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BACKGROUND: Patients with breast cancer brain metastases (BCBM) experience a rapid decline in their quality of life. Recently, tertiary lymphoid structures (TLSs), analogs of secondary lymphoid organs, have attracted extensive attention. However, the potential clinical implications of TLSs in BCBMs are poorly understood. In this study, we evaluated the density and composition of TLSs in BCBMs and described their prognostic value. METHODS: Clinicopathological data were collected from 98 patients (2015-2021). TLSs were evaluated, and a TLS scoring system was constructed. Differences in progression-free survival (PFS) and overall survival (OS) between groups were calculated using the Kaplan-Meier method. Immunohistochemistry and multiplex immunofluorescence (mIF) were used to assess TLSs heterogeneity. RESULTS: TLSs were identified in 47 patients with BCBM. High TLSs density indicated favorable survival (OS, p=0.003; PFS, p<0.001). TLS was positively associated with OS (p=0.0172) and PFS (p=0.0161) in the human epidermal growth factor receptor type 2-positive subtype, and with prolonged OS (p=0.0482) in the triple-negative breast cancer subtype. The mIF results showed significant differences in the percentages of T follicular helper (Tfh) cells, M2 macrophages, cytotoxic T lymphocytes, and CD8+TIM-3+ T lymphocytes between the groups of TLS scores 0-3 (cytotoxic T lymphocytes, p=0.044; Tfh, p=0.021; M2 macrophages, p=0.033; CD8+TIM-3+ T lymphocytes, p=0.018). Furthermore, novel nomograms incorporating the TLS scores and other clinicopathological predictors demonstrated prominent predictability of the 1-year, 3-year, and 5-year outcomes of BCBMs (area under the curve >0.800). CONCLUSION: Our results highlight the impact of TLSs abundance on the OS and PFS of patients with BCBM. Additionally, we described the immune composition of TLSs and proposed novel nomograms to predict the prognosis of patients with BCBM.
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Neoplasias Encefálicas , Neoplasias de la Mama , Estructuras Linfoides Terciarias , Humanos , Femenino , Estructuras Linfoides Terciarias/inmunología , Estructuras Linfoides Terciarias/patología , Neoplasias de la Mama/patología , Neoplasias de la Mama/inmunología , Neoplasias de la Mama/mortalidad , Neoplasias Encefálicas/secundario , Neoplasias Encefálicas/inmunología , Neoplasias Encefálicas/mortalidad , Persona de Mediana Edad , Pronóstico , Adulto , AncianoRESUMEN
PURPOSE: Isocitrate dehydrogenase (IDH) and cyclin-dependent kinase inhibitor (CDKN) 2A/B status holds important prognostic value in diffuse gliomas. We aimed to construct prediction models using clinically available and reproducible characteristics for predicting IDH-mutant and CDKN2A/B homozygous deletion in adult-type diffuse glioma patients. MATERIALS AND METHODS: This retrospective, two-center study analysed 272 patients with adult-type diffuse glioma (230 for primary cohort and 42 for external validation cohort). Two radiologists independently assessed the patients' images according to the Visually AcceSAble Rembrandt Images (VASARI) feature set. Least absolute shrinkage and selection operator (LASSO) regression analysis was used to optimise variable selection. Multivariable logistic regression analysis was used to develop the prediction models. Calibration plots, receiver operating characteristic (ROC) curves, and decision curve analysis (DCA) were used to validate the models. Nomograms were developed visually based on the prediction models. RESULTS: The interobserver agreement between the two radiologists for VASARI features was excellent (κ range, 0.813-1). For the IDH-mutant prediction model, the area under the curves (AUCs) was 0.88-0.96 in the internal and external validation sets, For the CDKN2A/B homozygous deletion model, the AUCs were 0.80-0.86 in the internal and external validation sets. The decision curves show that both prediction models had good net benefits. CONCLUSION: The prediction models which basing on VASARI and clinical features provided a reliable and clinically meaningful preoperative prediction for IDH and CDKN2A/B status in diffuse glioma patients. These findings provide a foundation for precise preoperative non-invasive diagnosis and personalised treatment approaches for adult-type diffuse glioma patients.
