RESUMO
Pituitary neuroendocrine tumors (PitNET) are known to be variably infiltrated by different immune cells. Nonetheless, their role in pituitary oncogenesis has only begun to be unveiled. The immune microenvironment could determine the biological and clinical behavior of a neoplasm and may have prognostic implications. To evaluate the expression of immune-related genes and to correlate such expression with the presence of infiltrating immune cells in forty-two PitNETs of different lineages, we performed whole transcriptome analysis and RT-qPCR. Deconvolution analysis was carried out to infer the immune cell types present in each tumor and the presence of immune cells was confirmed by immunofluorescence. We found characteristic expression profiles of immune-related genes including those encoding interleukins and chemokines for each tumor lineage. Genes such as IL4-I1, IL-36A, TIRAP, IL-17REL, and CCL5 were upregulated in all PitNETS, whereas IL34, IL20RA, and IL-2RB characterize the NR5A1-, TBX19-, and POU1F1-derived tumors, respectively. Transcriptome deconvolution analysis showed that M2 macrophages, CD4+ T cells, CD8+ T cells, NK cells, and neutrophils can potentially infiltrate PitNET. Furthermore, CD4+ and CD8+ T cells and NK cells infiltration was validated by immunofluorescence. Expression of CCL18, IL-5RA, and HLA-B as well as macrophage tumor infiltration could identify patients who can potentially benefit from treatment with immune checkpoint inhibitors.
Assuntos
Tumores Neuroendócrinos , Neoplasias Hipofisárias , Transcriptoma , Microambiente Tumoral , Humanos , Neoplasias Hipofisárias/genética , Neoplasias Hipofisárias/imunologia , Neoplasias Hipofisárias/patologia , Microambiente Tumoral/imunologia , Microambiente Tumoral/genética , Tumores Neuroendócrinos/genética , Tumores Neuroendócrinos/imunologia , Tumores Neuroendócrinos/patologia , Regulação Neoplásica da Expressão Gênica , Perfilação da Expressão Gênica/métodos , Masculino , Feminino , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Pessoa de Meia-Idade , AdultoRESUMO
BACKGROUND: The tumor microenvironment (TME) includes diverse cellular components such as mesenchymal stem cells (MSC) and immune cells among others. MSC have been isolated from different tumors and they favor tumor cell growth, however, their role in pituitary tumors (PT) remains unknown. Herein we report the presence of MSCs in 2 ACTH-secreting PT causing Cushing disease (MCU), 2 nonfunctioning adenomas of gonadotrope differentiation (MNF) and 2 non tumoral pituitary glands (MS). METHODS: We have analyzed their transcriptomic profiles by RNAseq and compared MSC in terms of their immunosuppressive effects against lymphoid T cell and macrophage populations by means of co-cultures and flow cytometry. RESULTS: Our transcriptomic analysis revealed molecular differences between MSC derived from non-tumoral pituitaries and MSC derived from PT. Two distinct subpopulations of MSC, one displaying immunosuppressive properties and the other with increased pro-proliferative capabilities, regardless of their origin. MSC derived from ACTH- and nonfunctioning PT, but not those derived from non-tumoral glands significantly inhibited the proliferation of activated T cells, favored the generation of Tregs and promote M2 macrophage polarization. Such immunosuppressive effects were correlated with an upregulation of programmed death ligand 1 and intracellular expression of macrophage colony stimulating factor (M-CSF) and IL-10. Importantly, MSC derived from ACTH-PT showed a higher immunosuppressive potential than MSC isolated from nonfunctioning tumors. CONCLUSION: This study demonstrates the presence of at least two MSC subpopulations in the pituitary gland and suggests that immunosuppressive effects of MSC may have important implications in PT growth.
