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Maurício Martins da Silva Laboratory of Endocrine Physiology, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brasil

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Lueni Lopes Felix Xavier Laboratory of Endocrine Physiology, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brasil

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Carlos Frederico Lima Gonçalves Laboratory of Endocrine Physiology, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brasil

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Ana Paula Santos-Silva Laboratory of Endocrine Physiology, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brasil
NUMPEX, Campus Duque de Caxias, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brasil

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Francisca Diana Paiva-Melo Laboratory of Endocrine Physiology, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brasil

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Mariana Lopes de Freitas Laboratory of Endocrine Physiology, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brasil

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Rodrigo Soares Fortunato Laboratory of Molecular Radiobiology, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brasil

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Leandro Miranda-Alves Laboratory of Endocrine Physiology, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brasil

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Andrea Claudia Freitas Ferreira Laboratory of Endocrine Physiology, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brasil
NUMPEX, Campus Duque de Caxias, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brasil

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Bisphenol A (BPA) is the most common monomer in polycarbonate plastics and an endocrine disruptor. Though some effects of BPA on thyroid hormone (TH) synthesis and action have been described, the impact of this compound on thyroid H2O2 generation remains elusive. H2O2 is a reactive oxygen species (ROS), which could have deleterious effect on thyrocytes if in excess. Therefore, herein we aimed at evaluating the effect of BPA exposition both in vivo and in vitro on H2O2 generation in thyrocytes, besides other essential steps for TH synthesis. Female Wistar rats were treated with vehicle (control) or BPA 40 mg/kg BW for 15 days, by gavage. We then evaluated thyroid iodide uptake, mediated by sodium-iodide symporter (NIS), thyroperoxidase (TPO) and dual oxidase (DOUX) activities (H2O2 generation). Hydrogen peroxide generation was increased, while iodide uptake and TPO activity were reduced by BPA exposition. We have also incubated the rat thyroid cell line PCCL3 with 10−9 M BPA and evaluated Nis and Duox mRNA levels, besides H2O2 generation. Similar to that found in vivo, BPA treatment also led to increased H2O2 generation in PCCL3. Nis mRNA levels were reduced and Duox2 mRNA levels were increased in BPA-exposed cells. To evaluate the importance of oxidative stress on BPA-induced Nis reduction, PCCL3 was treated with BPA in association to N-acetylcysteine, an antioxidant, which reversed the effect of BPA on Nis. Our data suggest that BPA increases ROS production in thyrocytes, what could lead to oxidative damage thus possibly predisposing to thyroid disease.

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Kristian Almstrup Department of Growth and Reproduction, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
International Center for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Rigshospitalet, University of Copenhagen, Copenhagen, Denmark

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Hanne Frederiksen Department of Growth and Reproduction, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
International Center for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Rigshospitalet, University of Copenhagen, Copenhagen, Denmark

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Anna-Maria Andersson Department of Growth and Reproduction, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
International Center for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Rigshospitalet, University of Copenhagen, Copenhagen, Denmark

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Anders Juul Department of Growth and Reproduction, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
International Center for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Rigshospitalet, University of Copenhagen, Copenhagen, Denmark

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Puberty marks a transition period, which leads to the attainment of adult sexual maturity. Timing of puberty is a strongly heritable trait. However, large genetic association studies can only explain a fraction of the observed variability and striking secular trends suggest that lifestyle and/or environmental factors are important. Using liquid-chromatography tandem-mass-spectrometry, we measured endocrine-disrupting chemicals (EDCs; triclosan, bisphenol A, benzophenone-3, 2,4-dichlorophenol, 11 metabolites from 5 phthalates) in longitudinal urine samples obtained biannually from peri-pubertal children included in the COPENHAGEN puberty cohort. EDC levels were associated with blood DNA methylation profiles from 31 boys and 20 girls measured both pre- and post-pubertally. We found little evidence of single methylation sites that on their own showed association with urinary excretion levels of EDCs obtained either the same-day or measured as the yearly mean of dichotomized EDC levels. In contrast, methylation of several promoter regions was found to be associated with two or more EDCs, overlap with known gene–chemical interactions, and form a core network with genes known to be important for puberty. Furthermore, children with the highest yearly mean of dichotomized urinary phthalate metabolite levels were associated with higher promoter methylation of the thyroid hormone receptor interactor 6 gene (TRIP6), which again was mirrored by lower circulating TRIP6 protein levels. In general, the mean TRIP6 promoter methylation was mirrored by circulating TRIP6 protein levels. Our results provide a potential molecular mode of action of how exposure to environmental chemicals may modify pubertal development.