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BACKGROUND: The emergence of digital whole slide image (WSI) has driven the development of computational pathology. However, obtaining patch-level annotations is challenging and time-consuming due to the high resolution of WSI, which limits the applicability of fully supervised methods. We aim to address the challenges related to patch-level annotations. METHODS: We propose a universal framework for weakly supervised WSI analysis based on Multiple Instance Learning (MIL). To achieve effective aggregation of instance features, we design a feature aggregation module from multiple dimensions by considering feature distribution, instances correlation and instance-level evaluation. First, we implement instance-level standardization layer and deep projection unit to improve the separation of instances in the feature space. Then, a self-attention mechanism is employed to explore dependencies between instances. Additionally, an instance-level pseudo-label evaluation method is introduced to enhance the available information during the weak supervision process. Finally, a bag-level classifier is used to obtain preliminary WSI classification results. To achieve even more accurate WSI label predictions, we have designed a key instance selection module that strengthens the learning of local features for instances. Combining the results from both modules leads to an improvement in WSI prediction accuracy. RESULTS: Experiments conducted on Camelyon16, TCGA-NSCLC, SICAPv2, PANDA and classical MIL benchmark datasets demonstrate that our proposed method achieves a competitive performance compared to some recent methods, with maximum improvement of 14.6 % in terms of classification accuracy. CONCLUSION: Our method can improve the classification accuracy of whole slide images in a weakly supervised way, and more accurately detect lesion areas.
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Interpretación de Imagen Asistida por Computador , Humanos , Interpretación de Imagen Asistida por Computador/métodos , Procesamiento de Imagen Asistido por Computador/métodos , AlgoritmosRESUMEN
Here, we identify a subset of vascular pericytes, defined by expression of platelet-derived growth factor receptor beta (PDGFR-ß) and G-protein-coupled receptor 91 (GPR91), that promote tumorigenesis and tyrosine kinase inhibitors (TKIs) resistance by functioning as the primary methionine source for cancer stem cells (CSCs) in clear cell renal cell carcinoma (ccRCC). Tumor-cell-derived succinate binds to GPR91 on pericyte to activate autophagy for methionine production. CSCs use methionine to create stabilizing N6-methyladenosine in ATPase-family-AAA-domain-containing 2 (ATAD2) mRNA, and the resulting ATAD2 protein complexes with SRY-box transcription factor 9 to assemble super enhancers and thereby dictate its target genes that feature prominently in CSCs. Targeting PDGFR-ß+GPR91+ pericytes with specific GRP91 antagonists reduce intratumoral methionine level, eliminate CSCs, and enhance TKIs sensitivity. These results unraveled the mechanisms by which PDGFR-ß+GPR91+ pericytes provide supportive niche for CSCs and could be used to develop targets for treating ccRCC.
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Carcinoma de Células Renales , Neoplasias Renales , Humanos , Pericitos/metabolismo , Carcinoma de Células Renales/patología , Metionina/metabolismo , Racemetionina/metabolismo , Receptor beta de Factor de Crecimiento Derivado de Plaquetas/metabolismo , Neoplasias Renales/patología , Células Madre Neoplásicas/metabolismo , ATPasas Asociadas con Actividades Celulares Diversas/metabolismo , Proteínas de Unión al ADN/metabolismoRESUMEN
The central nervous system (CNS) maintains homeostasis with its surrounding environment by restricting the ingress of large hydrophilic molecules, immune cells, pathogens, and other external harmful substances to the brain. This function relies heavily on the blood-cerebrospinal fluid (B-CSF) and blood-brain barrier (BBB). Although considerable research has examined the structure and function of the BBB, the B-CSF barrier has received little attention. Therapies for disorders associated with the central nervous system have the potential to benefit from targeting the B-CSF barrier to enhance medication penetration into the brain. In this study, we synthesized a nanoprobe ANG-PEG-UCNP capable of crossing the B-CSF barrier with high targeting specificity using a hydrocephalus model for noninvasive magnetic resonance ventriculography to understand the mechanism by which the CSF barrier may be crossed and identify therapeutic targets of CNS diseases. This magnetic resonance nanoprobe ANG-PEG-UCNP holds promising potential as a safe and effective means for accurately defining the ventricular anatomy and correctly locating sites of CSF obstruction.
