RESUMEN
Rationale: Understanding the immune mechanisms associated with liver transplantation (LT), particularly the involvement of tissue-resident memory T cells (TRMs), represents a significant challenge. Methods: This study employs a multi-omics approach to analyse liver transplant samples from both human (n = 17) and mouse (n = 16), utilizing single-cell RNA sequencing, bulk RNA sequencing, and immunological techniques. Results: Our findings reveal a comprehensive T cell-centric landscape in LT across human and mouse species, involving 235,116 cells. Notably, we found a substantial increase in CD8+ TRMs within rejected grafts compared to stable ones. The elevated presence of CD8+ TRMs is characterised by a distinct expression profile, featuring upregulation of tissue-residency markers (CD69, CXCR6, CD49A and CD103+/-,), immune checkpoints (PD1, CTLA4, and TIGIT), cytotoxic markers (GZMB and IFNG) and proliferative markers (PCNA and TOP2A) during rejection. Furthermore, there is a high expression of transcription factors such as EOMES and RUNX3. Functional assays and analyses of cellular communication underscore the active role of CD8+ TRMs in interacting with other tissue-resident cells, particularly Kupffer cells, especially during rejection episodes. Conclusions: These insights into the distinctive activation and interaction patterns of CD8+ TRMs suggest their potential utility as biomarkers for graft rejection, paving the way for novel therapeutic strategies aimed at enhancing graft tolerance and improving overall transplant outcomes.
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Linfocitos T CD8-positivos , Rechazo de Injerto , Trasplante de Hígado , Células T de Memoria , Análisis de la Célula Individual , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Humanos , Rechazo de Injerto/inmunología , Animales , Ratones , Células T de Memoria/inmunología , Células T de Memoria/metabolismo , Análisis de la Célula Individual/métodos , Análisis de Secuencia de ARN/métodos , Subunidad alfa 3 del Factor de Unión al Sitio Principal/genética , Subunidad alfa 3 del Factor de Unión al Sitio Principal/metabolismo , Memoria Inmunológica , Masculino , Ratones Endogámicos C57BL , Antígenos CD/metabolismo , Antígenos CD/genética , Femenino , Persona de Mediana Edad , Proteínas de Dominio T BoxRESUMEN
Metabolic imbalance leading to inflammatory hypoxia and stabilization of hypoxia-inducible transcription factors (HIFs) is a hallmark of inflammatory bowel diseases. We hypothesize that HIF could be stabilized in CD4+ T cells during intestinal inflammation and alter the functional responses of T cells via regulation of microRNAs. Our assays reveal markedly increased T cell-intrinsic hypoxia and stabilization of HIF protein during experimental colitis. microRNA screen in primary CD4+ T cells points us towards miR-29a and our subsequent studies identify a selective role for HIF-2α in CD4-cell-intrinsic induction of miR-29a during hypoxia. Mice with T cell-intrinsic HIF-2α deletion display elevated T-bet (target of miR-29a) levels and exacerbated intestinal inflammation. Mice with miR-29a deficiency in T cells show enhanced intestinal inflammation. T cell-intrinsic overexpression of HIF-2α or delivery of miR-29a mimetic dampen TH1-driven colitis. In this work, we show a previously unrecognized function for hypoxia-dependent induction of miR-29a in attenuating TH1-mediated inflammation.
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Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico , Colitis , MicroARNs , Células TH1 , Animales , MicroARNs/genética , MicroARNs/metabolismo , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Colitis/genética , Colitis/metabolismo , Colitis/inmunología , Células TH1/inmunología , Células TH1/metabolismo , Ratones , Ratones Endogámicos C57BL , Proteínas de Dominio T Box/metabolismo , Proteínas de Dominio T Box/genética , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD4-Positivos/inmunología , Ratones Noqueados , Humanos , Femenino , Modelos Animales de Enfermedad , MasculinoRESUMEN
HMGB1 (high-mobility group box-1) has been extensively studied as a damage-associated molecular pattern, with secreted cytokine function. However, its regulation on T cells, especially the function in the nucleus, has not been elucidated. Here, we use conditional knockout (HMGB1-f/f; CD2-cre) mice and find that HMGB1 potentiates the proliferation and interferon gamma (IFN-γ) expression of CD8 T cells rather than CD4 T cells. Notably, nuclear, but not secreted, HMGB1 supports the expression of IFN-γ in CD8 T cells via directly regulating the activity of Eomes, the transcription factor for IFN-γ. Functional study shows that HMGB1 promotes the anti-tumor ability of CD8 T cells in vitro and in vivo. Finally, tumor environmental interleukin-7 promotes HMGB1 and IFN-γ production via fatty acid oxidation in CD8 T cells. Overall, we identify the role of nuclear HMGB1 in CD8 T cell differentiation and demonstrate that it plays an important role in the anti-tumor programs of CD8 T cells.
