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Katherine U Gaynor, Irina V Grigorieva, Samantha M Mirczuk, Sian E Piret, Kreepa G Kooblall, Mark Stevenson, Karine Rizzoti, Michael R Bowl, M Andrew Nesbit, Paul T Christie, William D Fraser, Tertius Hough, Michael P Whyte, Robin Lovell-Badge and Rajesh V Thakker

Hypoparathyroidism is genetically heterogeneous and characterized by low plasma calcium and parathyroid hormone (PTH) concentrations. X-linked hypoparathyroidism (XLHPT) in two American families is associated with interstitial deletion-insertions involving deletions of chromosome Xq27.1 downstream of SOX3 and insertions of predominantly non-coding DNA from chromosome 2p25.3. These could result in loss, gain, or movement of regulatory elements, which include ultraconserved element uc482, which could alter SOX3 expression. To investigate this, we analysed SOX3 expression in EBV-transformed lymphoblastoid cells from three affected males, three unaffected males, and four carrier females from one XLHPT family. SOX3 expression was similar in all individuals, indicating that the spatiotemporal effect of the interstitial deletion-insertion on SOX3 expression postulated to occur in developing parathyroids did not manifest in lymphoblastoids. Expression of SNTG2, which is duplicated and inserted into the X chromosome, and ATP11C, which is moved telomerically, were also similarly expressed in all individuals. Investigation of male hemizygous (Sox3 −/Y and uc482 −/Y) and female heterozygous (Sox3 +/ and uc482 +/ ) knockout mice, together with wild-type littermates (male Sox3 +/Y and uc482 +/Y, and female Sox3 +/+ and uc482 +/+), revealed Sox3 −/Y, Sox3 +/ , uc482 /Y, and uc482 +/ mice to have normal plasma biochemistry, compared to their respective wild-type littermates. When challenged with a low calcium diet, all mice had hypocalcaemia, and elevated plasma PTH concentrations and alkaline phosphatase activities, and Sox3 −/Y, Sox3 +/ , uc482 −/Y, and uc482 +/ mice had similar plasma biochemistry, compared to wild-type littermates. Thus, these results indicate that absence of Sox3 or uc482 does not cause hypoparathyroidism and that XLHPT likely reflects a more complex mechanism.

Open access

Giovanni Tulipano

anti-tumor effects in endocrine malignancies ( 16 ). The last section of this review explores the results of preclinical studies aimed at investigating the effects of AMPK activation and the effects of metformin on pituitary tumor cells published in the

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Martin Zweifel, Beat Thürlimann, Salome Riniker, Patrik Weder, Roger von Moos, Olivia Pagani, Martin Bigler, Karin M Rothgiesser, Christiane Pilop, Hanne Hawle, Peter Brauchli, Coya Tapia, Wolfgang Schoenfeld, Cristiana Sessa and for the Swiss Group for Clinical Cancer Research (SAKK)

time point. Dotted lines indicate 1st and 3rd quartiles (the dotted 1st quartile line overlaps mostly with the solid mean line). Discussion In preclinical studies, CR1447 has been shown to inhibit human BC cell lines in their growth if

Open access

David P Sonne, Asger Lund, Jens Faber, Jens J Holst, Tina Vilsbøll and Filip K Knop

Bile acids are possible candidate agents in newly identified pathways through which energy expenditure may be regulated. Preclinical studies suggest that bile acids activate the enzyme type 2 iodothyronine deiodinase, which deiodinates thyroxine (T4) to the biologically active triiodothyronine (T3). We aimed to evaluate the influence of bile acid exposure and incretin hormones on thyroid function parameters in patients with type 2 diabetes. Thyroid-stimulating hormone (TSH) and thyroid hormones (total T3 and free T4) were measured in plasma from two human studies: i) 75 g-oral glucose tolerance test (OGTT) and three isocaloric (500 kcal) and isovolaemic (350 ml) liquid meals with increasing fat content with concomitant ultrasonographic evaluation of gallbladder emptying in 15 patients with type 2 diabetes and 15 healthy age, gender and BMI-matched controls (meal-study) and ii) 50 g-OGTT and isoglycaemic intravenous glucose infusions (IIGI) alone or in combination with glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide 1 (GLP1) and/or GLP2, in ten patients with type 2 diabetes (IIGI-study). In both studies, TSH levels declined (P<0.01) similarly following all meal and infusion stimuli. T3 and T4 concentrations did not change in response to any of the applied stimuli. TSH levels declined independently of the degree of gallbladder emptying (meal-study), route of nutrient administration and infusion of gut hormones. In conclusion, intestinal bile flow and i.v. infusions of the gut hormones, GIP, GLP1 and/or GLP2, do not seem to affect thyroid function parameters. Thus, the presence of a ‘gut–thyroid–pituitary’ axis seems questionable.

Open access

Emmanuelle Noirrit, Mélissa Buscato, Marion Dupuis, Bernard Payrastre, Coralie Fontaine, Jean-François Arnal and Marie-Cécile Valera

that VTE are rare events, especially in relatively young women (mean 54 years), indicate the need for further experimental preclinical studies. In addition, the impact of SERMs such as tamoxifen in hemostasis and thrombosis is controversial in ex vivo

Open access

Stefan Schulz, Anika Mann, Benjamin Novakhov, Hugh D Piggins and Amelie Lupp

the use of growth-inhibiting VIP/PACAP analogues for the treatment of human tumours. Moreover, a number of clinical and preclinical studies suggest that VPAC2 receptors may be promising molecular targets for tumour imaging and targeted radiotherapy

Open access

M L Gild, M Bullock, C K Pon, B G Robinson and R J Clifton-Bligh

developed. NVP-AUY922 is an isoxazole based compound that acts as a competitive inhibitor of ATP. Its administration renders HSP90 inefficient thereby destabilizing its client proteins. It has been used in preclinical studies of many recalcitrant cancers

Open access

Elizabeth Yan Zhang and Bao-Ting Zhu

suggested that ovulatory hormonal factors may act to suppress DTH reactions (17, 41, 42) . The findings of our present preclinical study, which demonstrate that administration of estrogens can strongly suppress the pathogenesis of allergic contact

Open access

Adrian F Daly, Liliya Rostomyan, Daniela Betea, Jean-François Bonneville, Chiara Villa, Natalia S Pellegata, Beatrice Waser, Jean-Claude Reubi, Catherine Waeber Stephan, Emanuel Christ and Albert Beckers

preclinical studies in somatotroph and corticotroph pituitary cells . Pituitary 2019 22 89 – 99 . ( https://doi.org/10.1007/s11102-018-0926-y ) 30483918 10.1007/s11102-018-0926-y 26 Villa C Lagonigro MS Magri F Koziak M Jaffrain-Rea ML Brauner R

Open access

K E Lines, R P Vas Nunes, M Frost, C J Yates, M Stevenson and R V Thakker

models for basic and preclinical studies . International Journal of Endocrine Oncology 2014 1 153 – 161 . ( doi:10.2217/ije.14.16 ) 40 Puri S Folias AE Hebrok M. Plasticity and dedifferentiation within the pancreas: development