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Intracerebral hemorrhage (ICH) is a severe stroke subtype with limited therapeutic options. Programmed cell death (PCD) is crucial for immunological balance, and includes necroptosis, pyroptosis, apoptosis, ferroptosis, and necrosis. However, the distinctions between these programmed cell death modalities after ICH remain to be further investigated. We used single-cell transcriptome (single-cell RNA sequencing) and spatial transcriptome (spatial RNA sequencing) techniques to investigate PCD-related gene expression trends in the rat brain following hemorrhagic stroke. Ferroptosis was the main PCD process after ICH, and primarily affected mature oligodendrocytes. Its onset occurred as early as 1 hour post-ICH, peaking at 24 hours post-ICH. Additionally, ferroptosis-related genes were distributed in the hippocampus and choroid plexus. We also elucidated a specific interaction between lipocalin-2 (LCN2)-positive microglia and oligodendrocytes that was mediated by the colony stimulating factor 1 (CSF1)/CSF1 receptor pathway, leading to ferroptosis induction in oligodendrocytes and subsequent neurological deficits. In conclusion, our study highlights ferroptosis as the primary PCD mechanism, emerging as early as 1 hour post-ICH. Early therapeutic intervention via the suppression of microglial LCN2 expression may alleviate ferroptosis-induced damage in oligodendrocytes and associated neurological deficits, thus offering a promising neuroprotective strategy following ICH.
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Ferroptose , Oligodendroglia , Transcriptoma , Animais , Ferroptose/genética , Oligodendroglia/metabolismo , Ratos , Masculino , Substância Branca/metabolismo , Substância Branca/patologia , Ratos Sprague-Dawley , Acidente Vascular Cerebral/metabolismo , Acidente Vascular Cerebral/genética , Hemorragia Cerebral/metabolismo , Hemorragia Cerebral/patologia , Hemorragia Cerebral/genética , Apoptose/genética , Análise de Célula ÚnicaRESUMO
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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Intracerebral hemorrhage (ICH) poses a formidable challenge in stroke management, with limited therapeutic options, particularly in the realm of immune-targeted interventions. Clinical trials targeting immune responses post-ICH have encountered setbacks, potentially attributable to the substantial cellular heterogeneity and intricate intercellular networks within the brain. Here, we present a pioneering investigation utilizing single-cell RNA sequencing and spatial transcriptome profiling at hyperacute (1 h), acute (24 h), and subacute (7 days) intervals post-ICH, aimed at unraveling the dynamic immunological landscape and spatial distributions within the cerebral tissue. Our comprehensive analysis revealed distinct cell differentiation patterns among myeloid and lymphocyte populations, along with delineated spatial distributions across various brain regions. Notably, we identified a subset of lymphocytes characterized by the expression of Spp1 and Lyz2, termed macrophage-associated lymphocytes, which exhibited close interactions with myeloid cells. Specifically, we observed prominent interactions between Lgmn+Macro-T cells and microglia through the spp1-cd44 pathway during the acute phase post-ICH in the choroid plexus. These findings represent a significant advancement in our understanding of immune cell dynamics at single-cell resolution across distinct post-ICH time points, thereby laying the groundwork for exploring critical temporal windows and informing the development of targeted therapeutic strategies.
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Glioma, the most common primary malignant tumor in the central nervous system (CNS), lacks effective treatments, and >60% of cases are glioblastoma (GBM), the most aggressive form. Despite advances in immunotherapy, GBM remains highly resistant. Approaches that target tumor antigens expedite the development of immunotherapies, including personalized tumor-specific vaccines, patient-specific target selection, dendritic cell (DC) vaccines, and chimeric antigen receptor (CAR) and T cell receptor (TCR) T cells. Recent studies show promising results in treating GBM and lower-grade glioma (LGG), fostering hope for future immunotherapy. This review discusses tumor vaccines against glioma, preclinical models in immunological research, and the role of CD4+ T cells in vaccine-induced antitumor immunity. We also summarize clinical approaches, challenges, and future research for creating more effective vaccines.
