RESUMO
Missense mutations of the tumor suppressor Neurofibromin 2 (NF2/Merlin/schwannomin) result in sporadic to frequent occurrences of tumorigenesis in multiple organs. However, the underlying pathogenicity of NF2-related tumorigenesis remains mostly unknown. Here we found that NF2 facilitated innate immunity by regulating YAP/TAZ-mediated TBK1 inhibition. Unexpectedly, patient-derived individual mutations in the FERM domain of NF2 (NF2m) converted NF2 into a potent suppressor of cGAS-STING signaling. Mechanistically, NF2m gained extreme associations with IRF3 and TBK1 and, upon innate nucleic acid sensing, was directly induced by the activated IRF3 to form cellular condensates, which contained the PP2A complex, to eliminate TBK1 activation. Accordingly, NF2m robustly suppressed STING-initiated antitumor immunity in cancer cell-autonomous and -nonautonomous murine models, and NF2m-IRF3 condensates were evident in human vestibular schwannomas. Our study reports phase separation-mediated quiescence of cGAS-STING signaling by a mutant tumor suppressor and reveals gain-of-function pathogenesis for NF2-related tumors by regulating antitumor immunity.
Assuntos
Imunidade Inata , Proteínas de Membrana/metabolismo , Mutação de Sentido Incorreto , Neoplasias/metabolismo , Neurofibromina 2/metabolismo , Nucleotidiltransferases/metabolismo , Evasão Tumoral , Animais , Feminino , Regulação Neoplásica da Expressão Gênica , Células HCT116 , Células HEK293 , Humanos , Fator Regulador 3 de Interferon/genética , Fator Regulador 3 de Interferon/metabolismo , Macrófagos Peritoneais/imunologia , Macrófagos Peritoneais/metabolismo , Masculino , Melanoma Experimental/genética , Melanoma Experimental/imunologia , Melanoma Experimental/metabolismo , Melanoma Experimental/patologia , Proteínas de Membrana/genética , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neoplasias/genética , Neoplasias/imunologia , Neoplasias/patologia , Neurofibromina 2/genética , Nucleotidiltransferases/genética , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Transdução de SinaisRESUMO
SIGNIFICANCE: Sarcoidosis is a variable, multisystem granulomatous disease, which can affect many organs including the lungs, lymph nodes, and eyes. It is difficult to differentiate sarcoidosis and tuberculosis because of their similar clinical and pathological features. PURPOSE: This study aimed to describe a sarcoidosis case with typical ocular and systemic manifestations combined with suspected tuberculosis infection. CASE REPORT: A 30-year-old Chinese man, initially diagnosed with tuberculosis, presented with typical ocular sarcoidosis during antituberculosis therapy. The ocular surface, anterior chamber, anterior chamber angle, ciliary body, vitreous, optic disc, and lacrimal gland of the patient all exhibited manifestations of sarcoidosis, although optic disc involvement has rarely been reported. Typical ocular sarcoidosis manifestations and positive responses to corticosteroid therapy of the patient helped us reach the diagnosis of systemic sarcoidosis. The patient was followed up for 48 months and showed significant improvement of miliary nodules and lymph nodes in both lungs. However, the appearance of uveitis in the right eye persisted because of nonadherence to steroid treatment. CONCLUSIONS: This case shows the importance of ophthalmic evaluation in the diagnosis and management of sarcoidosis and supports a possible role of Mycobacterium tuberculosis in the pathogenesis of sarcoidosis.
Assuntos
Sarcoidose , Uveíte , Adulto , Biópsia/efeitos adversos , Diagnóstico Diferencial , Granuloma/diagnóstico , Humanos , Masculino , Sarcoidose/diagnóstico , Uveíte/diagnóstico , Uveíte/etiologiaRESUMO
PURPOSE: This study aimed to analyze and evaluate the feasibility of using carbon nanoparticles (CNs) to track lymph nodes (LNs) metastases in right colon tumors, especially for patients who underwent laparoscopic-assisted radical right hemicolectomy. METHOD: A total of 99 patients were enrolled in this retrospective study between November 2015 and September 2017 (control group n = 47). One day before surgery, 1 ml of CNs suspension was injected into the submucosal layer around the site of the primary lesions by colonoscopy. Then complete mesocolic excision (CME) of laparoscopic right hemicolectomy was performed. CNs-stained LNs were identified and counted from all dissected LNs after surgery. RESULTS: The dates showed that the number of total harvested LNs and the number of positive patients in the experimental group increased significantly compared with the control group (respectively, P < 0.01 and P < 0.05). The increase of positive percentage shifted some patients toward higher stage, although the total number of positive LNs changed a little bit. In addition, the duration for pathologist to dissect LNs became shorter (26.4 vs. 31.1 min, P < 0.05). CONCLUSION: Therefore, the CNs are not only a good tattoo in laparoscopic-assisted operation, but could be regarded as a better pathological evaluating tool for tumor treatment.
Assuntos
Neoplasias do Colo/diagnóstico , Metástase Linfática/diagnóstico , Nanopartículas , Estadiamento de Neoplasias , Carbono , China , Colectomia , Neoplasias do Colo/patologia , Humanos , Laparoscopia , Excisão de Linfonodo , Linfonodos , Estudos RetrospectivosRESUMO
BACKGROUND: Ectopic pituitary adenomas (EPAs) are rare, and the suprasellar cistern seems to be the most common location. At this time, no detailed original classification, diagnosis, or treatment protocols for suprasellar pituitary adenomas (SPAs) have been described. CASE DESCRIPTION: A 19-year-old man showed visual disturbances and lack of libido for 3 years, he suffered a sharp decline in vision with only light perception in the last week. Magnetic resonance imaging scans revealed a large suprasellar cystic lesion with a normal pituitary in the sella turcica. Endocrinological findings showed an extremely high prolactin level of 1250 ng/mL. Because of the sharp decline in vision, the patient underwent total removal of the suprasellar lesion using a transfrontal interhemispheric approach. The tumor pedicle originated in the lower pituitary stalk without any connection to the anterior pituitary gland in the sella turcica, while the diaphragma sellae was incomplete. Clinical and endocrinological cure criteria were fulfilled and postoperative pathology confirmed a prolactin-secreting pituitary adenoma. CONCLUSION: Ectopic suprasellar pituitary adenomas (ESPAs) are extremely rare intracranial extracerebral tumors. SPAs can be classified into three types according to their origin and their relationship with surrounding tissue. Only type III is theoretically a true ectopic, based on previous reports. Thus, ESPAs are uncommon compared to other EPAs. Our case is the first reported case of a type IIa 'E'SPA and the first description of this subtype classification until now. The pars tuberalis may be different from the pars distalis, and each subtype of adenohypophyseal cells may have different migration characteristics, which leads to different proportions of each hormone-secreting subtype in SPAs and EPAs. Transsphenoidal surgery is minimally invasive, but transcranial surgery may remain a universal option for the treatment of suprasellar lesions.