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Linfocitos T CD8-positivos , Proteína HMGB1 , Interferón gamma , Proteína HMGB1/metabolismo , Animales , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Interferón gamma/metabolismo , Ratones , Ratones Endogámicos C57BL , Núcleo Celular/metabolismo , Proteínas de Dominio T Box/metabolismo , Ratones Noqueados , Proliferación Celular , Diferenciación Celular , Neoplasias/inmunología , Neoplasias/metabolismo , Neoplasias/patologíaRESUMEN
The cardiac conduction system (CCS) is a network of specialized cardiomyocytes that coordinates electrical impulse generation and propagation for synchronized heart contractions. Although the components of the CCS, including the sinoatrial node, atrioventricular node, His bundle, bundle branches, and Purkinje fibers, were anatomically discovered more than 100 years ago, their molecular constituents and regulatory mechanisms remain incompletely understood. Here, we demonstrate the transcriptomic landscape of the postnatal mouse CCS at a single-cell resolution with spatial information. Integration of single-cell and spatial transcriptomics uncover region-specific markers and zonation patterns of expression. Network inference shows heterogeneous gene regulatory networks across the CCS. Notably, region-specific gene regulation is recapitulated in vitro using neonatal mouse atrial and ventricular myocytes overexpressing CCS-specific transcription factors, Tbx3 and/or Irx3. This finding is supported by ATAC-seq of different CCS regions, Tbx3 ChIP-seq, and Irx motifs. Overall, this study provides comprehensive molecular profiles of the postnatal CCS and elucidates gene regulatory mechanisms contributing to its heterogeneity.
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Sistema de Conducción Cardíaco , Proteínas de Homeodominio , Miocitos Cardíacos , Proteínas de Dominio T Box , Animales , Proteínas de Dominio T Box/genética , Proteínas de Dominio T Box/metabolismo , Ratones , Miocitos Cardíacos/metabolismo , Sistema de Conducción Cardíaco/metabolismo , Proteínas de Homeodominio/genética , Proteínas de Homeodominio/metabolismo , Redes Reguladoras de Genes , Factores de Transcripción/metabolismo , Factores de Transcripción/genética , Regulación de la Expresión Génica , Animales Recién Nacidos , Análisis de la Célula Individual , Transcriptoma , Ramos Subendocárdicos/metabolismo , Ramos Subendocárdicos/fisiología , Nodo Atrioventricular/metabolismo , Nodo Sinoatrial/metabolismo , Fascículo Atrioventricular/metabolismoRESUMEN
22q11.2 deletion syndrome (22q11.2DS) is the most common chromosomal microdeletion disorder. Its phenotype is highly variable with incomplete penetrance. 22q11.2DS is a rare disease, and the research progress is relatively slow, which has restricted its treatment and intervention. In recent years, much progress has been made in the pathogenic mechanism and genome-wide association study of 22q11.2DS. In this review, the pathogenesis of 22q11.2DS was summarized. Thereafter, the molecular and pathological mechanisms of TBX1 and DGCR8 genes were clarified. Finally, factors affecting the penetrance of cardiac and immune system phenotypes were reviewed. This review may enhance the understanding of 22q11.2DS and has important clinical implications on the prenatal diagnosis, genetic counseling, treatment and intervention of this disease.
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Síndrome de DiGeorge , Humanos , Síndrome de DiGeorge/genética , Proteínas de Dominio T Box/genética , Cromosomas Humanos Par 22/genética , Deleción CromosómicaRESUMEN
Chordoma is a rare bone cancer with variable clinical outcomes. Here, we recruited 184 sporadic chordoma patients from the US and Canada and collected their clinical and treatment data. The average age at diagnosis was 45.5 years (Range 5-78) and the chordoma site distribution was 49.2% clivus, 26.2% spinal, and 24.0% sacral. Most patients (97.5%) received surgery as the primary treatment, among whom 85.3% also received additional treatment. Except for the most prevalent cancers like prostate, lung, breast, and skin cancer, there was no discernible enrichment for any specific cancer type among patients or their family members. Among a subset of patients (N = 70) with tumor materials, we conducted omics analyses and obtained targeted panel sequencing and SNP array genotyping data for 51 and 49 patients, respectively. The most recurrent somatic driver mutations included PIK3CA (12%), followed by chromatin remodeling genes PBRM1 and SETD2. Amplification of the 6q27 region, containing the chordoma susceptibility gene TBXT, was detected in eight patients (16.3%). Clival patients appeared to be less likely to carry driver gene mutations, chromosome arm level deletion events (e.g., 5p, 5p, and 9p), or 6q27 amplification compared to sacral patients. After adjusting for age, sex, tumor site, and additional treatment, patients with somatic deletions of 14q (OR = 13.73, 95% CI 1.96-96.02, P = 0.008) and 18p (OR = 13.68, 95% CI 1.77-105.89, P = 0.012) were more likely to have persistent chordoma. The study highlights genomic heterogeneity in chordoma, potentially linked to location and clinical progression.
