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ObjectiveThe differentiation program for human thyroid follicular cells (TFCs) relies on the interplay between sequence-specific transcription factors and transcriptional co-regulators. Transcriptional co-activator with PDZ-binding motif (TAZ) is a co-activator that regulates several transcription factors, including PAX8 and NKX2-1, which play a central role in thyroid-specific gene transcription. TAZ and PAX8/NKX2-1 are co-expressed in the nuclei of thyroid cells, and TAZ interacts directly with both PAX8 and NKX2-1, leading to their enhanced transcriptional activity on the thyroglobulin (TG) promoter and additional genes.MethodsThe use of a small molecule, ethacridine, recently identified as a TAZ activator, in the differentiation of thyroid cells from human embryonic stem (hES) cells was studied. First, endodermal cells were derived from hES cells using Activin A, followed by induction of differentiation into thyroid cells directed by ethacridine and thyrotropin (TSH).ResultsThe expression of TAZ was increased in the Activin A-derived endodermal cells by ethacridine in a dose-dependent manner and followed by increases in PAX8 and NKX2-1 when assessed by both quantitative polymerase chain reaction and immunostaining. Following further differentiation with the combination of ethacridine and TSH, the thyroid-specific genes TG, TPO, TSHR, and NIS were all induced in the differentiated hES cells. When these cells were cultured with extracellular matrix-coated dishes, thyroid follicle formation and abundant TG protein expression were observed. Furthermore, such hES cell-derived thyroid follicles showed a marked TSH-induced and dose-dependent increase in radioiodine uptake and protein-bound iodine accumulation.ConclusionThese data show that fully functional human thyroid cells can be derived from hES cells using ethacridine, a TAZ activator, which induces thyroid-specific gene expression and promotes thyroid cell differentiation from the hES cells. These studies again demonstrate the importance of transcriptional regulation in thyroid cell development. This approach also yields functional human thyrocytes, without any gene transfection or complex culture conditions, by directly manipulating the transcriptional machinery without interfering with intermediate signaling events.

Background The clinical presentation of patients with congenital hypothyroidism (CH) caused by paired box gene 8 ( PAX8 ) pathogenic variants is variable and PAX8 mutation rates differ significantly among different populations. This study was set to examine the PAX8 mutation spectrum and prevalence among patients with CH in Guangxi Zhuang Autonomous Region, China. Methods Peripheral venous blood samples were collected from the patients. Genomic DNA was extracted from peripheral blood leukocytes. All exons of the 11 known CH associated genes including PAX8 together with their exon–intron boundaries were screened by next-generation sequencing (NGS). Permanent or transient CH was determined using the results of thyroid function tests after temporary withdrawal of l -thyroxine ( l -T4) therapy at approximately 2 years of age. Results Next generation sequencing analysis of PAX8 in 378 CH patients revealed five different mutations in nine individuals (two are siblings). The mutations included two known missense variants, namely c.92G > A (p.R31H) and c.91C > T (p.R31C), and one novel missense variant c.68G > T (p.G23V), as well as two novel nonsense variants c.1090C > T (p. R364X) and c.658C > T (p.R220X). The variant c.92G > A (p.R31H) is highly recurrent in our patient cohort but the clinical phenotypes vary greatly among those carrying this variant. PAX8 pathogenic variants were mainly associated with permanent CH. Conclusion The prevalence of PAX8 pathogenic variants was 2.38% among patients with CH in Guangxi. Our study expanded the PAX8 mutation spectrum and provided the best estimation of PAX8 mutation rate among CH patients in Guangxi, China. [ABSTRACT FROM AUTHOR]

Objectives: To compare the immunohistochemical expression of diagnostic markers in primary clear cell renal cell carcinomas (RCCs) and their matched metastases. Methods: Tissue microarrays were constructed from 15 pairs of primary and metastatic clear cell RCCs and then evaluated for the immunohistochemical expression of renal cell carcinoma antigen (RCCA), kidney-specific cadherin, carbonic anhydrase IX (CAIX), and paired box genes 2 (PAX2) and 8 (PAX8). Results: There was significantly higher overall marker expression in metastatic tumors compared to their matched primaries (P < .001). Individually, there was greater CAIX, PAX2, and PAX8 expression and lower RCCA expression in metastatic tumors. Most importantly, a significant proportion of originally RCCA-positive tumors lost such expression in metastases. Conclusions: Metastatic RCCs have significantly higher expression of PAX2 and PAX8 compared to primary RCCs. RCCA is not very reliable in this diagnostic setting, both because of its lower overall sensitivity and loss of expression in metastatic RCCs. [ABSTRACT FROM AUTHOR]

Introduction: Thyroid dysgenesis (TD) is the main cause of congenital hypothyroidism (CH), affecting nearly 1 in 2000-3000 newborns worldwide, as the most common neonatal endocrine disorder. Paired box gene 8 (PAX8), expressed during all stages of thyroid follicular cell, plays a key role in thyroid morphogenesis by a complex regulatory network. In conclusion, the genetic mechanism of PAX8 mutant in TD is still ambiguous; therefore, further research is needed., Material and Methods: Blood samples were collected from 289 TD patients in Shandong Province, China. Genomic DNA was extracted from peripheral blood. All the exons of PAX8 along with their exon-intro boundaries were amplified by PCR and analysed by Sanger sequencing., Results: We identified three novel PAX8 nonsense mutations in three patients by sequence analysis of PAX8: Patient 1 (c.285C>G, p.Tyr95Ter), Patient 2 (c.747T>G, p.Tyr249Ter), and Patient 3 (c.786C>A, p.Tyr262Ter). All the three patients carrying PAX8 variants had obvious clinical phenotypes of thyroid anomaly, such as hypoplasia and athyreosis., Conclusion: We conducted the largest worldwide PAX8 mutation screening so far in TD patients. Three presumably pathogenic PAX8 mutations were detected in 289 TD cases for the first time, showing the mutation rate of PAX8 is 1.04% in Chinese TD patients. In addition, our study expands the gene mutation spectrum of TD.

Mediastinal cysts are typically of bronchogenic, thymic or neurenteric origin, but may also represent oesophageal duplication. Posterior paravertebral mediastinal Müllerian cysts of undetermined pathogenesis are very rare occurrences. The first case of a ciliated cyst arising in the mediastinum, of probable Müllerian origin, was reported by Hattori in 2005, which gave rise to the name cyst of Hatorri (COH) The number of reported cases in literature of a similar nature have since then increased significantly. One of the main concerns about this pathology is the possibility of malignant transformation of the Müllerian tissue. Over the course of this paper we will discuss the pathogenesis, immunohistochemistry and its role in differential diagnosis as well as optimal treatment of such cysts.