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M Krause Department of Growth and Reproduction & International Center for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Rigshospitalet, University of Copenhagen, Copenhagen, Denmark

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H Frederiksen Department of Growth and Reproduction & International Center for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Rigshospitalet, University of Copenhagen, Copenhagen, Denmark

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K Sundberg Center of Fetal Medicine and Pregnancy, Department of Obstetrics, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark

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F S Jørgensen Fetal Medicine Unit, Department of Obstetrics and Gynecology, Copenhagen University Hospital, Hvidovre, Denmark

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L N Jensen Center of Fetal Medicine and Pregnancy, Department of Obstetrics, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark

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P Nørgaard Fetal Medicine Unit, Department of Obstetrics and Gynecology, Copenhagen University Hospital, Hvidovre, Denmark

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C Jørgensen Center of Fetal Medicine and Pregnancy, Department of Obstetrics, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark

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P Ertberg Fetal Medicine Unit, Department of Obstetrics and Gynecology, Copenhagen University Hospital, Hvidovre, Denmark

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J H Petersen Department of Growth and Reproduction & International Center for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
Section of Biostatistics, Faculty of Health and Medical Science, University of Copenhagen, Copenhagen, Denmark

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U Feldt-Rasmussen Department of Endocrinology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark

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A Juul Department of Growth and Reproduction & International Center for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Rigshospitalet, University of Copenhagen, Copenhagen, Denmark

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K T Drzewiecki Department of Plastic Surgery, Breast Surgery and Burns Treatment, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark

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N E Skakkebaek Department of Growth and Reproduction & International Center for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Rigshospitalet, University of Copenhagen, Copenhagen, Denmark

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A M Andersson Department of Growth and Reproduction & International Center for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Rigshospitalet, University of Copenhagen, Copenhagen, Denmark

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Background

Several chemical UV filters/absorbers ('UV filters' hereafter) have endocrine-disrupting properties in vitro and in vivo. Exposure to these chemicals, especially during prenatal development, is of concern.

Objectives

To examine maternal exposure to UV filters, associations with maternal thyroid hormone, with growth factor concentrations as well as to birth outcomes.

Methods

Prospective study of 183 pregnant women with 2nd trimester serum and urine samples available. Maternal concentrations of the chemical UV filters benzophenone-1 (BP-1) and benzophenone-3 (BP-3) in urine and 4-hydroxy-benzophenone (4-HBP) in serum were measured by liquid chromatography–tandem mass spectrometry (LC–MS/MS). The relationships between 2nd trimester maternal concentrations of the three chemical UV filters and maternal serum concentrations of thyroid hormones and growth factors, as well as birth outcomes (weight, height, and head and abdominal circumferences) were examined.

Results

Positive associations between maternal serum concentrations of 4-HBP and triiodothyronine (T3), thyroxine (T4), insulin-like growth factor I (IGF-I) and its binding protein IGFBP3 were observed in mothers carrying male fetuses. Male infants of mothers in the middle 4-HBP exposure group had statistically significantly lower weight and shorter head and abdominal circumferences at birth compared to the low exposure group.

Conclusions

Widespread exposure of pregnant women to chemical UV filters and the possible impact on maternal thyroid hormones and growth factors, and on fetal growth, calls for further studies on possible long-term consequences of the exposure to UV filters on fetal development and children’s health.

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Maria Luisa Brandi Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy
Fondazione Italiana Ricerca sulle Malattie dell’Osso (FIRMO Onlus), Florence, Italy

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Stefania Bandinelli Geriatric Unit, Azienda Sanitaria Toscana Centro, Florence, Italy

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Teresa Iantomasi Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy

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Francesca Giusti Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy

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Eleonora Talluri Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy

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Giovanna Sini Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy

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Fabrizio Nannipieri Clinical Research, Abiogen Pharma, Pisa, Italy

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Santina Battaglia Clinical Research, Abiogen Pharma, Pisa, Italy

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Riccardo Giusti Clinical Research, Abiogen Pharma, Pisa, Italy

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Colin Gerard Egan CE Medical Writing SRLS, Pisa, Italy

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Luigi Ferrucci Longitudinal Study Section, Translation Gerontology Branch, National Institute on Aging, Baltimore, Maryland, USA

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Objective

This study aimed to evaluate the association between the endocrine-disrupting chemical, bisphenol A (BPA) on circulating levels of 25-hydroxy vitamin D (25(OD)D) and other vitamin D metabolites in an elderly population in Italy.