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Cordoma , Humanos , Cordoma/genética , Cordoma/patología , Masculino , Femenino , Persona de Mediana Edad , Anciano , Adulto , Adolescente , Adulto Joven , Niño , Preescolar , Proteínas de Unión al ADN/genética , Mutación , Fosfatidilinositol 3-Quinasa Clase I/genética , Proteínas de Dominio T Box/genética , Factores de Transcripción/genética , Proteínas Nucleares/genética , Neoplasias de la Base del Cráneo/genética , Neoplasias de la Base del Cráneo/patología , Neoplasias de la Columna Vertebral/genética , Neoplasias de la Columna Vertebral/patología , Canadá , Polimorfismo de Nucleótido Simple , Proteínas Fetales , N-Metiltransferasa de Histona-LisinaRESUMEN
Approximately 25% of cancers are preceded by chronic inflammation that occurs at the site of tumor development. However, whether this multifactorial oncogenic process, which commonly occurs in the intestines, can be initiated by a specific immune cell population is unclear. Here, we show that an intestinal T cell subset, derived from interleukin-17 (IL-17)-producing helper T (TH17) cells, induces the spontaneous transformation of the intestinal epithelium. This subset produces inflammatory cytokines, and its tumorigenic potential is not dependent on IL-17 production but on the transcription factors KLF6 and T-BET and interferon-γ. The development of this cell type is inhibited by transforming growth factor-ß1 (TGFß1) produced by intestinal epithelial cells. TGFß signaling acts on the pretumorigenic TH17 cell subset, preventing its progression to the tumorigenic stage by inhibiting KLF6-dependent T-BET expression. This study therefore identifies an intestinal T cell subset initiating cancer.
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Mucosa Intestinal , Factor 6 Similar a Kruppel , Proteínas de Dominio T Box , Células Th17 , Animales , Células Th17/inmunología , Ratones , Proteínas de Dominio T Box/metabolismo , Proteínas de Dominio T Box/genética , Factor 6 Similar a Kruppel/metabolismo , Mucosa Intestinal/inmunología , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patología , Transducción de Señal/inmunología , Ratones Endogámicos C57BL , Transformación Celular Neoplásica/inmunología , Transformación Celular Neoplásica/metabolismo , Factor de Crecimiento Transformador beta1/metabolismo , Factores de Transcripción de Tipo Kruppel/metabolismo , Factores de Transcripción de Tipo Kruppel/genética , Ratones Noqueados , Interferón gamma/metabolismo , Interferón gamma/inmunología , Interleucina-17/metabolismo , Interleucina-17/inmunología , Ratones Transgénicos , Proteínas Proto-Oncogénicas/metabolismo , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Neoplasias Intestinales/inmunología , Neoplasias Intestinales/patología , Neoplasias Intestinales/metabolismo , HumanosRESUMEN
BACKGROUND: Gene therapy has been proposed as a strategy to induce cardiac regeneration following acute myocardial infarction (AMI). Given that Tbx20, a transcription factor of the T-box subfamily, stimulates cell proliferation and angiogenesis, we designed a baculovirus overexpressing Tbx20 (Bv-Tbx20) and evaluated its effects in cultured cardiomyocytes and in an ovine model of AMI. METHODS AND RESULTS: Cell proliferation and angiogenesis were measured in cardiomyocytes transduced with Bv-Tbx20 or Bv-Null (control). Subsequently, in sheep with AMI, Bv-Tbx20 or Bv-Null was injected in the infarct border. Cardiomyocyte cell cycle activity, angioarteriogenesis, left ventricular function, and infarct size were assessed. Cardiomyocytes transduced with BvTbx20 increased cell proliferation, cell cycle regulatory and angiogenic gene expression, and tubulogenesis. At 7 days posttreatment, sheep treated with Bv-Tbx20 showed increased Tbx20, promitotic and angiogenic gene expression, decreased levels of P21, increased Ki67- (17.09±5.73 versus 7.77±7.24 cardiomyocytes/mm2, P<0.05) and PHH3 (phospho-histone H3)-labeled cardiomyocytes (10.10±3.51 versus 5.23±2.87 cardiomyocytes/mm2, P<0.05), and increased capillary (2302.68±353.58 versus 1694.52±211.36 capillaries/mm2, P<0.001) and arteriolar (146.95±53.14 versus 84.06±16.84 arterioles/mm2, P<0.05) densities. At 30 days, Bv-Tbx20 decreased infarct size (9.89±1.92% versus 12.62±1.33%, P<0.05) and slightly improved left ventricular function. Baculoviral gene transfer-mediated Tbx20 overexpression exerted angiogenic and cardiomyogenic effects in vitro. CONCLUSIONS: In sheep with AMI, Bv-Tbx20 induced angioarteriogenesis, cardiomyocyte cell cycle activity, infarct size limitation, and a slight recovery of left ventricular function, suggesting that Bv-Tbx20 gene therapy may contribute to cardiac regeneration following AMI.