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BACKGROUND: The diagnosis of glioma has advanced since the release of the WHO 2021 classification with more molecular alterations involved in the integrated diagnostic pathways. Our study aimed to present our experience with the clinical features and management of astrocytoma, IDH mutant based on the latest WHO classification. METHODS: Patients diagnosed with astrocytoma, IDH-mutant based on the WHO 5th edition classification of CNS tumors at our center from January 2009 to January 2022 were included. Patients were divided into WHO 2-3 grade group and WHO 4 grade group. Integrate diagnoses were retrospectively confirmed according to WHO 2016 and 2021 classification. Clinical and MRI characteristics were reviewed, and survival analysis was performed. RESULTS: A total of 60 patients were enrolled. 21.67% (13/60) of all patients changed tumor grade from WHO 4th edition classification to WHO 5th edition. Of these, 21.43% (6/28) of grade II astrocytoma and 58.33% (7/12) of grade III astrocytoma according to WHO 4th edition classification changed to grade 4 according to WHO 5th edition classification. Sex (p = 0.042), recurrent glioma (p = 0.006), and Ki-67 index (p < 0.001) of pathological examination were statistically different in the WHO grade 2-3 group (n = 27) and WHO grade 4 group (n = 33). CDK6 (p = 0.004), FGFR2 (p = 0.003), and MYC (p = 0.004) alterations showed an enrichment in the WHO grade 4 group. Patients with higher grade showed shorter mOS (mOS = 75.9 m, 53.6 m, 26.4 m for grade 2, 3, and 4, respectively, p = 0.01). CONCLUSIONS: Patients diagnosed as WHO grade 4 according to the 5th edition WHO classification based on molecular alterations are more likely to have poorer prognosis. Therefore, treatment should be tailored to their individual needs. Further research is needed for the management of IDH-mutant astrocytoma is needed in the future.
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Astrocitoma , Imageamento por Ressonância Magnética , Mutação , Gradação de Tumores , Organização Mundial da Saúde , Humanos , Astrocitoma/genética , Astrocitoma/classificação , Astrocitoma/patologia , Astrocitoma/diagnóstico por imagem , Masculino , Feminino , Estudos Retrospectivos , Pessoa de Meia-Idade , Adulto , Imageamento por Ressonância Magnética/métodos , Prognóstico , Isocitrato Desidrogenase/genética , Neoplasias do Sistema Nervoso Central/classificação , Neoplasias do Sistema Nervoso Central/genética , Neoplasias do Sistema Nervoso Central/patologia , Neoplasias do Sistema Nervoso Central/diagnóstico por imagem , Idoso , Adulto Jovem , Neoplasias Encefálicas/classificação , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/mortalidade , AdolescenteRESUMO
Anti-aging functional foods benefit the elderly. Telomeres are chromosomal ends that maintain genome stability extended by telomerase catalytic subunit TERT. Due to the end-replication problem, telomeres shorten after each cell cycle without telomerase in most human cells, and eventually the cell enters the senescence stage. Natural products can attenuate the aging process by increasing telomerase activity, such as TA-65. However, TA-65 is expensive. Other Chinese natural products may achieve comparable effects. Here, we found that Rosa roxburghii fruit extracts effectively increase TERT expression and telomerase activity in cultured human mesenchymal stem cells. Both R. roxburghii fruit extracts obtained by freeze-drying and spray-drying increased the activity of telomerase. R. roxburghii fruit extracts were able to reduce reactive oxygen species levels, enhance superoxide dismutase activity, and reduce DNA damage caused by oxidative stress or radiation. R. roxburghii fruit extracts promoted cell proliferation, improved senescent cell morphology, delayed replicative cellular senescence, attenuated cell cycle suppressors, and alleviated the senescence-associated secretory phenotype. Transcriptome and metabolic profiling revealed that R. roxburghii fruit extracts promote DNA replication and telomere maintenance pathways and decrease triglyceride levels. Overall, we provide a theoretical basis for the application of R. roxburghii fruit as an anti-aging product.
