Homeostatic and tumourigenic activity of SOX2+ pituitary stem cells is controlled by the LATS/YAP/TAZ cascade

SOX2 positive pituitary stem cells (PSCs) are specified embryonically and persist throughout life, giving rise to all pituitary endocrine lineages. We have previously shown the activation of the STK/LATS/YAP/TAZ signalling cascade in the developing and postnatal mammalian pituitary. Here, we investigate the function of this pathway during pituitary development and in the regulation of the SOX2 cell compartment. Through loss- and gain-offunction genetic approaches, we reveal that restricting YAP/TAZ activation during development is essential for normal organ size and specification from SOX2+ PSCs. Postnatal deletion of LATS kinases and subsequent upregulation of YAP/TAZ leads to uncontrolled clonal expansion of the SOX2+ PSCs and disruption of their differentiation, causing the formation of non-secreting, aggressive pituitary tumours. In contrast, sustained expression of YAP alone results in expansion of SOX2+ PSCs capable of differentiation and devoid of tumourigenic potential. Our findings identify the LATS/YAP/TAZ signalling cascade as an essential component of PSC regulation in normal pituitary physiology and tumourigenesis

Non-secreting pituitary tumours characterised by enhanced expression of YAP/TAZ

Tumours of the anterior pituitary can manifest from all endocrine cell types but the mechanisms for determining their specification are not known. The Hippo kinase cascade is a crucial signalling pathway regulating growth and cell fate in numerous organs. There is mounting evidence implicating this in tumour formation, where it is emerging as an anti-cancer target. We previously demonstrated activity of the Hippo kinase cascade in the mouse pituitary and nuclear association of its effectors YAP/TAZ with SOX2-expressing pituitary stem cells. Here we sought to investigate whether these components are expressed in the human pituitary and if they are deregulated in human pituitary tumours. Analysis of pathway components by immunofluorescence reveals pathway activity during normal human pituitary development and in the adult gland. Poorly differentiated pituitary tumours (null cell adenomas, adamantinomatous craniopharyngiomas (ΑCPs) and papillary craniopharyngiomas (PCPs)), displayed enhanced expression of pathway effectors YAP/TAZ. In contrast, differentiated adenomas displayed lower or absent levels. Knock-down of the kinase-encoding Lats1 in GH3 rat mammosomatotropinoma cells suppressed Prl and Gh promoter activity following an increase in YAP/TAZ levels. In conclusion, we have demonstrated activity of the Hippo kinase cascade in the human pituitary and association of high YAP/TAZ with repression of the differentiated state both in vitro and in vivo. Characterisation of this pathway in pituitary tumours is of potential prognostic value, opening up putative avenues for treatments

Medical therapy for craniopharyngiomas

Craniopharyngiomas are rare benign neoplasms presenting in two different types, adamantinomatous (ACP) or papillary (PCP), which are molecularly and clinically distinct. Traditional treatment includes surgical resection and radiotherapy, which are accompanied by a number of debilitating complications because of the tumours' proximity to important brain structures. Recent advances in the understanding of molecular pathogenesis of craniopharyngiomas have opened horizons to medical therapeutic options. ACPs are mainly characterized by mutations of β-catenin, which activate Wingless/Int (Wnt), and alter the mitogen extracellular kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway, as well as inflammatory, cellular senescence, programmed cell death and sonic hedgehog (SHH) pathways. PCPs are mainly characterized by Ras/Raf/MEK/ERK pathway activation secondary to BRAF-V600E mutations. MEK inhibitors, such as binimetinib, or anti-inflammatory mediators, such as tocilizumab or interferon, have been administered to patients with ACP and the efficacy is mostly favourable. On the other hand, BRAF inhibitors, such as dabrafenib or vemurafenib, either alone or in combination with the MEK inhibitors trametinib and cobimetinib, have been administered to patients with PCP resulting in favourable responses. A number of ongoing trials will shed light on schemes, doses, combined treatments and safety issues of the new molecular-targeted treatments, changing the management of patients with craniopharyngiomas by launching the era of personalized medicine in these rare neoplasms. We conducted a systematic review to identify case series or case reports with patients currently treated with systemic medical therapy. © 2021 Touch Briefings. All rights reserved

Hepatic enzyme abnormalities in Turner syndrome: A case report

Background: Liver dysfunction has been described in subjects with Turner syndrome. The mechanism involved is not known. Methods: Using appropriate methodology, we evaluated the hepatic enzymes serum glutamic-oxaloacetic transaminase, serum glutamic pyruvic transaminase and γ-glutamyl transpeptidase (γ-GT) in a girl with 45 XO/46 Xr mosaic karyotype. She was monitored from age 9 to 20 years while she underwent various therapeutic regimens. Results: Serum glutamic-oxaloacetic transaminase, serum glutamic pyruvic transaminase and particularly γ-GT concentrations ranged from normal to elevated values during human growth hormone therapy, estrogen replacement therapy (conjugated estrogens were replaced after 1 year with transdermal estrogens and medroxyprogesterone), and periods without therapy. The type of the therapeutic regimen did not seem to influence the hepatic enzyme values. A correlation was found between γ-GT values and body mass index (BMI). Conclusions: In our patient the waxing and waning of the liver enzymes was not influenced by the therapeutic regimen, but γ-GT seemed to correlate with BMI. Copyright © 2007 S. Karger AG