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Baculoviridae , Terapia Genética , Infarto del Miocardio , Miocitos Cardíacos , Neovascularización Fisiológica , Proteínas de Dominio T Box , Animales , Baculoviridae/genética , Proliferación Celular , Células Cultivadas , Modelos Animales de Enfermedad , Terapia Genética/métodos , Vectores Genéticos , Infarto del Miocardio/genética , Infarto del Miocardio/terapia , Infarto del Miocardio/metabolismo , Infarto del Miocardio/patología , Miocardio/metabolismo , Miocardio/patología , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Ovinos , Proteínas de Dominio T Box/genética , Proteínas de Dominio T Box/metabolismo , Función Ventricular IzquierdaRESUMEN
Group 1 innate lymphoid cells (ILC1s) are cytotoxic and interferon gamma-producing lymphocytes lacking antigen-specific receptors, which include ILC1s and natural killer (NK) cells. In mice, ILC1s differ from NK cells, as they develop independently of the NK-specifying transcription factor EOMES, while requiring the repressor ZFP683 (ZNF683 in humans) for tissue residency. Here we identify highly variable ILC1 subtypes across tissues through investigation of human ILC1 diversity by single-cell RNA sequencing and flow cytometry. The intestinal epithelium contained abundant mature EOMES- ILC1s expressing PRDM1 rather than ZNF683, alongside a few immature TCF7+PRDM1- ILC1s. Other tissues harbored NK cells expressing ZNF683 and EOMES transcripts; however, EOMES protein content was variable. These ZNF683+ NK cells are tissue-imprinted NK cells phenotypically resembling ILC1s. The tissue ILC1-NK spectrum also encompassed conventional NK cells and NK cells distinguished by PTGDS expression. These findings establish a foundation for evaluating phenotypic and functional changes within the NK-ILC1 spectrum in diseases.
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Inmunidad Innata , Células Asesinas Naturales , Linfocitos , Factor 1 de Unión al Dominio 1 de Regulación Positiva , Proteínas de Dominio T Box , Humanos , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/metabolismo , Proteínas de Dominio T Box/metabolismo , Proteínas de Dominio T Box/genética , Factor 1 de Unión al Dominio 1 de Regulación Positiva/metabolismo , Factor 1 de Unión al Dominio 1 de Regulación Positiva/genética , Linfocitos/inmunología , Linfocitos/metabolismo , Análisis de la Célula Individual , Mucosa Intestinal/inmunología , Mucosa Intestinal/metabolismo , Animales , Ratones , Subgrupos Linfocitarios/inmunología , Subgrupos Linfocitarios/metabolismo , Proteínas Represoras/metabolismo , Proteínas Represoras/genéticaRESUMEN
In the tumor microenvironment (TME), CD8+ T cells showed stage exhaustion due to the continuous stimulation of tumor antigens. To evaluate the status of CD8+ T cells and reverse the exhaustion is the key to evaluate the prognosis and therapeutic effect of tumor patients. The aim of this study was to establish a prognostic signature that could effectively predict prognosis and response to immunotherapy in patients with hepatocellular carcinoma (HCC). We used univariate Cox analysis to obtain transcription factors associated with CD8+ T cell exhaustion from The Cancer Genome Atlas dataset. Then, the prognostic signature for transcription factors basic leucine zipper ATF-like transcription factor, Eomesodermin, and T-box protein 21 regulating T cell exhaustion was constructed using LASSO Cox regression. The relative expression levels of the mRNA of the 3 transcription factors were detected by reverse transcription-quantitative polymerase chain reaction in 23 pairs of HCC and paracancer tissues, and verified internally in The Cancer Genome Atlas dataset and externally in the International Cancer Genome Consortium dataset. Cox regression analysis showed that risk score was an independent prognostic variable. The overall survival of the high-risk group was significantly lower than that of the low-risk group. The low-risk group had higher immune scores, matrix scores, and ESTIMATE scores, and significantly increased expression levels of most immune checkpoint genes in the low-risk group. Therefore, patients with lower risk scores benefit more from immunotherapy. The combination of the 3 transcription factors can evaluate the exhaustion state of CD8+ T cells in the TME, laying a foundation for evaluating the TME and immunotherapy efficacy in patients with HCC.
