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Ribosomal protein S6 (rpS6) phosphorylation mediates the hypertrophic growth of kidney proximal tubule cells. However, the role of rpS6 phosphorylation in podocyte hypertrophy and podocyte loss during the pathogenesis of focal segmental glomerulosclerosis (FSGS) remains undefined. Here, we examined rpS6 phosphorylation levels in kidney biopsy specimens from patients with FSGS and in podocytes from mouse kidneys with Adriamycin-induced FSGS. Using genetic and pharmacologic approaches in the mouse model of FSGS, we investigated the role of rpS6 phosphorylation in podocyte hypertrophy and loss during development and progression of FSGS. Phosphorylated rpS6 was found to be markedly increased in the podocytes of patients with FSGS and Adriamycin-induced FSGS mice. Genetic deletion of the Tuberous sclerosis 1 gene in kidney glomerular podocytes activated mammalian target of rapamycin complex 1 signaling to rpS6 phosphorylation, resulting in podocyte hypertrophy and pathologic features similar to those of patients with FSGS including podocyte loss, leading to segmental glomerulosclerosis. Since protein phosphatase 1 is known to negatively regulate rpS6 phosphorylation, treatment with an inhibitor increased phospho-rpS6 levels, promoted podocyte hypertrophy and exacerbated formation of FSGS lesions. Importantly, blocking rpS6 phosphorylation (either by generating congenic rpS6 knock-in mice expressing non-phosphorylatable rpS6 or by inhibiting ribosomal protein S6 kinase 1-mediated rpS6 phosphorylation with an inhibitor) significantly blunted podocyte hypertrophy, inhibited podocyte loss, and attenuated formation of FSGS lesions. Thus, our study provides genetic and pharmacologic evidence indicating that specifically targeting rpS6 phosphorylation can attenuate the development of FSGS lesions by inhibiting podocyte hypertrophy and associated podocyte depletion.
Assuntos
Glomerulosclerose Segmentar e Focal , Podócitos , Animais , Doxorrubicina , Glomerulosclerose Segmentar e Focal/metabolismo , Humanos , Hipertrofia , Mamíferos/metabolismo , Camundongos , Fosforilação , Podócitos/patologia , Proteínas Serina-Treonina Quinases , Proteína S6 Ribossômica/metabolismoRESUMO
BACKGROUND: Traumatic brain injury is a common and devastating injury that is the leading cause of neurological disability and death worldwide. Patients with cerebral lobe contusion received conservative treatment because of their mild manifestations, but delayed intracranial hematoma may increase and even become life-threatening. We explored the noninvasive method to predict the prognosis of progression and Glasgow Outcome Scale (GOS) by using a quantitative radiomics approach and statistical analysis. METHODS: Eighty-eight patients who were pathologically diagnosed were retrospectively studied. The radiomics method developed in this work included image segmentation, feature extraction, and feature selection. The nomograms were established based on statistical analysis and a radiomics method. We conducted a comparative study of hematoma progression and GOS between the clinical factor alone and fusion radiomics features. RESULTS: Nineteen clinical factors, 513 radiomics features, and 116 locational features were considered. Among clinical factors, international normalized ratio, prothrombin time, and fibrinogen were enrolled for hematoma progression. As for GOS, treatment strategy, age, Glasgow Coma Scale score, and blood platelet were associated factors. Eight features for GOS and five features for hematoma progression were filtered by using sparse representation and locality preserving projection-combined method. Four nomograms were constructed. After fusion radiomics features, area under the curve of hematoma progression prediction increased from 0.832 to 0.899, whereas GOS prediction went from 0.794 to 0.844. CONCLUSIONS: A radiomic-based model that merges radiomics and clinical features is a noninvasive approach to predict hematoma progression and clinical outcomes of cerebral contusions in traumatic brain injury.
