Publications by authors named "Florian Wernig"

21 Publications

  • Page 1 of 1

SDHC phaeochromocytoma and paraganglioma: A UK-wide case series.

Clin Endocrinol (Oxf) 2021 Sep 24. Epub 2021 Sep 24.

Department of Clinical Genetics, Birmingham Women's Hospital, Birmingham, UK.

Objective: Phaeochromocytomas and paragangliomas (PPGL) are rare, but strongly heritable tumours. Variants in succinate dehydrogenase (SDH) subunits are identified in approximately 25% of cases. However, clinical and genetic information of patients with SDHC variants are underreported.

Design: This retrospective case series collated data from 18 UK Genetics and Endocrinology departments.

Patients: Both asymptomatic and disease-affected patients with confirmed SDHC germline variants are included.

Measurements: Clinical data including tumour type and location, surveillance outcomes and interventions, SDHC genetic variant assessment, interpretation, and tumour risk calculation.

Results: We report 91 SDHC cases, 46 probands and 45 non-probands. Fifty-one cases were disease-affected. Median age at genetic diagnosis was 43 years (range: 11-79). Twenty-four SDHC germline variants were identified including six novel variants. Head and neck paraganglioma (HNPGL, n = 30, 65.2%), extra-adrenal paraganglioma (EAPGL, n = 13, 28.2%) and phaeochromocytomas (PCC) (n = 3, 6.5%) were present. One case had multiple PPGLs. Malignant disease was reported in 19.6% (9/46). Eight cases had non-PPGL SDHC-associated tumours, six gastrointestinal stromal tumours (GIST) and two renal cell cancers (RCC). Cumulative tumour risk (95% CI) at age 60 years was 0.94 (CI: 0.79-0.99) in probands, and 0.16 (CI: 0-0.31) in non-probands, respectively.

Conclusions: This study describes the largest cohort of 91 SDHC patients worldwide. We confirm disease-affected SDHC variant cases develop isolated HNPGL disease in nearly 2/3 of patients, EAPGL and PCC in 1/3, with an increased risk of GIST and RCC. One fifth developed malignant disease, requiring comprehensive lifelong tumour screening and surveillance.
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http://dx.doi.org/10.1111/cen.14594DOI Listing
September 2021

Utility of Cannulated Prolactin to Exclude Stress Hyperprolactinemia in Patients with Persistent Mild Hyperprolactinemia.

Clin Med Insights Endocrinol Diabetes 2021 22;14:11795514211025276. Epub 2021 Jun 22.

Department of Diabetes & Endocrinology, Imperial College Healthcare NHS Trust, London, UK.

Background: Stress-induced hyperprolactinemia can be difficult to differentiate from true hyperprolactinema and may result in patients having unnecessary investigations and imaging. We report the results of cannulated prolactin tests with serial prolactin measurements from an indwelling catheter to differentiate true from stress-induced hyperprolactinemia in patients with persistently mildly elevated prolactin levels in both referral and repeat samples.

Methods: Data were collected for 42 patients who had a cannulated prolactin test between January 2017 and May 2018. After cannula insertion, prolactin was measured at 0, 60, and 120 minutes. Normalization is defined as a decline in prolactin to gender-defined normal ranges.

Results: The mean age was 33.8 years ( ± 9.9), and 37 (88%) were female. Menstrual irregularities were the main presenting symptom in 28.57% of the patients. Prolactin normalized in 12 (28.6%) patients of whom cannulated prolactin test was done. Repeat random prolactin levels were significantly higher in patients whose prolactin did not normalize during the cannulated prolactin test. MRI of the pituitary gland showed an abnormality in 23 out of 28 (82%) patients who did not normalize prolactin, a microadenoma in the majority of patients (18 patients).

Conclusion: The cannulated prolactin test was useful in excluding true hyperprolactinemia in 28.6% of patients with previously confirmed mildly elevated random prolactin on two occasions, thus avoiding over-diagnosis and unnecessary imaging.
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http://dx.doi.org/10.1177/11795514211025276DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8221679PMC
June 2021

Synacthen Stimulation Test Following Unilateral Adrenalectomy Needs to Be Interpreted With Caution.

Front Endocrinol (Lausanne) 2021 11;12:654600. Epub 2021 May 11.

Department of Endocrinology, Hammersmith Hospital, Imperial College Healthcare NHS Trust, London, United Kingdom.