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Linfocitos T CD8-positivos , Carcinoma Hepatocelular , Neoplasias Hepáticas , Microambiente Tumoral , Humanos , Carcinoma Hepatocelular/inmunología , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/mortalidad , Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/inmunología , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/mortalidad , Neoplasias Hepáticas/patología , Pronóstico , Masculino , Femenino , Microambiente Tumoral/inmunología , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Persona de Mediana Edad , Factores de Transcripción/genética , Inmunoterapia/métodos , Biomarcadores de Tumor/metabolismo , Biomarcadores de Tumor/genética , Proteínas de Dominio T Box/genética , Proteínas de Dominio T Box/metabolismo , Modelos de Riesgos Proporcionales , Agotamiento de Células TRESUMEN
T-BOX factors belong to an evolutionarily conserved family of transcription factors. T-BOX factors not only play key roles in growth and development but are also involved in immunity, cancer initiation, and progression. Moreover, the same T-BOX molecule exhibits different or even opposite effects in various developmental processes and tumor microenvironments. Understanding the multiple roles of context-dependent T-BOX factors in malignancies is vital for uncovering the potential of T-BOX-targeted cancer therapy. We summarize the physiological roles of T-BOX factors in different developmental processes and their pathological roles observed when their expression is dysregulated. We also discuss their regulatory roles in tumor immune microenvironment (TIME) and the newly arising questions that remain unresolved. This review will help in systematically and comprehensively understanding the vital role of the T-BOX transcription factor family in tumor physiology, pathology, and immunity. The intention is to provide valuable information to support the development of T-BOX-targeted therapy.
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Neoplasias , Microambiente Tumoral , Humanos , Neoplasias/metabolismo , Neoplasias/genética , Neoplasias/tratamiento farmacológico , Neoplasias/inmunología , Neoplasias/terapia , Microambiente Tumoral/genética , Animales , Proteínas de Dominio T Box/metabolismo , Proteínas de Dominio T Box/genética , Terapia Molecular DirigidaRESUMEN
BACKGROUND: TBX6, a member of the T-box gene family, encodes the transcription factor box 6 that is critical for somite segmentation in vertebrates. It is known that the compound heterozygosity of disruptive variants in trans with a common hypomorphic risk haplotype (T-C-A) in the TBX6 gene contribute to 10% of congenital scoliosis (CS) cases. The deletion of chromosome 17q12 is a rare cytogenetic abnormality, which often leads to renal cysts and diabetes mellitus. However, the affected individuals often exhibit clinical heterogeneity and incomplete penetrance. METHODS: We here present a Chinese fetus who was shown to have CS by ultrasound examination at 17 weeks of gestation. Trio whole-exome sequencing (WES) was performed to investigate the underlying genetic defects of the fetus. In vitro functional experiments, including western-blotting and luciferase transactivation assay, were performed to determine the pathogenicity of the novel variant of TBX6. RESULTS: WES revealed the fetus harbored a compound heterozygous variant of c.338_340del (p.Ile113del) and the common hypomorphic risk haplotype of the TBX6 gene. In vitro functional study showed the p.Ile113del variant had no impact on TBX6 expression, but almost led to complete loss of its transcriptional activity. In addition, we identified a 1.85 Mb deletion on 17q12 region in the fetus and the mother. Though there is currently no clinical phenotype associated with this copy number variation in the fetus, it can explain multiple renal cysts in the pregnant woman. CONCLUSIONS: This study is the first to report a Chinese fetus with a single amino acid deletion variant and a T-C-A haplotype of TBX6. The clinical heterogeneity of 17q12 microdeletion poses significant challenges for prenatal genetic counseling. Our results once again suggest the complexity of prenatal genetic diagnosis.
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Cromosomas Humanos Par 17 , Haplotipos , Heterocigoto , Proteínas de Dominio T Box , Humanos , Proteínas de Dominio T Box/genética , Femenino , Cromosomas Humanos Par 17/genética , Embarazo , Adulto , Deleción Cromosómica , Secuenciación del Exoma , Eliminación de Secuencia , Feto/anomalías , Ultrasonografía PrenatalRESUMEN
Objective: To investigate the clinicopathological features of Crooke cell tumor of adrenocorticotropic hormone differentiation specific transcription factor (TPIT, also known as transcription factor 19, TBX19) lineage neuroendocrine tumors. Methods: Six cases of Crooke cell tumor diagnosed at the First Affiliated Hospital of University of Science and Technology of China, Hefei, China from October 2019 to October 2023 were collected. The clinical and pathological features of these cases were analyzed. Results: Among the six cases, one was male and five were female, with ages ranging from 26 to 75 years, and an average age of 44 years. All tumors occurred within the sella turcica. Clinical presentations included visual impairment in two cases, menstrual disorders in one case, Cushing's syndrome in one case, headache in one case, and one asymptomatic case discovered during a physical examination. Preoperative serum analyses revealed elevated levels of cortisol and adrenocorticotropic hormones in two cases, elevated cortisol in two cases, elevated adrenocorticotropic hormone in one case, and one case with a mild increase in prolactin due to the pituitary stalk effect. Magnetic resonance imaging revealed uneven enhancement of masses with maximum diameters ranging from 1.7 to 3.2 cm, all identified as macroadenomas. Microscopically, tumor cells exhibited irregular polygonal shapes, solid sheets, or pseudo-papillary arrangements around blood vessels. The cell nuclei were eccentric or centrally located, varying in size, with abundant cytoplasm. Some tumor cells showed perinuclear halo. Immunohistochemistry demonstrated diffuse strong positivity for TPIT in five cases, focal weak positivity for TPIT in one case, diffuse strong positivity for adrenocorticotropic hormone in all cases, and faint staining around the nuclei in a few cells. CK8/18 showed a strong positive ring pattern in more than 50% of tumor cells, focal weak positive expression of p53, and the Ki-67 positive index ranged 1%-5%. Periodic acid-Schiff staining revealed positive cytoplasm and negative perinuclear areas. Conclusions: Crooke cell tumor is a rare type of pituitary neuroendocrine tumors. Its pathological characteristics include a distinctive perinuclear clear zone and immunohistochemical markers, such as CK8/18 exhibiting a ring or halo pattern. This entity represents a high-risk subtype among pituitary neuroendocrine tumors, displaying a high risk of invasion and a propensity for recurrence. Accurate diagnosis is crucial for the postoperative follow-up and multimodal treatment planning.