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Contusão Encefálica , Lesões Encefálicas Traumáticas , Contusão Encefálica/diagnóstico por imagem , Lesões Encefálicas Traumáticas/complicações , Lesões Encefálicas Traumáticas/diagnóstico por imagem , Lesões Encefálicas Traumáticas/terapia , Escala de Resultado de Glasgow , Hematoma/diagnóstico por imagem , Hematoma/etiologia , Humanos , Nomogramas , Estudos RetrospectivosRESUMO
Focal segmental glomerulosclerosis (FSGS) is a chronic glomerular disease with poor clinical outcomes. Podocyte loss via apoptosis is one important mechanism underlying the pathogenesis of FSGS. Recently, Yes-associated-protein (YAP), a key downstream protein in the Hippo pathway, was identified as an activator for multiple gene transcriptional factors in the nucleus to control cell proliferation and apoptosis. To investigate the potential role of YAP in the progression of FSGS, we examined kidney samples from patients with minimal change disease or FSGS and found that increases in podocyte apoptosis is positively correlated with the cytoplasmic distribution of YAP in human FSGS. Utilizing an established mT/mG transgenic mouse model and primary cultured podocytes, we found that YAP was distributed uniformly in nucleus and cytoplasm in the podocytes of control animals. Adriamycin treatment induced gradual nuclear exclusion of YAP with enhanced phospho-YAP/YAP ratio, accompanied by the induction of podocyte apoptosis both in vivo and in vitro. Moreover, we used verteporfin to treat an Adriamycin-induced FSGS mouse model, and found YAP inhibition by verteporfin induced nuclear exclusion of YAP, thus increasing podocyte apoptosis and accelerating disease progression. Therefore, our findings suggest that YAP nuclear distribution and activation in podocytes is an important endogenous anti-apoptotic mechanism during the progression of FSGS.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal , Apoptose/genética , Glomerulosclerose Segmentar e Focal , Podócitos , Fatores de Transcrição , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Núcleo Celular/metabolismo , Células Cultivadas , Modelos Animais de Doenças , Progressão da Doença , Doxorrubicina/efeitos adversos , Glomerulosclerose Segmentar e Focal/genética , Glomerulosclerose Segmentar e Focal/metabolismo , Glomerulosclerose Segmentar e Focal/patologia , Humanos , Rim/citologia , Rim/metabolismo , Rim/patologia , Masculino , Camundongos , Camundongos Transgênicos , Podócitos/citologia , Podócitos/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Proteínas de Sinalização YAPRESUMO
Radiomics has potential advantages in the noninvasive histopathological and molecular diagnosis of gliomas. We aimed to develop a novel image signature (IS)-based radiomics model to achieve multilayered preoperative diagnosis and prognostic stratification of gliomas. Herein, we established three separate case cohorts, consisting of 655 glioma patients, and carried out a retrospective study. Image and clinical data of three cohorts were used for training (N = 188), cross-validation (N = 411), and independent testing (N = 56) of the IS model. All tumors were segmented from magnetic resonance (MR) images by the 3D U-net, followed by extraction of high-throughput network features, which were referred to as IS. IS was then used to perform noninvasive histopathological diagnosis and molecular subtyping. Moreover, a new IS-based clustering method was applied for prognostic stratification in IDH-wild-type lower-grade glioma (IDHwt LGG) and triple-negative glioblastoma (1p19q retain/IDH wild-type/TERTp-wild-type GBM). The average accuracies of histological diagnosis and molecular subtyping were 89.8 and 86.1% in the cross-validation cohort, while these numbers reached 83.9 and 80.4% in the independent testing cohort. IS-based clustering method was demonstrated to successfully divide IDHwt LGG into two subgroups with distinct median overall survival time (48.63 vs 38.27 months respectively, P = 0.023), and two subgroups in triple-negative GBM with different median OS time (36.8 vs 18.2 months respectively, P = 0.013). Our findings demonstrate that our novel IS-based radiomics model is an effective tool to achieve noninvasive histo-molecular pathological diagnosis and prognostic stratification of gliomas. This IS model shows potential for future routine use in clinical practice.