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BACKGROUND: Intratumoral hemorrhage, though less common, could be the first clinical manifestation of glioma and is detectable via MRI; however, its exact impacts on patient outcomes remain unclear and controversial. The 2021 WHO CNS 5 classification emphasised genetic and molecular features, initiating the necessity to establish the correlation between hemorrhage and molecular alterations. This study aims to determine the prevalence of intratumoral hemorrhage in glioma subtypes and identify associated molecular and clinical characteristics to improve patient management. METHODS: Integrated clinical data and imaging studies of patients who underwent surgery at the Department of Neurosurgery at Peking Union Medical College Hospital from January 2011 to January 2022 with pathological confirmation of glioma were retrospectively reviewed. Patients were divided into hemorrhage and non-hemorrhage groups based on preoperative magnetic resonance imaging. A comparison and survival analysis were conducted with the two groups. In terms of subgroup analysis, we classified patients into astrocytoma, IDH-mutant; oligodendroglioma, IDH-mutant, 1p/19q-codeleted; glioblastoma, IDH-wildtype; pediatric-type gliomas; or circumscribed glioma using integrated histological and molecular characteristics, according to WHO CNS 5 classifications. RESULTS: 457 patients were enrolled in the analysis, including 67 (14.7%) patients with intratumoral hemorrhage. The hemorrhage group was significantly older and had worse preoperative Karnofsky performance scores. The hemorrhage group had a higher occurrence of neurological impairment and a higher Ki-67 index. Molecular analysis indicated that CDKN2B, KMT5B, and PIK3CA alteration occurred more in the hemorrhage group (CDKN2B, 84.4% vs. 62.2%, p = 0.029; KMT5B, 25.0% vs. 8.9%, p = 0.029; and PIK3CA, 81.3% vs. 58.5%, p = 0.029). Survival analysis showed significantly worse prognoses for the hemorrhage group (hemorrhage 18.4 months vs. non-hemorrhage 39.1 months, p = 0.01). In subgroup analysis, the multivariate analysis showed that intra-tumoral hemorrhage is an independent risk factor only in glioblastoma, IDH-wildtype (162 cases of 457 overall, HR = 1.72, p = 0.026), but not in other types of gliomas. The molecular alteration of CDK6 (hemorrhage group p = 0.004, non-hemorrhage group p < 0.001), EGFR (hemorrhage group p = 0.003, non-hemorrhage group p = 0.001), and FGFR2 (hemorrhage group p = 0.007, non-hemorrhage group p = 0.001) was associated with shorter overall survival time in both hemorrhage and non-hemorrhage groups. CONCLUSIONS: Glioma patients with preoperative intratumoral hemorrhage had unfavorable prognoses compared to their nonhemorrhage counterparts. CDKN2B, KMT5B, and PIK3CA alterations were associated with an increased occurrence of intratumoral hemorrhage, which might be future targets for further investigation of intratumoral hemorrhage.
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Neoplasias Encefálicas , Glioma , Humanos , Masculino , Feminino , Glioma/complicações , Glioma/genética , Glioma/cirurgia , Glioma/patologia , Pessoa de Meia-Idade , Estudos Retrospectivos , Prognóstico , Adulto , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/complicações , Neoplasias Encefálicas/cirurgia , Neoplasias Encefálicas/patologia , Idoso , Estudos de Coortes , Adulto JovemRESUMO
BACKGROUND: To investigate whether the intraoperative superb microvascular imaging(SMI) technique helps evaluate lesion boundaries compared with conventional grayscale ultrasound in brain tumor surgery and to explore factors that may be associated with complete radiographic resection. METHODS: This study enrolled 57 consecutive brain tumor patients undergoing surgery. During the operation, B-mode and SMI ultrasound evaluated the boundaries of brain tumors. MRI before and within 48h after surgery was used as the gold standard to evaluate gross-total resection(GTR). The ultrasound findings and GTR results were analyzed to determine the imaging factors related to GTR. RESULTS: A total of 57 patients were enrolled in the study, including 32 males and 25 females, with an average age of 53.4 ± 14.1 years old(range 19 ~ 80). According to the assessment criteria of MRI, before and within 48 h after the operation, 37(63.9%) cases were classified as GTR, and 20(35.1%) cases were classified as GTR. In comparing tumor interface definition between B-mode and SMI mode, SMI improved HGG boundary recognition in 5 cases(P = 0.033). The results showed that the tumor size ≥ 5 cm and unclear ultrasonic boundary were independent risk factors for nGTR (OR>1, P<0.05). CONCLUSIONS: As an innovative intraoperative doppler technique in neurosurgery, SMI can effectively demarcate the tumor's boundary and help achieve GTR as much as possible.