Background: Cortisol levels in response to stress are highly variable. Baseline and stimulated cortisol levels are commonly used to determine adrenal function following unilateral adrenalectomy. We report the results of synacthen stimulation testing following unilateral adrenalectomy in a tertiary referral center.

Methods: Data were collected retrospectively for 36 patients who underwent synacthen stimulation testing one day post unilateral adrenalectomy. None of the patients had clinical signs of hypercortisolism preoperatively. No patient received pre- or intraoperative steroids. Patients with overt Cushing's syndrome were excluded.

Results: The median age was 58 (31-79) years. Preoperatively, 16 (44%) patients had a diagnosis of pheochromocytoma, 12 (33%) patients had primary aldosteronism and 8 (22%) patients had non-functioning adenomas with indeterminate/atypical imaging characteristics necessitating surgery. Preoperative overnight dexamethasone suppression test results revealed that 6 of 29 patients failed to suppress cortisol to <50 nmol/L. Twenty (56%) patients achieved a stimulated cortisol ≥450 nmol/L at 30 minutes and 28 (78%) at 60 minutes. None of the patients developed clinical adrenal insufficiency necessitating steroid replacement.

Conclusions: Synacthen stimulation testing following unilateral adrenalectomy using standard stimulated cortisol cut-off values would wrongly label many patients adrenally insufficient and may lead to inappropriate prescriptions of steroids to patients who do not need them.
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http://dx.doi.org/10.3389/fendo.2021.654600DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8147556PMC
May 2021

Production of octanoic acid in Saccharomyces cerevisiae: Investigation of new precursor supply engineering strategies and intrinsic limitations.

Biotechnol Bioeng 2021 08 18;118(8):3046-3057. Epub 2021 May 18.

Department of Biological Sciences, Institute of Molecular Biosciences, Goethe University Frankfurt, Frankfurt am Main, Germany.

The eight-carbon fatty acid octanoic acid (OA) is an important platform chemical and precursor of many industrially relevant products. Its microbial biosynthesis is regarded as a promising alternative to current unsustainable production methods. In Saccharomyces cerevisiae, the production of OA had been previously achieved by rational engineering of the fatty acid synthase. For the supply of the precursor molecule acetyl-CoA and of the redox cofactor NADPH, the native pyruvate dehydrogenase bypass had been harnessed, or the cells had been additionally provided with a pathway involving a heterologous ATP-citrate lyase. Here, we redirected the flux of glucose towards the oxidative branch of the pentose phosphate pathway and overexpressed a heterologous phosphoketolase/phosphotransacetylase shunt to improve the supply of NADPH and acetyl-CoA in a strain background with abolished OA degradation. We show that these modifications lead to an increased yield of OA during the consumption of glucose by more than 60% compared to the parental strain. Furthermore, we investigated different genetic engineering targets to identify potential factors that limit the OA production in yeast. Toxicity assays performed with the engineered strains suggest that the inhibitory effects of OA on cell growth likely impose an upper limit to attainable OA yields.
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http://dx.doi.org/10.1002/bit.27814DOI Listing
August 2021

Fusing α and β subunits of the fungal fatty acid synthase leads to improved production of fatty acids.

Sci Rep 2020 06 17;10(1):9780. Epub 2020 Jun 17.

Institute of Molecular Biosciences, Faculty of Biological Sciences, Goethe University Frankfurt, Frankfurt am Main, Germany.

Most fungal fatty acid synthases assemble from two multidomain subunits, α and β, into a heterododecameric FAS complex. It has been recently shown that the complex assembly occurs in a cotranslational manner and is initiated by an interaction between the termini of α and β subunits. This initial engagement of subunits may be the rate-limiting phase of the assembly and subject to cellular regulation. Therefore, we hypothesized that bypassing this step by genetically fusing the subunits could be beneficial for biotechnological production of fatty acids. To test the concept, we expressed fused FAS subunits engineered for production of octanoic acid in Saccharomyces cerevisiae. Collectively, our data indicate that FAS activity is a limiting factor of fatty acid production and that FAS fusion proteins show a superior performance compared to their split counterparts. This strategy is likely a generalizable approach to optimize the production of fatty acids and derived compounds in microbial chassis organisms.
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http://dx.doi.org/10.1038/s41598-020-66629-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7300031PMC
June 2020

A Case Series of Patients with Isolated IgG4-related Hypophysitis Treated with Rituximab.

J Endocr Soc 2020 Jun 21;4(6):bvaa048. Epub 2020 Apr 21.

Department of Endocrinology, Hammersmith Hospital, Imperial College Healthcare NHS Trust, London, UK.