Assuntos
Neoplasias Encefálicas/diagnóstico por imagem , Aprendizado Profundo , Glioma/diagnóstico por imagem , Interpretação de Imagem Assistida por Computador/métodos , Adolescente , Adulto , Idoso , Neoplasias Encefálicas/patologia , Feminino , Glioma/patologia , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Técnicas de Diagnóstico Molecular , Prognóstico , Estudos Retrospectivos , Adulto JovemRESUMO
OBJECTIVE: Exploring the role of amygdala enlargement (AE) in temporal lobe epilepsy (TLE) without ipsilateral mesial temporal sclerosis (MTS) using comprehensive presurgical workup tools including traditional tools, automatically volumetric analysis, high-density EEG (HD-EEG) source imaging (HD-ESI), and stereoelectroencephalography (SEEG). METHODS: Nine patients diagnosed with TLE-AE who underwent resective surgeries encompassing the amygdala were retrospectively studied. HD-ESI was obtained using 256-channel HD-EEG on the individualized head model. For automatic volumetric analysis, 48 matched controls were enrolled. Diagnosis and surgical strategies were based on a comprehensive workup following the anatomo-electro-clinical principle. RESULTS: At post-operative follow-up (average 30.9 months), eight patients had achieved Engel class I and one Engel class II recovery. HD-ESI yielded unifocal source estimates in anterior mesial temporal region in 85.7% of cases. Automatic volumetric analysis showed the AE sides were consistent with the values determined through other preoperative workup tools. Furthermore, the amygdala volume of the affected sides in AE was significantly greater than that of the larger sides in controls (p < 0.001). Meanwhile, the amygdala volume lateral index (LI) of AE was significantly higher than in controls (p < 0.001). SEEG analysis showed that ictal onsets arose from the enlarged amygdala (and hippocampus) in all cases. CONCLUSION: In addition to traditional workup tools, automatic volumetric analysis, HD-ESI on individualized head model, and invasive SEEG can provide evidence of epileptogenicity in TLE-AE. Resective surgical strategies encompassing the amygdala result in better prognosis. In suspected TLE cases, more attention should be focused on detecting enlargement of amygdala which sometimes is "hidden" in "MR-negative" non-MTS cases.
Assuntos
Epilepsia do Lobo Temporal , Tonsila do Cerebelo/diagnóstico por imagem , Tonsila do Cerebelo/cirurgia , Eletroencefalografia , Epilepsia do Lobo Temporal/diagnóstico por imagem , Epilepsia do Lobo Temporal/cirurgia , Hipocampo , Humanos , Imageamento por Ressonância Magnética , Estudos Retrospectivos , Lobo TemporalRESUMO
Recent research has indicated that the Phyllagathis (raphides) clade (Sonerileae, Melastomataceae) is only distantly related to the type of Phyllagathis and should be separated as a distinct genus. Phylogeny of this clade is here reconstructed with expanded taxon sampling. Four strongly supported subclades have been identified. The possible affinities of taxa that were not sampled in the analysis are discussed, based on morphological data. Perilimnastes is resurrected as the generic name of the Phyllagathis (raphides) clade. A generic description, colour figures, map of distribution, a list of included species and a key are provided for Perilimnastes. Fifteen new combinations are made plus the description of a new species. As interpreted here, Perilimnastes consists of twenty species and two varieties.
RESUMO
Medulloblastoma (MB) stands as one of the prevalent malignant brain tumors among pediatric patients. Despite its prevalence, the intricate interplay between the regulatory program driving malignancy in MB cells and their interactions with the microenvironment remains insufficiently understood. Leveraging the capabilities of single-cell Assay for Transposase-Accessible Chromatin sequencing (scATAC-seq), the chromatin accessibility landscape is unveiled across 59,015 distinct MB cells. This expansive dataset encompasses cells belonging to discrete molecular subgroups, namely SHH, WNT, Group3, and Group4. Within these chromatin accessibility profiles, specific regulatory elements tied to individual subgroups are uncovered, shedding light on the distinct activities of transcription factors (TFs) that likely orchestrate the tumorigenesis process. Moreover, it is found that certain neurotransmitter receptors (NTRs) are subgroup-specific and can predict MB subgroup classification when combined with their associated transcription factors. Notably, targeting essential NTRs within tumors influences both the in vitro sphere-forming capability and the in vivo tumorigenic capacity of MB cells. These findings collectively provide fresh insights into comprehending the regulatory networks and cellular dynamics within MBs. Furthermore, the significance of the TF-NTR regulatory circuits is underscored as prospective biomarkers and viable therapeutic targets.
