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Objective: To observe the diagnostic value of four serum inflammatory biomarkers, including interleukin 6 (IL-6), interleukin 12P70 (IL-12P70), serum amyloid A (SAA), and procalcitonin (PCT), in rheumatoid arthritis (RA) and to analyze their relationship with the disease activity. Methods: The study included 60 RA patients admitted to the Department of Rheumatology at Anhui Provincial Hospital of Traditional Chinese Medicine between December 2022 and December 2023. Thirty healthy individuals from the hospital's physical examination center served as the control group. Serum levels of IL-6 and IL-12P70 were detected using flow cytometry. SAA levels were determined by immunoturbidimetry, and PCT levels were assessed by chemiluminescence. Erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), rheumatoid factor (RF), and anticyclic citrullinated peptide (ACCP) were detected using an automated biochemical analyzer. The 28-joint disease activity scores (DAS28-ESR) based on ESR were observed. Statistical analysis included t-tests, rank-sum tests, and Kruskal-Wallis H tests to compare the expression differences of the biomarkers among different groups. The diagnostic value of these biomarkers for RA was analyzed by ROC curve analysis. Spearman correlation analysis was performed to assess the relationships between the four inflammatory biomarkers and CRP, ESR, RF, ACCP, and DAS28-ESR. Results: 1) The expression levels of SAA, IL-6, and IL-12P70 in the RA group were significantly higher than those in the control group (P<0.01). 2) ROC curve analysis showed that the area under the curve (AUC) for PCT was 0.611 (95% confidence interval [CI]: 0.488-0.735, P>0.05), for SAA, it was 0.819 (95% CI: 0.733-0.906, P<0.01), for IL-6, it was 0.875 (95% CI: 0.803-0.946, P<0.01), and for IL-12P70, it was 0.832 (95% CI: 0.746-0.917, P<0.01). The combined index of IL-6, IL-12P70, SAA, and PCT had an AUC of 0.973 (95% CI: 0.942-1.000, P<0.01). This indicates that the four inflammatory biomarkers can assist in the diagnosis of rheumatoid arthritis. 3) The expression levels of PCT and SAA varied significantly among the high, moderate, and low activity RA groups (P<0.01). 4) In RA patients, CRP was positively correlated with SAA (rs =0.75, P<0.01), and IL-6 (rs =0.52, P<0.01). ESR was positively correlated with SAA (rs =0.36, P<0.01). DAS28-ESR was positively correlated with PCT (rs =0.34, P=0.01), SAA (rs =0.51, P<0.01) and IL-6 (rs =0.33, P=0.01). Conclusion: The four inflammatory biomarkers (PCT, SAA, IL-6, and IL-12P70) are closely related to rheumatoid arthritis disease activity and can serve as serum indicators to assist in the diagnosis and assessment of RA.
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Artritis Reumatoide , Biomarcadores , Interleucina-12 , Interleucina-6 , Polipéptido alfa Relacionado con Calcitonina , Proteína Amiloide A Sérica , Humanos , Artritis Reumatoide/diagnóstico , Artritis Reumatoide/sangre , Proteína Amiloide A Sérica/metabolismo , Polipéptido alfa Relacionado con Calcitonina/sangre , Interleucina-6/sangre , Biomarcadores/sangre , Interleucina-12/sangre , Sedimentación Sanguínea , Masculino , Femenino , Proteína C-Reactiva/metabolismo , Proteína C-Reactiva/análisis , Persona de Mediana Edad , Curva ROCRESUMEN
BACKGROUND: Chordoma, a rare malignant tumor arising from notochordal tissue, usually occurs along the spinal axis. Only a few published reports of primary lung chordomas exist. Herein, we present a case of primary lung chordoma and discuss important considerations for diagnosing rare chordomas. CASE PRESENTATION: We report a case of primary lung chordoma in a 39-year-old male with a history of testicular mixed germ-cell tumor of yolk sac and teratoma. Computed tomography revealed slow-growing solid lesions in the left lower lobe. We performed wedge resection for suspected germ-cell tumor lung metastasis. Histologically, large round or oval cells with eosinophilic cytoplasm were surrounded by large cells with granular, lightly eosinophilic cytoplasm. Tumor cells were physaliphorous. Immunohistochemistry was positive for brachyury, S-100 protein, epithelial membrane antigen, vimentin, and cytokeratin AE1/AE3, suggesting pulmonary chordoma. Re-examination of the testicular mixed germ-cell tumor revealed no notochordal elements. Although some areas were positive for brachyury staining, hematoxylin and eosin (HE) staining did not show morphological features typical of chordoma. Complementary fluorescence in situ hybridization (FISH) of the lung tumor confirmed the absence of isochromosome 12p and 12p amplification. Thus, a final diagnosis of primary lung chordoma was established. CONCLUSIONS: In patients with a history of testicular mixed germ cell tumors, comparison of histomorphology using HE and Brachyury staining of lung and testicular tumors, and analyzing isochromosome 12p and 12p amplification in lung tumors using FISH is pivotal for the diagnosis of rare lung chordomas.