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Hormona Adrenocorticotrópica , Tumores Neuroendocrinos , Neoplasias Hipofisarias , Humanos , Masculino , Persona de Mediana Edad , Femenino , Neoplasias Hipofisarias/patología , Neoplasias Hipofisarias/metabolismo , Neoplasias Hipofisarias/diagnóstico , Adulto , Anciano , Tumores Neuroendocrinos/metabolismo , Tumores Neuroendocrinos/patología , Tumores Neuroendocrinos/diagnóstico , Hormona Adrenocorticotrópica/metabolismo , Proteínas de Dominio T Box/metabolismo , Imagen por Resonancia Magnética , Hidrocortisona/metabolismo , Proteínas de HomeodominioRESUMEN
Autism spectrum disorders (ASDs) are considered neural dysconnectivity syndromes. To better understand ASD and uncover potential treatments, it is imperative to know and dissect the connectivity deficits under conditions of autism. Here, we apply a whole-brain immunostaining and quantification platform to demonstrate impaired structural and functional connectivity and aberrant whole-brain synchronization in a Tbr1+/- autism mouse model. We express a channelrhodopsin variant oChIEF fused with Citrine at the basolateral amygdala (BLA) to outline the axonal projections of BLA neurons. By activating the BLA under blue light theta-burst stimulation (TBS), we then evaluate the effect of BLA activation on C-FOS expression at a whole brain level to represent neural activity. We show that Tbr1 haploinsufficiency almost completely disrupts contralateral BLA axonal projections and results in mistargeting in both ipsilateral and contralateral hemispheres, thereby globally altering BLA functional connectivity. Based on correlated C-FOS expression among brain regions, we further show that Tbr1 deficiency severely disrupts whole-brain synchronization in the absence of salient stimulation. Tbr1+/- and wild-type (WT) mice exhibit opposing responses to TBS-induced amygdalar activation, reducing synchronization in WT mice but enhancing it in Tbr1+/- mice. Whole-brain modular organization and intermodule connectivity are also affected by Tbr1 deficiency and amygdalar activation. Following BLA activation by TBS, the synchronizations of the whole brain and the default mode network, a specific subnetwork highly relevant to ASD, are enhanced in Tbr1+/- mice, implying a potential ameliorating effect of amygdalar stimulation on brain function. Indeed, TBS-mediated BLA activation increases nose-to-nose social interactions of Tbr1+/- mice, strengthening evidence for the role of amygdalar connectivity in social behaviors. Our high-resolution analytical platform reveals the inter- and intrahemispheric connectopathies arising from ASD. Our study emphasizes the defective synchronization at a whole-brain scale caused by Tbr1 deficiency and implies a potential beneficial effect of deep brain stimulation at the amygdala for TBR1-linked autism.