Context: The acute presentation of immunoglobulin G4 (IgG4)-related hypophysitis can be indistinguishable from other forms of acute hypophysitis, and histology remains the diagnostic gold standard. The high recurrence rate necessitates long-term immunosuppressive therapy. Rituximab (RTX) has been shown to be effective in systemic IgG4-related disease (IgG4-RD), but experience with isolated pituitary involvement remains limited.

Case Description: We report 3 female patients with MRI findings suggestive of hypophysitis. All patients underwent transsphenoidal biopsy and fulfilled diagnostic criteria for IgG4-related hypophysitis. Treatment with glucocorticoids (GCs) resulted in good therapeutic response in Patients 1 and 2, but the disease recurred on tapering doses of GCs. GC treatment led to emotional lability in Patient 3, necessitating a dose reduction. All 3 patients received RTX and Patients 2 and 3 received further courses of treatment when symptoms returned and B-cells repopulated. Patient 3 did not receive RTX until 12 months from the onset of symptoms. Patient 1 was not able to have further RTX treatments due to an allergic reaction when receiving the second dose. Rituximab treatment resulted in sustained remission and full recovery of anterior pituitary function in Patients 1 and 2, with complete resolution of pituitary enlargement. By contrast, Patient 3 only showed a symptomatic response following RTX treatment, but pituitary enlargement and hypofunction persisted.

Conclusion: Rituximab treatment for IgG4-related hypophysitis resulted in sustained remission in 2 patients treated early in the disease process but only achieved partial response in a patient with chronic disease, suggesting that early therapeutic intervention may be crucial in order to avoid irreversible changes.
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http://dx.doi.org/10.1210/jendso/bvaa048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7278280PMC
June 2020

Pharmacodynamic Response to Anti-thyroid Drugs in Graves' Hyperthyroidism.

Front Endocrinol (Lausanne) 2020 12;11:286. Epub 2020 May 12.

Section of Endocrinology and Investigative Medicine, Division of Diabetes, Endocrinology and Metabolism, Hammersmith Hospital, Imperial College London, London, United Kingdom.

Graves' disease is the commonest cause of hyperthyroidism in populations with sufficient dietary iodine intake. Anti-thyroid drugs (ATD) are often used as the initial treatment for Graves' hyperthyroidism, however there is a paucity of data relating the dose of ATD therapy to the effect on thyroid hormone levels, increasing the risk of both over- and under-treatment. We aimed to determine the pharmacodynamic response to the ATD carbimazole. Retrospective cohort study. Participants were patients ( = 441) diagnosed with Graves' disease at Imperial College Healthcare NHS Trust between 2009 and 2018. The main outcome measure was change in thyroid hormone levels in response to ATD. Baseline thyroid hormone levels were positively associated with TSH receptor antibody titres ( < 0.0001). Baseline free triiodothyronine (fT3) were linearly related to free thyroxine (fT4) levels in the hyperthyroid state (fT3 = fT40.97-11), and fell proportionately with carbimazole. The percentage falls in fT4 and fT3 per day were associated with carbimazole dose ( < 0.0001). The magnitude of fall in thyroid hormones after the same dose of carbimazole was lower during follow up than at the initiation visit. The fall in thyroid hormone levels approximated to a linear response if assessed at least 3 weeks after commencement of carbimazole. Following withdrawal of antithyroid drug treatment, the risk of relapse was greater in patients with higher initial fT4, initial TSH receptor antibody titre, males, smokers, and British Caucasian ethnicity. We identify a dose-response relationship for fall in thyroid hormones in response to carbimazole to aid in the selection of dose for Graves' hyperthyroidism.
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http://dx.doi.org/10.3389/fendo.2020.00286DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7236601PMC
May 2021

A rare cause of severe Cushing's syndrome.

Endocrinol Diabetes Metab Case Rep 2020 Mar 13;2020. Epub 2020 Mar 13.

Hammersmith Hospital, Imperial College Healthcare NHS Trust, London, UK.