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Biomarcadores de Tumor , Cordoma , Neoplasias Pulmonares , Neoplasias de Células Germinales y Embrionarias , Neoplasias Testiculares , Humanos , Masculino , Cordoma/patología , Cordoma/diagnóstico , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/diagnóstico , Adulto , Biomarcadores de Tumor/análisis , Neoplasias de Células Germinales y Embrionarias/patología , Neoplasias de Células Germinales y Embrionarias/química , Neoplasias de Células Germinales y Embrionarias/diagnóstico , Neoplasias Testiculares/patología , Neoplasias Testiculares/diagnóstico , Neoplasias Testiculares/química , Inmunohistoquímica , Hibridación Fluorescente in Situ , Teratoma/patología , Teratoma/química , Teratoma/diagnósticoRESUMEN
OBJECTIVE: We present prenatal diagnosis of de novo 10p12.1p11.23 microdeletion encompassing the WAC gene in a fetus associated with bilateral hydronephrosis on prenatal ultrasound. CASE REPORT: A 40-year-old, gravida 2, para 1, woman underwent amniocentesis at 17 weeks of gestation because of advanced maternal age. Amniocentesis revealed a karyotype of 46,XY. Level II ultrasound at 22 weeks of gestation revealed bilateral hydronephrosis and right clubfoot. At 23 weeks of gestation, repeat amniocentesis revealed the result of arr [GRCh37] 10p12.1p11.23 (26,182,512-29,826,276) × 1 dn with a 3.6-Mb microdeletion of 10p12.1p11.23 encompassing the genes of MYO3A, GAD2, APBB1IP, PDSS1, ABI1, ANKRD26, YME1L1, MASTL, ACBD5, PTCHD3, RAB18, MKX, ODAD2, MPP7, WAC and BAMBI. The pregnancy was subsequently terminated, and a malformed fetus was delivered with facial dysmorphism of low-set ears, broad forehead and flat nasal bridge. Array comparative genomic hybridization (aCGH) analysis of umbilical cord confirmed a 3.6-Mb 10p12.1p11.23 microdeletion encompassing WAC. CONCLUSION: Application of aCGH is useful in the pregnancy with a normal fetal karyotype and abnormal fetal ultrasound.
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Amniocentesis , Deleción Cromosómica , Cromosomas Humanos Par 10 , Pie Equinovaro , Hidronefrosis , Ultrasonografía Prenatal , Humanos , Femenino , Pie Equinovaro/genética , Pie Equinovaro/diagnóstico por imagen , Embarazo , Adulto , Hidronefrosis/genética , Hidronefrosis/diagnóstico por imagen , Cromosomas Humanos Par 10/genética , Aborto InducidoRESUMEN
Background: Postoperative atrial fibrillation (POAF) is a frequent complication of heart surgery, prolonging hospital stays, as well as increasing morbidity and mortality rates. While previous studies have investigated the determinants influencing atrial fibrillation (AF) following heart surgery, the specific risk factors contributing to POAF occurrence after coronary artery bypass graft surgery (CABG) are not well understood. Here we used the human magnetic Luminex assay to assess whether biomarkers, particularly cytokines, within intraoperative pericardial fluid could serve as predictive markers for POAF onset among CABG individuals. Methods: In this study we identified 180 patients who underwent CABG with no atrial arrhythmia history. The human magnetic Luminex assay was used to quantify the levels of 36 cytokines in pericardial fluid samples collected during the surgery. The occurrence of POAF was continuously monitored, using both postoperative electrocardiograms and telemetry strips, until the time of discharge. Results: In our cohort of 124 patients, POAF was observed in 30 patients, accounting for 24.19% of the study population. These patients exhibited significantly higher levels of interleukin (IL)-12p70 in their intraoperative pericardial fluids compared to those with normal sinus rhythms (SR, p < 0.001). Subsequently, IL-12p70 was found to be an independent risk factor for POAF, and receiver operating characteristic (ROC) analysis established a cut-off threshold for predicting POAF onset of 116.435 pg/mL, based on the maximum Youden index (area under the curve: 0.816). Conclusions: this study establishes a significant association between elevated IL-12p70 levels in intraoperative pericardial fluid and the risk of POAF, particularly when IL-12p70 concentrations exceed the identified cut-off value of 116.435 pg/mL. These findings suggest that IL-12p70 levels could potentially be utilized as a predictive biomarker for the onset of POAF in patients undergoing CABG. This marker may aid in the early identification and management of patients at heightened risk for this complication.