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Barrera Hematoencefálica , Encéfalo , Encéfalo/diagnóstico por imagen , Sistema Nervioso Central , Transporte Biológico/fisiología , Imagen por Resonancia MagnéticaRESUMEN
RATIONALE: Anti-N-methyl-D-aspartate receptor (NMDAR) is the most common type of autoimmune encephalitis mediated by NMDAR antibodies. The pathological process remains unclear, especially in patients without tumors or infections. Autopsy and biopsy studies have rarely been reported because of the favorable prognosis. Pathological findings generally demonstrate mild-to-moderate inflammation. This case report presents severe anti-NMDAR encephalitis in a 43-year-old man without any identified triggers. The biopsy in this patient showed extensive inflammatory infiltration with evident B cell accumulation, which enriches the pathological study of male anti-NMDAR encephalitis patients without comorbidities. PATIENT CONCERNS: A 43-year-old previously healthy man presented with new-onset seizures with recurrent jerks. The initial autoimmune antibody test with serum and cerebrospinal fluid yielded negative results. After ineffective treatment for viral encephalitis, based on the imaging results indicating the possibility of diffuse glioma, the patient underwent a brain biopsy in the right frontal lobe to rule out malignancy. DIAGNOSIS: The immunohistochemical study showed extensive inflammatory cell infiltration, consistent with the pathological changes in encephalitis. Cerebrospinal fluid and serum samples were then retested and tested positive for IgG antibodies against NMDAR. Therefore, the patient was diagnosed with anti-NMDAR encephalitis. INTERVENTIONS: The patient was administered intravenous immunoglobulin (0.4 g/kg/d for 5 days), intravenous methylprednisolone (1 g/d for 5 days, 500 mg/d for 5 days, subsequently reduced to oral administration), and intravenous cyclophosphamide cycles. OUTCOMES: The patient developed refractory epilepsy 6 weeks later and required mechanical ventilation. Despite brief clinical improvement after extensive immunotherapy, the patient died from bradycardia and circulation. LESSONS: Anti-NMDAR encephalitis cannot be ruled out even if the initial autoantibody test result is negative. For progressive encephalitis of unknown etiology, it is necessary to recheck cerebrospinal fluid for anti-NMDAR antibodies.
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Encefalitis Antirreceptor N-Metil-D-Aspartato , Humanos , Masculino , Adulto , Encefalitis Antirreceptor N-Metil-D-Aspartato/tratamiento farmacológico , Células Plasmáticas , Inmunoglobulinas Intravenosas/uso terapéutico , Autoanticuerpos , Biopsia , Encéfalo/diagnóstico por imagenRESUMEN
Hepatitis B virus (HBV) DNA is much higher during HBeAg-positive chronic HBV infection (EP-CBI) than during HBeAg-negative chronic HBV infection (EN-CBI), although the necroinflammation in liver is minimal and the adaptive immune response is similar in both phases. We previously reported that mRNA levels of EVA1A were higher in EN-CBI patients. In this study, we aimed to investigate whether EVA1A inhibits HBV gene expression and examine the underlying mechanisms. The available cell models for HBV replication and model HBV mice were used to investigate how EVA1A regulates HBV replication and the antiviral activity based on gene therapy. The signaling pathway was determined through RNA sequencing analysis. The results demonstrated that EVA1A can inhibit HBV gene expression in vitro and in vivo. In particular, EVA1A overexpression resulted in accelerated HBV RNA degradation and activation of the PI3K-Akt-mTOR pathway, two processes that directly and indirectly inhibiting HBV gene expression. EVA1A is a promising candidate for treating chronic hepatitis B (CHB). In conclusion, EVA1A is a new host restriction factor that regulates the HBV life cycle via a nonimmune process.