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Neoplasias Encefálicas , Imageamento por Ressonância Magnética , Humanos , Feminino , Pessoa de Meia-Idade , Masculino , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/cirurgia , Adulto , Idoso , Imageamento por Ressonância Magnética/métodos , Idoso de 80 Anos ou mais , Microvasos/diagnóstico por imagem , Adulto Jovem , Ultrassonografia/métodosRESUMO
Glioblastoma (GBM) is the most common malignant brain tumor and has a dismal prognosis even under the current first-line treatment, with a 5-year survival rate less than 7%. Therefore, it is important to understand the mechanism of treatment resistance and develop new anti-tumor strategies. Induction of programmed cell death (PCD) has become a promising anti-tumor strategy, but its effectiveness in treating GBM remains controversial. On the one hand, PCD triggers tumor cell death and then release mediators to draw in immune cells, creating a pro-inflammatory tumor microenvironment (TME). One the other hand, mounting evidence suggests that PCD and inflammatory TME will force tumor cells to evolve under survival stress, leading to tumor recurrence. The purpose of this review is to summarize the role of PCD and inflammatory TME in the tumor evolution of GBM and promising methods to overcome tumor evolution.
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Neoplasias Encefálicas , Glioblastoma , Inflamação , Microambiente Tumoral , Glioblastoma/patologia , Glioblastoma/genética , Humanos , Inflamação/patologia , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/genética , Apoptose , AnimaisRESUMO
BACKGROUND: Immune checkpoint inhibitors (ICIs) are a promising immunotherapy approach, but glioblastoma clinical trials have not yielded satisfactory results. OBJECTIVE: To screen glioblastoma patients who may benefit from immunotherapy. METHODS: Eighty-one patients receiving anti-PD1/PD-L1 treatment from a large-scale clinical trial and 364 patients without immunotherapy from The Cancer Genome Atlas (TCGA) were included. Patients in the ICI-treated cohort were divided into responders and nonresponders according to overall survival (OS), and the most critical responder-relevant features were screened using random forest (RF). We constructed an artificial neural network (ANN) model and verified its predictive value with immunotherapy response and OS. RESULTS: We defined two groups of ICI-treated glioblastoma patients with large differences in survival benefits as nonresponders (OS ≤6 months, n = 18) and responders (OS ≥17 months, n = 8). No differentially mutated genes were observed between responders and nonresponders. We performed RF analysis to select the most critical responder-relevant features and developed an ANN with 20 input variables, five hidden neurons and one output neuron. Receiver operating characteristic analysis and the DeLong test demonstrated that the ANN had the best performance in predicting responders, with an AUC of 0.97. Survival analysis indicated that ANN-predicted responders had significantly better OS rates than nonresponders. CONCLUSION: The 20-gene panel developed by the ANN could be a promising biomarker for predicting immunotherapy response and prognostic benefits in ICI-treated GBM patients and may guide oncologists to accurately select potential responders for the preferential use of ICIs.
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Antígeno B7-H1 , Glioblastoma , Inibidores de Checkpoint Imunológico , Imunoterapia , Receptor de Morte Celular Programada 1 , Feminino , Humanos , Masculino , Antígeno B7-H1/antagonistas & inibidores , Biomarcadores Tumorais/genética , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/imunologia , Glioblastoma/tratamento farmacológico , Glioblastoma/genética , Glioblastoma/mortalidade , Glioblastoma/imunologia , Glioblastoma/terapia , Inibidores de Checkpoint Imunológico/uso terapêutico , Imunoterapia/métodos , Redes Neurais de Computação , Prognóstico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Resultado do TratamentoRESUMO
Mammalian embryos produced in vitro have poor embryo quality and low developmental ability compared with in vivo embryos. The main manifestations are the low number of blastocysts, the low ratio of the number of inner cell mass cells to the number of trophoblastic cells, and the high apoptosis rate of blastocysts, resulting in low embryo implantation rate. Therefore, optimizing in vitro culture conditions has become a key technology to im-prove the quality of preimplantation embryos. Oviduct Epithelial cells exosomes (OEVs) can be absorbed and internalized by embryos to improve the blastocyst rate and blastocyst quality of embryos in vitro. As a special nuclear structure, Paraspeckles are involved in the fate determination of mammalian early embryonic mammalian cells. However, the regulation of embryonic cell differentiation by OEVs remains unknown. We aimed to investigate the effects of OEVs on paraspeckle formation and cell fate determination in yak in vitro fertilization (IVF) of em-bryos. To simulate the in vivo oviduct environment after ovulation, we used follicular fluid exosomes (FEVs) to stimulate yak oviduct epithelial cells and collect OEVs. OEVs were added to the yak IVF embryo culture system. Paraspeckle formation, cell differentiation, and blastocyst quality in yak embryos were determined. Our results show that, development of yak embryos is unique compared to other bovine species, and OEVs can be used as a supplement to the in vitro culture system of yak embryos to improve embryonic development and blas-tocyst quality. And also Paraspeckles/CARM1 mediated the regulation of OEVs on cell differentiation during in vitro yak embryo production. These results provide new insights into the study of yak embryonic development and the role of OEVs in embryonic development.