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Abstract: This report from the Australian Rotavirus Surveillance Program describes the circulating rotavirus genotypes identified in children and adults during the period 1 January to 31 December 2022. After two years of a lower number of stool samples received as a result of the coronavirus disease 2019 (COVID-19) pandemic, this reporting period saw the highest number of samples received since the 2017 surveillance period, with samples received from all states and territories. During this period, 1,379 faecal specimens had been referred for rotavirus G- and P- genotype analysis, of which 1,276 were confirmed as rotavirus positive. In total, 1,119/1,276 were identified as wildtype rotavirus, 155/1,276 identified as the Rotarix vaccine strain and 2/1,276 that could not be confirmed as vaccine or wildtype due to sequencing failure. Whilst G12P[8] was the dominant genotype nationally among wildtype samples (28.2%; 315/1,119), multiple genotypes were identified at similar frequencies including G9P[4] (22.3%; 249/1,119) and G2P[4] (20.3%; 227/1,119). Geographical differences in genotype distribution were observed, largely driven by outbreaks reported in some jurisdictions. Outbreaks and increased reports of rotavirus disease were reported in the Northern Territory, Queensland, and New South Wales. A small number of unusual genotypes, potentially zoonotic in nature, were identified, including: G8P[14]; G10[14]; caninelike G3P[3]; G6P[9]; and G11P[25]. Ongoing rotavirus surveillance is crucial to identify changes in genotypic patterns and to provide diagnostic laboratories with quality assurance by reporting incidences of wildtype, vaccine-like, or false positive rotavirus results.
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Heces , Genotipo , Infecciones por Rotavirus , Vacunas contra Rotavirus , Rotavirus , Humanos , Infecciones por Rotavirus/epidemiología , Infecciones por Rotavirus/virología , Rotavirus/genética , Australia/epidemiología , Heces/virología , Preescolar , Lactante , Niño , Adulto , COVID-19/epidemiología , COVID-19/virología , SARS-CoV-2/genética , Adolescente , Femenino , Masculino , Brotes de Enfermedades , Vacunas Atenuadas , Recién Nacido , Informes Anuales como Asunto , Monitoreo Epidemiológico , Persona de Mediana EdadRESUMEN
Aberrant male germline development can lead to the formation of seminoma, a testicular germ cell tumor. Seminomas are biologically similar to primordial germ cells (PGCs) and many bear an isochromosome 12p [i(12p)] with two additional copies of the short arm of chromosome 12. By mapping seminoma transcriptomes and open chromatin landscape onto a normal human male germline trajectory, we find that seminoma resembles premigratory/migratory PGCs; however, it exhibits enhanced germline and pluripotency programs and upregulation of genes involved in apoptosis, angiogenesis, and MAPK/ERK pathways. Using pluripotent stem cell-derived PGCs from Pallister-Killian syndrome patients mosaic for i(12p), we model seminoma and identify gene dosage effects that may contribute to transformation. As murine seminoma models do not exist, our analyses provide critical insights into genetic, cellular, and signaling programs driving seminoma transformation, and the in vitro platform developed herein permits evaluation of additional signals required for seminoma tumorigenesis.
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Epigénesis Genética , Células Germinativas , Seminoma , Neoplasias Testiculares , Humanos , Seminoma/genética , Seminoma/patología , Seminoma/metabolismo , Masculino , Células Germinativas/metabolismo , Neoplasias Testiculares/genética , Neoplasias Testiculares/patología , Neoplasias Testiculares/metabolismo , Transcripción Genética , Regulación Neoplásica de la Expresión Génica , Transcriptoma/genéticaRESUMEN
Accurate screening of COVID-19 infection status for symptomatic patients is a critical public health task. Although molecular and antigen tests now exist for COVID-19, in resource-limited settings, screening tests are often not available. Furthermore, during the early stages of the pandemic tests were not available in any capacity. We utilized an automated machine learning (ML) approach to train and evaluate thousands of models on a clinical dataset consisting of commonly available clinical and laboratory data, along with cytokine profiles for patients (n = 150). These models were then further tested for generalizability on an out-of-sample secondary dataset (n = 120). We were able to develop a ML model for rapid and reliable screening of patients as COVID-19 positive or negative using three approaches: commonly available clinical and laboratory data, a cytokine profile, and a combination of the common data and cytokine profile. Of the tens of thousands of models automatically tested for the three approaches, all three approaches demonstrated > 92% sensitivity and > 88 specificity while our highest performing model achieved 95.6% sensitivity and 98.1% specificity. These models represent a potential effective deployable solution for COVID-19 status classification for symptomatic patients in resource-limited settings and provide proof-of-concept for rapid development of screening tools for novel emerging infectious diseases.