Assuntos
Neoplasias Cerebelares , Cromatina , Meduloblastoma , Análise de Célula Única , Fatores de Transcrição , Meduloblastoma/genética , Meduloblastoma/metabolismo , Humanos , Análise de Célula Única/métodos , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Cromatina/metabolismo , Cromatina/genética , Neoplasias Cerebelares/genética , Neoplasias Cerebelares/metabolismo , Neoplasias Cerebelares/patologia , Camundongos , Animais , Linhagem Celular TumoralRESUMO
Metabolic reprogramming is one of the essential features of tumors that may dramatically contribute to cancer metastasis. Employing liquid chromatography-tandem mass spectrometry-based metabolomics, we analyzed the metabolic profile from 12 pairwise serum samples of NSCLC brain metastasis patients before and after CyberKnife Stereotactic Radiotherapy. We evaluated the histopathological architecture of 144 surgically resected NSCLC brain metastases. Differential metabolites were screened and conducted for functional clustering and annotation. Metabolomic profiling identified a pathway that was enriched in the metabolism of branched-chain amino acids (BCAAs). Pathologically, adenocarcinoma with a solid growth pattern has a higher propensity for brain metastasis. Patients with high BCAT1 protein levels in lung adenocarcinoma tissues were associated with a poor prognosis. We found that brain NSCLC cells had elevated catabolism of BCAAs, which led to a depletion of α-KG. This depletion, in turn, reduced the expression and activity of the m6A demethylase ALKBH5. Thus, ALKBH5 inhibition participated in maintaining the m6A methylation of mesenchymal genes and promoted the occurrence of epithelial-mesenchymal transition (EMT) in NSCLC cells and the proliferation of NSCLC cells in the brain. BCAA catabolism plays an essential role in the metastasis of NSCLC cells.
Assuntos
Homólogo AlkB 5 da RNA Desmetilase , Neoplasias Encefálicas , Carcinoma Pulmonar de Células não Pequenas , Transição Epitelial-Mesenquimal , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/genética , Transição Epitelial-Mesenquimal/genética , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/secundário , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/genética , Homólogo AlkB 5 da RNA Desmetilase/metabolismo , Homólogo AlkB 5 da RNA Desmetilase/genética , Masculino , Feminino , Aminoácidos de Cadeia Ramificada/metabolismo , Pessoa de Meia-Idade , Linhagem Celular Tumoral , TransaminasesRESUMO
Glioma is the most common and lethal intrinsic primary tumor of the brain. Its controversial origins may contribute to its heterogeneity, creating challenges and difficulties in the development of therapies. Among the components constituting tumors, glioma stem cells are highly plastic subpopulations that are thought to be the site of tumor initiation. Neural stem cells/progenitor cells and oligodendrocyte progenitor cells are possible lineage groups populating the bulk of the tumor, in which gene mutations related to cell-cycle or metabolic enzymes dramatically affect this transformation. Novel approaches have revealed the tumor-promoting properties of distinct tumor cell states, glial, neural, and immune cell populations in the tumor microenvironment. Communication between tumor cells and other normal cells manipulate tumor progression and influence sensitivity to therapy. Here, we discuss the heterogeneity and relevant functions of tumor cell state, microglia, monocyte-derived macrophages, and neurons in glioma, highlighting their bilateral effects on tumors. Finally, we describe potential therapeutic approaches and targets beyond standard treatments.
Assuntos
Neoplasias Encefálicas , Glioma , Células-Tronco Neurais , Humanos , Glioma/metabolismo , Neuroglia/metabolismo , Carcinogênese/genética , Carcinogênese/metabolismo , Carcinogênese/patologia , Células-Tronco Neurais/metabolismo , Microglia/metabolismo , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Microambiente TumoralRESUMO
Human gliomas are lethal brain cancers. Emerging evidence revealed the regulatory role of long noncoding RNAs (lncRNAs) in tumors. Here, we performed a comprehensive analysis of the expression profiles of RNAs in histologically lower-grade glioma (LGG). Enrichment analysis revealed that glioma is influenced by immune-related signatures. Survival analysis further established the close correlation between network features and glioma prognosis. Subsequent experiments showed lncRNA RP11-770J1.4 regulates CTXN1 expression through hsa-miR-124-3p. Correlation analysis identified lncRNA RP11-770J1.4 was immune related, specifically involved in the cytosolic DNA sensing pathway. Downregulated lncRNA RP11-770J1.4 resulted in increased spontaneous gene expression of the cGAS-STING pathway. Single-cell RNA sequencing analysis, along with investigations in a glioblastoma stem cell model and patient sample analysis, demonstrated the predominant localization of CTXN1 within tumor cores rather than peripheral regions. Immunohistochemistry staining established a negative correlation between CTXN1 expression and infiltration of CD8+ T cells. In vivo, Ctxn1 knockdown in GL261 cells led to decreased tumor burden and improved survival while increasing infiltration of CD8+ T cells. These findings unveil novel insights into the lncRNA RP11-770J1.4-CTXN1 as a potential immune regulatory axis, highlighting its therapeutic implications for histologically LGGs.
