and ultimately modulating the self-renewal of GBM cells. Moreover, the activated JNK pathway promoted the phosphorylation of IκBα. Overall, targeting LINC01127-mediated axis impeded orthotopic tumor growth in GBM xenografts. Taken together these results revealed that warburg effect-induced histone lactylation drives NF-κB-related LINC01127 expression, thereby promoting the self-renewal of GBM cells through the MAP4K4/JNK/NF-κB axis, and providing substantial evidence that LINC01127 might provide a novel therapeutic strategy for GBM patients.
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Neoplasias Encefálicas , Glioblastoma , ARN Largo no Codificante , Humanos , Glioblastoma/patología , FN-kappa B/metabolismo , Sistema de Señalización de MAP Quinasas , Histonas/metabolismo , ARN Largo no Codificante/metabolismo , Neoplasias Encefálicas/patología , Línea Celular Tumoral , Células Madre/metabolismo , Regulación Neoplásica de la Expresión Génica , Proliferación Celular , Proteínas Serina-Treonina Quinasas/metabolismo , Péptidos y Proteínas de Señalización Intracelular/metabolismoRESUMEN
BACKGROUND: Glioma is the most common and lethal type of brain tumor, and it is characterized by unfavorable prognosis and high recurrence rates. The reprogramming of energy metabolism and an immunosuppressive tumor microenvironment (TME) are two hallmarks of tumors. Complex and dynamic interactions between neoplastic cells and the surrounding microenvironment can generate an immunosuppressive TME, which can accelerate the malignant progression of glioma. Therefore, it is crucial to explore associations between energy metabolism and the immunosuppressive TME and to identify new biomarkers for glioma prognosis. METHODS: In our work, we analyzed the co-expression relationship between glycolytic genes and immune checkpoints based on the transcriptomic data from The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) and found the correlation between HK3 expression and glioma tumor immune status. To investigate the biological role of HK3 in glioma, we performed bioinformatics analysis and established a mouse glioblastoma (GBM) xenograft model. RESULTS: Our study showed that HK3 significantly stimulated immune cell infiltration into the glioma TME. Tissue samples with higher HK3 expressive level showed increasing levels of immune cells infiltration, including M2 macrophages, neutrophils, and various subtypes of activated memory CD4+ T cells. Furthermore, HK3 expression was significantly increasing along with the elevated tumor grade, had a higher level in the mesenchymal subtype compared with those in other subtypes of GBM and could independently predict poor outcomes of GBM patients. CONCLUSION: The present work mainly concentrated on the biological role of HK3 in glioma and offered a novel insight of HK3 regulating the activation of immune cells in the glioma microenvironment. These findings could provide a new theoretical evidence for understanding the metabolic molecular within the glioma microenvironment and identifying new therapeutic targets.
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BACKGROUND: N6-methyladenosine (m6A), 5-methylcytosine (m5C) and N1-methyladenosine (m1A) are the main RNA methylation modifications involved in the progression of cancer. However, it is still unclear whether RNA methylation-related long noncoding RNAs (lncRNAs) affect the prognosis of glioma. METHODS: We summarized 32 m6A/m5C/m1A-related genes and downloaded RNA-seq data and clinical information from The Cancer Genome Atlas (TCGA) database. Differential expression analysis and weighted gene co-expression network analysis (WGCNA) were used to identify differentially expressed (DE-) RNA methylation-related lncRNAs in order to construct a prognostic signature of glioma and in order to determine their correlation with immune function, immune therapy and drug sensitivity. In vitro and in vivo assays were performed to elucidate the effects of RNA methylation-related lncRNAs on glioma. RESULTS: A total of ten RNA methylation-related lncRNAs were used to construct a survival and prognosis signature, which had good independent prediction ability for patients. It was found that the high-risk group had worse overall survival (OS) than the low-risk group in all cohorts. In addition, the risk group informed the immune function, immunotherapy response and drug sensitivity of patients with glioma in different subgroups. Knockdown of RP11-98I9.4 and RP11-752G15.8 induced a more invasive phenotype, accelerated cell growth and apparent resistance to temozolomide (TMZ) both in vitro and in vivo. We observed significantly elevated global RNA m5C and m6A levels in glioma cells. CONCLUSION: Our study determined the prognostic implication of RNA methylation-related lncRNAs in gliomas, established an RNA methylation-related lncRNA prognostic model, and elucidated that RP11-98I9.4 and RP11-752G15.8 could suppress glioma proliferation, migration and TMZ resistance. In the future, these RNA methylation-related lncRNAs may become a new choice for immunotherapy of glioma.