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COVID-19 , Citocinas , Aprendizaje Automático , Humanos , COVID-19/diagnóstico , Citocinas/sangre , SARS-CoV-2/aislamiento & purificación , SARS-CoV-2/inmunología , Tamizaje Masivo/métodos , Masculino , Femenino , Sensibilidad y Especificidad , Persona de Mediana Edad , Adulto , AncianoRESUMEN
The interleukin-12 (IL-12) family is a class of heterodimeric cytokines that play crucial roles in pro-inflammatory and pro-stimulatory responses. Although some IL-12 and IL-23 paralogues have been found in fish, their functional activity in fish remains poorly understood. In this study, Pf_IL-12p35a/b, Pf_IL-23p19 and Pf_IL-12p40a/b/c genes were cloned from yellow catfish (Pelteobagrus fulvidraco), four α-helices were found in Pf_IL-12p35a/b and Pf_IL-23p19. The transcripts of these six genes were relatively high in mucus and immune tissues of healthy individuals, and in gill leukocytes. Following Edwardsiella ictaluri infection, Pf_IL-12p35a/b and Pf_IL-23p19 mRNAs were induced in brain and kidney (or head kidney), Pf_IL-12p40a mRNA was induced in gill, and Pf_IL-12p40b/c mRNAs were induced in brain and liver (or skin). The mRNA expression of these genes in PBLs was induced by phytohaemagglutinin (PHA) and polyinosinic-polycytidylic acid (poly I:C), while lipopolysaccharides (LPS) induced the mRNA expression of Pf_IL-12p35a and Pf_IL-12p40b/c in PBLs. After stimulation with recombinant (r) Pf_IL-12 and rPf_IL-23 subunit proteins, either alone or in combination, mRNA expression patterns of genes related to T helper cell development exhibited distinct differences. The results suggest that Pf_IL-12 and Pf_IL-23 subunits may play important roles in regulating immune responses to pathogens and T helper cell development.
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Bagres , Infecciones por Enterobacteriaceae , Enfermedades de los Peces , Proteínas de Peces , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Inmunidad Innata , Subunidad p40 de la Interleucina-12 , Animales , Bagres/genética , Bagres/inmunología , Proteínas de Peces/genética , Proteínas de Peces/inmunología , Proteínas de Peces/química , Infecciones por Enterobacteriaceae/inmunología , Infecciones por Enterobacteriaceae/veterinaria , Enfermedades de los Peces/inmunología , Regulación de la Expresión Génica/inmunología , Subunidad p40 de la Interleucina-12/genética , Subunidad p40 de la Interleucina-12/inmunología , Perfilación de la Expresión Génica/veterinaria , Inmunidad Innata/genética , Edwardsiella ictaluri/fisiología , Subunidad p35 de la Interleucina-12/genética , Subunidad p35 de la Interleucina-12/inmunología , Filogenia , Secuencia de Aminoácidos , Alineación de Secuencia/veterinaria , Subunidad p19 de la Interleucina-23/genética , Subunidad p19 de la Interleucina-23/inmunología , Poli I-C/farmacologíaRESUMEN
Spermatocytic tumors are rare testicular tumors occurring predominantly in older men. Most show a classical tripartite morphology (different from seminoma) and are benign. However, well-documented cases of malignant spermatocytic tumors exist. Our previous work showed that a subset of spermatocytic tumors exhibiting TP53 mutations, DNA methylation profiles closer to seminomas, and/or gains in chromosome 12p exhibited aggressive characteristics, including sarcomatoid transformation and metastatic dissemination. The microRNA-371-373 cluster is a promising biomarker which is upregulated in non-teratoma germ cell tumors with malignant behavior. In this work we analyze microRNAs-371-373 b y quantitative real-time polymerase chain reaction in 18 spermatocytic tumors representative of the whole clinical spectrum, including 6 with aggressive features (sarcomatoid transformation, metastases, or gains in chromosome 12p). The levels of microRNAs-371-373 were significantly higher in non-teratoma germ cell tumors compared to spermatocytic tumors, overall (p < 0.0001). Importantly, levels of microRNA-371-373 were higher in spermatocytic tumors with aggressive features compared to non-aggressive neoplasms. The highest levels were observed in one tumor showing isochromosome 12p. These results further support our previous findings that a subset of spermatocytic tumors are intermediate between so-called type II and type III germ cell tumors and that embryonic microRNAs play a role in aggressive behavior in spermatocytic tumors. Accordingly, this subset of tumors may behave aggressively and require close follow up. In the future, this opens an opportunity for microRNA testing in serum of spermatocytic tumor patients for risk stratification purposes.