Diabetes insipidus secondary to sellar/parasellar lesions

Diabetes insipidus (DI) is a well-recognised transient or permanent complication following transsphenoidal surgery for pituitary adenomas or other sellar/parasellar lesions. However, data regarding the prevalence of pre-operative DI in sellar/parasellar lesions other than pituitary adenomas are scarce. We systematically reviewed the existing data for defining the prevalence of DI before any treatment in adult patients with sellar/parasellar lesions, excluding pituitary adenomas and metastatic lesions. In total, 646 patients with sellar/parasellar lesions presenting with DI at diagnosis were identified. The most common pathologies of sellar/parasellar lesions presenting with DI at diagnosis were lymphocytic hypophysitis (26.5%), craniopharyngiomas (23.4%), Langerhans's cell histiocytosis (18.9%) and Rathke's cleft cyst (12.7%), accounting for the vast majority (more than 80%) of these lesions. Overall, DI at diagnosis was found in 23.4% of all patients with sellar/parasellar lesions, albeit with a wide range from 10.6% to 76.7%, depending on the nature of the pathology. The highest prevalence of DI was found in less commonly encountered lesions namely germ-cell tumours (76.7%), abscesses (55.4%) and neurosarcoidosis (54.5%), each accounting for less than 3% of all sellar/parasellar lesions. Most DI cases (68.8%) were associated with anterior pituitary hormonal deficiencies, in contrast to pituitary adenomas that rarely present with DI. The enlargement and enhancement of the pituitary stalk were the most common findings on magnetic resonance imaging besides the loss of the high signal of the posterior pituitary on T1-weighted images. Resolution of DI spontaneously or following systemic and surgical management occurred in 22.4% of cases. Post-operative DI, not evident before surgery, was found in 27.8% of non-adenomatous sellar/parasellar lesions, and was transient in 11.6% of them. Besides distinctive imaging features and symptoms, early recognition of DI in such lesions is important because it directs the diagnosis towards a non-adenomatous sellar/parasellar tumour and the early initiation of appropriate treatment. © 2021 British Society for Neuroendocrinolog

Homeostatic and tumourigenic activity of SOX2+ pituitary stem cells is controlled by the LATS/YAP/TAZ cascade

SOX2 positive pituitary stem cells (PSCs) are specified embryonically and persist throughout life, giving rise to all pituitary endocrine lineages. We have previously shown the activation of the STK/LATS/YAP/TAZ signalling cascade in the developing and postnatal mammalian pituitary. Here, we investigate the function of this pathway during pituitary development and in the regulation of the SOX2 cell compartment. Through loss- and gain-of-function genetic approaches, we reveal that restricting YAP/TAZ activation during development is essential for normal organ size and specification from SOX2+ PSCs. Postnatal deletion of LATS kinases and subsequent upregulation of YAP/TAZ leads to uncontrolled clonal expansion of the SOX2+ PSCs and disruption of their differentiation, causing the formation of non-secreting, aggressive pituitary tumours. In contrast, sustained expression of YAP alone results in expansion of SOX2+ PSCs capable of differentiation and devoid of tumourigenic potential. Our findings identify the LATS/YAP/TAZ signalling cascade as an essential component of PSC regulation in normal pituitary physiology and tumourigenesis

Comparison of Hospital Consultation and Summer Camp Lifestyle Intervention Programs for Sustained Body Weight Loss in Overweight/Obese Greek Children

Two lifestyle intervention programs of a health initiative named “Evrostia” were conducted at (a) an outpatient obesity clinic of a children’s hospital and (b) summer camp (SC), respectively. Thirty overweight/obese children were randomly selected to participate in each intervention arm to assess the efficacy of the SC intervention and its possible superiority over usual hospital consultation (HC) practice. There was a statistically significant decrease in body weight (BW), and body mass index (BMI) in both programs. A higher duration of reduced BW was observed in the SC compared to HC intervention. Regarding the nutritional behavior, there was a significant increase in the consumption of breakfast, fruit and vegetables, and a reduction in the consumption of beverages and sweets in the SC group. A significant increase in the hours of weekly physical activity was also observed in children of the SC program. The comparison between the two lifestyle intervention programs showed that the SC program improved nutritional behaviors and physical activity and promoted longer preservation of BW loss than that of the HC program. Thus, the holistic and experiential approach of the SC program was more successful in the treatment of overweight and obesity in children than a conventional HC program