Methods

This was a retrospective analysis of the InCHIANTI Biobank in Italy. The association between vitamin D metabolites namely 1,25(OH)D, 25(OH)D, parathyroid hormone (PTH) and BPA levels were evaluated. Multiple regression models were used to examine the association between predictor variables with 1,25(OH)D or 25(OH)D levels.

Results

Samples from 299 individuals aged 72.8 ± 15.7 years were examined. Mean levels of BPA, 1,25(OH)D and 25(OH)D were 351.2 ± 511.6 ng/dL, 43.7 ± 16.9 pg/mL and 20.2 ± 12.1 ng/mL, respectively. One hundred eighty individuals (60.2%) were deficient (<20 ng/mL) in 25(OH)D and this population also presented higher BPA levels (527.9 ± 1289.5 ng/dL vs 86.9 ± 116.8 ng/dL, P  < 0.0001). Univariate analysis revealed that BPA levels were negatively correlated with both 1,25(OH)D (r= −0.67, P  < 0.0001) and 25(OH)D (r= −0.69, P  < 0.0001). Multivariate regression revealed that PTH (β: −0.23, 95% CI: −0.34, −0.13, P  < 0.0001) and BPA (β: −0.25, 95% CI: −0.3, −0.19, P  < 0.0001) remained significantly associated with 25(OH)D levels while BPA was also associated with 1,25(OH)D levels (β: −0.19, 95% CI: −0.22, −0.15, P  < 0.0001). Receiver operating characteristic curve analysis showed that a BPA concentration of >113 ng/dL was the best cut-off to predict individuals deficient in 25(OH)D (area under the curve: 0.87, 95% CI: 0.82–0.90, P  < 0.0001).

Conclusion

The strong negative association between BPA and vitamin D in this elderly population warrants further investigation, particularly since this population is already at greatest risk of hypovitaminosis and fracture.

Open access
Daniel Alexander Hescheler Department of Nuclear Medicine, University Hospital Münster, Münster, Germany
European Institute for Molecular Imaging (EIMI), University of Münster, Münster, Germany

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Milan Janis Michael Hartmann Department of General, Visceral, Tumor and Transplant Surgery, University Hospital Cologne, Cologne, Germany

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Burkhard Riemann Department of Nuclear Medicine, University Hospital Münster, Münster, Germany

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Maximilian Michel Institute of Zoology, University of Cologne Germany, Cologne, Germany

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Christiane Josephine Bruns Department of General, Visceral, Tumor and Transplant Surgery, University Hospital Cologne, Cologne, Germany

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Hakan Alakus Department of General, Visceral, Tumor and Transplant Surgery, University Hospital Cologne, Cologne, Germany

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Costanza Chiapponi Department of General, Visceral, Tumor and Transplant Surgery, University Hospital Cologne, Cologne, Germany

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Objective

Anaplastic thyroid cancer (ATC) is one of the most lethal human cancers with meager treatment options. We aimed to identify the targeted drugs already approved by the Food and Drug Administration (FDA) for solid cancer in general, which could be effective in ATC.

Design

Database mining.

Methods

FDA-approved drugs for targeted therapy were identified by screening the databases of MyCancerGenome and the National Cancer Institute. Drugs were linked to the target genes by querying Drugbank. Subsequently, MyCancerGenome, CIViC, TARGET and OncoKB were mined for genetic alterations which are predicted to lead to drug sensitivity or resistance. We searched the Cancer Genome Atlas database (TCGA) for patients with ATC and probed their sequencing data for genetic alterations which predict a drug response.