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Biomarcadores de Tumor , MicroARNs , Neoplasias de Células Germinales y Embrionarias , Neoplasias Testiculares , Humanos , Masculino , MicroARNs/genética , Neoplasias Testiculares/genética , Neoplasias Testiculares/patología , Neoplasias de Células Germinales y Embrionarias/genética , Neoplasias de Células Germinales y Embrionarias/patología , Adulto , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/análisis , Persona de Mediana Edad , Anciano , Reacción en Cadena en Tiempo Real de la Polimerasa , Regulación Neoplásica de la Expresión Génica , Adulto JovenRESUMEN
Extragonadal germ cell tumors (EGCTs) are rare, representing <5% of all germ cell tumors (GCTs). Whilst EGCTs share morphological and immunohistochemical features with their gonadal counterparts, they tend to be more aggressive and are frequently associated with secondary somatic malignancies. The aim of our study was to evaluate the clinical, morphological and immunohistochemical features, and to analyze tumors for chromosomal abnormalities of 12p, in addition to any novel genetic alterations, in a series of EGCTs. Seventy-seven EGCTs were included. Anterior mediastinum was the most common anatomic site, followed by central nervous system, retroperitoneum, sacroccygeal area, and neck. Whole genome SNP array identified isochromosome 12p in 26% of tumors. Additional cytogenetic abnormalities included the presence of gain of chr 21 in 37% of tumors. Somatic-type malignancies were identified in 8% of patients. Disease progression (metastasis and/or recurrence) was documented in 8 patients, most of whom died from their relapse. Three patients who died of disease had somatic-type malignancies. Mediastinal seminomas had a significantly better overall survival when compared to mediastinal non-seminomatous GCTs. Our study demonstrates that EGCTs share similar histologic features, but diverse clinical outcomes compared to their gonadal counterparts. Outcomes vary according to anatomic location and histologic subtypes. Our data corroborate that somatic-type malignancies are frequently encountered in mediastinal EGCTs and that their presence portends a poorer prognosis.
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Neoplasias de Células Germinales y Embrionarias , Humanos , Neoplasias de Células Germinales y Embrionarias/patología , Neoplasias de Células Germinales y Embrionarias/genética , Masculino , Adulto , Femenino , Adulto Joven , Adolescente , Persona de Mediana Edad , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/análisis , Niño , Neoplasias Primarias Secundarias/patología , Neoplasias Primarias Secundarias/genética , Neoplasias del Mediastino/patología , Neoplasias del Mediastino/genética , Neoplasias del Mediastino/mortalidad , Inmunohistoquímica , Cromosomas Humanos Par 12/genética , Anciano , Recurrencia Local de Neoplasia/patología , Progresión de la Enfermedad , Polimorfismo de Nucleótido Simple , Aberraciones Cromosómicas , Predisposición Genética a la Enfermedad , Neoplasias TesticularesRESUMEN
Multiple genome sequencing studies have identified genetic abnormalities as major causes of severe intellectual disability (ID). However, many children affected by mild ID and borderline intellectual functioning (BIF) lack a genetic diagnosis because known causative ID genetic mutations have not been identified or the role of genetic variants in mild cases is less understood. Genetic variant testing in mild cases is necessary to provide information on prognosis and risk of occurrence. In this study, we report two sibling patients who were 5 years 9 months old and 3 years 3 months old and presented to the hospital due to developmental delay. Clinical assessment and chromosomal microarray analysis were performed. The patients were diagnosed with mild intellectual disability (ID) and borderline intellectual functioning (BIF). Genetic analysis identified a loss of 12p11.22, including the OVCH1-AS1, OVCH1, and TMTC1 genes, which was the only variant that occurred in both sisters. Identical variants were found in their father with probable BIF. Neither patient presented any brain structural abnormalities or dysmorphism, and no exogenous factors or parenting problems were reported. Thus, loss of 12p11.22 may be associated with our patients' cognitive impairment. The OVCH1, OVCH1-AS1 and TMTC1 variants identified in this study are the most likely disease-causing genes in the sisters. Our findings may expand as yet limited knowledge on mild ID and BIF causative variants, which would further support the diagnosis even if the severity is mild.
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BACKGROUND: The interleukin (IL) -12 p40 subunit is the common subunit of IL-12 and IL-23. It affects the immune inflammatory response, which may be closely related to cardiac remodeling. In this study, the regulatory effect of IL-12p40 knockout (KO) on cardiac remodeling was investigated, and the underlying mechanism was explored. METHODS AND RESULTS: Mice were subjected to transverse aortic constriction (TAC) to establish a model of cardiac remodeling. First, IL-12p40 was deleted to observe its effects on cardiac remodeling and cardiac inflammation, and the results showed that IL-12p40 deletion reduced both T helper 17 (Th17) and γδT17 cell differentiation, decreased proinflammatory macrophage differentiation, alleviated cardiac remodeling, and relieved cardiac dysfunction in TAC mice. Next, we explored whether IL-17 regulated TAC-induced cardiac remodeling, and the results showed that IL-17 neutralization alleviated proinflammatory macrophage differentiation and cardiac remodeling in IL-12p40 knockout mice and WT mice. Neutralization with cluster of differentiation 4 receptor (CD4) and γδ T-cell receptor (γδTCR) antibodies inhibited pro-inflammatory macrophage polarization and improved cardiac remodeling, and CD4 neutralizing antibody (NAb) had more significant effects. Finally, adoptive transfer of Th17 cells aggravated proinflammatory macrophage differentiation and cardiac remodeling in TAC-treated CD4 KO mice, while neutralization with the IL-12p40 antibody alleviated these pathological changes. CONCLUSION: Mainly Th17 cells but not γδT17 cells secrete IL-17, which mediates IL-12p40, promotes the polarization of proinflammatory macrophages, and exacerbates cardiac remodeling in TAC mice. IL-12p40 may be a potential target for the prevention and treatment of cardiac remodeling.