Summary: Ectopic adrenocorticotropic hormone (ACTH) production is an uncommon cause of Cushing's syndrome and, rarely, the source can be a phaeochromocytoma. A 55-year-old man presented following an episode of presumed gastroenteritis with vomiting and general malaise. Further episodes of diarrhoea, joint pains and palpitations followed. On examination, he was hypertensive with no clinical features to suggest hypercortisolaemia. He was subsequently found to have raised plasma normetanephrines of 3.98 nmol/L (NR <0.71) and metanephrines of 0.69 nmol/L (NR <0.36). An adrenal CT showed a 3.8 cm right adrenal nodule, which was not MIBG-avid but was clinically and biochemically consistent with a phaeochromocytoma. He was started on alpha blockade and referred for right adrenalectomy. Four weeks later, on the day of admission for adrenalectomy, profound hypokalaemia was noted (serum potassium 2.0 mmol/L) with non-specific ST-segment ECG changes. He was also diagnosed with new-onset diabetes mellitus (capillary blood glucose of 28 mmol/L). He reported to have gained weight and his skin had become darker over the course of the last 4 weeks. Given these findings, he underwent overnight dexamethasone suppression testing, which showed a non-suppressed serum cortisol of 1099 nmol/L. Baseline serum ACTH was 273 ng/L. A preliminary diagnosis of ectopic ACTH secretion from the known right-sided phaeochromocytoma was made and he was started on metyrapone and insulin. Surgery was postponed for 4 weeks. Following uncomplicated laparoscopic adrenalectomy, the patient recovered with full resolution of symptoms.

Learning Points: Phaeochromocytomas are a rare source of ectopic ACTH secretion. A high clinical index of suspicion is therefore required to make the diagnosis. Ectopic ACTH secretion from a phaeochromocytoma can rapidly progress to severe Cushing's syndrome, thus complicating tumour removal. Removal of the primary tumour often leads to full recovery. The limited literature suggests that the presence of ectopic Cushing's syndrome does not appear to have any long-term prognostic implications.
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http://dx.doi.org/10.1530/EDM-20-0011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7077516PMC
March 2020

Pachydermoperiostosis mimicking the acral abnormalities of acromegaly.

Endocrine 2020 02 8;67(2):499-500. Epub 2020 Jan 8.

Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, EC1M 6BQ, UK.

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http://dx.doi.org/10.1007/s12020-019-02168-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7026203PMC
February 2020

biosynthesis of 8-hydroxyoctanoic acid via a medium-chain length specific fatty acid synthase and cytochrome P450 in .

Metab Eng Commun 2020 Jun 18;10:e00111. Epub 2019 Nov 18.

Institute of Molecular Biosciences, Faculty of Biological Sciences, Goethe University Frankfurt, Frankfurt am Main, Germany.

Terminally hydroxylated fatty acids or dicarboxylic acids are industrially relevant compounds with broad applications. Here, we present the proof of principle for the biosynthesis of 8-hydroxyoctanoic acid from glucose and ethanol in the yeast . Toxicity tests with medium-chain length ω-hydroxy fatty acids and dicarboxylic acids revealed little or no growth impairments on yeast cultures even at higher concentrations. The ability of various heterologous cytochrome P450 enzymes in combination with their cognate reductases for ω-hydroxylation of externally fed octanoic acid were compared. Finally, the most efficient P450 enzyme system was expressed in a yeast strain, whose fatty acid synthase was engineered for octanoic acid production, resulting in biosynthesis of 8-hydroxyoctanoic acid up to 3 ​mg/l. Accumulation of octanoic acid revealed that cytochromes P450 activities were limiting 8-hydroxyoctanoic acid synthesis. The hydroxylation of both externally added and intracellularly produced octanoic acid was strongly dependent on the carbon source used, with ethanol being preferred. We further identified the availability of heme, a cofactor needed for P450 activity, as a limiting factor of 8-hydroxyoctanoic acid biosynthesis.
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http://dx.doi.org/10.1016/j.mec.2019.e00111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6906673PMC
June 2020

Ga-DOTATATE PET/CT parameters predict response to peptide receptor radionuclide therapy in neuroendocrine tumours.

Radiother Oncol 2019 12 18;141:108-115. Epub 2019 Sep 18.

Department of Surgery and Cancer, Imperial College London, UK; Department of Nuclear Medicine, Imperial College NHS Trust, UK.

Purpose: [Lu]DOTATATE prolongs progression free survival (PFS) in metastatic neuroendocrine tumours (NETs). However, objective response rate is low. This, coupled with long duration of therapy and expense suggest need for better selection. We aim to assess whether baseline [Ga]DOTATATE-PET/CT parameters, and whether response assessment by PET accurately predicts clinical outcome to [Lu]DOTATATE.