RESUMO
The quality of magnetic resonance (MR) images obtained with different instruments and imaging parameters varies greatly. A large number of heterogeneous images are collected, and they suffer from acquisition variation. Such imaging quality differences will have a great impact on the radiomics analysis. The main differences in MR images include modality mismatch (M), intensity distribution variance (I), and layer-spacing differences (L), which are referred to as MIL differences in this paper for convenience. An MIL normalization system is proposed to reconstruct uneven MR images into high-quality data with complete modality, a uniform intensity distribution and consistent layer spacing. Three radiomics tasks, including tumor segmentation, pathological grading and genetic diagnosis of glioma, were used to verify the effect of MIL normalization on radiomics analysis. Three retrospective glioma datasets were analyzed in this study: BraTs (285 cases), TCGA (112 cases) and HuaShan (403 cases). They were used to test the effect of MIL on three different radiomics tasks, including tumor segmentation, pathological grading and genetic diagnosis. MIL normalization included three components: multimodal synthesis based on an encoder-decoder network, intensity normalization based on CycleGAN, and layer-spacing unification based on Statistical Parametric Mapping (SPM). The Dice similarity coefficient, areas under the curve (AUC) and six other indicators were calculated and compared after different normalization steps. The MIL normalization system can improved the Dice coefficient of segmentation by 9% (P < .001), the AUC of pathological grading by 32% (P < .001), and IDH1 status prediction by 25% (P < .001) when compared to non-normalization. The proposed MIL normalization system provides high-quality standardized data, which is a prerequisite for accurate radiomics analysis.
Assuntos
Glioma , Imageamento por Ressonância Magnética , Humanos , Área Sob a Curva , Glioma/diagnóstico por imagem , Estudos RetrospectivosRESUMO
Podocyte loss is one of the determining factors for the progression toward glomerulosclerosis. Podocyte is terminally differentiated and does not typically proliferate following injury and loss. However, recent evidence suggested that during renal injury, podocyte could re-enter the cell cycle, sensitizing the cells to injury and death, but the molecular mechanisms underlying it, as well as the cell fate determination still remained unclear. Here, using NPHS2 Cre; mT/mG transgenic mice and primary podocytes isolated from the mice, we investigated the effect of mammalian target of rapamycin complex 1 (mTORC1)/4E-binding protein 1 (4E-BP1) signaling pathway on cell cycle re-entry and apoptosis of podocyte induced by adriamycin. It was found that podocyte cell cycle re-entry could be induced by adriamycin as early as the 1st week in vivo and the 2nd hour in vitro, accompanied with 4E-BP1 activation and was followed by podocyte loss or apoptosis from the 4th week in vivo or the 4th hour in vitro. Importantly, targeting 4E-BP1 activation by the RNA interference of 4E-BP1 or pharmacologic rapamycin (inhibitor of mTORC1, blocking mTORC1-dependent phosphorylation of its substrate 4E-BP1) treatment was able to inhibit the increases of PCNA, Ki67, and the S-phase fraction of cell cycle in primary podocyte during 2-6 h of adriamycin treatment, and also attenuated the following apoptotic cell death of podocyte detected from the 4th hour, suggesting that 4E-BP1 could be a regulator to manipulate the amount of cell cycle re-entry provided by differentiated podocyte, and thus regulate the degree of podocyte apoptosis, bringing us a new potential podocyte-protective substance that can be used for therapy.