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Virus de la Hepatitis B , Hepatitis B Crónica , Ratones , Animales , Virus de la Hepatitis B/genética , Antígenos e de la Hepatitis B/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Replicación ViralRESUMEN
BACKGROUND: "Primary papillary epithelial tumor of the sella (PPETS)" is a recently described rare tumor entity of the central nervous system (CNS) with stereotypic location in the sella. Comprehensive molecular investigations and epigenetic profiles of PPETS have not been performed to date. METHODS: We report a comprehensive clinical, histopathologic, and molecular assessment of 5 PPETS cases in comparison with a cohort composed of 7 choroid plexus papilloma (CPP), 7 central neurocytoma (CN), 15 posterior pituitary tumor (PPT) including 4 pituicytoma, 6 granular cell tumors of the sellar region (GCT), and 5 spindle cell oncocytoma. RESULTS: All PPETS had good outcomes. Immunohistochemically, PPETS tumors showed positive staining with TTF1, EMA, AE1/AE3, MAP2, and Vimentin, but were negatively stained with Syn, GFAP, CgA, and S100, and sporadically stained with Ki-67. In unsupervised hierarchical clustering and t-distributed stochastic neighbor embedding analyses of DNA-methylation data, PPETS and PPT tumors formed a distinct cluster irrespective of their histologic types. However, PPETS tumors did not cluster together with CPP and CN samples. Similar findings were obtained when our samples were projected into the reference cohort of the brain tumor classifier. Substantial fractions of the PPETS and PPT tumors shared broadly similar chromosomal copy number alterations. No mutations were detected using targeted next-generation sequencing. CONCLUSIONS: Though more cases are needed to further elucidate the molecular pathogenesis of these tumors, our findings indicate that PPETS and PPT tumors may constitute a single neurooncological entity.
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Adenoma Oxifílico , Neoplasias Glandulares y Epiteliales , Neoplasias Hipofisarias , Humanos , Neoplasias Hipofisarias/genética , Neoplasias Hipofisarias/patología , Adenoma Oxifílico/genética , Adenoma Oxifílico/patología , Metilación de ADN , Sistema Nervioso Central/patologíaRESUMEN
BACKGROUND & AIMS: Aberrant epigenetic events mediated by histone methyltransferases and demethylases contribute to malignant progression of colorectal cancer (CRC). However, the role of the histone demethylase ubiquitously transcribed tetratricopeptide repeat on chromosome X (UTX) in CRC remains poorly understood. METHODS: UTX conditional knockout mice and UTX-silenced MC38 cells were used to investigate UTX function in tumorigenesis and development of CRC. We performed time of flight mass cytometry to clarify the functional role of UTX in remodeling immune microenvironment of CRC. To investigate metabolic interaction between myeloid-derived suppressor cells (MDSCs) and CRC, we analyzed metabolomics data to identify metabolites secreted by UTX-deficient cancer cells and taken up by MDSCs. RESULTS: We unraveled a tyrosine-mediated metabolic symbiosis between MDSC and UTX-deficient CRC. Loss of UTX in CRC resulted in methylation of phenylalanine hydroxylase, preventing its degradation and subsequently increasing tyrosine synthesis and secretion. Tyrosine taken up by MDSCs was metabolized to homogentisic acid by hydroxyphenylpyruvate dioxygenase. Homogentisic acid modified protein inhibitor of activated STAT3 via carbonylation of Cys 176, and relieved the inhibitory effect of protein inhibitor of activated STAT3 on signal transducer and activator of transcription 5 transcriptional activity. This in turn, promoted MDSC survival and accumulation, enabling CRC cells to acquire invasive and metastatic traits. CONCLUSIONS: Collectively, these findings highlight hydroxyphenylpyruvate dioxygenase as a metabolic checkpoint to restrict immunosuppressive MDSCs and to counteract malignant progression of UTX-deficient CRC.