Experimental Design: Retrospective study of patients receiving [Lu]DOTATATE was conducted. Patients were followed 3-monthly until disease progression. Four [Ga]DOTATATE-PET parameters (single lesion SUV, tumour to spleen and liver SUV ratios, and SUV using up to five target lesions in multiple organ sites) were determined at baseline and follow-up. The association between these PET parameters either at baseline, or any changes following treatment, and PET response criteria (PERCIST and modified PERCIST) to predict PFS were determined. Patients were followed 3-monthly until disease progression. Response was determined using RECIST 1.1. Baseline SSTR2 expression was assessed and compared with PET parameters.

Results: 55 patients with metastatic NETs were identified predominantly small bowel (N = 18) and pancreatic (N = 8) in origin. 16 were low grade, 15 intermediate and 3 high grade. Response to PRRT (N = 47): partial response (PR) 28%, stable disease (SD) 60% progressive disease (PD) 13%. Response to PRRT predicted PFS: PR 71.8 months (95%CI: not achieved), SD 29.1 months (95%CI: 15.2-43.1), and PD 9.7 months (95%CI: 0-21.02). Baseline, single lesion SUV predicted both response and PFS with SUV cut-off of 13.0 giving high sensitivity and specificity. Tumoural SUV correlated with SSTR2 expression, Spearman's rho - 0.69, p < 0.01.

Conclusions: Baseline single lesion SUV and SUV predicts response to [Lu]DOTATATE. Objective response following PRRT defines a subset of patients with markedly improved PFSBaseline SUV 13.0 defines a threshold below which patients have poor response to PRRT and worse PFS. SUV threshold analysis should be taken forward into prospective studies.
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http://dx.doi.org/10.1016/j.radonc.2019.09.003DOI Listing
December 2019

Antigen-Specific Immunotherapy with Thyrotropin Receptor Peptides in Graves' Hyperthyroidism: A Phase I Study.

Thyroid 2019 07 13;29(7):1003-1011. Epub 2019 Jun 13.

14Department of Medicine I, Johannes Gutenberg University Medical Center, Mainz, Germany.

Graves' disease is one of the most common autoimmune conditions, but treatment remains imperfect. This study explores the first-in-human use of antigen-specific immunotherapy with a combination of two thyrotropin receptor (TSHR) peptides (termed ATX-GD-59) in Graves' hyperthyroidism. Twelve participants (11 female) with previously untreated mild to moderate Graves' hyperthyroidism were enrolled in a Phase I open label trial to receive 10 doses of ATX-GD-59 administered intradermally over an 18-week period. Adverse events, tolerability, changes in serum free thyroid hormones, and TSHR autoantibodies were measured. Ten subjects received all 10 doses of ATX-GD-59, five (50%) of whom had free triiodothyronine within the reference interval by the 18-week visit. Two further subjects had improved free thyroid hormones by the end of the study (7/10 responders), whereas three subjects showed worsening thyrotoxicosis during the study. Serum TSHR autoantibody concentrations reduced during the study and correlated with changes in free thyroid hormones ( = 0.85,  = 0.002 for TSHR autoantibody vs. free triiodothyronine). Mild injection-site swelling and pain were the most common adverse events. These preliminary data suggest that ATX-GD-59 is a safe and well-tolerated treatment. The improvement in free thyroid hormones in 70% of subjects receiving the medication suggests potential efficacy as a novel treatment for Graves' hyperthyroidism.
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http://dx.doi.org/10.1089/thy.2019.0036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6648194PMC
July 2019

A 61 year old man with pancreatitis, pituitary dysfunction, and painful exophthalmos.

BMJ 2019 Feb 21;364:l93. Epub 2019 Feb 21.

Imperial Centre for Endocrinology, Imperial College Healthcare NHS Trust, London, UK.

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http://dx.doi.org/10.1136/bmj.l93DOI Listing
February 2019

Clinical and biochemical characteristics of patients presenting with pituitary apoplexy.

Endocr Connect 2018 08 23. Epub 2018 Aug 23.

N Martin, Imperial College Healthcare NHS Trust, London, United Kingdom of Great Britain and Northern Ireland

Purpose: To review the clinical and biochemical characteristics and clinical outcome of patients presenting with pituitary apoplexy to a tertiary centre.

Methods: We retrospectively reviewed the clinical features, predisposing factors, biochemistry and clinical outcome of patients presenting with pituitary apoplexy to Imperial College Healthcare NHS Trust between 1991 to 2015.