RESUMO
Rosai Dorfman Destombes (RDD) disease is a non-Langerhans histiocytosis. The central nervous system is affected in < 5% of cases. We report the case of a 59-year-old man, who began 8 months before admission with headache, diminished visual acuity in the temporal hemifields, hyposmia, and seizures. Magnetic resonance imaging showed three midline skull-base lesions in anterior, media, and posterior fossae. We performed a complete resection of symptomatic lesions using a bifrontal craniotomy. The histopathological analysis determined RDD, therefore, we started steroid treatment. Our case description is due to the diagnosis and location, one of the rarest reported to date in the literature.
La enfermedad de Rosai-Dorfman-Destombes (RDD) es una histiocitosis no Langerhans. El SNC se ve afectado en menos del 5% de los casos. Presentamos el caso de un hombre de 59 años quien inició ocho meses previos al ingreso con cefalea, hemianopsia bitemporal, hiposmia y convulsiones. La resonancia magnética mostró tres lesiones de la base del cráneo en las fosas anterior, media y posterior. Realizamos una resección completa de las lesiones sintomáticas mediante una craneotomía bifrontal. El análisis histopatológico determinó RDD. Nuestro caso es debido al diagnóstico y localización, uno de los más raros reportados hasta la fecha en la literatura.
RESUMO
Parkinson's disease is a neurodegenerative disease whose progression and clinical characteristics have a close bidirectional and multilevel relationship with the process of neuroinflammation. In this context, it is necessary to understand the mechanisms involved in this neuroinflammation-PD link. This systematic search was, hereby, conducted with a focus on the four levels where alterations associated with neuroinflammation in PD have been described (genetic, cellular, histopathological and clinical-behavioral) by consulting the PubMed, Google Scholar, Scielo and Redalyc search engines, including clinical studies, review articles, book chapters and case studies. Initially, 585,772 articles were included, and, after applying the inclusion and exclusion criteria, 84 articles were obtained that contained information about the multilevel association of neuroinflammation with alterations in gene, molecular, cellular, tissue and neuroanatomical expression as well as clinical-behavioral manifestations in PD.
Assuntos
Doenças Neurodegenerativas , Doença de Parkinson , Humanos , Doença de Parkinson/genética , Doenças Neurodegenerativas/genética , Doenças NeuroinflamatóriasRESUMO
Corticotroph cells give rise to aggressive and rare pituitary neoplasms comprising ACTH-producing adenomas resulting in Cushing disease (CD), clinically silent ACTH adenomas (SCA), Crooke cell adenomas (CCA) and ACTH-producing carcinomas (CA). The molecular pathogenesis of these tumors is still poorly understood. To better understand the genomic landscape of all the lesions of the corticotroph lineage, we sequenced the whole exome of three SCA, one CCA, four ACTH-secreting PA causing CD, one corticotrophinoma occurring in a CD patient who developed Nelson syndrome after adrenalectomy and one patient with an ACTH-producing CA. The ACTH-producing CA was the lesion with the highest number of single nucleotide variants (SNV) in genes such as USP8, TP53, AURKA, EGFR, HSD3B1 and CDKN1A. The USP8 variant was found only in the ACTH-CA and in the corticotrophinoma occurring in a patient with Nelson syndrome. In CCA, SNV in TP53, EGFR, HSD3B1 and CDKN1A SNV were present. HSD3B1 and CDKN1A SNVs were present in all three SCA, whereas in two of these tumors SNV in TP53, AURKA and EGFR were found. None of the analyzed tumors showed SNV in USP48, BRAF, BRG1 or CABLES1. The amplification of 17q12 was found in all tumors, except for the ACTH-producing carcinoma. The four clinically functioning ACTH adenomas and the ACTH-CA shared the amplification of 10q11.22 and showed more copy-number variation (CNV) gains and single-nucleotide variations than the nonfunctioning tumors.