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Neoplasias Colorrectales , Dioxigenasas , Animales , Ratones , Dioxigenasas/metabolismo , Ácido Homogentísico , Histona Demetilasas/genética , Histona Demetilasas/metabolismo , Metilación , Microambiente TumoralRESUMEN
BACKGROUND: Lymphoplasmacyte-rich meningioma (LPRM) is a rare form of meningioma characterized by prominent lymphoplasmacytic infiltrates into the tumor. Report of flat growth of LPRM mimicking pachymeningitis is rare in the literature. CASE PRESENTATION: A 55-year-old female who suffered from episodes of headache and seizures has been diagnosed with pachymeningitis for 4 years because post contrast brain MRI demonstrated enhanced carpet-like dura lesion in the left frontal lobe. The lesion kept unchanged on yearly follow-ups until a recent brain MRI found the lesion grew significantly into a mass. The lesion was resected and pathology suggested LPRM. CONCLUSION: LPRM may present as carpet-like growth pattern on MRI. Long-term follow-up in patients with pachymeningitis is necessary.
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Neoplasias Meníngeas , Meningioma , Meningitis , Duramadre/diagnóstico por imagen , Duramadre/patología , Femenino , Humanos , Imagen por Resonancia Magnética , Neoplasias Meníngeas/diagnóstico por imagen , Neoplasias Meníngeas/patología , Meningioma/diagnóstico por imagen , Meningioma/patología , Meningitis/diagnóstico , Meningitis/patología , Persona de Mediana Edad , NeuroimagenRESUMEN
Macrophage polarization mediates the development of inflammatory diseases. However, the polarization status at various stages of gout is not fully understood. Our study aimed to define the evolution of macrophage polarization in acute and chronic gout. Normal human synovium and synovium with tophi were collected for immunofluorescence (IF). Rat gouty joints were collected for joint thickness assessment and pathological evaluation. Tissue mRNA expression of inducible nitric oxide synthase (iNOS) and arginase-1 (Arg-1) were evaluated. Mouse peritoneal macrophages and THP-1 derived macrophages were stimulated by monosodium urate (MSU) crystals and were collected for detection of interleukin (IL) -1ß and IL-37 levels and iNOS/Arg-1 ratio. Arg-1 and IL-37 were highly expressed in normal synovium and synovium with tophi. In rat gouty joints, the inflammatory cell counts and ankle thickness began to increase at 2 h, peaked at 24 h, and was decreased spontaneously. An increase in macrophages preceded the neutrophils infiltration. Infiltration of M1 was positively related with the severity of arthritis. M2 appeared in an early stage (at 2 h) of inflammation. The number of M1 macrophages was comparable to that of M2 from 2 to 12 h and exceeded M2 number at 18 h and 24 h. The ratios of M2/M1 reversed at 48 h and remained reversed until 120 h. In mice gouty joints, iNOS/Arg-1 mRNA ratio was significantly higher than the that in control group at 8 h. The proportion of neutrophils and M1-macrophages reached peak at 4 h in mice model with peritoneal gout. Concentration of IL-1ß and ratio of iNOS/Arg-1 were increased at 6 h, peaked at 48 h, and were then decreased at 72 h in vitro, while the concentration of IL-37 peaked at 2 h and then decreased. In summary, altered macrophage polarization was observed in various stages of gouty inflammation. Macrophages in acute gout were polarized into M1 at early stage and into M2 at later stage while the macrophages in chronic gout mainly were only polarized towards M2. The number of M1 rose with the progression of inflammation. Early increase of M2 was observed, which might be generated directly from M0.
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Arginasa , Gota , Animales , Gota/metabolismo , Humanos , Inflamación/metabolismo , Macrófagos/metabolismo , Ratones , Óxido Nítrico Sintasa de Tipo II/genética , Óxido Nítrico Sintasa de Tipo II/metabolismo , ARN Mensajero/metabolismo , Ácido Úrico/metabolismoRESUMEN
BACKGROUND: The surgical resection of the tumor spreading into the cavernous sinus (CS) is complicated and challenging. METHOD: We report a left recurrent CS chondromyxoid fibroma occupying the clival-petrous apex-parasellar-suprasellar area, which was totally removed by the micro-endo combination technique via the middle cranial fossa extradural approach. CONCLUSION: This case demonstrates the value of the micro-endoscopic combination technique for complicated skull base surgery.