Results

In the study,155 FDA-approved drugs with 136 potentially targetable genes were identified. Seventeen (52%) of 33 patients found in TCGA had at least one genetic alteration in targetable genes. The point mutation BRAF V600E was seen in 45% of patients. PIK3CA occurred in 18% of cases. Amplifications of ALK and SRC were detected in 3% of cases, respectively. Fifteen percent of the patients displayed a co-mutation of BRAF and PIK3CA. Besides BRAF-inhibitors, the PIK3CA-inhibitor copanlisib showed a genetically predicted response. The 146 (94%) remaining drugs showed no or low (under 4% cases) genetically predicted drug response.

Conclusions

While ATC carrying BRAF mutations can benefit from BRAF inhibitors and this effect might be enhanced by a combined strategy including PIK3CA inhibitors in some of the patients, alterations in BRAFWT ATC are not directly targeted by currently FDA-approved options.

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Bernardo Maia Neuroendocrinology Research Center/Endocrinology Division – Medical School and Hospital Universitário Clementino Fraga Filho – Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil

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Leandro Kasuki Neuroendocrinology Research Center/Endocrinology Division – Medical School and Hospital Universitário Clementino Fraga Filho – Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
Neuroendocrinology Division – Instituto Estadual do Cérebro Paulo Niemeyer, Rio de Janeiro, Brazil
Endocrinology Division – Hospital Federal de Bonsucesso, Rio de Janeiro Brazil

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Mônica R Gadelha Neuroendocrinology Research Center/Endocrinology Division – Medical School and Hospital Universitário Clementino Fraga Filho – Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
Neuroendocrinology Division – Instituto Estadual do Cérebro Paulo Niemeyer, Rio de Janeiro, Brazil
Neuropatology and Molecular Genetics Laboratory – Instituto Estadual do Cérebro Paulo Niemeyer, Rio de Janeiro, Brazil

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Acromegaly is a systemic disease associated with increased morbidity and mortality. Most of these comorbidities can be prevented or delayed with adequate disease treatment. Although three modalities of treatment (surgery, medical treatment, and radiotherapy) are available and new drugs were approved in the last decades, there are still some patients that maintain disease activity despite treatment. Therefore, there is a need for novel therapies for acromegaly and for that purpose new formulations of currently used drugs and also new drugs are currently under study. In this review, we summarize the novel therapies for acromegaly.

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Zhenyu Liu Department of Clinical Medicine, Beijing Luhe Hospital, Capital Medical University, Tongzhou District, Beijing, China

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Huixi Kong Department of Clinical Medicine, Beijing Shijitan Hospital, Capital Medical University, Haidian District, Beijing, China

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Baoyu Zhang Center for Endocrine Metabolism and Immune Diseases, Beijing Luhe Hospital, Capital Medical University, Tongzhou District, Beijing, China

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To optimize the treatment plan for patients with type 2 diabetes mellitus (T2DM) and hyperuricemia, this narrative literature review summarizes the effect of antidiabetic drugs on serum uric acid (SUA) levels using data from observational studies, prospective clinical trials, post hoc analyses, and meta-analyses. SUA is an independent risk factor for T2DM, and evidence has shown that patients with both gout and T2DM exhibit a mutually interdependent effect on higher incidences. We find that insulin and dipeptidyl peptidase 4 inhibitor (DPP-4i) except linagliptin could increase the SUA and other drugs including metformin, thiazolidinediones (TZDs), glucagon-like peptide-1 receptor agonists (GLP-1 RAs), linagliptin, sodium–glucose cotransporter 2 inhibitors (SGLT2i), and α-glucosidase inhibitors have a reduction effect on SUA. We explain the mechanisms of different antidiabetic drugs above on SUA and analyze them compared with actual data. For sulfonylureas, meglitinides, and amylin analogs, the underlying mechanism remains unclear. We think the usage of linagliptin and SGLT2i is the most potentially effective treatment of patients with T2DM and hyperuricemia currently. Our review is a comprehensive summary of the effects of antidiabetic drugs on SUA, which includes actual data, the mechanisms of SUA regulation, and the usage rate of drugs.

