The TALE homeodomain of PBX1 is involved in human primary testis-determination.

Human sex-determination is a poorly understood genetic process, where gonad development depends on a cell fate decision that occurs in a somatic cell to commit to Sertoli (male) or granulosa (female) cells. A lack of testis-determination in the human results in 46,XY gonadal dysgenesis. A minority of these cases is explained by mutations in genes known to be involved in sex-determination.

Clinical presentation, treatment and outcome of anaplastic thyroid carcinoma: results of a multicenter study in Germany.

Context: Anaplastic thyroid carcinoma (ATC) is an orphan disease and confers a dismal prognosis. Standard treatment is not established.

Objective: The aim of this study is to describe clinical characteristics, current treatment regimens and outcome of ATC and to identify clinical prognostic markers and treatment factors associated with improved prognosis.

Life-threatening events in patients with pheochromocytoma.

Objective: Pheochromocytomas are rare chromaffin cell-derived tumors causing paroxysmal episodes of headache, palpitation, sweating and hypertension. Life-threatening complications have been described in case reports and small series. Systematic analyses are not available.

Frequency and clinical correlates of somatic Ying Yang 1 mutations in sporadic insulinomas.

Context: Insulinomas represent pancreatic neuroendocrine neoplasms that cause severe morbidity attributed to their often pronounced endocrine activity. Apart from hereditary forms such as multiple endocrine neoplasia type 1 (MEN-1), genetic causes for sporadic insulinoma development had remained obscure until recently. Applying next-generation sequencing methods, disease-causing genetic alterations have been identified in various endocrine tumors.

Presence of brown adipocytes in retroperitoneal fat from patients with benign adrenal tumors: relationship with outdoor temperature.

Context: Brown adipose tissue (BAT) is a metabolically highly active organ with increased thermogenic activity in rodents exposed to cold temperature. Recently its presence in the cervical adipose tissue of human adults and its association with a favorable metabolic phenotype have been reported.

Objective: The objective of the study was to determine the prevalence of retroperitoneal BAT in human adults.

Somatic mutations in ATP1A1 and ATP2B3 lead to aldosterone-producing adenomas and secondary hypertension.

Primary aldosteronism is the most prevalent form of secondary hypertension. To explore molecular mechanisms of autonomous aldosterone secretion, we performed exome sequencing of aldosterone-producing adenomas (APAs). We identified somatic hotspot mutations in the ATP1A1 (encoding an Na(+)/K(+) ATPase α subunit) and ATP2B3 (encoding a Ca(2+) ATPase) genes in three and two of the nine APAs, respectively.

The side population phenomenon enriches for designated adrenocortical progenitor cells in mice.

Somatic adrenal stem cells are believed to reside in the periphery of the adrenal cortex throughout life for organ maintenance. Herein, we used the side population (SP) phenomenon to enrich for these progenitors, which made up to 0.01-0.

Identification of adrenal genes regulated in a potassium-dependent manner.

Potassium and angiotensin II are the main stimulators of aldosterone secretion from the adrenal cortex. As potassium-induced in vivo gene regulation in the adrenal cortex has not been studied in detail, we applied a stepwise screening approach: first, we investigated the effects of chronic potassium substitution in mice. Microarray analysis of adrenal glands revealed a set of genes (set A) that were counter-regulated in a high potassium (HP) and low potassium substitution group, while others (set B) were highly upregulated in the HP intake group.

PBX1 is dispensable for neural commitment of RA-treated murine ES cells.

Experimentation with PBX1 knockout mice has shown that PBX1 is necessary for early embryogenesis. Despite broad insight into PBX1 function, little is known about the underlying target gene regulation. Utilizing the Cre-loxP system, we targeted a functionally important part of the homeodomain of PBX1 through homozygous deletion of exon-6 and flanking intronic regions leading to exon 7 skipping in embryonic stem (ES) cells.

The tumor stem cell concept-implications for endocrine tumors?

The cancer stem cell hypothesis has recently evolved from an increasing body of evidence suggesting that in some cancers a small population of tumor cells with stem cell-like properties represents a critical component that dictates the malignant behavior of a given tumor. These observations challenge classical cancer biology and its theory, that tumor growth is mainly based on genomic alterations followed by modulation of cell cycle pathways, which finally result in uncontrolled clonal proliferation. Over the last few years, much progress in the field of tumor stem cells has been achieved in non-endocrine malignancies.

Major role of cathepsin L for producing the peptide hormones ACTH, beta-endorphin, and alpha-MSH, illustrated by protease gene knockout and expression.

The pituitary hormones adrenocorticotropic hormone (ACTH), beta-endorphin, and alpha-melanocyte stimulating hormone (alpha-MSH) are synthesized by proteolytic processing of their common proopiomelanocortin (POMC) precursor. Key findings from this study show that cathepsin L functions as a major proteolytic enzyme for the production of POMC-derived peptide hormones in secretory vesicles. Specifically, cathepsin L knock-out mice showed major decreases in ACTH, beta-endorphin, and alpha-MSH that were reduced to 23, 18, and 7% of wild-type controls (100%) in pituitary.

Side population does not define stem cell-like cancer cells in the adrenocortical carcinoma cell line NCI h295R.

Recent evidence suggests the existence of a stem cell-like subpopulation of cells in hematological and solid tumor entities, which determine the malignant phenotype of a given tumor through their proliferative potential and chemotherapy resistance. A recently used technique for the isolation of this cell population is through exclusion of the vital dye Hoechst 33342, which defines the so-called side population (SP). Herein we demonstrate the presence of SP cells in a variety of adrenal specimens, including primary cultures of human adrenocortical tumors and normal adrenal glands as well as established human and murine adrenocortical cancer cell lines by fluorescence-activated cell sorter analysis and confocal microscopy.

Pre-B-cell transcription factor 1 and steroidogenic factor 1 synergistically regulate adrenocortical growth and steroidogenesis.

A variety of transcription factors including Wilms tumor gene (Wt-1), steroidogenic factor 1 (Sf-1), dosage-sensitive sex reversal, adrenal hypoplasia congenita on the X-chromosome, Gene 1 (Dax-1), and pre-B-cell transcription factor 1 (Pbx1) have been defined as necessary for regular adrenocortical development. However, the role of Pbx1 for adrenal growth and function in the adult organism together with the molecular relationship between Pbx1 and these other transcription factors have not been characterized. We demonstrate that Pbx haploinsufficiency (Pbx1(+/-)) in mice is accompanied by a significant lower adrenal weight in adult animals compared with wild-type controls.