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PURPOSE: Glioblastoma (GBM) is a highly vascularized tumor with few treatment options after disease recurrence. Here, we report the efficacy and safety of anlotinib hydrochloride plus temozolomide in patients with recurrent GBM. PATIENTS AND METHODS: Patients with first definite postsurgical progression of histologically confirmed GBM preceded by standard radiotherapy and temozolomide chemotherapy were eligible for inclusion. All patients received temozolomide (150-200 mg/m2, orally, every day (QD) d1-5/4 wk) and anlotinib (10 mg, orally, QD, d1-14/3 wk) until disease progression or unacceptable toxicity. The primary endpoint was investigator-assessed 6-month progression-free survival (PFS) rate by the Response Assessment in Neuro-Oncology (RANO) criteria. RESULTS: Twenty-one patients were enrolled between May 2020 and July 2021, with a median age of 55 (range 27-68) years old. According to the Response Assessment in Neuro-Oncology (RANO) criteria, tumor response occurred in 17 patients, of which 9 patients had a complete response, and the objective response rate was 81.0% [95% confidence interval (CI), 62.6-99.3]. The disease control rate was 95.2% (95% CI, 76.2-99.9), with three additional patients achieving a stable disease without tumor progression. The median PFS was 7.3 months (95% CI, 4.9-9.7), and the 6-month PFS rate was 61.9% (95% CI, 39.3-84.6). The median overall survival was 16.9 months (95% CI, 7.8-26.0). The most common adverse events were leukocytopenia (66.7%), thrombocytopenia (38.1%), and hypertriglyceridemia (38.1%). Five patients had nine grade 3 adverse events, with a 23.8% incidence rate. Two patients discontinued therapy due to ischemic stroke (grade 3) and wound dehiscence (grade 1), respectively. No grade 4 or treatment-related deaths occurred in this study. CONCLUSIONS: Anlotinib combined with temozolomide is efficacious and tolerated in patients with recurrent GBM.
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Neoplasias Encefálicas , Glioblastoma , Humanos , Adulto , Persona de Mediana Edad , Anciano , Temozolomida/efectos adversos , Glioblastoma/patología , Dacarbazina , Neoplasias Encefálicas/patología , Recurrencia Local de Neoplasia/patología , Inhibidores de la Angiogénesis/uso terapéuticoRESUMEN
Background: Glioma is a highly heterogeneous disease, causing the prognostic prediction a challenge. Pyroptosis, a programmed cell death mediated by gasdermin (GSDM), is characterized by cell swelling and the release of inflammatory factors. Pyroptosis occurs in several types of tumor cells, including gliomas. However, the value of pyroptosis-related genes (PRGs) in the prognosis of glioma remains to be further clarified. Methods: In this study, mRNA expression profiles and clinical data of glioma patients were acquired from TCGA and CGGA databases, and one hundred and eighteen PRGs were obtained from the Molecular Signatures Database and GeneCards. Then, consensus clustering analysis was performed to cluster glioma patients. The least absolute shrinkage and selection operator (LASSO) Cox regression model was used to establish a polygenic signature. Functional verification of the pyroptosis-related gene GSDMD was achieved by gene knockdown and western blotting. Moreover, the immune infiltration status between two different risk groups were analyzed through the "gsva" R package. Results: Our results demonstrated that the majority of PRGs (82.2%) were differentially expressed between lower-grade gliomas (LGG) and glioblastoma (GBM) in the TCGA cohort. In univariate Cox regression analysis, eighty-three PRGs were shown to be associated with overall survival (OS). A five-gene signature was constructed to divide patients into two risk groups. Compared with patients in the low-risk group, patients in the high-risk group had obviously shorter OS (p < 0.001). Also, we found that the high-risk group showed a higher infiltrating score of immune cells and immune-related functions. Risk score was an independent predictor of OS (HR > 1, p < 0.001). Furthermore, knockdown of GSDMD decreased the expression of IL-1ß and cleaved caspase-1. Conclusion: Our study constructed a new PRGs signature, which can be used to predict the prognosis of glioma patients. Targeting pyroptosis might serve as a potential therapeutic strategy for glioma.