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Nassim Ghaffari-Tabrizi-Wizsy Otto Loewi Research Center – Immunology and Pathophysiology, Medical University of Graz, Graz, Austria

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Christina Angelika Passegger Otto Loewi Research Center – Immunology and Pathophysiology, Medical University of Graz, Graz, Austria

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Laura Nebel Otto Loewi Research Center – Immunology and Pathophysiology, Medical University of Graz, Graz, Austria

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Fabian Krismer Otto Loewi Research Center – Immunology and Pathophysiology, Medical University of Graz, Graz, Austria

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Gudrun Herzer-Schneidhofer Otto Loewi Research Center – Immunology and Pathophysiology, Medical University of Graz, Graz, Austria

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Gert Schwach Otto Loewi Research Center – Immunology and Pathophysiology, Medical University of Graz, Graz, Austria

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Roswitha Pfragner Otto Loewi Research Center – Immunology and Pathophysiology, Medical University of Graz, Graz, Austria

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Preclinical trials of medullary thyroid cancer (MTC) therapeutics require both in vitro and in vivo analyses. Human tumour xenografted rodent models, which are considered the ‘gold standard’ to study and validate the efficacy and toxicity of lead compounds before translation to clinical trials, are very expensive, subject to organismal variability and ethical controversies. The avian chorioallantoic membrane (CAM) assay provides an alternative versatile, cost-effective and ethically less objectionable short-term, in vivo model for reliable screening of drugs. In this work, we grafted two MTC cell lines and patient-derived MTC tumour samples onto the avian CAM and characterised the resulted tumours histologically and immunohistochemically. Our findings provide the evidence that the CAM assay is a suitable model for studying the pathophysiology of MTC and can even be used as in vivo system for drug testing.

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Ruixin Hu School of pharmacy, Qing Dao University, Qingdao, China

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Yanting Yuan School of pharmacy, Qing Dao University, Qingdao, China

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Chaolong Liu School of pharmacy, Qing Dao University, Qingdao, China

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Ji Zhou School of pharmacy, Qing Dao University, Qingdao, China

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Lixia Ji School of pharmacy, Qing Dao University, Qingdao, China

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Guohui Jiang School of pharmacy, Qing Dao University, Qingdao, China

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In patients with type 2 diabetes mellitus (T2DM), the intestinal flora is out of balance and accompanied by leaky gut. The flora is characterized by an increase in mucus-degrading bacteria and a decrease in fiber-degrading bacteria. Short-chain fatty acids (SCFAs), as the major fiber-degrading bacteria fermentation, not only ameliorate the leaky gut, but also activate GPR43 to increase the mass of functional pancreatic β-cells and exert anti-inflammation effect. At present, the gut microbiota is considered as the potential target for anti-diabetes drugs, and how to reverse the imbalance of gut microbiota has become a therapeutic strategy for T2DM. This review briefly summarizes the drugs or compounds that have direct or potential therapeutic effects on T2DM by modulating the gut microbiota, including biguanides, isoquinoline alkaloids, stilbene and C7N-aminocyclic alcohols.

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Maria Cristina De Martino Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands
Dipartimento di Medicina Clinica e Chirurgia, Università Federico II, Naples, Italy

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Richard A Feelders Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands

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Claudia Pivonello Dipartimento di Medicina Clinica e Chirurgia, Università Federico II, Naples, Italy

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Chiara Simeoli Dipartimento di Medicina Clinica e Chirurgia, Università Federico II, Naples, Italy

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Fortuna Papa Dipartimento di Medicina Clinica e Chirurgia, Università Federico II, Naples, Italy

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Annamaria Colao Dipartimento di Medicina Clinica e Chirurgia, Università Federico II, Naples, Italy

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Rosario Pivonello Dipartimento di Medicina Clinica e Chirurgia, Università Federico II, Naples, Italy

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Leo J Hofland Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands

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Adrenocortical carcinomas (ACCs) are rare tumors with scant treatment options for which new treatments are required. The mTOR pathway mediates the intracellular signals of several growth factors, including the insulin-like growth factors (IGFs), and therefore represents a potential attractive pathway for the treatment of several malignancies including ACCs. Several mTOR inhibitors, including sirolimus, temsirolimus and everolimus, have been clinically developed. This review summarizes the results of the studies evaluating the expression of the mTOR pathway components in ACCs, the effects of the mTOR inhibitors alone or in combination with other drugs in preclinical models of ACCs and the early experience with the use of these compounds in the clinical setting. The mTOR pathway seems a potential target for treatment of patients with ACC, but further investigation is still required to define the potential role of mTOR inhibitors alone or in combination with other drugs in the treatment of ACC patients.

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