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Trastorno del Espectro Autista , Complejo Nuclear Basolateral , Estimulación Encefálica Profunda , Modelos Animales de Enfermedad , Conducta Social , Proteínas de Dominio T Box , Animales , Trastorno del Espectro Autista/fisiopatología , Trastorno del Espectro Autista/metabolismo , Trastorno del Espectro Autista/genética , Proteínas de Dominio T Box/metabolismo , Proteínas de Dominio T Box/genética , Complejo Nuclear Basolateral/metabolismo , Complejo Nuclear Basolateral/fisiopatología , Ratones , Estimulación Encefálica Profunda/métodos , Masculino , Amígdala del Cerebelo/metabolismo , Amígdala del Cerebelo/fisiopatología , Encéfalo/metabolismo , Encéfalo/fisiopatología , Ratones Endogámicos C57BL , Vías Nerviosas/fisiopatología , Vías Nerviosas/metabolismo , Proteínas Proto-Oncogénicas c-fos/metabolismoRESUMEN
Type 2 diabetes mellitus negatively affects the immune system, resulting in reduced natural killer (NK) cell activity. Vitamin D has been shown to regulate innate and adaptive immune cells. However, the effects of vitamin D on NK cells remain inconclusive, especially in the context of diabetes. We hypothesized that dietary vitamin D3 supplementation can enhance NK cell activity in diabetic mice. Therefore, we investigated the effects of dietary vitamin D3 on NK cell activity in control and diabetic mice and explored the mechanisms of NK cell activity modulation by vitamin D3. Control (CON) and diabetic mice (db/db) were randomly divided into 2 groups, then fed either a control diet (948 IU vitamin D3/kg diet, vDC) or a diet supplemented with vitamin D3 (9,477 IU vitamin D3/kg diet, vDS) for 8 weeks. Diabetic mice exhibited lower NK cell activity than control mice. The vDS group had significantly higher NK cell activity than the vDC group in both control and diabetic mice. The vDS group had a higher percentage of CD11b single-positive NK cells than the vDC group (CON-vDS 34%; db/db-vDS 30%; CON-vDC 27%; db/db-vDC 22%). The intracellular expression of splenic TGF-ß was significantly higher in the db/db group than in the CON group. Overall, vDS group had higher Bcl2 and Tbx21 mRNA expressions than the vDC group. In conclusion, the present study shows that NK cell activity is impaired under diabetic conditions, possibly due to the reduced percentage of mature NK cells. Moreover, NK activity is enhanced by dietary supplementation in both control and diabetic mice that may be associated with changes in the proportion of mature NK cells.
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Colecalciferol , Diabetes Mellitus Tipo 2 , Suplementos Dietéticos , Células Asesinas Naturales , Bazo , Animales , Células Asesinas Naturales/efectos de los fármacos , Células Asesinas Naturales/metabolismo , Masculino , Colecalciferol/farmacología , Colecalciferol/administración & dosificación , Bazo/metabolismo , Ratones , Diabetes Mellitus Tipo 2/dietoterapia , Diabetes Mellitus Experimental/dietoterapia , Ratones Endogámicos C57BL , Proteínas de Dominio T Box/metabolismo , Proteínas de Dominio T Box/genéticaRESUMEN
The extensive degeneration of functional somatic cells and the depletion of endogenous stem/progenitor populations present significant challenges to tissue regeneration in degenerative diseases. Currently, a cellular reprogramming approach enabling directly generating corresponding progenitor populations from degenerative somatic cells remains elusive. The present study focused on intervertebral disc degeneration (IVDD) and identified a three-factor combination (OCT4, FOXA2, TBXT [OFT]) that could induce the dedifferentiation-like reprogramming of degenerative nucleus pulposus cells (dNPCs) toward induced notochordal-like cells (iNCs). Single-cell transcriptomics dissected the transitions of cell identity during reprogramming. Further, OCT4 was found to directly interact with bromodomain PHD-finger transcription factor to remodel the chromatin during the early phases, which was crucial for initiating this dedifferentiation-like reprogramming. In rat models, intradiscal injection of adeno-associated virus carrying OFT generated iNCs from in situ dNPCs and reversed IVDD. These results collectively present a proof-of-concept for dedifferentiation-like reprogramming of degenerated somatic cells into corresponding progenitors through the development of a factor-based strategy, providing a promising approach for regeneration in degenerative disc diseases.
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Desdiferenciación Celular , Reprogramación Celular , Degeneración del Disco Intervertebral , Notocorda , Núcleo Pulposo , Núcleo Pulposo/metabolismo , Núcleo Pulposo/citología , Núcleo Pulposo/patología , Animales , Reprogramación Celular/genética , Degeneración del Disco Intervertebral/terapia , Degeneración del Disco Intervertebral/patología , Degeneración del Disco Intervertebral/metabolismo , Ratas , Notocorda/metabolismo , Notocorda/citología , Humanos , Modelos Animales de Enfermedad , Factor 3 de Transcripción de Unión a Octámeros/metabolismo , Factor 3 de Transcripción de Unión a Octámeros/genética , Análisis de la Célula Individual , Proteínas de Dominio T Box/metabolismo , Proteínas de Dominio T Box/genética , Células CultivadasRESUMEN
The neurons of the three cerebellar nuclei (CN) are the primary output neurons of the cerebellum. The excitatory neurons (e) of the medial (m) CN (eCNm) were recently divided into molecularly defined subdomains in the adult; however, how they are established during development is not known. We define molecular subdomains of the mouse embryonic eCNm using single-cell RNA-sequencing and spatial expression analysis, showing that they evolve during embryogenesis to prefigure the adult. Furthermore, eCNm are transcriptionally divergent from cells in the other nuclei by embryonic day 14.5. We previously showed that loss of the homeobox genes En1 and En2 leads to loss of approximately half of the embryonic eCNm. We demonstrate that mutation of En1/2 in the embryonic eCNm results in death of specific posterior eCNm molecular subdomains and downregulation of TBR2 (EOMES) in an anterior embryonic subdomain, as well as reduced synaptic gene expression. We further reveal a similar function for EN1/2 in mediating TBR2 expression, neuron differentiation and survival in the other excitatory neurons (granule and unipolar brush cells). Thus, our work defines embryonic eCNm molecular diversity and reveals conserved roles for EN1/2 in the cerebellar excitatory neuron lineage.