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Seno Cavernoso , Fibroma , Neoplasias de la Base del Cráneo , Seno Cavernoso/cirugía , Fosa Craneal Media , Fosa Craneal Posterior/cirugía , Endoscopía , Fibroma/patología , Humanos , Neoplasias de la Base del Cráneo/diagnóstico por imagen , Neoplasias de la Base del Cráneo/patología , Neoplasias de la Base del Cráneo/cirugíaRESUMEN
The authors report a 34-year-old male with antineutrophil cytoplasmic autoantibody (ANCA) associated vasculitis (AAV) which only involved the central nervous system and presented with an isolated mass in the left parietal lobe. Constitutional symptoms were lacking and the only symptom was progressive right-sided hemiparesis. Pathology suggested necrotizing vasculitis without eosinophils and granulomas. Cytoplasmic ANCA was elevated to 103.9 IU/ml (>5 times the upper limit) in serum. He obtained a regression following treatment of cyclophosphamide and steroids. Prompt diagnosis of AAV is essential since early and aggressive initiation of immunosuppressive therapy can avoid further neurological sequelae.
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Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/diagnóstico , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/patología , Lóbulo Parietal/patología , Adulto , Humanos , MasculinoRESUMEN
Paragangliomas are rare neuroendocrine tumors originating from neural crest-derived paraganglion cells. Primary cauda equina paraganglioma (CEP) pose both diagnostic and surgical challenges. We report 12 cases of CEP to characterize the diagnostic and operative approach to these rare tumors. 12 cases with primary CEP were studied; 5 patients were male (41.7%) and 7 were female (56.3%). The median age was 44 years (range: 15-64 years). The most common symptom was lower back pain of variable duration. Radiologically, the lesions were intradural and extramedullary with well-defined margins, and ranged from 1 to 4.5 cm. in diameter (mean: 1.65 cm). 9 tumors were composed of sheets and nests of cells with a neuroendocrine pattern and intense vascularity and displayed a characteristic Zellballen pattern. Interestingly, CAM 5.2 was diffusely or focally positive with a dot-like or membrane pattern in 8/11 cases (72.7%). Similarly, CK was diffusely or focally positive with membrane and cytoplasmic staining or with a dot-like pattern in 7/11 (63.6%) and 2/11 cases (18.2%). None of the cases showed deletion of SDHB nor expression of GATA3. CEP can display aberrant keratin positivity, and this should be considered in the differential diagnosis of these lesions. This finding also raises the possibility that CEP may be an entirely different entity than non-spinal paragangliomas.
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Cauda Equina , Tumores Neuroendocrinos , Paraganglioma , Neoplasias del Sistema Nervioso Periférico , Adulto , Cauda Equina/patología , Cauda Equina/cirugía , Femenino , Humanos , Queratinas , Masculino , Tumores Neuroendocrinos/patología , Paraganglioma/diagnóstico , Paraganglioma/cirugía , Neoplasias del Sistema Nervioso Periférico/diagnóstico , Neoplasias del Sistema Nervioso Periférico/patología , Neoplasias del Sistema Nervioso Periférico/cirugíaRESUMEN
Type 2 diabetes mellitus (T2DM) is one of the most common chronic diseases among the elderly people. The T2DM increases the risk of cardio-cerebrovascular disease (CCD), and the main pathological change of the CCD is atherosclerosis (AS). Meanwhile, the carbonic anhydrases (CAs) are involved in the formation and progression of plaques in AS. However, the exact physiological mechanism of carbonic anhydrase III (CAIII) has not been clear yet, and there are also no correlation study between CAIII protein and T2DM with CCD. The 8-week old diabetic mice (db/db-/- mice) and wild-type mice (wt mice) were feed by a normal diet till 32 weeks, and detected the carotid artery vascular opening angle using the method of biomechanics; The changes of cerebral cortex and myocardium were watched by the ultrastructure, and the autophagy were observed by electron microscope; The tissue structure, inflammation and cell injury were observed by Hematoxylin and eosin (HE) staining; The apoptosis of cells were observed by TUNEL staining; The protein levels of CAIII, IL-17, p53 were detected by immunohistochemical and Western Blot, and the Beclin-1, LC3, NF-κB were detected by Western Blot. All statistical analysis is performed using PRISM software. Compared with wt mice, db/db-/- mice' carotid artery open angle increased significantly. Electron microscope results indicated that autophagy in db/db-/- mice cerebral cortex and heart tissue decreased and intracellular organelle ultrastructure were damaged. HE staining indicated that, db/db-/- mice' cerebral cortex and heart tissue stained lighter, inflammatory cells infiltration, cell edema were obvious, myocardial fibers were disorder, and myocardial cells showed different degrees of degeneration. Compared with wt mice, TUNEL staining showed that there was obviously increase in db/db-/- mice cortex and heart tissue cell apoptosis. The results of immunohistochemistry and Western Blot indicated that CAIII, Beclin-1 and LC3II/I expression levels conspicuously decreased in cortex and heart tissue of db/db-/- mice, and the expression level of IL-17, NF-κB and p53 obviously increased. The carotid artery' vascular stiffness was increased and which was probably related with formation of AS in diabetic mice. And the autophagy participated in the occurrence and development of diabetic CCD. CAIII protein might somehow be involved in the regulation of autophagy probably through affecting cell apoptosis and inflammation, but the underlying mechanism remains to be further studied.