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BACKGROUND: Personality traits are the basic components of an individual's personality. Although there are many published articles about the impact of personality traits on medical students, there is a lack of integrative reviews of existing articles. To close this gap, this review aims to summarize the impact of personality traits on medical students from two perspectives: life and work. METHODS: The search was performed using the following databases: PubMed, Web of Science, Google Scholar, and EMBASE. All publications that assessed the impact of personality traits on life and work until February 2022 were selected. RESULTS: Ninety-seven studies were included. The results suggest that personality traits could affect life performance, health outcomes, life satisfaction, the formation of doctor-patient relationships, mastery of knowledge, academic performance, and career planning. Different personality traits can have positive or negative impacts on these aspects. CONCLUSIONS: The results of this review suggest that personality traits can affect medical students' lives and work. Therefore, based on the evaluation of the personality traits of medical students, it is necessary to design targeted courses and training for students to improve their personality traits, to bring about better results in their lives and work.
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Estudiantes de Medicina , Humanos , PersonalidadRESUMEN
TTFields is a novel treating modality of glioblastoma (GBM) which can significantly prolong the overall survival (OS) of newly diagnosed or recurrent glioblastoma. Some researchers have revealed that a variety of factors can affect the efficacy of TTFields. So, we review the available literature about the influencing factors on efficacy of TTFields and then choose two experimentally supported factors: the dose of dexamethasone and compliance of TTFields to perform a meta-analysis. The PubMed, Embase, and the Cochrane Library are searched. Five articles are identified between 2014 and 2017. Three articles are about the compliance of TTFields. Two articles are about the dose of dexamethasone. The Newcastle-Ottawa Quality Assessment Scale (NOS) is used as an assessment tool to evaluate the methodological quality of all included trials. The scale's range varies from 0 to 9 stars. According to the Cochrane Handbook for Systematic Reviews of Interventions, articles are graded in six items to evaluate the risk of bias. Two reviewers rate the studies independently and the final decision is reached by consensus.Our data shows that the median OS is conspicuously longer in the TTFields group in which the dose of dexamethasone is ≤ 4.1 mg, WMD = 9.23 [95% CI 5.69-12.78]; P < 0.05). And the patients whose compliance of TTFields treatment ≥ 75% (≥ 18 h per day) have a significant lower overall survival risk than the patients whose compliance of TTFields treatment < 75% (HR = 0.57 [95% CI 0.46-0.70]; P < 0.00001).TTFields is a safe and efficient novel treatment modality. The dose of dexamethasone ≤ 4.1 mg of TTFields treatment and the compliance of TTFields treatment ≥ 75%, ≥ 18 h per day are beneficial to the prognosis of the glioblastoma patients.