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Diferenciação Celular , Técnicas de Cultura Embrionária , Desenvolvimento Embrionário , Células Epiteliais , Exossomos , Animais , Feminino , Desenvolvimento Embrionário/fisiologia , Bovinos/embriologia , Células Epiteliais/fisiologia , Células Epiteliais/metabolismo , Técnicas de Cultura Embrionária/veterinária , Exossomos/metabolismo , Fertilização in vitro/veterinária , Tubas Uterinas/citologia , Blastocisto/fisiologia , OviductosAssuntos
Acrilamidas , Compostos de Anilina , Anticorpos Monoclonais , Carcinoma Pulmonar de Células não Pequenas , Quimiorradioterapia , Receptores ErbB , Neoplasias Pulmonares , Mutação , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Acrilamidas/uso terapêutico , Receptores ErbB/genética , Anticorpos Monoclonais/uso terapêutico , Quimiorradioterapia/métodos , Compostos de Anilina/uso terapêutico , Indóis , PirimidinasRESUMO
Heavy metal resistance mechanisms and heavy metal response genes are crucial for microbial utilization in heavy metal remediation. Here, Corynebacterium crenatum was proven to possess good tolerance in resistance to copper. Then, the transcriptomic responses to copper stress were investigated, and the vital pathways and genes involved in copper resistance of C. crenatum were determined. Based on transcriptome analysis results, a total of nine significantly upregulated DEGs related to metal ion transport were selected for further study. Among them, GY20_RS0100790 and GY20_RS0110535 belong to transcription factors, and GY20_RS0110270, GY20_RS0100790, and GY20_RS0110545 belong to copper-binding peptides. The two transcription factors were studied for the function of regulatory gene expression. The three copper-binding peptides were displayed on the C. crenatum surface for a copper adsorption test. Furthermore, the nine related metal ion transport genes were deleted to investigate the effect on growth in copper stress. This investigation provided the basis for utilizing C. crenatum in copper bioremediation.
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BACKGROUND: Glioma is the main subtype of primary central nervous system (CNS) tumor with high malignancy and poor prognosis under current therapeutic approaches. Glycolysis and suppressive tumor microenvironment (TME) are key markers of glioma with great importance for aggressive features of glioma and inferior clinical outcomes. Hexokinase 3 (HK3) is an important rate-limiting enzyme in glycolysis, but its function in glioma remains unknown. METHODS: This study comprehensively assessed the expression distribution and immunological effect of HK3 via pan-cancer analysis based on datasets from Genotype Tissue Expression (GTEx), Cancer Cell Line Encyclopedia (CCLE), and The Cancer Genome Atlas (TCGA). Furthermore, it explored the malignant phenotype and genomic landscape between low-HK3 and high-HK3 expression groups in gliomas from Chinese Glioma Genome Atlas (CGGA) and TCGA. Moreover, data from the TIMER website predicted the relationship between macrophage infiltration and HK3 expression. Also, single-cell sequencing data were used to validate the relationship. RESULTS: For pan-cancer patients, HK3 was expressed in various cancers. The results showed that HK3 was highly expressed in gliomas and positively correlated with tumor-infiltrating immune cells (TIICs), immune checkpoints, immunomodulators, and chemokines. Meanwhile, HK3 expression was highest in normal immune cells and tissues. In gliomas, the expression of HK3 was found to be closely correlated with the malignant clinical characteristics and the infiltration of macrophages. Also, HK3 was proven to be positively associated with macrophage through single-cell sequencing data and immunohistochemistry techniques. Finally, it is predicted that samples with high HK3 expression are often malignant entities and also significant genomic aberrations of driver oncogenes. CONCLUSIONS: This is the first comprehensive research to figure out the relationship between HK3 and TME characteristics in gliomas. HK3 is positively associated with macrophage infiltration and can induce the immunosuppressive TME and malignant phenotype of gliomas.