Assuntos
Adenoma Hipofisário Secretor de ACT , Adenoma , Carcinoma , Genômica , Síndrome de Nelson , Neoplasias Hipofisárias , Adenoma Hipofisário Secretor de ACT/genética , Adenoma/genética , Adenoma/patologia , Hormônio Adrenocorticotrópico , Aurora Quinase A , Carcinoma/genética , Corticotrofos/patologia , Receptores ErbB , Humanos , Melanocortinas , Complexos Multienzimáticos , Nucleotídeos , Neoplasias Hipofisárias/genéticaRESUMO
BACKGROUND: Pituitary adenomas (PA) are the second most common intracranial tumors and are classified according to hormone they produce, and the transcription factors they express. The majority of PA occur sporadically, and their molecular pathogenesis is incompletely understood. METHODS: Here we performed transcriptome and proteome analysis of tumors derived from POU1F1 (GH-, TSH-, and PRL-tumors, N = 16), NR5A1 (gonadotropes and null cells adenomas, n = 17) and TBX19 (ACTH-tumors, n = 6) lineages as well as from silent ACTH-tumors (n = 3) to determine expression of kinases, cyclins, CDKs and CDK inhibitors. RESULTS: The expression profiles of genes encoding kinases were distinctive for each of the three PA lineage: NR5A1-derived tumors showed upregulation of ETNK2 and PIK3C2G and alterations in MAPK, ErbB and RAS signaling, POU1F1-derived adenomas showed upregulation of PIP5K1B and NEK10 and alterations in phosphatidylinositol, insulin and phospholipase D signaling pathways and TBX19-derived adenomas showed upregulation of MERTK and STK17B and alterations in VEGFA-VEGFR, EGF-EGFR and Insulin signaling pathways. In contrast, the expression of the different genes encoding cyclins, CDK and CDK inhibitors among NR5A1-, POU1F1- and TBX19-adenomas showed only subtle differences. CDK9 and CDK18 were upregulated in NR5A1-adenomas, whereas CDK4 and CDK7 were upregulated in POUF1-adenomas. CONCLUSIONS: The kinome of PA clusters these lesions into three distinct groups according to the transcription factor that drives their terminal differentiation. And these complexes could be harnessed as molecular therapy targets.
Assuntos
Adenoma , Neoplasias Hipofisárias , Adenoma/metabolismo , Hormônio Adrenocorticotrópico/genética , Proteínas Reguladoras de Apoptose/genética , Quinases Ciclina-Dependentes/genética , Quinases Ciclina-Dependentes/metabolismo , Ciclinas/genética , Ciclinas/metabolismo , Humanos , Insulina , Neoplasias Hipofisárias/genética , Neoplasias Hipofisárias/metabolismo , Neoplasias Hipofisárias/patologia , Proteínas Serina-Treonina Quinases , Fatores de Transcrição/genética , TranscriptomaAssuntos
Humanos , Feminino , Adulto , Cistos Coloides , Neuropatologia/métodos , Autopsia , Medicina LegalRESUMO
Obesity is a global health problem with a broad set of comorbidities, such as malnutrition, metabolic syndrome, diabetes, systemic hypertension, heart failure, and kidney failure. This review describes recent findings of neuroimaging and two studies of cell density regarding the roles of overnutrition-induced hypothalamic inflammation in neurodegeneration. These studies provided consistent evidence of smaller cortical thickness or reduction in the gray matter volume in people with overweight and obesity; however, the investigated brain regions varied across the studies. In general, bilateral frontal and temporal areas, basal nuclei, and cerebellum are more commonly involved. Mechanisms of volume reduction are unknown, and neuroinflammation caused by obesity is likely to induce neuronal loss. Adipocytes, macrophages of the adipose tissue, and gut dysbiosis in overweight and obese individuals result in the secretion of the cytokines and chemokines that cross the blood-brain barrier and may stimulate microglia, which in turn also release proinflammatory cytokines. This leads to chronic low-grade neuroinflammation and may be an important factor for apoptotic signaling and neuronal death. Additionally, significant microangiopathy observed in rat models may be another important mechanism of induction of apoptosis. Neuroinflammation in neurodegenerative diseases (such as Alzheimer's and Parkinson's diseases) may be similar to that in metabolic diseases induced by malnutrition. Poor cognitive performance, mainly in executive functions, in individuals with obesity is also discussed. This review highlights the neuroinflammatory and neurodegenerative mechanisms linked to obesity and emphasizes the importance of developing effective prevention and treatment intervention strategies for overweight and obese individuals.