Results: We identified 64 patients with pituitary apoplexy (more complete clinical records were available in 52 patients). The median age at presentation was 46.7 years (IQR 31.5-57.0 years). Pituitary apoplexy was the first presentation of pituitary disease in 38/52 of patients and predisposing factors were identified in 28/52. Pituitary apoplexy predominantly occurred in patients with non-functioning pituitary adenomas (47/52). Headache was most commonly described as sudden-onset, severe, lateralising to the frontal or temporal regions. Symptoms of meningeal irritation were reported in 7/18 and visual abnormalities in 22/35. A pre-treatment serum cortisol <100nmol/l was recorded in 12/31 of patients. All patients with visual disturbance had some resolution of their visual symptoms whether managed surgically (14/14) or conservatively (5/5), although pituitary endocrine function did not fully recover in any patient.

Conclusions: In conclusion, these data describe the clinical features of pituitary apoplexy to aid the clinician in diagnosing this rare emergency presentation of pituitary disease. Prospective multicentre studies of the presentation of pituitary apoplexy are required to further characterise presentation and outcomes.
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http://dx.doi.org/10.1530/EC-18-0255DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6198188PMC
August 2018

A patient with a germline mutation presenting with an isolated pituitary macroprolactinoma.

Endocrinol Diabetes Metab Case Rep 2018 21;2018. Epub 2018 Jul 21.

Endocrinology, Imperial College Healthcare NHS Trust, London, UK.

Symptomatic pituitary adenomas occur with a prevalence of approximately 0.1% in the general population. It is estimated that 5% of pituitary adenomas occur in a familial setting, either in isolated or syndromic form. Recently, loss-of-function mutations in genes encoding succinate dehydrogenase subunits () or MYC-associated factor X ( have been found to predispose to pituitary adenomas in co-existence with paragangliomas or phaeochromocytomas. It is rare, however, for a familial mutation to manifest as an isolated pituitary adenoma. We present the case of a pituitary lactotroph adenoma in a patient with a heterozygous germline mutation, in the absence of concomitant neoplasms. Initially, the adenoma showed biochemical response but poor tumour shrinkage in response to cabergoline; therefore, transsphenoidal surgery was performed. Following initial clinical improvement, tumour recurrence was identified 15 months later. Interestingly, re-initiation of cabergoline proved successful and the lesion demonstrated both biochemical response and tumour shrinkage. Our patient's mutation was identified when we realised that her father had a metastatic paraganglioma, prompting genetic testing. Re-inspection of the histopathological report of the prolactinoma confirmed cells with vacuolated cytoplasm. This histological feature is suggestive of an mutation and should prompt further screening for mutations by immunohistochemistry and/or genetic testing. Surprisingly, immunohistochemistry of this pituitary adenoma demonstrated normal expression, despite loss of expression in the patient's father's paraganglioma.

Learning Points: Pituitary adenomas may be the presenting and/or sole feature of mutation-related disease. mutated pituitary adenomas may display clinically aggressive behaviour and demonstrate variable response to medical treatment.Histological evidence of intracytoplasmic vacuoles in a pituitary adenoma might suggest an SDH-deficient tumour and should prompt further screening for mutations.Immunohistochemistry may not always predict the presence of mutations.
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http://dx.doi.org/10.1530/EDM-18-0078DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6063986PMC
July 2018

A Eukaryotic Sensor for Membrane Lipid Saturation.

Mol Cell 2016 07 16;63(1):49-59. Epub 2016 Jun 16.

Institute of Biochemistry and Buchmann and Institute for Molecular Life Sciences, Goethe University Frankfurt, I 60438 Frankfurt, Germany. Electronic address:

Maintaining a fluid bilayer is essential for cell signaling and survival. Lipid saturation is a key factor determining lipid packing and membrane fluidity, and it must be tightly controlled to guarantee organelle function and identity. A dedicated eukaryotic mechanism of lipid saturation sensing, however, remains elusive. Here we show that Mga2, a transcription factor conserved among fungi, acts as a lipid-packing sensor in the ER membrane to control the production of unsaturated fatty acids. Systematic mutagenesis, molecular dynamics simulations, and electron paramagnetic resonance spectroscopy identify a pivotal role of the oligomeric transmembrane helix (TMH) of Mga2 for intra-membrane sensing, and they show that the lipid environment controls the proteolytic activation of Mga2 by stabilizing alternative rotational orientations of the TMH region. This work establishes a eukaryotic strategy of lipid saturation sensing that differs significantly from the analogous bacterial mechanism relying on hydrophobic thickness.
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http://dx.doi.org/10.1016/j.molcel.2016.05.015DOI Listing
July 2016

Mechanical stress-activated PKCdelta regulates smooth muscle cell migration.