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Diferenciación Celular , Subunidad p40 de la Interleucina-12 , Macrófagos , Ratones Endogámicos C57BL , Ratones Noqueados , Células Th17 , Remodelación Ventricular , Animales , Masculino , Ratones , Polaridad Celular/efectos de los fármacos , Eliminación de Gen , Subunidad p40 de la Interleucina-12/metabolismo , Subunidad p40 de la Interleucina-12/genética , Interleucina-17/metabolismo , Macrófagos/inmunología , Macrófagos/metabolismo , Receptores de Antígenos de Linfocitos T gamma-delta/metabolismo , Receptores de Antígenos de Linfocitos T gamma-delta/genética , Células Th17/inmunologíaRESUMEN
INTRODUCTION: Research regarding the role of the IL-12 cytokine family in modulating immune and inflammatory responses is continuously evolving. In this study, the contribution of the p35 and p40 subunits as monomers (noted as IL-12p35 and IL-12p40) and heterodimers (noted as IL-12p70 or IL-12p35/p40) was analysed in the pathophysiology and progression of chronic spontaneous urticaria (CSU). MATERIALS AND METHODS: We conducted a longitudinal, case-control study involving 42 CSU cases and 40 control cases comprising adults without associated conditions. Serial measurements were performed to assess the serum levels of IL-12p70, IL-12p35, and IL-12p40 at the onset of the disease (pre-therapy phase) and 6 weeks after the initiation of the treatment (post-therapy phase). RESULTS: During the pre-therapeutic phase of CSU, elevated serum levels of IL-12 cytokine subtypes were detected compared to the control group. The relationship between IL-12 profiles and the course of CSU highlighted the pro-inflammatory role of IL-12p70 and the anti-inflammatory role of IL-12p35. Significant correlations were observed between IL-12p70 levels and the duration of the disease, as well as between IL-12 and the effectiveness of H1-antihistamines. CONCLUSIONS: The molecular background for the pleiotropic activities mediated by IL-12-derived cytokines in patients with CSU lies in the strict regulation of the production, signalling pathways, and cytokine-specific influences on the same pathophysiological events. The results of the present study suggest that the superficial layers of the skin serve as a cellular source of IL-12, a cytokine produced through antigenic stimulation. In patients with CSU, we identified independent, additive, or divergent functions of IL-12p70, IL-12p35, and IL-12p40, all relevant to systemic inflammation. These findings prove that the prototype programming of IL-12 is abnormal in CSU.
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Macrophages are myeloid phagocytic leukocytes whose functions are to protect against infections, mediate T-cell responses, and maintain tissue homeostasis. IL-12p40 monomer is a cytokine that is largely produced by macrophages, and it has, for the longest time, been considered a largely non-functional cytokine of the IL-12 family. However, new research has emerged that demonstrates that this p40 monomer may play a bigger role in shaping immune environments. To shed light on the specific effects of p40 monomer on macrophages and their surrounding environment, we showed, through cell culture studies, qPCR, ELISA, and immunofluorescence analyses, that the direct administration of recombinant p40 monomer to RAW 264.7 cells and primary lung macrophages stimulated the production of both pro-inflammatory (TNFα) and anti-inflammatory (IL-10) signals. Accordingly, p40 monomer prevented the full pro-inflammatory effects of LPS, and the neutralization of p40 monomer by mAb a3-3a stimulated the pro-inflammatory effects of LPS. Furthermore, we demonstrated that the intranasal administration of p40 monomer upregulated TNFα+IL-10+ macrophages in vivo in the lungs of mice. Collectively, these results indicate an important immunoregulatory function of p40 monomer in the upregulation of both pro- and anti-inflammatory molecules in macrophages.