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Neoplasias Encefálicas , Glioma , Hexoquinase , Microambiente Tumoral , Humanos , Glioma/patologia , Glioma/genética , Glioma/imunologia , Glioma/enzimologia , Hexoquinase/metabolismo , Hexoquinase/genética , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/enzimologia , Neoplasias Encefálicas/imunologia , Microambiente Tumoral/imunologia , Macrófagos/metabolismo , Macrófagos/patologia , Regulação Neoplásica da Expressão GênicaRESUMO
PURPOSE: Umeclidinium plus vilanterol (UMEC/VI) is an inhaled long-acting muscarinic antagonist/long-acting beta2-agonist (LAMA/LABA), recently approved as once-daily maintenance therapy for chronic obstructive pulmonary disease (COPD). This meta-analysis aims to assess the efficacy and safety of UMEC/VI compared with fluticasone propionate plus salmeterol (FP/SAL). METHODS: A systematic search was conducted by a trained medical research librarian across MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), and Chinese Biomedical Literature Database (CBM) for randomized controlled trials comparing UMEC/VI with FP/SAL in COPD patients. Two reviewers independently assessed the risk of bias and extracted data. The primary outcome was 0-24 h weighted mean (wm) forced expiratory volume in the first second (FEV1), trough FEV1. The secondary outcomes were other lung functions, symptoms, quality of life, and safety. RESULTS: Three studies with 2119 patients were included in the meta-analysis. UMEC/VI showed improvement in 0-24 h wm FEV1 (mean difference (MD) 0.08 L, 95% confidence interval (CI) 0.06 to 0.10, P < 0.01, moderate quality) and trough FEV1 (MD 0.09 L, 95% CI 0.07 to 0.11, P < 0.01, moderate quality) in comparison with FP/SAL. UMEC/VI statistically significantly improved all other lung functions compared with FP/SAL. However, there were no significant differences between UMEC/VI and FP/SAL in rescue-medication use, symptomatic endpoints, and health outcomes. UMEC/VI also demonstrated fewer drug-related adverse effects (risk ratio 0.47, 95% CI 0.27 to 0.82, P = 0.01, low quality). CONCLUSIONS: UMEC/VI, when compared with FP/SAL, demonstrated significant improvements in lung functions with fewer drug-related adverse effects. However, the conclusion was limited by the scarcity of studies and long-term trials.
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Background: The 2021 World Health Organization Classification of Central Nervous System Tumors updates glioma subtyping and grading system, and incorporates EGFR amplification (Amp) as one of diagnostic markers for glioblastoma (GBM). Purpose: This study aimed to describe the frequency, clinical value and molecular correlation of EGFR Amp in diffuse gliomas based on the latest classification. Methods: We reviewed glioma patients between 2011 and 2022 at our hospital, and included 187 adult glioma patients with available tumor tissue for detection of EGFR Amp and other 59 molecular markers of interest. Clinical, radiological and pathological data was analyzed based on the status of EGFR Amp in different glioma subtypes. Results: 163 gliomas were classified as adult-type diffuse gliomas, and the number of astrocytoma, oligodendroglioma and GBM was 41, 46, and 76. EGFR Amp was more common in IDH-wildtype diffuse gliomas (66.0%) and GBM (85.5%) than IDH-mutant diffuse gliomas (32.2%) and its subtypes (astrocytoma, 29.3%; oligodendroglioma, 34.8%). EGFR Amp did not stratify overall survival (OS) in IDH-mutant diffuse gliomas and astrocytoma, while was significantly associated with poorer OS in IDH-wildtype diffuse gliomas, histologic grade 2 and 3 IDH-wildtype diffuse astrocytic gliomas and GBM. Conclusion: Our study validated EGFR Amp as a diagnostic marker for GBM and still a useful predictor for shortened OS in this group.
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Pituitary neuroendocrine tumors (pitNETs) are the second most common primary brain tumors. Despite their prevalence, the tumor immune microenvironment (TIME) and its clinical implications remain largely unexplored. This review provides a comprehensive overview of current knowledge on the immune landscape and advancements in targeted immunotherapy for pitNETs. Macrophages and T cells are principal immune infiltrates within the TIME. Different subtypes of pitNETs display distinct immune patterns, influencing tumor progressive behaviors. PD-L1, the most extensively studied immune checkpoint, is prominently expressed in hormonal pitNETs and correlates with tumor growth and invasion. Cytokines and chemokines including interleukins, CCLs, and CXCLs have complex correlations with tumor subtypes and immune cell infiltration. Crosstalk between macrophages and pitNET cells highlights bidirectional regulatory roles, suggesting potential macrophage-targeted strategies. Recent preclinical studies have demonstrated the efficacy of anti-PD-L1 therapy in a mouse model of corticotroph pitNET. Moreover, anti-PD-1 and/or anti-CTLA-4 immunotherapy has been applied globally in 28 cases of refractory pitNETs, showing more favorable responses in pituitary carcinomas than aggressive pitNETs. In conclusion, the TIME of pitNETs represents a promising avenue for targeted immunotherapy and warrants further investigation.