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BACKGROUND AIMS: To explore the long-term safety and benefit of umbilical cord mesenchymal stromal cell (MSCs) plus autologous bone marrow mononuclear cell (aBM-MNC) stem cell transplantation (SCT) without immunotherapy in established type 1 diabetes (T1D). METHODS: In the primary completion of this trial (ClinicalTrials.gov identifier: NCT01374854), the authors randomized patients (n = 21 per group) to either SCT or standard care (control) and previously reported effects on insulin secretion. The authors report about the incidence of chronic diabetes complications (primary endpoint) after 8 years of follow-up. The authors also report on secondary endpoints, safety, islet function and metabolic control. RESULTS: Data were obtained from 14 of 21 patients in the SCT group and 15 of 21 patients in the control group who completed follow-up. At 8 years, the incidence of peripheral neuropathy was 7.1% (one of 14) in the SCT group versus 46.7% (seven of 15) in the control group (P = 0.017). The incidence of diabetic nephropathy was 7.1% (one of 14) in the SCT group versus 40.0% (six of 15) in the control group (P = 0.039). The incidence of retinopathy was 7.1% (one of 14) in the SCT group versus 33.3% (five of 15) in the control group (P = 0.081). Two patients (two of 14, 14.3%) in the SCT group and 11 patients (11 of 15, 73.3%) in the control group developed at least one complication (P = 0.001). One and six patients in the SCT group and control group, respectively, had at least two complications (P = 0.039). No malignancies were reported in the treated group. CONCLUSIONS: Co-transplantation of umbilical cord MSCs and aBM-MNCs in patients with established T1D was associated with reduced incidence of chronic diabetes complications.
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Complicaciones de la Diabetes , Diabetes Mellitus Tipo 1 , Enfermedad Injerto contra Huésped , Trasplante de Células Madre Mesenquimatosas , Células Madre Mesenquimatosas , Médula Ósea , Diabetes Mellitus Tipo 1/complicaciones , Diabetes Mellitus Tipo 1/terapia , Estudios de Seguimiento , Humanos , Trasplante de Células Madre Mesenquimatosas/efectos adversos , Proyectos Piloto , Cordón UmbilicalRESUMEN
The Drug Response Gene Expression Associated Map, also referred as "DREAM" ( http://bio-big-data.cn:8080/DREAM ), is a manually curated database of experimentally supported protein-coding RNAs and drugs associations in human cancers. The current version of the DREAM documents 3048 entries about scientific literatures supported drug sensitivity or drug intervention related protein-coding RNAs from PubMed database and 195 high-throughput microarray data about drug sensitivity or drug intervention related protein-coding RNAs data from GEO database. Each entry in DREAM database contains detailed information on protein-coding RNA, drug, cancer, and other information including title, PubMed ID, journal, publish time. The DREAM database also provides some data visualization and online analysis services such as volcano plot, GO/KEGG enrichment function analysis, and novel drug discovery analysis. We hope the DREAM database should serve as a valuable resource for clinical practice and basic research, which could help researchers better understand the effects of protein-coding RNAs on drug response in human cancers.
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Bases de Datos Genéticas , Descubrimiento de Drogas , Regulación de la Expresión Génica/efectos de los fármacos , Sistemas de Lectura Abierta , ARN Mensajero/genética , Descubrimiento de Drogas/métodos , HumanosRESUMEN
Glioblastoma (GBM), the most common malignant primary brain cancer in adults, nearly always becomes resistant to current treatments, including the chemotherapeutic temozolomide (TMZ). The long noncoding RNA (lncRNA) TMZ-associated lncRNA in GBM recurrence (lnc-TALC) promotes GBM resistance to TMZ. Exosomes can release biochemical cargo into the tumor microenvironment (TME) or transfer their contents, including lncRNAs, to other cells as a form of intercellular communication. In this study, we found that lnc-TALC could be incorporated into exosomes and transmitted to tumor-associated macrophages (TAM) and could promote M2 polarization of the microglia. This M2 polarization correlated with secretion of the complement components C5/C5a, which occurred downstream of lnc-TALC binding to ENO1 to promote the phosphorylation of p38 MAPK. In addition, C5 promoted the repair of TMZ-induced DNA damage, leading to chemotherapy resistance, and C5a-targeted immunotherapy showed improved efficacy that limited lnc-TALC-mediated TMZ resistance. Our results reveal that exosome-transmitted lnc-TALC could remodel the GBM microenvironment and reduce tumor sensitivity to TMZ chemotherapy, indicating that the lnc-TALC-mediated cross-talk between GBM cells and microglia could attenuate chemotherapy efficacy and pointing to potential combination therapy strategies to overcome TMZ resistance in GBM.See related Spotlight by Zhao and Xie, p. 1372.