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Pallister-Killian syndrome (PKS) is a rare inherited disease with multiple congenital anomalies, profound intellectual disability, and the presence in the karyotype of sSMC - i(12)(p10). The frequency of PKS may be underestimated due to problems with cytogenetic diagnosis caused by tissue-specific mosaicism and usually a low percentage of peripheral blood cells containing sSMC. Such tissue-specific mosaicism also complicates a detailed analysis of the sSMC, which, along with the assessment of mosaicism in different tissues, is an important part of cytogenetic diagnosis in PKS. Unfortunately, a full-fledged diagnosis in PKS is either practically impossible or complicated. On the one hand, this is due to problems with the biopsy of various tissues (skin biopsy with fibroblast culture is most often used in practice); on the other - a low percentage of dividing peripheral blood cells containing sSMC, which often significantly complicates the analysis of its composition and organization. In the present study, a detailed analysis of sSMC was carried out in a patient with a characteristic clinical picture of PKS. A relatively high percentage of peripheral blood cells with sSMC (50%) made it possible to perform a detailed molecular cytogenetic analysis of de novo sSMC using chromosomal in situ suppression hybridization (CISS-hybridization), multicolor FISH (mFISH), multicolor chromosome banding (MCB), array CGH (aCGH), and quantitative real-time PCR (qPCR), and short tandem repeat (STR) - analysis. As a result, it was found that the sSMC is not a typical PKS derivative of chromosome 12. In contrast to the classical i(12)(p10) for PKS, the patient's cells contained an acrocentric chromosome consisting of 12p material. Clusters of telomeric repeats were found at the both ends of the sSMC. Furthemore, the results of aCGH and qPCR indicate the presence of interstitial 8.9 Mb duplication at 12p13.1-p12.1 within the sSMC, which leads to different representations of DNA from different segments of 12p within cells containing sSMC. The obtained data raise the question of the instability of the sSMC and, as a consequence, the possible presence of additional rearrangements, which, in traditional cytogenetic analysis of patients with PKS, are usually described as i(12)(p10).
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Objective: To compare the serum levels of 12 cytokines in migraine group, encephalitis with headache symptoms group, pneumonia without headache symptoms group and migraine subgroups to explore the cytokines associated with migraine in children and their levels. Methods: A total of 44 children with migraine, 27 children in the encephalitis group with headache symptoms and 44 children in the pneumonia group without headache symptoms were selected from January 2022 to August 2023 in Hebei Children's Hospital. They were all tested for serum cytokines by immunofluorescence assay. The migraine group was further divided into subgroups according to different age, gender, course of disease, and presence of coinfection. The differences of serum cytokine levels among the above groups were compared, and the correlation analysis was carried out. Results: Except IL-5, there were no significant differences in the expression levels of other 11 inflammatory cytokines between migraine subgroups. Compared with encephalitis with headache symptoms group and pneumonia without headache symptoms group the serum levels of IL-4, TNF-α, IL-17A, and IL-12p70 were higher in migraine group than in pneumonia group, and the levels of IL-12p70 were higher than those in encephalitis group (p < 0.05). An increase in serum IL-12p70 (OR = 1.267, 95%CI 1.054-1.523, p = 0.012) and IL-17A (OR = 1.066, 95%CI 1.016-1.119, p = 0.010) levels had a significant effect on migraine. Conclusion: Elevated serum levels of IL-12p70 and IL-17A may increase the risk of migraine in children, which has certain diagnostic and predictive value.
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In yeast, ras-like small G proteins, Gtr1p and Gtr2p, form heterodimers that affect cell division, detect amino acids, and regulate the activity of TORC1, a protein complex that integrates various signals, including those related to nutrient availability, growth factors, and stress signals. To explore novel roles of Gtr2p, yeast two-hybrid screening was performed using gtr2S23Np, an active form of Gtr2p, which identified Rps31p and Rpl12p as Gtr2p-interacting proteins. In the present study, we found that Gtr2p, but not Gtr1p, interacts with Rps31p, a 40S ribosomal subunit, and a component of the ubiquitin fusion protein Ubi3p, which is essential for the initiation and elongation of translation. In yeast cells expressing gtr2Q66Lp, an inactive form of Gtr2p, the interaction between Rps31p and gtr2Q66Lp, as well as the level of exogenous expression of Rps31p, was reduced. However, the level of exogenous expression of Rpl12p was unaffected. Introducing a mutation in ubiquitin target lysine residues to arginine (rps31-K5R) restored the level of exogenously expressed Rps31p and rescued the rapamycin and caffeine sensitivity of gtr2Q66L cells. Sucrose density gradient centrifugation of yeast cell lysate expressing Rps31p and gtr2Q66Lp revealed that exogenously expressed Rps31p was poorly incorporated, whereas rps31-K5Rp was efficiently incorporated, into ribosomes. These results suggest that Gtr2p influences incorporation of Rps31p into ribosomes and contributes to drug resistance through its interaction with Rps31p.