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Anhidrasa Carbónica III , Trastornos Cerebrovasculares , Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Animales , Autofagia , RatonesRESUMEN
OBJECTIVE: To improve the understanding and the diagnosis of intracranial ependymal tumors. METHODS: The clinical, radiological and prognostic features of 48 supratentorial extraventricular ependymomas and 74 intraventricular ependymomas were summarized and compared. RESULTS: Supratentorial extraventricular ependymomas, most often located in the frontal lobe (33.3%) and classified as grade III (75.0%), had relatively large eccentric cysts (3.07 ± 2.03 cm), significant enhancement (84.8%), low apparent diffusion coefficient (ADC) values, and associated with higher mortality (41.3%). The majority of intraventricular lesions occurred in the fourth ventricle (86.5%) and classified as grade II (78.4%), had relatively small and multiple cystic changes (1.04 ± 0.87 cm), slight or moderate enhancement (76.9%), high ADC values and associated with lower mortality (20.7%). There were few significant differences between grade II and grade III tumors in these 2 groups, respectively. Young age, high grade and low ADC values are worse prognostic indicators for patients with supratentorial extraventricular ependymomas, but not for those with intraventricular ependymomas. CONCLUSIONS: Conventional radiological features, combined with clinical manifestations and quantitative information provided by diffusion-weighted imaging, may not only enhance the diagnosis and assist in determining prognosis but also provide a better pathophysiological understanding of intracranial ependymal tumors.
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Neoplasias Encefálicas/diagnóstico por imagen , Imagen de Difusión por Resonancia Magnética/métodos , Ependimoma/diagnóstico por imagen , Neoplasias Supratentoriales/diagnóstico por imagen , Tomografía Computarizada por Rayos X/métodos , Adolescente , Adulto , Factores de Edad , Neoplasias Encefálicas/mortalidad , Neoplasias Encefálicas/patología , Ependimoma/mortalidad , Ependimoma/patología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mortalidad , Clasificación del Tumor , Pronóstico , Neoplasias Supratentoriales/mortalidad , Neoplasias Supratentoriales/patología , Adulto JovenRESUMEN
DDX60, an interferon (IFN)-inducible gene, plays a promotional role in many tumors. However, its function in glioma remains unknown. In this study, bioinformatic analysis (TCGA, CGGA, Rembrandt) illustrated the upregulation and prognostic value of DDX60 in gliomas. Immunohistochemical staining of clinical samples (n = 49) validated the DDX60 expression is higher in gliomas than in normal tissue (n = 20, P < 0.0001). It also could be included in nomogram as a parameter to predict the 3- and 5-year survival risk (C-index = 0.86). The biological process of DDX60 in glioma was mainly enriched in the inflammatory and immune response by GSEA and GO analysis. DDX60 expression had a positive association with most inflammatory-related functions, such as hematopoietic cell kinase (HCK) (R = 0.31), interferon (R = 0.72), STAT1 (R = 54), and a negative correlation with IgG (R = -0.24). Furthermore, DDX60 expression tends to be positively related to multiple infiltrating immune cells, while negatively related to CD56 dim nature killer cell in glioma. Some important immune checkpoints, like CTLA-4, PD-L1, EGF, CD96, and CD226, were all positively related with DDX60 (all Pearson correlation R > 0.26). The expression and correlation between DDX60, EGF, and PD-L1 were confirmed by western blot in clinical samples (n = 14, P < 0.0001) and GBM cells. These results indicated that DDX60 might have important clinical significance in glioma and could serve as a potential immune therapeutic target.