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Complemento C5/genética , Resistencia a Antineoplásicos/efectos de los fármacos , Exosomas/genética , Glioblastoma/tratamiento farmacológico , Glioblastoma/genética , Microglía/metabolismo , ARN Largo no Codificante/genética , Animales , Línea Celular Tumoral , Modelos Animales de Enfermedad , Humanos , Ratones , Transfección , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Accompanying the development of biomedicine, our knowledge of glioma, one of the most common primary intracranial carcinomas, is becoming more comprehensive. Unfortunately, patients with glioblastoma (GBM) still have a dismal prognosis and a high relapse rate, even with standard combination therapy, namely, surgical resection, postoperative radiotherapy and chemotherapy. The absence of validated biomarkers is responsible for the majority of these poor outcomes, and reliable therapeutic targets are indispensable for improving the prognosis of patients suffering from gliomas. Identification of both precise diagnostic and accurate prognostic markers and promising therapeutic targets has therefore attracted considerable attention from researchers. Encouragingly, accumulating evidence has demonstrated that long noncoding RNAs (lncRNAs) play important roles in the pathogenesis and oncogenesis of various categories of human tumors, including gliomas. Nevertheless, the underlying mechanisms by which lncRNAs regulate diverse biological behaviors of glioma cells, such as proliferation, invasion and migration, remain poorly understood. Consequently, this review builds on previous studies to further summarize the progress in the field of lncRNA regulation of gliomas over recent years and addresses the potential of lncRNAs as diagnostic and prognostic markers and therapeutic targets.
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A brain organoid is a self-organizing three-dimensional tissue derived from human embryonic stem cells or pluripotent stem cells and is able to simulate the architecture and functionality of the human brain. Brain organoid generation methods are abundant and continue to improve, and now, an in vivo vascularized brain organoid has been encouragingly reported. The combination of brain organoids with immune-staining and single-cell sequencing technology facilitates our understanding of brain organoids, including the structural organization and the diversity of cell types. Recent publications have reported that brain organoids can mimic the dynamic spatiotemporal process of early brain development, model various human brain disorders, and serve as an effective preclinical platform to test and guide personalized treatment. In this review, we introduce the current state of brain organoid differentiation strategies, summarize current progress and applications in the medical domain, and discuss the challenges and prospects of this promising technology.
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Encéfalo/crecimiento & desarrollo , Organoides/crecimiento & desarrollo , Células Madre Pluripotentes/metabolismo , Diferenciación Celular , Células Madre Embrionarias/metabolismo , HumanosRESUMEN
Introduction: Proneural and mesenchymal subtypes are the most distinct demarcated categories in classification scheme, and there is often a shift from proneural type to mesenchymal subtype in the progression of glioblastoma (GBM). The molecular characters are determined by specific genomic methods, however, the application of radiography in clinical practice remains to be further studied. Here, we studied the topography features of GBM in proneural subtype, and further demonstrated the survival characteristics and proneural-mesenchymal transition (PMT) progression of samples by combining with the imaging variables. Methods: Data were acquired from The Cancer Imaging Archive (TCIA, http://cancerimagingarchive.net). The radiography image, clinical variables and transcriptome subtype from 223 samples were used in this study. Proneural and mesenchymal subtype on GBM topography based on overlay and Voxel-based lesion-symptom mapping (VLSM) analysis were revealed. Besides, we carried out the comparison of survival analysis and PMT progression in and outside the VLSM-determined area. Results: The overlay of total GBM and separated image of proneural and mesenchymal subtype revealed a correlation of the two subtypes. By VLSM analysis, proneural subtype was confirmed to be related to left inferior temporal medulla, and no significant voxel was found for mesenchymal subtype. The subsequent comparison between samples in and outside the VLSM-determined area showed difference in overall survival (OS) time, tumor purity, epithelial-mesenchymal transition (EMT) score and clinical variables. Conclusions: PMT progression was determined by radiography approach. GBM samples in the VLSM-determined area tended to harbor the signature of proneural subtype. This study provides a valuable VLSM-determined area related to the predilection site, prognosis and PMT progression by the association between GBM topography and molecular characters.