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Proteínas de Unión al GTP Monoméricas , Proteínas de Saccharomyces cerevisiae , Proteínas de Unión al GTP Monoméricas/metabolismo , Proteínas Ribosómicas/genética , Proteínas Ribosómicas/metabolismo , Ribosomas/metabolismo , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Ubiquitinas/metabolismoRESUMEN
Somatic-type malignancy (STM) can occur infrequently within a primary or metastatic testicular germ cell tumor (TGCT) and is associated with dismal prognosis and survival. STM with chondrosarcomatous features is exceedingly rare and head and neck involvement has not been previously documented. A 39-year-old white man presented with nasal obstruction and epistaxis. Imaging disclosed a 6.9-cm expansile tumor involving the nasal cavity and skull base with intraorbital and intracranial extension. The histopathologic properties of the tumor were compatible with chondrosarcoma, grade II-III. Immunohistochemically, malignant cells were strongly and diffusely positive for S100 and epithelial markers, and showed loss of SMARCB1 expression. IDH1/2 mutations were not detected. Following whole-body PET scan, a 7.0-cm left testicular mass was discovered and diagnosed as seminoma with syncytiotrophoblastic cells, stage pT3NXM1b. Extensive retroperitoneal, mediastinal, and supraclavicular lymphadenopathy was also noticed. Histopathologic examination of the left supraclavicular lymph node revealed metastatic seminoma. By FISH, most metastatic nodal seminoma cells harbored 1 to 4 copies of isochromosome 12p, while the chondrosarcoma featured duplication of 12p. Presence of a malignant TGCT with disseminated supradiaphragmatic lymphadenopathy, the unique immunophenotypic properties of the skull-based chondrosarcoma and lack of IDH1/2 aberrations with gain of 12p strongly support the diagnosis of STM chondrosarcoma arising from metastatic TGCT. The patient did not respond to chemotherapy and succumbed three months after diagnosis. Although exceedingly uncommon, metastasis to the head and neck may occur in patients with TGCT. This case of STM chondrosarcoma demonstrated divergent immunophenotypic and molecular characteristics compared to "typical" examples of head and neck chondrosarcoma. High index of suspicion is advised regarding the diagnosis of lesions that present with otherwise typical histomorphology but unexpected immunohistochemical or molecular features.
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Neoplasias Óseas , Condrosarcoma , Linfadenopatía , Neoplasias de Células Germinales y Embrionarias , Neoplasias Primarias Secundarias , Seminoma , Neoplasias Testiculares , Masculino , Humanos , Adulto , Condrosarcoma/genética , Base del Cráneo , Neoplasias Testiculares/genética , Neoplasias Óseas/genética , Proteína SMARCB1RESUMEN
The level of IL-2 increases markedly in serum and central nervous system (CNS) of patients with multiple sclerosis (MS) and animals with experimental allergic encephalomyelitis (EAE). However, mechanisms by which IL-2 is induced under autoimmune demyelinating conditions are poorly understood. The present study underlines the importance of IL-12p40 homodimer (p402), the so-called biologically inactive molecule, in inducing the expression of IL-2 in mouse BV-2 microglial cells, primary mouse and human microglia, mouse peritoneal macrophages, RAW264.7 macrophages, and T cells. Interestingly, we found that p402 and IL-12p70 (IL-12), but not IL-23, dose-dependently induced the production of IL-2 and the expression of IL-2 mRNA in microglial cells. Similarly, p402 also induced the activation of IL-2 promoter in microglial cells and RAW264.7 cells. Among various stimuli tested, p402 was the most potent stimulus followed by IFN-γ, bacterial lipopolysaccharide, HIV-1 gp120, and IL-12 in inducing the activation of IL-2 promoter in microglial cells. Moreover, p402, but not IL-23, increased NFATc2 mRNA expression and the transcriptional activity of NFAT. Furthermore, induction of IL-2 mRNA expression by over-expression of p40, but not by p19, cDNA indicated that p40, but not p19, is responsible for the induction of IL-2 mRNA in microglia. Finally, by using primary microglia from IL to 12 receptor ß1 deficient (IL-12Rß1-/-) and IL-12 receptor ß2 deficient (IL-12Rß2-/-) mice, we demonstrate that p402 induces the expression of IL-2 via IL-12Rß1, but not IL-12Rß2. In experimental autoimmune encephalomyelitis, an animal model of MS, neutralization of p402 by mAb a3-1d led to decrease in clinical symptoms and reduction in IL-2 in T cells and microglia. These results delineate a new biological function of p402, which is missing in the so-called autoimmune cytokine IL-23, and raise the possibility of controlling increased IL-2 and the disease process of MS via neutralization of p402.
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Encefalomielitis Autoinmune Experimental , Esclerosis Múltiple , Humanos , Animales , Ratones , Interleucina-12/metabolismo , Microglía/metabolismo , Interleucina-2/metabolismo , Macrófagos/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Interleucina-23RESUMEN
This article will review current aspects of the histopathological, immunohistochemical and molecular analysis of primary mediastinal germ cell tumours (PMGCTs) as well as their aetiological, epidemiological, clinical and therapeutic features. PMGCTs represent an important differential diagnosis in the spectrum of mediastinal tumours, and their diagnosis is usually made on small tissue samples from core needle biopsies in combination with diagnostic imaging and serum tumour markers. As in lymphomas, a small biopsy is often the only viable tumour sample available from these patients, as they receive chemotherapy prior to eventual surgical resection. Pathologists therefore need to apply an efficient combination of immunohistochemical markers to confirm the diagnosis of a PMGCT and to exclude morphological mimics.