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Imunoterapia , Tumores Neuroendócrinos , Neoplasias Hipofisárias , Microambiente Tumoral , Humanos , Tumores Neuroendócrinos/terapia , Tumores Neuroendócrinos/imunologia , Microambiente Tumoral/imunologia , Imunoterapia/métodos , Animais , Neoplasias Hipofisárias/imunologia , Neoplasias Hipofisárias/terapia , Neoplasias Hipofisárias/patologia , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/imunologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Inibidores de Checkpoint Imunológico/farmacologiaRESUMO
Rheb is a small G protein that functions as the direct activator of the mechanistic target of rapamycin complex 1 (mTORC1) to coordinate signaling cascades in response to nutrients and growth factors. Despite extensive studies, the guanine nucleotide exchange factor (GEF) that directly activates Rheb remains unclear, at least in part due to the dynamic and transient nature of protein-protein interactions (PPIs) that are the hallmarks of signal transduction. Here, we report the development of a rapid and robust proximity labeling system named Pyrococcus horikoshii biotin protein ligase (PhBPL)-assisted biotin identification (PhastID) and detail the insulin-stimulated changes in Rheb-proximity protein networks that were identified using PhastID. In particular, we found that the lysosomal V-ATPase subunit ATP6AP1 could dynamically interact with Rheb. ATP6AP1 could directly bind to Rheb through its last 12 amino acids and utilizes a tri-aspartate motif in its highly conserved C-tail to enhance Rheb GTP loading. In fact, targeting the ATP6AP1 C-tail could block Rheb activation and inhibit cancer cell proliferation and migration. Our findings highlight the versatility of PhastID in mapping transient PPIs in live cells, reveal ATP6AP1's role as an unconventional GEF for Rheb, and underscore the importance of ATP6AP1 in integrating mTORC1 activation signals through Rheb, filling in the missing link in Rheb/mTORC1 activation.
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Proteína Enriquecida em Homólogo de Ras do Encéfalo , Humanos , Proteína Enriquecida em Homólogo de Ras do Encéfalo/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Células HEK293 , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Ligação Proteica , Transdução de Sinais , Linhagem Celular TumoralRESUMO
BACKGROUD: Glioblastoma multiforme (GBM) is among the most aggressive cancers, with current treatments limited in efficacy. A significant hurdle in the treatment of GBM is the resistance to the chemotherapeutic agent temozolomide (TMZ). The methylation status of the MGMT promoter has been implicated as a critical biomarker of response to TMZ. METHODS: To explore the mechanisms underlying resistance, we developed two TMZ-resistant GBM cell lines through a gradual increase in TMZ exposure. Transcriptome sequencing of TMZ-resistant cell lines revealed that alterations in histone post-translational modifications might be instrumental in conferring TMZ resistance. Subsequently, multi-omics analysis suggests a strong association between histone H3 lysine 9 acetylation (H3K9ac) levels and TMZ resistance. RESULTS: We observed a significant correlation between the expression of H3K9ac and MGMT, particularly in the unmethylated MGMT promoter samples. More importantly, our findings suggest that H3K9ac may enhance MGMT transcription by facilitating the recruitment of the SP1 transcription factor to the MGMT transcription factor binding site. Additionally, by analyzing single-cell transcriptomics data from matched primary and recurrent GBM tumors treated with TMZ, we modeled the molecular shifts occurring upon tumor recurrence. We also noted a reduction in tumor stem cell characteristics, accompanied by an increase in H3K9ac, SP1, and MGMT levels, underscoring the potential role of H3K9ac in tumor relapse following TMZ therapy. CONCLUSIONS: The increase in H3K9ac appears to enhance the recruitment of the transcription factor SP1 to its binding sites within the MGMT locus, consequently upregulating MGMT expression and driving TMZ resistance in GBM.