FASEB J 2003 Nov 4;17(14):2106-8. Epub 2003 Sep 4.

Institute for Biomedical Aging Research, Austrian Academy of Sciences, Innsbruck, Austria.

Vascular smooth muscle cells (SMCs) are exposed to altered mechanical stress that may contribute to SMC migration in the development of atherosclerosis. Signal transduction pathways in SMCs activated by mechanical stress that instigate cell migration are undefined. Herein, we provide evidence that mechanical stress enhances SMC migration, which is mediated, at least in part, by protein kinase C (PKC)delta. When rat SMCs cultivated on a flexible membrane were subjected to cyclic strain stress (60 cycles/min, 5, 15, or 20% elongation), PKCdelta was translocated to the Triton-insoluble fraction, whereas PKCalpha was translocated to the membrane, which was confirmed by PKC kinase assays. Immunofluorescence and actin staining revealed a cytoskeleton translocation of PKCdelta in SMCs stimulated by cyclic strain. PKCdelta-deficient SMCs cultivated from PKCdelta-/- mice showed an abnormal cytoskeleton structure, which was related to a diminished phosphorylation of paxillin, focal adhesion kinase, and vinculin in response to mechanical stress. Mechanical stress enhanced SMC migration, which was diminished in PKCdelta-/- SMCs. Taken together, our data demonstrated that mechanical stress activates PKCdelta translocation to the cytoskeleton, which is related to decreased SMC migration and indicates that PKCdelta is a key signal transducer between mechanical stress and cell migration.
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http://dx.doi.org/10.1096/fj.03-0150fjeDOI Listing
November 2003

Activation of heat shock transcription factor 1 in atherosclerosis.

Am J Pathol 2003 May;162(5):1669-76

Department of Internal Medicine, Division of Cardiology, University Hospital of Innsbruck, Innsbruck, Austria.

Previous work established that increased expression of heat shock proteins (HSPs) in the vessel wall might evoke proinflammatory and autoimmune reactions in the pathogenesis of atherosclerosis. The present study was designed to further scrutinize the molecular mechanisms of HSP expression involving activation of heat shock transcription factors (HSFs) in atherosclerotic lesions in animal models. Severe atherosclerotic lesions developed in the aortas of rabbits 16 weeks after feeding a 0.2% cholesterol diet. When protein extracts from the aortas were subjected to Western blot analysis, the level of HSF1 in proteins from atherosclerotic lesions of hypercholesterolemic rabbits were significantly higher than those of normal vessels. Gel mobility shift assays revealed the formation of protein-heat shock element complexes containing HSF1 in protein extracts from atherosclerotic lesion. Furthermore, triglyceride-rich lipoprotein, oxidized-triglyceride-rich lipoprotein, low-density lipoprotein, and oxidized low-density lipoprotein did not activate HSF1 in cultured smooth muscle cells, whereas HSF1 was highly activated in cells treated with tumor necrosis factor-alpha. Interestingly, mechanical stretching of smooth muscle cells resulted in HSF1 translocation from the cytoplasm to the nucleus and hyperphosphorylation followed by increased HSP70 expression. Thus, our findings provide the first evidence that HSF1 is activated and highly expressed in atherosclerotic lesions and that cytokine stimulation and disturbed mechanical stress to the vessel wall may be responsible for such activation.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1851193PMC
http://dx.doi.org/10.1016/S0002-9440(10)64301-5DOI Listing
May 2003

Mechanical stretch-induced apoptosis in smooth muscle cells is mediated by beta1-integrin signaling pathways.

Hypertension 2003 Apr 17;41(4):903-11. Epub 2003 Mar 17.

Department of Cardiological Sciences, St George's Hospital Medical School, Cranmer Terrace, Tooting, London SW17 0RE, UK.