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Regulación del Desarrollo de la Expresión Génica , Proteínas de Homeodominio , Neuronas , Animales , Proteínas de Homeodominio/metabolismo , Proteínas de Homeodominio/genética , Ratones , Neuronas/metabolismo , Neuronas/citología , Supervivencia Celular/genética , Diferenciación Celular/genética , Cerebelo/embriología , Cerebelo/metabolismo , Cerebelo/citología , Proteínas de Dominio T Box/metabolismo , Proteínas de Dominio T Box/genética , Núcleos Cerebelosos/metabolismo , Núcleos Cerebelosos/embriología , Núcleos Cerebelosos/citología , Análisis de la Célula Individual , Proteínas del Tejido NerviosoRESUMEN
Integrated human genetics and molecular/developmental biology studies have revealed that truncus arteriosus is highly associated with 22q11.2 deletion syndrome. Other congenital malformation syndromes and variants in genes encoding TBX, GATA, and NKX transcription factors and some signaling proteins have also been reported as its etiology.
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Tronco Arterial Persistente , Humanos , Tronco Arterial Persistente/genética , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Tronco Arterial/metabolismo , Síndrome de DiGeorge/genética , Proteínas de Dominio T Box/genética , Proteínas de Dominio T Box/metabolismo , Predisposición Genética a la Enfermedad/genéticaRESUMEN
Chordomas, arising from notochord remnants, are rare neoplasms with aggressive growth patterns despite their histologically low-grade nature. This review explores their embryological origins, molecular markers like brachyury, and genetic alterations driving pathogenesis. Diagnosis relies on advanced imaging and biopsy confirmation due to overlapping features with chondrosarcoma. The WHO classification distinguishes conventional, dedifferentiated, and poorly differentiated chordomas, each with distinct prognostic implications. Recent genomic analyses uncovered recurrent mutations in PI3K signaling pathways and chromatin remodeling genes, informing prognostic models. Surgery remains the cornerstone of treatment, though adjuvant radiation complements surgical resection. Although chordomas are generally considered refractory to medical therapy, emerging targeted molecular strategies show potential promise in ongoing trials. This review aims to provide a concise yet comprehensive overview of chordomas, guiding clinicians in diagnosis, treatment, and prognostication for improved patient outcomes.
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Cordoma , Humanos , Cordoma/genética , Cordoma/terapia , Cordoma/patología , Cordoma/diagnóstico , Pronóstico , Biomarcadores de Tumor/genética , Mutación , Proteínas de Dominio T Box/genética , Proteínas de Dominio T Box/metabolismo , Manejo de la Enfermedad , Proteínas FetalesRESUMEN
Introduction: Toxoplasma gondii is an intracellular parasite of importance to human and veterinary health. The structure and diversity of the genotype population of T. gondii varies considerably with respect to geography, but three lineages, type I, II and III, are distributed globally. Lineage III genotypes are the least well characterized in terms of biology, host immunity and virulence. Once a host is infected with T.gondii, innate immune mechanisms are engaged to reduce the parasite burden in tissues and create a pro-inflammatory environment in which the TH1 response develops to ensure survival. This study investigated the early cellular immune response of Swiss-Webster mice post intraperitoneal infection with 10 tachyzoites of four distinct non-clonal genotypes of lineage III and a local isolate of ToxoDB#1. The virulence phenotype, cumulative mortality (CM) and allele profiles of ROP5, ROP16, ROP18 and GRA15 were published previously. Methods: Parasite dissemination in different tissues was analyzed by real-time PCR and relative expression levels of IFNγ, IL12-p40, IL-10 and TBX21 in the cervical lymph nodes (CLN), brain and spleen were calculated using the ΔΔCt method. Stage conversion was determined by detection of the BAG1 transcript in the brain. Results: Tissue dissemination depends on the virulence phenotype but not CM, while the TBX21 and cytokine levels and kinetics correlate better with CM than virulence phenotype. The earliest detection of BAG1 was seven days post infection. Only infection with the genotype of high CM (69.4%) was associated with high T-bet levels in the CLN 24 h and high systemic IFNγ expression which was sustained over the first week, while infection with genotypes of lower CM (38.8%, 10.7% and 6.8%) is characterized by down-regulation and/or low systemic levels of IFNγ. The response intensity, as assessed by cytokine levels, to the genotype of high CM wanes over time, while it increases gradually to genotypes of lower CM. Discussion: The results point to the conclusion that the immune response is not correlated with the virulence phenotype and/or allele profile, but an early onset, intense pro-inflammatory response is characteristic of genotypes with high CM. Additionally, high IFNγ level in the brain may hamper stage conversion.