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Rationale: Metastasis, the development of secondary malignant growth at a distance from a primary tumor, is the main cause of cancer-associated death. However, little is known about how metastatic cancer cells adapt to and colonize in the new organ environment. Here we sought to investigate the functional mechanism of cholesterol metabolic aberration in colorectal carcinoma (CRC) liver metastasis. Methods: The expression of cholesterol metabolism-related genes in primary colorectal tumors (PT) and paired liver metastases (LM) were examined by RT-PCR. The role of SREBP2-dependent cholesterol biosynthesis pathway in cell growth and CRC liver metastasis were determined by SREBP2 silencing in CRC cell lines and experimental metastasis models including, intra-splenic injection models and liver orthotropic injection model. Growth factors treatment and co-culture experiment were performed to reveal the mechanism underlying the up-regulation of SREBP2 in CRC liver metastases. The in vivo efficacy of inhibition of cholesterol biosynthesis pathway by betulin or simvastatin were evaluated in experimental metastasis models. Results: In the present study, we identify a colorectal cancer (CRC) liver metastasis-specific cholesterol metabolic pathway involving the activation of SREBP2-dependent cholesterol biosynthesis, which is required for the colonization and growth of metastatic CRC cells in the liver. Inhibiting this cholesterol biosynthesis pathway suppresses CRC liver metastasis. Mechanically, hepatocyte growth factor (HGF) from liver environment activates SREBP2-dependent cholesterol biosynthesis pathway by activating c-Met/PI3K/AKT/mTOR axis in CRC cells. Conclusion: Our findings support the notion that CRC liver metastases show a specific cholesterol metabolic aberration. Targeting this cholesterol biosynthesis pathway could be a promising treatment for CRC liver metastasis.
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Adenocarcinoma/secundario , Colesterol/biosíntesis , Neoplasias Colorrectales/metabolismo , Neoplasias Hepáticas/secundario , Adenocarcinoma/metabolismo , Animales , Técnicas de Cocultivo , Neoplasias Colorrectales/patología , Vectores Genéticos/farmacología , Factor de Crecimiento de Hepatocito/fisiología , Humanos , Neoplasias Hepáticas/metabolismo , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Proteínas de Neoplasias/metabolismo , Especificidad de Órganos , Proteínas Proto-Oncogénicas c-met/fisiología , Interferencia de ARN , ARN Interferente Pequeño/genética , Distribución Aleatoria , Transducción de Señal , Simvastatina/uso terapéutico , Proteína 2 de Unión a Elementos Reguladores de Esteroles/metabolismo , Serina-Treonina Quinasas TOR/fisiología , Ensayo de Tumor de Célula MadreRESUMEN
Developing effective internal wound dressing materials is important for postoperative tissue regeneration while remains a challenge due to the poor biological environment-adaptability of conventional materials. Here, we report an example of injectable self-healing hydrogel based on gastric environment-adaptive supramolecular assembly, and have explored its application for gastric perforation healing. By leveraging the gastric environment-modulated supramolecular interactions, the self-assembled hydrogel network is orchestrated with sensitive thermo-responsibility, injectability, printability and rapid self-healing capability. The hydrogel dressing can effectively inhibit the attachment of microorganisms and demonstrates outstanding antibiofouling property. In vivo rat model further demonstrates the as-prepared hydrogel dressing simplifies the surgical procedures, reduces postoperative complications as well as enhances the healing process of gastric perforation compared with the conventional treatment. This work provides useful insights into the development of biological environment-adaptive functional materials for various biomedical applications.