Recently we demonstrated that mechanical stress induces apoptosis of vascular smooth muscle cells in vitro and in vein grafts (Mayr et al. FASEB J. 2000;15:261-270). The current study was designed to investigate molecular mechanisms of mechanical stretch-induced apoptosis. Smooth muscle cells cultivated on silicone elastomer plates precoated with collagen I, elastin, laminin, or Pronectin were subjected to cyclic mechanical stretch. Interestingly, in response to mechanical stress, the number of apoptotic cells increased significantly in cells growing on collagen I-coated plates but not on other matrixes. We therefore thought that receptors mediating binding to collagen I, such as integrin beta1 containing receptors, might be involved in signaling pathways leading to stretch-induced apoptosis. On collagen plates, mechanical stress rapidly activated p38 MAPK that phosphorylated p53 in smooth muscle cells. Lack of functional Rac completely abrogated p38 MAPK-p53 activation as well as apoptosis. Furthermore, mechanical stress resulted in increases of both integrin beta1 protein expression and activity as identified by Western blotting and Shc immunoprecipitation assays. Treatment with a beta1-integrin-blocking antibody or integrin signaling inhibitor cytochalasin B but not growth factor receptor inhibitor suramin abrogated both stretch-induced phosphorylation of p38 MAPK and p53 expression. Akin to the inhibition of p38 MAPK-p53 signaling, pretreatment with a beta1-integrin-blocking antibody or cytochalasin B but not suramin inhibited stretch-induced apoptosis on collagen plates. These results suggest that mechanical stress-induced apoptosis in vascular smooth muscle cells is mediated by beta1-integrin-rac-p38-p53 signaling pathways.
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http://dx.doi.org/10.1161/01.HYP.0000062882.42265.88DOI Listing
April 2003

Mechanical stress-induced apoptosis in the cardiovascular system.

Prog Biophys Mol Biol 2002 Feb-Apr;78(2-3):105-37

Department of Cardiological Sciences, St George's Hospital Medical School, Cranmer Terrace, Tooting, London SW17 0RE, UK.

All tissues in the body are subjected to physical forces originating either from tension, created by cells themselves, or from the environment. Particularly, the cardiovascular system is continuously subjected to haemodynamic forces created by blood flow and blood pressure. While biomechanical force at physiological levels is essential to develop and maintain organic structure and function, elevated mechanical stress may result in cell death leading to pathological conditions. In recent years, however, it has been widely recognized that cell death, namely apoptosis, is not just the response to an injury but a highly regulated and controlled process. Therefore, physical stimuli must be sensed by cells and transmitted through intracellular signal transduction pathways to the nucleus, resulting in cell apoptosis. Disturbances in the regulatory mechanisms of apoptosis often precede the development of a disease. Exploration of the molecular signalling mechanisms leading to mechanical stress-induced apoptosis in cardiovascular disorders revealed the crucial role of apoptosis in the pathogenesis of these diseases. For instance, heart failure, hypertension and atherosclerosis are believed to be related to sustained mechanical overloading or stress. In this review we summarize the recent data focusing on molecular mechanisms of mechanical stress-induced apoptosis and highlight the role of apoptosis in the development of cardiovascular disorders, which may lead to new therapeutic strategies for these diseases.
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http://dx.doi.org/10.1016/s0079-6107(02)00008-1DOI Listing
December 2002

Loss of p53 accelerates neointimal lesions of vein bypass grafts in mice.

Circ Res 2002 Feb;90(2):197-204

Institute for Pathophysiology, University of Innsbruck, Austria.

The transcription factor p53 is essentially involved in regulation of cell death and proliferation. Recently, we have established a mouse model for vein graft arteriosclerosis by grafting autologous jugular veins or vena cava to carotid arteries. Using this model, we studied the role of p53 in the development of vein graft arteriosclerosis in p53(-/-) mice. Four weeks after grafting, neointimal hyperplasia of vein grafts in p53(-/-) mice was increased 2-fold compared with that of wild-type controls. Cell component analysis revealed that neointimal lesions in p53(-/-) mice consisted mainly of alpha-actin positive smooth muscle cells (SMCs), whereas the majority of cells in wild-type mice were MAC-1 (CD11b/18)-positive at 4 weeks. Importantly, SMC apoptosis as determined by TUNEL assay was significantly reduced in p53(-/-) vein grafts. TUNEL positive cells in wild-type vein grafts markedly increased from 0.5% to 6.4% of total cells 4 weeks postoperatively, but remained virtually unchanged in p53(-/-) grafts (0.8%). Immunofluorescence analysis revealed that increased p53 expression in neointimal SMCs of wild-type, but not p53(-/-), mice coincided with oxidative DNA damage in vein grafts. Interestingly, SMCs of p53(-/-) mice showed increased apoptosis in response to TNFalpha and decreased apoptosis in response to sodium nitroprusside. Additionally, p53-deficient SMCs showed a higher rate of proliferation and migration and expressed higher levels of matrix metalloproteinases. Thus, p53 deficiency accelerates neointima formation by facilitating SMC proliferation as well as abrogating cell apoptosis.
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http://dx.doi.org/10.1161/hh0202.103715DOI Listing
February 2002
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