Assuntos
Doenças Neurodegenerativas , Obesidade , Animais , Encéfalo , Inflamação , Obesidade/complicações , Sobrepeso , RatosRESUMO
BACKGROUND: Mucormycosis is a rare, invasive disease associated with high mortality rates, produced by opportunistic pathogens related to the Mucorales order and characterised by a diverse range of clinical forms; acute rhino-orbital-cerebral and pulmonary symptoms are the most reported ones. OBJECTIVES: To report the experience of mucormycosis observed in a tertiary-care hospital in Mexico for 35 years. METHODS: This was a retrospective, descriptive and observational study on mucormycosis at a tertiary-care hospital in Mexico from January 1985 to December 2019. Demographic and clinical data and mycological and histopathological records were selected. RESULTS: Two hundred fourteen proven cases of mucormycosis for 35 years at a tertiary-care hospital in Mexico were included. Most of the cases were male patients with a median age of 45 years. The two most associated underlying diseases were diabetes mellitus (76.6%) and haematologic malignancy (15.4%). The three primary clinical forms were as follows: rhino-orbito-cerebral (75.9%), cutaneous (8.41%) and pulmonary (7.47%) mucormycosis. The most isolated agents were Rhizopus arrhizus (58.4%) and Lichtheimia corymbifera (12.3%). The overall therapeutic response was 58.5%, and the best response was observed with amphotericin B deoxycholate and surgical debridement. CONCLUSION: Mucormycosis is an emerging disease, and its incidence has increased at our hospital over the years. In this study, the rhino-cerebral clinical type was the most frequent in patients with uncontrolled diabetes; the main aetiological agent was R. arrhizus. Early diagnosis, control of the underlying disease and prompt management may increase the survival rate.
Assuntos
Mucormicose/epidemiologia , Mucormicose/mortalidade , Centros de Atenção Terciária/estatística & dados numéricos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anfotericina B/uso terapêutico , Antifúngicos/uso terapêutico , Criança , Pré-Escolar , Ácido Desoxicólico/uso terapêutico , Combinação de Medicamentos , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Prontuários Médicos , México/epidemiologia , Pessoa de Meia-Idade , Mucorales/genética , Mucorales/patogenicidade , Mucormicose/tratamento farmacológico , Estudos Retrospectivos , Fatores de Tempo , Adulto JovemRESUMO
BACKGROUND: Pituitary adenomas (PA) are the second most common tumor in the central nervous system and have low counts of mutated genes. Splicing occurs in 95% of the coding RNA. There is scarce information about the spliceosome and mRNA-isoforms in PA, and therefore we carried out proteomic and transcriptomic analysis to identify spliceosome components and mRNA isoforms in PA. METHODS: Proteomic profile analysis was carried out by nano-HPLC and mass spectrometry with a quadrupole time-of-flight mass spectrometer. The mRNA isoforms and transcriptomic profiles were carried out by microarray technology. With proteins and mRNA information we carried out Gene Ontology and exon level analysis to identify splicing-related events. RESULTS: Approximately 2000 proteins were identified in pituitary tumors. Spliceosome proteins such as SRSF1, U2AF1 and RBM42 among others were found in PA. These results were validated at mRNA level, which showed up-regulation of spliceosome genes in PA. Spliceosome-related genes segregate and categorize PA tumor subtypes. The PA showed alterations in CDK18 and THY1 mRNA isoforms which could be tumor specific. CONCLUSIONS: Spliceosome components are significant constituents of the PA molecular machinery and could be used as molecular markers and therapeutic targets. Splicing-related genes and mRNA-isoforms profiles characterize tumor subtypes.