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With the gradual understanding of tumor development, many tumor therapies have been invented and applied in clinical work, and immunotherapy has been widely concerned as an emerging hot topic in the last decade. It is worth noting that immunotherapy is nowadays applied under too harsh conditions, and many tumors are defined as "cold tumors" that are not sensitive to immunotherapy, and brain tumors are typical of them. However, there is much evidence that suggests a link between DNA damage repair mechanisms and immunotherapy. This may be a breakthrough for the application of immunotherapy in brain tumors. Therefore, in this review, first, we will describe the common pathways of DNA damage repair. Second, we will focus on immunotherapy and analyze the mechanisms of DNA damage repair involved in the immune process. Third, we will review biomarkers that have been or may be used to evaluate immunotherapy for brain tumors, such as TAMs, RPA, and other molecules that may provide a precursor assessment for the rational implementation of immunotherapy for brain tumors. Finally, we will discuss the rational combination of immunotherapy with other therapeutic approaches that have an impact on the DNA damage repair process in order to open new pathways for the application of immunotherapy in brain tumors, to maximize the effect of immunotherapy on DNA damage repair mechanisms, and to provide ideas and guidance for immunotherapy in brain tumors.
Asunto(s)
Antineoplásicos Inmunológicos/farmacología , Neoplasias Encefálicas/genética , Daño del ADN , Reparación del ADN , Inmunoterapia , Animales , Antineoplásicos Inmunológicos/efectos adversos , Antineoplásicos Inmunológicos/uso terapéutico , Biomarcadores de Tumor , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/inmunología , Neoplasias Encefálicas/metabolismo , Humanos , Inmunidad Innata , Inmunoterapia/efectos adversos , Inmunoterapia/métodos , Terapia Molecular Dirigida/efectos adversos , Terapia Molecular Dirigida/métodos , Transducción de Señal , Escape del TumorRESUMEN
PURPOSE: Isocitrate dehydrogenase 1 (IDH1) mutations are the most common genetic abnormalities in low-grade gliomas and secondary glioblastomas. Glioma patients with these mutations had better clinical outcomes. However, the effect of IDH1 mutation on drug sensitivity is still under debate. MATERIALS AND METHODS: IDH1-R132H mutant cells were established by lentivirus. IDH1-R132H protein expression was confirmed by western blot. The expression of ataxia telangiectasia mutated (ATM) signaling pathway and apoptosis-related proteins were detected by immunofluorescence and western blot. Temozolomide (TMZ) induced cell apoptosis was detected by flow cytometry. Tumor cell proliferation was detected by Cell Counting Kit-8. In vivo nude mice were used to confirm the in vitro roles of IDH1 mutation. RESULTS: We established glioma cell lines that expressed IDH1-R132H mutation stably. We found that TMZ inhibited glioma cells proliferation more significantly in IDH1 mutant cells compared to wild type. The IC50 of TMZ in IDH1-R132H mutant group was less than half that of wild-type group (p < 0.01). TMZ significantly induced more DNA damage (quantification of γH2AX expression in IDH1 mutation vs. wild type, p < 0.05) and apoptosis (quantification of AnnexinV+propidium iodide-cells in IDH1 mutation versus wild type, p < 0.01) in IDH1 mutant gliomas compared to wild-type gliomas. The ATM-associated DNA repair signal was impaired in IDH1 mutant cells. Inhibiting the ATM/checkpoint kinase 2DNA repair pathway further sensitized IDH1 mutant glioma cells to chemotherapy. We found that IDH1 mutation significantly inhibited tumor growth in vivo (the tumor size was analyzed statistically, p < 0.05). Moreover, we confirmed that gliomas with IDH1 mutation were more sensitive to TMZ in vivo compared to wild type significantly and the results were consistent with the in vitro experiment. CONCLUSION: These results provide evidence that combination of TMZ and ATM inhibitor enhances the antitumor effect in IDH1 mutant gliomas.